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[Display omitted] • The self-standing COFM PDI-THSTZ is synthesized via liquid–liquid interfacial method. • The semiconductor characteristics of PDI and multi-channel structure of COF endow the sensor with real-time sensing properties. • The mechanism for the enhanced TMA sensing response of COFM PDI-THSTZ is investigated. • The TMA sensor can be used for the quality monitoring in IoT. The unprecedented demand for highly selective, real-time monitoring and low-power gas sensors used in food quality control has been driven by the increasing popularity of the Internet of Things (IoT). Herein, the self-standing perylene diimide based covalent organic framework membranes (COFM PDI-THSTZ) were prepared via liquid–liquid interfacial synthesis method. By incorporating the perylene diimide monomer into the COFM through molecular engineering, COFM PDI-THSTZ based sensor demonstrated an outstanding trimethylamine (TMA)-sensing performance at room temperature. Benefited from the TMA-accessible self-standing membrane morphology, π-electron delocalization effect, and extensive surface area with continuous nanochannels, the specific and highly sensitive TMA measurement has been achieved within the range of 0.03–400 ppm, with an exceptional theoretical detection limit as low as 10 ppb. Moreover, the primary internal mechanism of COFM PDI-THSTZ for this efficient TMA detection was investigated through in-situ FT-IR spectra, thereby directly elucidating that the chemisorption interaction of oxygen modulated the depletion layers on sensing material surface, resulting in alterations in sensor resistance upon exposure to the target gas. For practical usage, COFM PDI-THSTZ based sensor exhibited exceptional real-time in-situ sensing capabilities, further confirmed their potential for application in dynamic prediction evaluation of marine fish products and quality monitoring in IoT. [ABSTRACT FROM AUTHOR]

'Neuroinflammation', one of the hallmarks of many neurodegenerative diseases, causes inadvertent damage to neuronal tissue due to the immune system's response to the underlying pathology. The role of the immune system in the development and progression of many neurodegenerative diseases remains elusive, with conflicting evidence in similar model systems. Due to the complexity of the immune system's involvement and the limitations of preclinical models, indiscriminate targeting of any single immune cell population could lead to inadvertent effects in neurodegenerative disease. The concept of cellular immunotherapy and personalized immunotherapeutic approaches is becoming feasible with current technological advancements, and might provide a new avenue for treating neurodegenerative diseases. We draw a compelling analogy between the immune system's role in neurodegeneration and a construction crew, underscoring the potential of cellular immunotherapies (especially T cell-based) to remodel and repair the central nervous system (CNS). We advocate for the development of personalized immunotherapies that leverage advanced technologies such as single-cell V(D)J sequencing and chimeric antigen receptor T (CAR-T) cell therapy. These approaches could transform the immune system from an inadvertent enabler of neurodegeneration to a precise tool for restoring the CNS: a novel strategy to combat neurodegenerative diseases. Neurodegenerative disorders present major challenges to global health, exacerbated by an aging population and the absence of therapies. Despite diverse pathological manifestations, they share a common hallmark, loosely termed 'neuroinflammation'. The prevailing dogma is that the immune system is an active contributor to neurodegeneration; however, recent evidence challenges this. By analogy with road construction, which causes temporary closures and disruptions, the immune system's actions in the central nervous system (CNS) might initially appear destructive, and might even cause harm, while aiming to combat neurodegeneration. We propose that the application of cellular immunotherapies to coordinate the immune response towards remodeling might pave the way for new modes of tackling the roadblocks of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

N- and O-glycosylation modifications of proteins are closely linked to the onset and development of many diseases and have gained widespread attention as potential targets for therapy and diagnosis. However, the low abundance and low ionization efficiency of glycopeptides as well as the high heterogeneity make glycosylation analysis challenging. Here, an enrichment strategy, using Knoevenagel copolymers modified with polydopamine–adenosine (denoted as PDA–ADE@KCP), was firstly proposed for simultaneous enrichment of N- and O-glycopeptides through the synergistic effects of hydrophilic and electrostatic interactions. The adjustable charged surface and hydrophilic properties endow the material with the capability to achieve effective enrichment of intact N- and O-glycopeptides. The experimental results exhibited excellent selectivity (1 : 5000) and sensitivity (0.1 fmol μL−1) of the prepared material for N-glycopeptides from standard protein digest samples. Moreover, it was further applied to simultaneous capturing of N- and O-glycopeptides from mouse liver protein digests. Compared to the commercially available zwitterionic hydrophilic interaction liquid chromatography (ZIC-HILIC) material, the number of glycoproteins corresponding to all N- and O-glycopeptides enriched with PDA–ADE@KCP was much more than that with ZIC-HILIC. Furthermore, PDA–ADE@KCP captured more O-glycopeptides than ZIC-HILIC, revealing its superior performance in O-glycopeptide enrichment. All these results indicated that the strategy holds immense potential in characterizing N- and O-intact glycopeptides in the field of proteomics. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD), one of the most devastating neurodegenerative brain disorders, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) and deposits of α-synuclein aggregates. Currently, pharmacological interventions for PD remain inadequate. The cell necroptosis executor protein MLKL (Mixed-lineage kinase domain-like) is involved in various diseases, including inflammatory bowel disease and neurodegenerative diseases; however, its precise role in PD remains unclear. Here, we investigated the neuroprotective role of MLKL inhibition or ablation against primary neuronal cells and human iPSC-derived midbrain organoids induced by toxic α-Synuclein preformed fibrils (PFFs). Using a mouse model (Tg-Mlkl−/−) generated by crossbreeding the SNCA A53T synuclein transgenic mice with MLKL knockout (KO)mice, we assessed the impact of MLKL deficiency on the progression of Parkinsonian traits. Our findings demonstrate that Tg-Mlkl−/− mice exhibited a significant improvement in motor symptoms and reduced phosphorylated α-synuclein expression compared to the classic A53T transgenic mice. Furthermore, MLKL deficiency alleviated tyrosine hydroxylase (TH)-positive neuron loss and attenuated neuroinflammation by inhibiting the activation of microglia and astrocytes. Single-cell RNA-seq (scRNA-seq) analysis of the SN of Tg-Mlkl−/− mice revealed a unique cell type-specific transcriptome profile, including downregulated prostaglandin D synthase (PTGDS) expression, indicating reduced microglial cells and dampened neuron death. Thus, MLKL represents a critical therapeutic target for reducing neuroinflammation and preventing motor deficits in PD. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) induces early-stage breast cancer progression and increases breast cancer patients' mortality and morbidity. Insulin-like peptide 6 (INSL6) overexpression can impede cardiotoxin-induced injury through myofiber regeneration, playing a significant role in MI progression. To investigate the diverse significance of INSL6 in a variety of malignant tumors, we explored INSL6 through MI GEO dataset and multiple omics data integrative analysis, such as gene expression level, enriched pathway analysis, protein-protein interaction (PPI) analysis, and immune subtypes as well as diagnostic value and prognostic value in pancancer. INSL6 expression was downregulated in the MI group, and overall survival analysis demonstrated that INSL6 could be the prognostic biomarkers in the overall survival of breast cancer (BRCA). INSL6 expression differs significantly not only in most cancers but also in different molecular and immune subtypes of cancers. INSL6 might be a potential diagnostic and prognostic biomarker of cancers due to the high accuracy in diagnostic and prognostic value. Furthermore, we focused on BRCA and further investigated INSL6 from the perspective of the correlations with clinical characteristics, prognosis in different clinical subgroups, coexpression genes, and differentially expressed genes (DEGs) and PPI analysis. Overall survival and disease-specific survival analysis of subgroups in BRCA demonstrated that lower INSL6 expression had a worse prognosis. Therefore, INSL6 aberrant expression is associated with the progression and immune cell infiltration of the tumor, especially in KIRP and BRCA. Therefore, INSL6 may serve as a potential prognostic biomarker and the crosstalk between MI and tumor progression. [ABSTRACT FROM AUTHOR]

