COSMIC-based mutation database enhances identification efficiency of HLA-I immunopeptidome.

BACKGROUND: Neoantigens have emerged as a promising area of focus in tumor immunotherapy, with several established strategies aiming to enhance their identification. Human leukocyte antigen class I molecules (HLA-I), which present intracellular immunopeptides to T cells, provide an ideal source for identifying neoantigens. However, solely relying on a mutation database generated through commonly used whole exome sequencing (WES) for the identification of HLA-I immunopeptides, may result in potential neoantigens being missed due to limitations in sequencing depth and sample quality. METHOD: In this study, we constructed and evaluated an extended database for neoantigen identification, based on COSMIC mutation database. This study utilized mass spectrometry-based proteogenomic profiling to identify the HLA-I immunopeptidome enriched from HepG2 cell. HepG2 WES-based and the COSMIC-based mutation database were generated and utilized to identify HepG2-specific mutant immunopeptides. RESULT: The results demonstrated that COSMIC-based database identified 5 immunopeptides compared to only 1 mutant peptide identified by HepG2 WES-based database, indicating its effectiveness in identifying mutant immunopeptides. Furthermore, HLA-I affinity of the mutant immunopeptides was evaluated through NetMHCpan and peptide-docking modeling to validate their binding to HLA-I molecules, demonstrating the potential of mutant peptides identified by the COSMIC-based database as neoantigens. CONCLUSION: Utilizing the COSMIC-based mutation database is a more efficient strategy for identifying mutant peptides from HLA-I immunopeptidome without significantly increasing the false positive rate. HepG2 specific WES-based database may exclude certain mutant peptides due to WES sequencing depth or sample heterogeneity. The COSMIC-based database can effectively uncover potential neoantigens within the HLA-I immunopeptidomes.

Enrichment of microbial consortia for MEOR in crude oil phase of reservoir-produced liquid and their response to environmental disturbance.

Developing microbial consortiums is necessary for microbial enhanced oil recovery (MEOR) in heavy crude oil production. The aqueous phase of produced fluid has long been considered an ideal source of microorganisms for MEOR. However, it is recently found that rich microorganisms (including hydrocarbon-degrading bacteria) are present in the crude oil phase, which is completely different from the aqueous phase of produced fluid. So, in this study, the microbial consortia from the crude oil phase of produced fluids derived from four wells were enriched, respectively. The microbial community structure during passage was dynamically tracked, and the response of enriched consortia to successive disturbance of environmental factors was investigated. The results showed the crude oil phase had high microbial diversity, and the original microbial community structure from four wells was significantly different. After ten generations of consecutive enrichment, different genera were observed in the four enriched microbial consortia, namely, Geobacillus, Bacillus, Brevibacillus, Chelativorans, Ureibacillus, and Ornithinicoccus. In addition, two enriched consortia (eG1614 and eP30) exhibited robustness to temperature and oxygen perturbations. These results further suggested that the crude oil phase of produced fluids can serve as a potential microbial source for MEOR.

A Dual-Responsive Liquid Crystal Elastomer for Multi-Level Encryption and Transient Information Display.

Information security has gained increasing attention in the past decade, leading to the development of advanced materials for anti-counterfeiting, encryption and instantaneous information display. However, it remains challenging to achieve high information security with simple encryption procedures and low-energy stimuli. Herein, a series of strain/temperature-responsive liquid crystal elastomers (LCEs) are developed to achieve dual-modal, multi-level information encryption and real-time, rewritable transient information display. The as-prepared polydomain LCEs can change from an opaque state to a transparent state under strain or temperature stimuli, with the transition strains or temperatures highly dependent on the concentration of long-chain flexible spacers. Information encrypted by different LCE inks can be decrypted under specific strains or temperatures, leading to multi-level protection of information security. Furthermore, with the combination of the phase transition of polydomain LCEs and the photothermal effect of multi-walled carbon nanotubes (MWCNTs), we achieved a repeatable transient information display by using near-infrared (NIR) light as a pen for writing. This study provides new insight into the development of advanced encryption materials with versatility and high security for broad applications.

Highly directive plasmonic structure with double resonance at excitation and emission for molecule-enhanced fluorescence.