• A novel bimetallic nanozyme (COF Fe/CoP-Ph) displayed excellent triple-enzyme mimetic activities. • The multiple enzyme-driven cascade catalysis strategy was proposed. • The colorimetric determination of malathion was achieved without the addition exogenous H 2 O 2. • A smartphone POCT analysis platform with integrated paper chip sensors was developed. Enzyme-induced biological cascade catalysis can achieve selective and efficient transformations of substrates in vivo. Thus, the biomimetic cascade systems have attracted much attention in biological detection on account of their ingenious strategies for signal conduction and amplification. In this study, a porphyrin-based covalent organic framework (COF Fe/CoP-Ph) with bimetal-nitrogen-coordinate centers (M − N 4) were constructed via Schiff base reaction. The synergistic effect of the highly exposed M − N 4 bimetallic active sites and the unique topology overcame the self-limitation of nanozyme, resulting in a significant enhancement of the triple-enzyme mimetic activities of COF Fe/CoP-Ph , namely oxidase (OXD)-, peroxidase (POD)-, and catalase (CAT)-like activities. Simultaneously, a multiple enzyme-driven cascade catalysis strategy for signal amplification was proposed utilizing the OXD- and POD-like mimetic mechanisms of COF Fe/CoP-Ph , enabling the colorimetric determination of malathion without the addition exogenous H 2 O 2. The established colorimetric sensor exhibited an exceptional linear relationship within the range of 1–18 μM and a low detection limit of 11 nM. Subsequently, a portable smartphone platform was developed by integrating paper chip, facilitating successful malathion point-of-care testing (POCT) in real samples. This work not only creates a bimetallic COF nanozyme and establishes an efficient cascade amplification strategy, but also introduces a novel design approach for development of a low-cost and user-friendly POCT method. [ABSTRACT FROM AUTHOR]

Protein glycosylation is of great significance in various physiological processes. Nevertheless, it remains a huge challenge to identify glycopeptides in complex biosamples by the direct mass spectrometry analysis due to the low ion efficiency and low abundance of glycopeptides. In this study, a novel hydrogel (denoted as ZIF-8/SAP) with a stable three-dimensional (3D) network structure and excellent hydrophilicity was successfully fabricated to capture glycopeptides with high efficiency. Owing to the unique characteristics, ZIF-8/SAP exhibited great selectivity (1 : 1000), great sensitivity (1 fmol μL−1), large binding capacity (300 mg g−1) and satisfactory reusability (seven cycles). Inspired by the great enrichment performance of the as-prepared material toward glycopeptides, ZIF-8/SAP was further applied to capture glycopeptides from a real human serum sample. The experimental results demonstrated that 217 N-glycosylation sites were identified in 283 N-glycopeptides, corresponding to 95 glycoproteins identified from 10 μL human serum by the nano-LC-MS/MS analysis, revealing the great potential of the novel ZIF-8/SAP hydrogel for glycopeptide enrichment and glycoproteomic research. [ABSTRACT FROM AUTHOR]

A novel nano-floral inter-polymeric material (λ-Carr-Ag-SA) was developed to effectively capture N-linked glycopeptides from biological samples. A simple one-step reduction of silver ions was involved in the synthesis of the material in which λ-carrageenan and sodium alginate, with abundant hydrophilic groups, were used as the reducing agent and stabilizer. The performance of λ-Carr-Ag-SA was evaluated experimentally by enriching glycopeptides from horse radish peroxidase (HRP) and human serum. All the results demonstrated that λ-Carr-Ag-SA had a great selectivity, low detection limit and a large binding capacity toward glycopeptides. The successful application exhibits great potential of λ-Carr-Ag-SA for further glycoproteome analysis. [ABSTRACT FROM AUTHOR]

A novel hydrophilic porous biocomposite was fabricated by incorporating graphene oxide (GO) @chitosan (CS) foam substrate (GO@CS@ZIF-8 foam) with ZIF-8 crystals in situ via a facile stirring method for simultaneous enrichment of glycopeptides and phosphopeptides from complex biological samples. The experimental results demonstrated that GO@CS@ZIF-8 foam exhibited favorable specificity for simultaneous enrichment of N-glycopeptides and phosphopeptides under the same condition for HRP and β-casein tryptic digest mixtures. The novel material was further applied to enriching both glycopeptides and phosphopeptides simultaneously from 4 μL complex human serum, and 423 N-glycopeptides and 40 phosphopeptides corresponding to 133 glycoproteins and 29 phosphoproteins were identified, respectively. [ABSTRACT FROM AUTHOR]

Rationale: Field asymmetric waveform ion mobility spectrometry (FAIMS) has a great potential to become a portable technology for rapid detection of chemical and biological agents. However, the ion current signals, measured at the exit of the planar FAIMS directly, may contain different types of noises. The peak information in the FAIMS spectrum, such as the compensation voltage (CV) value at the maximum peak intensity (CVP) and the peak width at half maximum (Wh), could not be accurately determined under the weak signal condition, which significantly limits the achievable instrument sensitivity, and there are no existing solutions to the problem. Methods: This study analyzed the noise type of FAIMS signal in detail, and three different signal processing algorithms, such as median filtering (MF), discrete wavelet transform (DWT), and zero‐phase digital filtering (ZDF), were evaluated for their performance in denoising the FAIMS signal. Results: The results show that the standard deviation of CVp obtained from the signal denoised using ZDF algorithm is at least 31.82% smaller as compared to using MF and DWT algorithms. The standard deviation of Wh is at least 45.45% smaller using ZDF algorithm. Moreover, only ZDF algorithm can keep the percentage error for the CV value of the denoised signal to be within 0.50 ± 0.47% of the true CV value, implying the effectiveness of ZDF algorithm in denoising while retaining the integrity of the signal. Conclusions: The ZDF algorithm greatly reduces the analyte peak extraction error and improves the limit of detection in FAIMS measurements. [ABSTRACT FROM AUTHOR]