An improved bull's eye nanostructure is proposed as a substrate for surface-enhanced fluorescence. Optimized by finite-difference time-domain, annular corrugation on both upper and lower surfaces is placed around a nanobow tie in the middle. The whole structure is designed for the excitation and emission process of a certain fluorescence simultaneously, which can enhance the fluorescence intensity enormously (35 times for an excitation field and 120 times for radiation, independently). Meanwhile, it is able to confine the far-field emission energy within a divergence angle of ±3.5°. The dual-resonant enhancement and directivity of such a substrate allows higher sensitivity during fluorescence detection. Furthermore, the designed resonance and directional light control at emission may effectively reduce the required energy at excitation, which is ideal for those molecules with low laser damage threshold.

Phthalorubines: Fused-Ring Compounds Synthesized from Phthalonitrile.

A series of dibenzo[a,f][1,3,5]triazino[2,1,6-cd] pyrrolizine compounds have been synthesized from phthalonitriles by a facile intramolecular cyclization process using "half-phthalocyanine" precursors, and they were characterized by X-ray crystallography, 1 H NMR spectroscopy, UV/Vis, and theoretical calculations. These compounds have spectroscopic profiles similar to phthalocyanines and porphyrins, although their inner-core structures and coordination types are totally different. They can be regarded as a new class of aromatic fused-ring compounds. The low-energy absorption of these new fused-ring compounds are located at around 600 nm. Such a low-energy π-π* transition is scarce in aromatic compounds having a similar molecular size. According to the nomenclature of phthalocyanines, these types of compounds have been named phthalorubines (Prs).

Optimization of Flow Channels in a PEM Fuel Cell Based on a Multiobjective Evaluation.

Proton exchange membrane fuel cells (PEMFCs) are known for their cleanliness and high efficiency. However, the limited energy density and high cost are the main obstacles to this technology. This study aims to overcome these challenges and enhance the overall performance of the PEMFC. Five types of PEMFCs with different blockages are proposed and simulated in this study. Afterward, the Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) method is performed as a multiobjective evaluation. This study shows that the nozzle effect in the channel enhances the mass transfer of PEMFC and improves water and thermal management, resulting in a reduction of liquid water by up to 35.8%. The blockages benefit the output performance of the PEMFC. For example, the elliptical blockage shows the highest improvement in electrochemical conversion efficiency at 3.42%. The TOPSIS examines indices of power, exergy, economy, environment, and water and thermal management. The multiobjective evaluation shows that the elliptical blockage is more beneficial for PEMFC. This study provides an optimized design of the PEMFC flow channel and a new perspective to evaluate the structural improvement of PEMFC.

Pathological features and molecular signatures of early olfactory dysfunction in 3xTg-AD model mice.

BACKGROUND: Olfactory dysfunction is known to be an early manifestation of Alzheimer's disease (AD). However, the underlying mechanism, particularly the specific molecular events that occur during the early stages of olfactory disorders, remains unclear. METHODS: In this study, we utilized transcriptomic sequencing, bioinformatics analysis, and biochemical detection to investigate the specific pathological and molecular characteristics of the olfactory bulb (OB) in 4-month-old male triple transgenic 3xTg-AD mice (PS1M146V/APPSwe/TauP301L). RESULTS: Initially, during the early stages of olfactory impairment, no significant learning and memory deficits were observed. Correspondingly, we observed significant accumulation of amyloid-beta (Aß) and Tau pathology specifically in the OB, but not in the hippocampus. In addition, significant axonal morphological defects were detected in the olfactory bulb, cortex, and hippocampal brain regions of 3xTg-AD mice. Transcriptomic analysis revealed a significant increase in the expression of neuroinflammation-related genes, accompanied by a significant decrease in neuronal activity-related genes in the OB. Moreover, immunofluorescence and immunoblotting demonstrated an activation of glial cell biomarkers Iba1 and GFAP, along with a reduction in the expression levels of neuronal activity-related molecules Nr4a2 and FosB, as well as olfaction-related marker OMP. CONCLUSION: In sum, the early accumulation of Aß and Tau pathology induces neuroinflammation, which subsequently leads to a decrease in neuronal activity within the OB, causing axonal transport deficits that contribute to olfactory disorders. Nr4a2 and FosB appear to be promising targets for intervention aimed at improving early olfactory impairment in AD.

H3K4 Trimethylation Mediate Hyperhomocysteinemia Induced Neurodegeneration via Suppressing Histone Acetylation by ANP32A.

Homocysteine (Hcy) is an independent and serious risk factor for dementia, including Alzheimer's disease (AD), but the precise mechanisms are still poorly understood. In the current study, we observed that the permissive histone mark trimethyl histone H3 lysine 4 (H3K4me3) and its methyltransferase KMT2B were significantly elevated in hyperhomocysteinemia (HHcy) rats, with impairment of synaptic plasticity and cognitive function. Further research found that histone methylation inhibited synapse-associated protein expression, by suppressing histone acetylation. Inhibiting H3K4me3 by downregulating KMT2B could effectively restore Hcy-inhibited H3K14ace in N2a cells. Moreover, chromatin immunoprecipitation revealed that Hcy-induced H3K4me3 resulted in ANP32A mRNA and protein overexpression in the hippocampus, which was regulated by increased transcription Factor c-fos and inhibited histone acetylation and synapse-associated protein expression, and downregulating ANP32A could reverse these changes in Hcy-treated N2a cells. Additionally, the knockdown of KMT2B restored histone acetylation and synapse-associated proteins in Hcy-treated primary hippocampal neurons. These data have revealed a novel crosstalk mechanism between KMT2B-H3K4me3-ANP32A-H3K14ace, shedding light on its role in Hcy-related neurogenerative disorders.

Lactic acid fermentation of goji berries (Lycium barbarum) prevents acute alcohol liver injury and modulates gut microbiota and metabolites in mice.

Juice fermented with lactic acid bacteria (LAB) has received attention due to its health benefits, such as antioxidant and anti-inflammatory. Previous research on LAB-fermented goji juice mainly focused on exploring the changes in the metabolite profile and antioxidant activity in vitro, whereas the liver protection properties of LAB-fermented goji juice in vivo are still unknown. This study aimed to investigate the effects of Lacticaseibacillus paracasei E10-fermented goji juice (E10F), Lactiplantibacillus plantarum M-fermented goji juice (MF), Lacticaseibacillus rhamnosus LGG-fermented goji juice (LGGF) on preventing acute alcoholic liver injury with physiology, gut microbial, and metabolic profiles in mice. Compared with goji juice, E10F, MF, and LGGF enhanced the protective effect against liver injury by reducing serum alanine transaminase (ALT) levels, improving the hepatic glutathione (GSH) antioxidant system, and attenuating inflammation by decreasing the levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-ß. Furthermore, E10F, MF, and LGGF increased intestinal integrity, restructured the gut microbiota including Bacteroides and Lactobacillus, and altered gut microbial metabolites including kyotorphin, indolelactic acid, and N-methylserotonin. Pretreatment of different LAB-fermented goji juice in mice showed significant differences in gut microbiota and metabolism. The correlation analysis demonstrated that the increase of Lactobacillus, indolelactic acid, and N-methylserotonin by E10F, MF, and LGGF was positively correlated with reduced inflammation and improved liver and gut function. Taken together, E10F, MF, and LGGF all have the potential to be converted into dietary interventions to combat acute alcoholic liver injury. It provided a reference for the study of the hepatoprotective effect of LAB-fermented goji juice.

Archaea predominate in the ammonia oxidation process in the sediments of the Yap and Mariana Trenches.

Ammonia-oxidizing archaea (AOA) and bacteria (AOB) play an important role in oxidizing ammonia to nitrite in different marine environments; however, their relative contribution to ammonia oxidation in the deep-sea sediments is still largely unknown. Sediment samples from seamounts and the Challenger Deep along the arc of the Yap Trench and the Mariana Trench were used for the investigation of the geographical distribution of AOA and AOB at the cDNA level, with associated potential nitrification rates (PNRs) being measured. AOA was predominated by Candidatus Nitrosopumilus and Nitrosopumilaceae, while Methylophaga was the major group of AOB. Significantly higher transcript abundance of the AOA amoA gene than that of AOB appeared in all samples, corresponding to the much higher RNRs contributed to AOA. Both the total and AOA PNRs were significantly higher in the deeper layers due to the high sensitivity of AOA to ammonia and oxygen than in AOB. In the surface layers, TN and TOC had significant positive and negative effects on the distribution of the AOA amoA gene transcripts, respectively, while NH4+ concentration was positively correlated with the AOB amoA gene transcripts. Our study demonstrated that AOA played a more important role than AOB in the ammonia-oxidizing process that occurred in the sediments of the Yap and Mariana Trenches and would expand the understanding of their ecological contribution to the nitrification process and nitrogen flux of trenches.