The diluent significantly influences the structure and properties of the oxygenated membrane prepared via thermally induced phase separation (TIPS). With the increasing concern of damage to human body and environment from diluents, non-toxic and environmental-friendly diluents are gradually gaining more attention. In this study, green binary diluents acetyl trioctyl citrate (ATOC) and acetyl tributyl citrate (ATBC) are used to prepare poly-4-methyl-1-pentene (PMP) flat sheet membranes and hollow fiber membranes (HFMs) via TIPS. Firstly, the effects of ATOC/ATBC mass ratio on the morphology, gas permeability, mechanical properties, and crystallization behaviors of flat sheet membranes are investigated. When the ATOC/ATBC mass ratio is 6/4, the membrane has high gas permeability and mechanical properties. Furthermore, the optimal polymer-diluent composition is applied to the preparation of HFMs. The effects of spinning parameters (flow rate of core liquid, and spinning speed) on morphology, gas permeability, and blood oxygenation performance of PMP HFMs are studied. Under optimized preparation conditions, the PMP HFM exhibits high gas permeability (the permeability of O 2 is 39.4 ± 2.1 mL min−1 cm−2 bar−1 and the permeability of CO 2 is 42.3 ± 2.3 mL min−1 cm−2 bar−1), which is higher than the results reported in previous research. The PMP HFM also shows excellent blood oxygenation performance. This study may contribute to the green preparation of PMP oxygenated membranes for artificial membrane lungs. [Display omitted] • PMP flat sheet membranes and hollow fiber membranes were fabricated with green binary diluents ATOC/ATBC via TIPS. • Effects of ATOC/ATBC mass ratios on flat sheet membrane performance were revealed. • Effects of spinning parameters on hollow fiber membrane performance were revealed. • The PMP HFM shows the high gas permeability and excellent blood oxygenation performance. [ABSTRACT FROM AUTHOR]

The ultrasensitive detection of trace hydrogen peroxide (H 2 O 2) has been a fascinating research topic owing to its significant application in environmental monitoring, food safety, and scientific research. In this study, bimetallic porphyrin-based covalent organic framework composites (MWCNTs@Mn/Fe-COF) was prepared by in situ polymerization of Mn porphyrin (MnPor) and Fe porphyrin (FePor) on multi-walled carbon nanotubes (MWCNTs), and a biomimetic enzyme electrochemical sensor was constructed for determination of trace H 2 O 2. The unique topological structure features of COF and the high conductivity of MWCNTs not only ensured highly independent M−N 4 electrochemical active sites, but also guaranteed efficient electron transfer pathways. Especially, the introduction of Mn sites formed a self-accelerated redox cycling between valence states, which significantly improved the electrocatalytic efficiency. Taking advantage of the above advantages, the MWCNTs@Mn/Fe-COF based sensor achieved ultrasensitive detection of H 2 O 2 with a low detection limit of 2 nM. Moreover, the developed sensor has been successfully used to measure trace H 2 O 2 induced by lab-equipped ultrasonic cleaners and in disinfector and apple juice. The constructed sensor in this study has potential application value in the rapid detection of trace H 2 O 2 in real samples, which opened up a new way for the synthesis of bimetallic analog enzymes and the construction of ultra-sensitive electrochemical sensors. • Bimetallic MWCNTs@Mn/Fe-COF was prepared by in situ growth method. • The unique topological structure of Mn/Fe-COF provided highly exposed active sites. • The bimetallic M−N 4 active sites accelerated the catalytic cycle of H 2 O 2. • The highly sensitive detection of trace H 2 O 2 in real samples was realized. [ABSTRACT FROM AUTHOR]

Rationale: Quantitative detection of the FGF‐21 biomarker at the sub‐nanogram per mL level in human serum has generally been achieved using nanoflow liquid chromatography/tandem mass spectrometry (LC/MS/MS) due to its high sensitivity. However, a nano‐LC/MS/MS‐based assay can suffer from limited reproducibility and MS signal instability making it challenging to employ it as a robust analytical method for routine clinical applications. Methods: To tackle these limitations, parallel reaction monitoring (PRM)‐based targeted protein quantification using normal‐flow liquid chromatography coupled with high‐resolution, accurate mass instrumentation was evaluated as a possible alternative. Different from the conventional selected reaction monitoring (SRM) using triple quadrupole MS, the proposed strategy used high‐resolution orbitrap MS coupled with conventional normal‐flow liquid chromatography. The primary goal of this assay development effort is to significantly improve the robustness of the LC/MS/MS‐based assay while maintaining high sensitivity by the use of high‐resolution MS and a large sample loading volume. Results: The performance of the normal‐flow LC/MS/MS assay was evaluated by using it to quantify the FGF‐21 protein, a potential biomarker for non‐alcoholic fatty liver disease, in serum samples. Multiple replicated PRM sample quantification results demonstrated the excellent reproducibility and operational robustness of the assay. A limit of quantification of less than 0.4 ng/mL for FGF‐21 in a complex serum matrix could be achieved by using the heavy‐isotope‐labeled peptide technique, a result which is comparable with the sensitivity obtained using the nano‐LC/SRM MS‐based assay. Conclusions: The strategy offered an effective alternative to nano‐LC/SRM MS for the quantification of protein biomarkers in a complex biomatrix with much improved reproducibility and operational robustness. [ABSTRACT FROM AUTHOR]

Rationale: Quantitative detection of the FGF‐21 biomarker at the sub‐nanogram per mL level in human serum has generally been achieved using nanoflow liquid chromatography/tandem mass spectrometry (LC/MS/MS) due to its high sensitivity. However, a nano‐LC/MS/MS‐based assay can suffer from limited reproducibility and MS signal instability making it challenging to employ it as a robust analytical method for routine clinical applications. Methods: To tackle these limitations, parallel reaction monitoring (PRM)‐based targeted protein quantification using normal‐flow liquid chromatography coupled with high‐resolution, accurate mass instrumentation was evaluated as a possible alternative. Different from the conventional selected reaction monitoring (SRM) using triple quadrupole MS, the proposed strategy used high‐resolution orbitrap MS coupled with conventional normal‐flow liquid chromatography. The primary goal of this assay development effort is to significantly improve the robustness of the LC/MS/MS‐based assay while maintaining high sensitivity by the use of high‐resolution MS and a large sample loading volume. Results: The performance of the normal‐flow LC/MS/MS assay was evaluated by using it to quantify the FGF‐21 protein, a potential biomarker for non‐alcoholic fatty liver disease, in serum samples. Multiple replicated PRM sample quantification results demonstrated the excellent reproducibility and operational robustness of the assay. A limit of quantification of less than 0.4 ng/mL for FGF‐21 in a complex serum matrix could be achieved by using the heavy‐isotope‐labeled peptide technique, a result which is comparable with the sensitivity obtained using the nano‐LC/SRM MS‐based assay. Conclusions: The strategy offered an effective alternative to nano‐LC/SRM MS for the quantification of protein biomarkers in a complex biomatrix with much improved reproducibility and operational robustness. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A fuzzy-precise positioning pre-search method is presented for acceleration of compound recognition. • The spectral library pre-search space is significantly compressed in fuzzy matching stage. • The spectral library pre-search time consumption is reduced. • The spectral library pre-search accuracy is improved. Abstract A mass spectral library pre-search algorithm, fuzzy-precise positioning (FPP), is described for rapid and accurate identification of chemical compound. This algorithm works on the basis of the molecular ion feature peaks and fragment ion feature peaks of mass spectra. The algorithm mainly includes three stages: feature peaks selection, fuzzy positioning and precise positioning. For query spectra and reference spectra, four molecular ion feature peaks and six fragment ion feature peaks are selected and their corresponding mass-to-charge ratio (m/z) values are recorded, respectively. After that, fuzzy positioning is conducted to skip some unrelated spectra in the reference library by comparing maximum and minimum m/z values of feature peaks of query spectra with those of reference spectra. Finally, in the precise positioning stage, ten m/z values of feature peaks of the query spectra are matched with those of remaining reference spectra one by one. If the matching number is larger than five, this reference spectrum can be remained as a candidate spectrum. After traversing all the reference spectra remained after fuzzy positioning, final pre-search results can be obtained. To evaluate the performace of the the proposed algorithm, a series of experiments are designed by using main library and replicate library of NIST11 as reference library and query library, respectively. Moreover, real application data are used to verify the performance of FPP method. Compared to two-step spectral library pre-search (TSLP) algorithm and "ten-peak" method, the results show that FPP method can obtain higher accuracy, smaller pre-search space, shorter time consumption and less remaining spectra. [ABSTRACT FROM AUTHOR]