Systemic alterations of tricarboxylic acid cycle enzymes in Alzheimer's disease.

Mitochondrial dysfunction, especially tricarboxylic acid (TCA) cycle arrest, is strongly associated with Alzheimer's disease (AD), however, its systemic alterations in the central and peripheral of AD patients are not well defined. Here, we performed an integrated analysis of AD brain and peripheral blood cells transcriptomics to reveal the expression levels of nine TCA cycle enzymes involving 35 genes. The results showed that TCA cycle related genes were consistently down-regulated in the AD brain, whereas 11 genes were increased and 16 genes were decreased in the peripheral system. Pearson analysis of the TCA cycle genes with Aß, Tau and mini-mental state examination (MMSE) revealed several significant correlated genes, including pyruvate dehydrogenase complex subunit (PDHB), isocitrate dehydrogenase subunits (IDH3B, IDH3G), 2-oxoglutarate dehydrogenase complex subunit (DLD), succinyl-CoA synthetase subunit (SUCLA2), malate dehydrogenase subunit (MDH1). In addition, SUCLA2, MDH1, and PDHB were also uniformly down-regulated in peripheral blood cells, suggesting that they may be candidate biomarkers for the early diagnosis of AD. Taken together, TCA cycle enzymes were systemically altered in AD progression, PDHB, SUCLA2, and MDH1 may be potential diagnostic and therapeutic targets.

Exploring the Potential of GaN-Based Power HEMTs with Coherent Channel.

The GaN industry always demands further improvement in the power transport capability of GaN-based high-energy mobility transistors (HEMT). This paper presents a novel enhancement-type GaN HEMT with high power transmission capability, which utilizes a coherent channel that can form a three-dimensional electron sea. The proposed device is investigated using the Silvaco simulation tool, which has been calibrated against experimental data. Numerical simulations prove that the proposed device has a very high on-state current above 3 A/mm, while the breakdown voltage (above 800 V) is not significantly affected. The calculated Johnson's and Baliga's figure-of-merits highlight the promise of using such a coherent channel for enhancing the performance of GaN HEMTs in power electronics applications.

A variable-stiffness and healable pneumatic actuator.

Pneumatic-powered actuators are receiving increasing attention due to their widespread applications. However, their inherent low stiffness makes them incompetent in tasks requiring high load capacity or high force output. On the other hand, soft pneumatic actuators are susceptible to damage caused by over-pressuring or punctures by sharp objects. In this work, we designed and synthesized a coordination adaptable network (PETMP-AIM-Cu) with high mechanical rigidity (Young's modulus of 1.9 GPa and elongation <2% before fracturing) as well as excellent variable stiffness property (soft-rigid switching ability σ as high as 3 268 000 when ΔT = 90 °C). Combining PETMP-AIM-Cu with a self-healing elastomer based on dynamic disulfide bonds (LP-PDMS), we fabricated a new pneumatic actuator which shows high load capacity at room temperature, but can also easily deform upon heating and thus can be actuated pneumatically. Benefiting from the excellent self-healing ability of PETMP-AIM-Cu and LP-PDMS, the entire pneumatic actuator can still be actuated after being cut and healed. Such a variable-stiffness and healable pneumatic actuator would be useful for complex environmental applications.

Improving flavor, bioactivity, and changing metabolic profiles of goji juice by selected lactic acid bacteria fermentation.