Rationale: In the field of separation science, ion mobility spectrometry (IMS) plays an important role as an analytical tool. However, the lack of sufficient structural resolution is a common problem in qualitative and quantitative analysis using IMS. A method is needed to solve the problem of overlapping peaks caused by insufficient resolution. Methods: The method uses multiple strategies to more effectively use population information to balance exploration and exploitation capabilities, prevent local optimization, accurately resolve overlapping peaks, quickly obtain optimal spectral peak model coefficients, and accurately identify compounds. Results: Multistrategy JAYA algorithm's (MSJAYA) performance is compared with improved particle swarm optimization (IPSO), dynamic inertia weight particle swarm optimization (DIWPSO), and multiobjective dynamic teaching‐learning‐based optimization (MDTLBO). The analysis shows that MSJAYA's maximum separation error is within 0.6%, a level of accuracy not guaranteed by the other algorithms. In addition, the separation error fluctuates within a much smaller range, demonstrating MSJAYA's superior robustness. Conclusions: Compared with other overlapping peak separation algorithms, MSJAYA is more applicable because no special parameters are used. The method allows fast deconvolution analysis of strong overlapping peaks with multiple components, which greatly improves the resolution of IMS. [ABSTRACT FROM AUTHOR]

Pyroptosis was long regarded as caspase-1-mediated monocyte death in response to certain bacterial insults. Caspase-1 is activated upon various infectious and immunological challenges through different inflammasomes. The discovery of caspase-11/4/5 function in sensing intracellular lipopolysaccharide expands the spectrum of pyroptosis mediators and also reveals that pyroptosis is not cell type specific. Recent studies identified the pyroptosis executioner, gasdermin D (GSDMD), a substrate of both caspase-1 and caspase-11/4/5. GSDMD represents a large gasdermin family bearing a novel membrane pore-forming activity. Thus, pyroptosis is redefined as gasdermin-mediated programmed necrosis. Gasdermins are associated with various genetic diseases, but their cellular function and mechanism of activation (except for GSDMD) are unknown. The gasdermin family suggests a new area of research on pyroptosis function in immunity, disease, and beyond. [ABSTRACT FROM AUTHOR]

A detailed experimental characterization and theoretical analysis on the sensitivity, resolution and ion transmission efficiency of a planar FAIMS under different operating conditions including electrospray flow rate, solution concentration, curtain voltage and dispersion voltage are reported in the study based on the direct measurements of the ion current on the FAIMS detector. The sensitivity of FAIMS was shown to increase initially with the increase of electrospray flow rate. At a certain flow rate, which is typically compound dependent, an optimum FAIMS sensitivity was observed. Further increasing the electrospray flow rate would result in the decrease of the FAIMS sensitivity. Interestingly, the ion transmission efficiency of the FAIMS was shown experimentally to monotonically increase with the decrease of the electrospray flow rates. Both the ion transmission efficiency/sensitivity and the resolution of the FAIMS were significantly affected by the dispersion voltage. There is a strong tradeoff between the FAIMS ion transmission efficiency/sensitivity and separation resolution. As the FAIMS dispersion voltage increases, the separation resolution increases while the ion transmission efficiency/sensitivity decreases. The curtain voltage can also dramatically affect the performance of FAIMS, especially in the ion separation mode. The sensitivity of FAIMS at curtain voltage of 1.8 kV is about two-fold higher than the one at 1.0 kV. This study allows one to select the desirable FAIMS operating conditions based on the actual analysis needs. [Display omitted] • A high performance standalone FAIMS device was developed. • A detailed characterization on the sensitivity, resolution and ion transmission efficiency of FAIMS were reported. • The standalone FAIMS device could be used for quantitative analysis with a detection limit of less than 5 μM. [ABSTRACT FROM AUTHOR]

Mass spectrometry (MS) data is susceptible to random noises and alternating baseline, posing great challenges to spectral peak detection, especially for weak peaks and overlapping peaks. Herein, an efficient peak detection algorithm combining continuous wavelet transform (CWT) and genetic algorithm-based threshold segmentation (denoted as WSTGA) for mass spectrometry was proposed. Firstly, Mexican Hat wavelet was selected as the mother wavelet by comparing the matching degree between the difference of Gaussian (DOG) and different wavelets. Subsequently, the ridges and valleys were identified from 2D wavelet coefficient matrix. Afterward, an improved threshold segmentation method, Otsu method based on genetic algorithm, was introduced to find optimal segmentation threshold and achieve better image segmentation, overcoming the deficiency of traditional Otsu method that cannot handle long-tailed unimodal histograms. Finally, the characteristic peaks were successfully identified by utilizing the ridge-valley lines in wavelet space and original spectrum. Receiver operating characteristic (ROC) curve, area under curve (AUC) and F₁ measure are used as criterions to evaluate performance of peak detection algorithms. Compared with multi-scale peak detection (MSPD) and CWT and image segmentation (CWT-IS) methods, all the results showed that WSTGA can achieve better peak detection. More importantly, the experimental results from MALDI-TOF spectra demonstrated that WSTGA can effectively detect more weak peaks and overlapping peaks while maintaining a lower false peak detection rate than MSPD and CWT-IS methods, indicating its great advantages in characteristic peak identification. • An efficient peak detection algorithm for MS using CWT and genetic algorithm-based Otsu (WSTGA) was proposed. • The genetic algorithm-based Otsu was introduced to find optimal threshold segmentation. • The ridge determination condition was improved to enhance the denoising ability of WSTGA. • WSTGA can detect more weak peaks and overlapping peaks while maintaining a lower false peak detection rate. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is the second-deadliest infectious disease worldwide. Emerging evidence shows that the elongation factor EF-Tu could be an excellent target for treating Mtb infection. Here, we report the crystal structures of Mtb EF-Tu•EF-Ts and EF-Tu•GDP complexes, showing the molecular basis of EF-Tu's representative recycling and inactive forms in protein translation. Mtb EF-Tu binds with EF-Ts at a 1:1 ratio in solution and crystal packing. Mutation and SAXS analysis show that EF-Ts residues Arg13, Asn82, and His149 are indispensable for the EF-Tu/EF-Ts complex formation. The GDP binding pocket of EF-Tu dramatically changes conformations upon binding with EF-Ts, sharing a similar GDP-exchange mechanism in E. coli and T. ther. Also, the FDA-approved drug Osimertinib inhibits the growth of M. smegmatis, H37Ra, and M. bovis BCG strains by directly binding with EF-Tu. Thus, our work reveals the structural basis of Mtb EF-Tu in polypeptide synthesis and may provide a promising candidate for TB treatment. Crystal structures of M. tuberculosis elongation factors EF-Tu and EF-Ts in complex and GDP-bound Ef-Tu reveal the molecular basis of EF-Tu's representative recycling and inactive forms in protein translation. [ABSTRACT FROM AUTHOR]