Lactic acid bacteria (LAB) have exhibited strain/species specificity for different food matrices. We investigated the impact of LAB fermentation on the flavor, chemical profile, and bioactivity of goji juice. The colony counts of five selected strains reached above 8.5 log CFU/mL. The fermentation increased the organic acids, decreased the sugars, and improved the sensory quality of goji juice. The majority of the strains had increased acetic acid, heptanoic acid, ethyl phenylacetate, and linalool levels. Specific strains suppressed α-glucosidase and pancreatic lipase activities and increased the antioxidant activities of fermented goji juice. Based on non-targeted metabolomics and activities, 23 important differential metabolites were screened among 453 metabolites. The quantification results showed that isoquercitrin and m-coumaric content varied among strains, reflecting the strain specificity in flavone and flavonol biosynthesis and phenylalanine, tyrosine, and tryptophan biosynthesis. These findings will provide useful information for fermented goji juice biochemistry research.

Comprehensive analysis and immune landscape of chemokines- and chemokine receptors-based signature in hepatocellular carcinoma.

Background: Despite encouraging results from immunotherapy combined with targeted therapy for hepatocellular carcinoma (HCC), the prognosis remains poor. Chemokines and their receptors are an essential component in the development of HCC, but their significance in HCC have not yet been fully elucidated. We aimed to establish chemokine-related prognostic signature and investigate the association between the genes and tumor immune microenvironment (TIME). Methods: 342 HCC patients have screened from the TCGA cohort. A prognostic signature was developed using least absolute shrinkage and selection operator regression and Cox proportional risk regression analysis. External validation was performed using the LIHC-JP cohort deployed from the ICGC database. Single-cell RNA sequencing (scRNA-seq) data from the GEO database. Two nomograms were developed to estimate the outcome of HCC patients. RT-qPCR was used to validate the differences in the expression of genes contained in the signature. Results: The prognostic signature containing two chemokines-(CCL14, CCL20) and one chemokine receptor-(CCR3) was successfully established. The HCC patients were stratified into high- and low-risk groups according to their median risk scores. We found that patients in the low-risk group had better outcomes than those in the high-risk group. The results of univariate and multivariate Cox regression analyses suggested that this prognostic signature could be considered an independent risk factor for the outcome of HCC patients. We discovered significant differences in the infiltration of various immune cell subtypes, tumor mutation burden, biological pathways, the expression of immune activation or suppression genes, and the sensitivity of different groups to chemotherapy agents and small molecule-targeted drugs in the high- and low-risk groups. Subsequently, single-cell analysis results showed that the higher expression of CCL20 was associated with HCC metastasis. The RT-qPCR results demonstrated remarkable discrepancies in the expression of CCL14, CCL20, and CCR3 between HCC and its paired adjacent non-tumor tissues. Conclusion: In this study, a novel prognostic biomarker explored in depth the association between the prognostic model and TIME was developed and verified. These results may be applied in the future to improve the efficacy of immunotherapy or targeted therapy for HCC.

Integrated transcriptomics reveals the brain and blood biomarkers in Alzheimer's disease.

BACKGROUND: The systematic molecular associations between the peripheral blood cells and brain in Alzheimer's disease (AD) remains unclear, which hinders our understanding of AD pathological mechanisms and the exploration of new diagnostic biomarkers. METHODS: Here, we performed an integrated analysis of the brain and peripheral blood cells transcriptomics to establish peripheral biomarkers of AD. By employing multiple statistical analyses plus machine learning, we identified and validated multiple regulated central and peripheral network in patients with AD. RESULTS: By bioinformatics analysis, a total of 243 genes were differentially expressed in the central and peripheral systems, mainly enriched in three modules: immune response, glucose metabolism and lysosome. In addition, lysosome related gene ATP6V1E1 and immune response related genes (IL2RG, OSM, EVI2B TNFRSF1A, CXCR4, STAT5A) were significantly correlated with Aß or Tau pathology. Finally, receiver operating characteristic (ROC) analysis revealed that ATP6V1E1 showed high-diagnostic potential for AD. CONCLUSION: Taken together, our data identified the main pathological pathways in AD progression, particularly the systemic dysregulation of the immune response, and provided peripheral biomarkers for AD diagnosis.

Damaged collagen detected by collagen hybridizing peptide as efficient diagnosis marker for early hepatic fibrosis.