Abstract: Androgens function as sex hormone primarily via activation of a single androgen receptor (AR, or NR3C4). AR is an important therapeutic target for the treatment of diseases such as hypogonadism and prostate cancer. AR ligands of different chemical structures and/or pharmacological properties are widely used for these therapeutic applications, and all of the AR ligands currently available for therapy modulate AR function via direct binding to the ligand-binding pocket (LBP) of the receptor. In the past ten years, our understanding of AR structure and molecular mechanism of action has progressed extensively, which has encouraged the rapid development of newer generation of AR ligands, particularly tissue-selective AR ligands. With improved tissue selectivity, future generations of AR ligands are expected to greatly expand the therapeutic applications of this class of drugs. This review will provide an overview of the common therapeutic applications of currently available AR ligands, and discussion of the major challenges as well as novel therapeutic strategies proposed for future drug development. [ABSTRACT FROM AUTHOR]

Selective androgen receptor modulators (SARMs) are a novel class of androgen receptor (AR) ligands that might change the future of androgen therapy dramatically. With improved pharmacokinetic characteristics and tissue-selective pharmacological activities, SARMs are expected to greatly extend the clinical applications of androgens to osteoporosis, muscle wasting, male contraception and diseases of the prostate. Mechanistic studies with currently available SARMs will help to define the contributions of differential tissue distribution, tissue-specific expression of 5α-reductase, ligand-specific regulation of gene expression and AR interactions with tissue-specific coactivators to their observed tissue selectivity, and lead to even greater expansion of selective anabolic therapies. [Copyright &y& Elsevier]

Carcinoma of the prostate is the most commonly diagnosed cancer in men. The current pharmacological treatment of choice for progressive androgen-dependent prostate cancer is the nonsteroidat antiandrogen, bicalutamide, either as monotherapy or with adjuvant castration or luteinizing hormone-releasing hormone superagonists to block the synthesis of endogenous testosterone. To date, no nonsteroidal or antagonist-bound androgen receptor (AR) structure is available. We solved the x-ray crystal structure of the mutant W741L AR ligand-binding domain bound to R-bicalu- tamide at 1.8-Å resolution. This mutation confers agonist activity to bicalutamide and is likely involved in bicalutamide withdrawal syndrome. The three-dimensional structure demonstrates that the B ring of R-bicalutamide in the W741L mutant is accommodated at the location of the indole ring of Trp-741 in the WT AR bound to dihydrotestosterone. Knowledge of the binding mechanism for R-bicalutamide will provide molecular rationale for the development of new antiandrogens and selective AR modulators. [ABSTRACT FROM AUTHOR]

Mass spectrometry data may be affected by random noise and baseline drift due to experimental instruments and conditions, posing significant challenges for detecting spectral peaks, particularly when identifying weak and separating overlapping peaks. To increase the sensitivity and enhance the resolution, we propose a mass spectral peak detection algorithm that integrates resolution enhancement and image segmentation. Initially, the extended Mexican hat wavelet is proposed by integrating the peak sharpening method with its wavelet. This approach accurately transforms mass spectra into wavelet space using the continuous wavelet transform. Subsequently, the triangular single-peak thresholding method, a more suitable threshold segmentation approach for spectral analysis, is introduced to identify ridges in the two-dimensional wavelet space. Compared to traditional Otsu and its improved variants, long-tailed single-peaked histograms are more effectively processed by this method with lower computational complexity, enabling faster identification of segmentation thresholds and image segmentation. Ultimately, peak positions are determined by utilizing ridge and valley lines in wavelet space along with the original spectrum. To evaluate the performance of the peak recognition algorithm, two metrics are introduced: the receiver operating characteristic (ROC) curve and the balanced F score (F1 score). When compared to multi-scale peak detection (MSPD), continuous wavelet transform and image segmentation (CWT-IS), the developed approach is more suitable for weak and highly overlapping peaks. The robustness and practicality of the method are verified through peak detection using matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectra. [ABSTRACT FROM AUTHOR]

Compute‐in‐memory (CIM) is a pioneering approach using parallel data processing to eliminate traditional data transmission bottlenecks for faster, energy‐efficient data handling. Crossbar arrays with two‐terminal devices such as memristors and phase‐change memory are commonly employed in CIM, but they encounter challenges such as leakage current and increased power usage. Three‐terminal transistor arrays have potential solutions, yet large‐scale electrolyte‐gated transistors (EGTs) demonstrations are uncommon due to compatibility issues with existing photolithography processes. Herein, a 20 × 20 EGTs array is designed using indium‐gallium‐zinc‐oxide as the semiconductor channel and polyacrylonitrile (PAN) doped with C2F6LiNO4S2 as the electrolyte. Each transistor unit in the array can serve as a synapse, exhibiting a large conductance range, low energy consumption (6.984 fJ) for read–write operations, excellent repeatability, and quasilinear update characteristics. It has been confirmed that the EGTs array not only enables precise device programming but also virtually eliminates signal interference between neighboring devices during the programming process. Using 54 transistors in the EGTs array, unsupervised learning with a winner‐takes‐all neural network is successfully demonstrated. After 50 training iterations, the neural network achieves perfect 100% accuracy in classifying test‐set letters. The work demonstrates the potential of EGTs for constructing large‐scale integration synaptic array toward efficient computing architectures. [ABSTRACT FROM AUTHOR]

Peak detection is an important step in mass spectrometry as accurately identifying characteristic peaks is key to data analysis. In order to address the issue of false peak detection, while simultaneously ensuring accurate detection of weak and overlapped peaks, this paper introduces an improved algorithm for mass spectrometry integrating weighted continuous wavelet transform with particle swarm optimization-based Otsu (WWTPO). The algorithm applies the weighted continuous wavelet transform (WCWT) to compress the frequency spectrum signal into a smaller scale range, which allows for the acquisition of more distinct and informative peak information. Moreover, the algorithm employs the particle swarm optimization (PSO) algorithm to iteratively evaluate the optimal image segmentation threshold, which addresses the challenge of inaccurate Otsu image segmentation. The method was applied to detect simulated peaks as well as matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) datasets. The performance evaluation was conducted using receiver operating characteristic (ROC) curves, F1 measure and F-scores. Through comparison with continuous wavelet transform (CWT) and genetic algorithm-based threshold segmentation (WSTGA), multi-scale peak detection (MSPD) and CWT and image segmentation (CWT-IS), the results demonstrate that WWTPO exhibits excellent performance in peak detection. The determination of 4-isopropyltoluene also demonstrates that WWTPO has excellent practical application. This method not only maintains a low false peak identification rate but also detects more weak peaks and overlapping peaks, further improving the accuracy and efficiency of peak detection in mass spectrometry. [ABSTRACT FROM AUTHOR]

The cover image is based on the RESEARCH ARTICLE FGF‐21 biomarker detection at sub‐nanogram per mL level in human serum using normal‐flow liquid chromatography‐tandem mass spectrometry by Wenqing Gao et al., https://doi.org/10.1002/rcm.8817. [ABSTRACT FROM AUTHOR]

• The crystal structure of the HArch was revealed. • The NTD of the HArch is significantly different from its homologous proteins. • HArch interacts and colocalizes with RNA ligase RTCB in cells. The human archease, hereafter named HArch, is identified as a key cofactor of the tRNA-splicing ligase complex, and a potential therapeutic target for treating nervous system injuries. However, little is known about the structural basis of HArch in tRNA maturation, mRNA splicing, and RNA repair. Here we report the crystal structures of HArch and its two mutants D51A and D178A with resolutions ranging from 1.96 Å to 3.4 Å. HArch is composed of an extended N-terminal protrusion domain (NTD) and one compacted C-terminal domain (CTD). Unlike previously reported homologous proteins, the NTD of the first subunit interacts with the CTD of the second one, and this interaction might be important for maintaining protein stability. Moreover, HArch interacts and colocalizes with RNA ligase RTCB in cells. Our current study reveals the atomic structure of HArch and may help us understand its function in mRNA splicing. [ABSTRACT FROM AUTHOR]

Rationale: Ion mobility spectrometry (IMS), as a promising analytical tool, has been widely employed in the structural characterization of biomolecules. Nevertheless, the inherent limitation in the structural resolution of IMS frequently results in peak overlap during the analysis of isomers exhibiting comparable structures. Methods: The radial basis function (RBF) neural network optimization algorithm based on dynamic inertial weight particle swarm optimization (DIWPSO) was proposed for separating overlapping peaks in IMS. The RBF network structure and parameters were optimized using the DIWPSO algorithm. By extensively training using a large dataset, an adaptive model was developed to effectively separate overlapping peaks in IMS data. This approach successfully overcomes issues related to local optima, ensuring efficient and precise separation of overlapping peaks. Results: The method's performance was evaluated using experimental validation and analysis of overlapping peaks in the IMS spectra of two sets of isomers: 3′/6′‐sialyllactose; fructose‐6‐phosphate, glucose‐1‐phosphate, and glucose‐6‐phosphate. A comparative analysis was conducted using other algorithms, including the sparrow search algorithm, DIWPSO algorithm, and multi‐objective dynamic teaching‐learning‐based optimization algorithm. The comparison results show that the DIWPSO‐RBF algorithm achieved remarkably low maximum relative errors of only 0.42%, 0.092%, and 0.41% for ion height, mobility, and half peak width, respectively. These error rates are significantly lower than those obtained using the other three algorithms. Conclusions: The experimental results convincingly demonstrate that this method can adaptively, rapidly, and accurately separate overlapping peaks of multiple components, improving the structural resolution of IMS. [ABSTRACT FROM AUTHOR]

AbstractEthanol abuse is increasingly becoming a global issue, adversely affecting both society and families. In blood alcohol concentration (BAC) detection, traditional techniques have long experimental cycles and harsh experimental conditions and often fail to produce timely results. Consequently, achieving swift and precise on-site detection of ethanol poisoning in humans poses a formidable challenge in analytical science. We designed a novel assay for swift on-site analysis of ethanol and BTEX (benzene, toluene, ethylbenzene, and xylene) poisoning in humans using a custom portable headspace injector (portable HS) and portable gas chromatography-mass spectrometry (portable GC-MS). This setup, known for its lightweight design and speed, allows on-site sampling and delivers rapid results. We established a calibration curve (R2 > 0.99) for ethanol in blood using portable gas chromatography-mass spectrometry (portable GC-MS). This on-site blood alcohol concentration (BAC) assay proves simpler than traditional methods, enabling rapid analysis of each sample within a short timeframe and requiring only a small blood volume (0.1 ml). In addition to our investigation on ethanol, we developed a portable method for detecting BTEX in blood. This method provides a favorable coefficient of determination (R2 > 0.99) for various substances, thereby broadening the utility of portable mass spectrometry in areas such as traffic inspection and forensic identification. [ABSTRACT FROM AUTHOR]

Objective and design: This study aimed to investigate Axin2 effects on myocardial infarction (MI) using a macrophage Axin2 conditional knockout (cKO) mouse model, RAW264.7 cell line, and human subepicardial tissues from patients with coronary artery bypass graft (CABG). Material or subjects: Axin2 cKO mice showed decreased cardiac function, reduced edema, increased lymphangiogenesis, and improved repair in MI Few studies border zones. Hypoxic macrophages with Axin2 depletion exhibited decreased senescence, elevated IL6 expression, and increased LYVE1 transcription. Senescent macrophages decreased in patients with CABG and low Axin2 expression. Treatment: Treatment options included in this study were MI induction in Axin2 cKO mice, in vitro experiments with RAW264.7 cells, and analysis of human subepicardial tissues. Methods: Assays included MI induction, in vitro experiments, and tissue analysis with statistical tests applied. Results: Axin2 cKO improved cardiac function, reduced edema, enhanced lymphangiogenesis, and decreased senescence. Hypoxic macrophages with Axin2 depletion showed reduced senescence, increased IL6 expression, and elevated LYVE1 transcription. Senescent macrophages decreased in patients with CABG and low Axin2 expression. Conclusion: Targeting Axin2 emerges as a novel therapeutic strategy for regulating cardiac lymphatics and mitigating cell senescence post-MI, evidenced by improved outcomes in Axin2-deficient conditions. [ABSTRACT FROM AUTHOR]