Liver fibrosis is characterized by excessive synthesis and deposition of extracellular matrix (ECM) in liver tissues. However, it still has been lacking of early detection and diagnosis methods. The collagen hybridizing peptide (CHP) is a novel synthetic peptide that enables detection of collagen damage and tissue remodeling. Here, we showed that obvious CHP-positive staining could be detected in the liver while given CCl4 for only 3 days, which was significantly enhanced while given CCl4 for 7 days. However, H&E staining showed no significant changes in fibrous tissue, and sirius red-positive staining could only be observed while given CCl4 for 14 days. Moreover, CHP-positive staining enhanced initially at portal area which further extended into the hepatic lobule, which was increased more significantly than sirius red-positive staining in the model of 10 and 14 days. Further proteomic analysis of CHP-positive staining revealed that pathways associated with ECM remodeling were significantly increased, while retinol metabolism was downregulated. Meanwhile, proteins enriched in cellular gene transcription and signal transduction involved in fibrogenesis were also upregulated, suggesting that fibrosis occurred in CHP-positive staining. Our study provided evidence that CHP could detect the collagen damage in liver, which might be an efficient indicator for the diagnosis of liver fibrosis at a very early stage.

Exploration of street space architectural color measurement based on street view big data and deep learning-A case study of Jiefang North Road Street in Tianjin.

Urban space architectural color is the first feature to be perceived in a complex vision beyond shape, texture and material, and plays an important role in the expression of urban territory, humanity and style. However, because of the difficulty of color measurement, the study of architectural color in street space has been difficult to achieve large-scale and fine development. The measurement of architectural color in urban space has received attention from many disciplines. With the development and promotion of information technology, the maturity of street view big data and deep learning technology has provided ideas for the research of street architectural color measurement. Based on this background, this study explores a highly efficient and large-scale method for determining architectural colors in urban space based on deep learning technology and street view big data, with street space architectural colors as the research object. We conducted empirical research in Jiefang North Road, Tianjin. We introduced the SegNet deep learning algorithm to semantically segment the street view images, extract the architectural elements and optimize the edges of the architecture. Based on K-Means clustering model, we identified the colors of the architectural elements in the street view. The accuracy of the building color measurement results was cross-sectionally verified by means of a questionnaire survey. The validation results show that the method is feasible for the study of architectural colors in street space. Finally, the overall coordination, sequence continuity, and primary and secondary hierarchy of architectural colors of Jiefang North Road in Tianjin were analyzed. The results show that the measurement model can realize the intuitive expression of architectural color information, and also can assist designers in the analysis of architectural color in street space with the guidance of color characteristics. The method helps managers, planners and even the general public to summarize the characteristics of color and dig out problems, and is of great significance in the assessment and transformation of the color quality of the street space environment.

Aerobic exercise attenuates autophagy-lysosomal flux deficits by ADRB2/ß2-adrenergic receptor-mediated V-ATPase assembly factor VMA21 signaling in APP-PSEN1/PS1 mice.

Growing evidence suggests that macroautophagy/autophagy-lysosomal pathway deficits contribute to the accumulation of amyloid-ß (Aß) in Alzheimer disease (AD). Aerobic exercise (AE) has long been investigated as an approach to delay and treat AD, although the exact role and mechanism are not well known. Here, we revealed that AE could reverse autophagy-lysosomal deficits via activation of ADRB2/ß2-adrenergic receptor, leading to significant attenuation of amyloid-ß pathology in APP-PSEN1/PS1 mice. Molecular mechanism research found that AE could reverse autophagy deficits by upregulating the AMP-activated protein kinase (AMPK)-MTOR (mechanistic target of rapamycin kinase) signaling pathway. Moreover, AE could reverse V-ATPase function by upregulating VMA21 levels. Inhibition of ADRB2 by propranolol (antagonist, 30 µM) blocked AE-attenuated Aß pathology and cognitive deficits by inhibiting autophagy-lysosomal flux. AE may mitigate AD via many pathways, while ADRB2-VMA21-V-ATPase could improve cognition by enhancing the clearance of Aß through the autophagy-lysosomal pathway, which also revealed a novel theoretical basis for AE attenuating pathological progression and cognitive deficits in AD.