The role of ATP6AP1 in colorectal cancer (CRC) remains elusive despite its observed upregulation in pan-cancer. Therefore, the current study aimed to assess the clinical significance of ATP6AP1 and its relationship with the immune infiltration in CRC. Transcriptome data of CRC were obtained from The Cancer Genome Atlas (TCGA) database and analyzed using the combination of R packages and tumor-related databases, including TIMER2, TISIDB, cBioPortal, and MethSurv. The tissue arrays and immunohistochemical staining were performed to verify the expression and clinical characteristics of ATP6AP1. The results revealed that ATP6AP1 expression was significantly elevated in CRC and associated with poor clinicopathological characteristics and prognosis. Furthermore, the analysis demonstrated ATP6AP1 expression was correlated with the infiltration of immune cells and cancer-associated fibroblasts in the microenvironment of CRC. Moreover, ATP6AP1 was found to be linked to various immune checkpoints and chemokines, with enrichment of cytoplasmic vesicle lumen, endopeptidase regulator activity, and endopeptidase inhibitor activity observed in the high ATP6AP1 expressional group. In conclusion, the findings of this study suggest that ATP6AP1 upregulation may serve as a biomarker for poor diagnosis in CRC and offer a potential target for immunotherapy in CRC. [ABSTRACT FROM AUTHOR]

Despite the popularity of ion mobility spectrometry (IMS) for glycan analysis, its limited structural resolution hinders the effective separation of many glycan isomers. This leads to the overlap of IMS peaks, consequently impacting the accurate identification of glycan compositions. To this end, an improved algorithm, namely second-order differentiation combined with a simulated annealing particle swarm optimization algorithm based on sine adaptive weights (DWSA-PSO), was proposed for the separation of overlapping IMS peaks formed by glycan isomers. DWSA-PSO first performed second-order differentiation to automatically determine the number of components in overlapping peaks and exclude impossible single-peak combinations. It then introduced sinusoidal adaptive weights and a simulated annealing mechanism to improve the algorithm's search capability and global optimization performance, thereby enabling accurate and efficient separation of individual peaks. To evaluate the performance of DWSA-PSO and its application to the separation of glycan isomers, multiple sets of overlapping peaks with different degrees of overlap were simulated, and various types of multi-component overlapping peaks were formed using six disaccharide and four trisaccharide isomers. The experimental results consistently demonstrated that the DWSA-PSO algorithm outperformed both the improved particle swarm optimization (IPSO) algorithm and the dynamic inertia weight particle swarm optimization (DIWPSO) algorithm in terms of separation accuracy, running time, and fitness values. In addition, the DWSA-PSO algorithm was successfully applied to the separation of glycan isomers in malt milk beverage. All these results reveal the capability of the DWSA-PSO algorithm to facilitate the accurate identification of glycan isomers. [ABSTRACT FROM AUTHOR]

A detailed experimental characterization on the ion storage biases in an ion funnel trap, related to ion structure, charge state and RF voltage applied to the ion funnel trap, is reported by using both cytochrome C and ubiquitin samples. It was first observed experimentally that an unavoidable ion overflow would occur when the incoming ions exceeded the capacity of ion funnel trap. The conformers with extended structures would lose preferentially in the ion overflow process. Accordingly, a significant structural bias in the ion mobility spectrometry/time of flight mass spectrometry (IMS-TOF MS) spectrum was created, as the peak intensities for conformers with compact structures and extended structures would continuously increase and decrease, respectively, when the ion overflow time of the ion funnel trap was increased. Furthermore, the experimental results also showed that the effect of this ion structural bias was more significant when the RF voltage applied to the ion funnel trap was increased. In addition, an ion charge state bias in the ion funnel trap was also observed. The effect of the ion structural bias depends significantly on the specific charge state of the ions. For a given analyte, its lower charge state ions show a greater sensitivity to the ion structural bias than the higher charge state ones under the same ion funnel trap operating conditions. Therefore, it is extremely important to set a reasonable operation condition for the ion funnel trap to avoid ion storage biases in IMS-TOF MS. [Display omitted] • An ion storage bias in the ion funnel trap of an IMS-QTOF MS was observed. • Ion storage bias was proved to be related to ion structure, charge state and so on. • The method to eliminate the ion storage bias in ion funnel trap was reported. • The optimum operation condition for the ion funnel trap was reported. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO), as a critical transcellular messenger, participates in a variety of physiological and pathological processes. However, its real-time detection still faces challenges due to its short half-life and trace amounts. Here, MWCNTs@COF-366-Co was prepared by in situ growth of a cobalt porphyrin-based covalent organic framework (COF-366-Co) on multi-walled carbon nanotubes (MWCNTs), and a unique biosensing platform for ultrasensitive real-time NO determination was established. Remarkably, MWCNTs@COF-366-Co contains plenty of atomically arranged M–N4 active sites for electrocatalysis, which provides more efficient electron transfer pathways and resolves the random arrangement issue of active sites. COF-366-Co with a high surface area contains a large number of exposed active M–N4 sites, providing faster NO transport/diffusion and more efficient electron transfer pathways. Due to the synergy of atomic-level periodic structural features of COF-366-Co and high conductivity of MWCNTs, the MWCNTs@COF-366-Co electrochemical biosensor exhibited excellent NO determination performance in a wide range from 0.09 to 400 μM, with high sensitivity (8.9 μA μM−1 cm−2) and a low limit of detection (16 nM). Moreover, the biosensor has been successfully used to sensitively monitor NO molecules released from human umbilical vein endothelial cells (HUVECs). This research not only designed a multifunctional intelligent biosensor platform, but also provided a broad prospect for continuous dynamic monitoring of the activity of living cells and their released metabolites. [ABSTRACT FROM AUTHOR]

Summary: GDP‐L‐galactose phosphorylase (VTC2) catalyses the conversion of GDP‐L‐galactose to L‐galactose‐1‐P, a vital step of ascorbic acid (AsA) biosynthesis in plants. AsA is well known for its function in the amelioration of oxidative stress caused by most pathogen infection, but its function against viral infection remains unclear. Here, we have identified a VTC2 gene in wheat named as TaVTC2 and investigated its function in association with the wheat yellow mosaic virus (WYMV) infection. Our results showed that overexpression of TaVTC2 significantly increased viral accumulation, whereas knocking down TaVTC2 inhibited the viral infection in wheat, suggesting a positive regulation on viral infection by TaVTC2. Moreover, less AsA was produced in TaVTC2 knocking down plants (TaVTC2‐RNAi) which due to the reduction in TaVTC2 expression and subsequently in TaVTC2 activity, resulting in a reactive oxygen species (ROS) burst in leaves. Furthermore, the enhanced WYMV resistance in TaVTC2‐RNAi plants was diminished by exogenously applied AsA. We further demonstrated that WYMV NIb directly bound to TaVTC2 and inhibited TaVTC2 enzymatic activity in vitro. The effect of TaVTC2 on ROS scavenge was suppressed by NIb in a dosage‐dependent manner, indicating the ROS scavenging was highly regulated by the interaction of TaVTC2 with NIb. Furthermore, TaVTC2 RNAi plants conferred broad‐spectrum disease resistance. Therefore, the data indicate that TaVTC2 recruits WYMV NIb to down‐regulate its own enzymatic activity, reducing AsA accumulation to elicit a burst of ROS which confers the resistance to WYMV infection. Thus, a new mechanism of the formation of plant innate immunity was proposed. [ABSTRACT FROM AUTHOR]

Rationale: The existing particle swarm optimization (PSO) algorithms are only effective in deconvoluting the overlapping peaks in ion mobility spectra with fewer than four component peaks, which limits the applicability of these algorithms. Methods: A high‐performance two‐step particle swarm optimization (TSPSO) algorithm was developed. Compared to the existing PSO algorithms, TSPSO can narrow the search ranges of all coefficients for the overlapping peaks through Gaussian model calculation, and thus can deconvolute various overlapping peaks with high accuracy, even for 30‐component overlapping peaks. In addition, the TSPSO could be further applied to enhance the resolution of the spectra by narrowing the peak widths after the peak deconvolution. Results: Simulated overlapping peaks were first used to evaluate the performance of TSPSO as compared to the dynamic inertia weight particle swarm optimization (DIWPSO) algorithm. The results showed that the profiles of the peaks deconvoluted by using TSPSO were more consistent with the original ones. The fitness values and the standard deviations of the fitness values from TSPSO were also at least an order of magnitude less than those from DIWPSO. By applying TSPSO, the overlapping peaks from both mass spectrometry (MS) and field asymmetric waveform ion mobility spectrometry (FAIMS) spectra can also be well deconvoluted. In addition, the resolutions of the MS and FAIMS spectra can be effectively enhanced after peak deconvolution. The enhanced spectra matched excellently with the experimental ones acquired at high‐resolution modes. Conclusions: The experiment results convincingly demonstrate that the TSPSO algorithm is capable of both deconvoluting complex overlapping peaks and enhancing the spectrum resolution with high accuracy. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC), ranking third in cancer prevalence and second in mortality worldwide, is mainly derived from colorectal adenoma (CRA). CRA is a common benign disease in the intestine with rapidly increasing incidence and malignant potential. Therefore, this study aimed to recognize significant biomarkers and original pathogenesis in CRA. Methods: Transcriptome data of GSE8671, GSE37364, and GSE15960 were downloaded from the Gene Expression Omnibus (GEO) datasets, and differentially expressed genes (DEGs) were screened. Functional pathways enrichment, protein–protein interaction (PPI) network, stem-correlation analysis, CIBERSORT, risk score and survival analyses were performed. RT-qPCR and immunohistochemical staining were applied to verify our results. Results: Screening for significant DEGs in each dataset, we identified 230 robust DEGs, including 127 upregulated and 103 downregulated genes. Functional pathways enrichment showed that these DEGs were distinctly enriched in various tumor-associated pathways, such as growth factor activity, extracellular structure organization, neutrophil activation, and inflammatory response. We filtered out two hub genes via STRING and Modules analysis, including CA2 and HSD11B2. Stem-correlation analysis displayed that hub genes were negatively associated with stem-related genes (Olfm4, CD44, CCND1 and MYC). The CIBERSORT algorithm indicated that Macrophage2, activated mast cells, and Neutrophils promoted CRA progression through inflammation. Survival analysis showed that CA2 and HSD11B2 were positively associated with survival outcomes in CRC. Conclusion: Our study has successfully identified the critical role of two core genes in the development and oncogenesis of CRA, which provides novel insight into the underlying pathogenesis, potential biomarkers and therapeutic targets. [ABSTRACT FROM AUTHOR]

Inflammation, oxidative stress, and apoptosis contribute to myocardial ischemia/reperfusion injury (I/RI). Alpha-lipoic acid (ALA) plays a critical role in I/RI by impeding apoptosis and inflammation. Here, we aimed to explore the underlying mechanisms of ALA after I/RI. The left anterior descending coronary artery (LAD) was ligated, and H9c2 cells were exposed to hypoxia/reoxygenation (H/R) to establish an I/RI model. Prior to this, H9c2 cells and rats were treated using an appropriate amount of ALA. The cardiac function, inflammatory factors, and myocardial pathology were assessed in vitro. We detected cell viability, apoptosis, and oxidative stress-related factors in vivo. Moreover, proteins of the HMGB1/TLR4/NF-κB signaling pathway were detected both in vivo and in vitro. We observed that ALA increased cell viability in vitro and decreased apoptosis in vitro and in vivo. ALA inhibited reactive oxygen species production, decreased malondialdehyde, and increased superoxide dismutase activity to resist oxidative stress in vitro. ALA also reduced the expression of inflammatory cytokines (IL-6, IL-1β, and TNF-α) in vivo. ALA also suppressed the levels of the apoptotic protein, Bax, and increased the expression of the anti-apoptotic protein Bcl-2, in vitro and in vivo. Moreover, we observed that ALA significantly inhibited the cytoplasmic localization of HMGB1, which might attenuate MI/RI or H/R via HMGB1/TLR4/NF-κB pathway. ALA regulates HMGB1 translocation and attenuates I/R via the HMGB1/TLR4/NF-κB signaling pathway, thus impeding apoptosis, oxidation, and inflammation, and might be a potential target for myocardial ischemia/reperfusion injury. [ABSTRACT FROM AUTHOR]

Nafamostat mesylate (NM) affects coagulation and fibrinolysis and impedes obesity-associated protein demethylase activity, which regulates Na+/K+ transport properties and the NF-κB signaling pathway. NM significantly decreases macrophage, neutrophil, and T lymphocyte infiltration, thereby reducing inflammation and apoptosis after reperfusion and promoting recovery in patients with severe conditions such as near-fatal asthma and cardiac arrest. Extracorporeal life support (ECLS) devices are used for cardiac and/or pulmonary support as a bridge to recovery, decision, surgery, or transplant in patients with refractory cardio-circulatory or respiratory diseases and provide essential opportunities for organ support and patient survival. However, they can lead to some potential adverse events such as hemorrhage and thrombosis. NM provides a sustained innate immune response of coagulation and anti-inflammation in extracorporeal circuits, principally due to its activation of the contact and complement systems. Heparin is the main anticoagulant used in extracorporeal circuits; however, it may cause massive bleeding and heparin-induced thrombocytopenia. Although no antidote is available, NM has a very short half-life of approximately 8–10 min and might have positive effects on patients who require coagulation and anti-inflammation. NM has been used for anticoagulation in continuous renal replacement therapy, extracorporeal membrane oxygenation, hemodialysis, and left ventricular assist devices. In this review, we focused on the pharmacology, monitoring parameters, and considerations for the special use of NM in patients receiving ECLS. Our findings suggest that systemic anticoagulation with NM during ECLS might be a feasible and safe alternative with several advantages for critically ill patients with high-risk bleeding and might improve their prognosis. • Nafamostat Mesilate affects anticoagulation and reduce the risk of bleeding • Nafamostat Mesilate shown anti-inflammatory effects for patients with ECMO • Nafamostat Mesilate has a very short half-time compared to other anticoagulation drugs [ABSTRACT FROM AUTHOR]

The main characteristics of the myocardial ischemia/reperfusion injury (MI/RI) are oxidative stress, apoptosis, and an inflammatory response. Aucubin (AU) is an iridoid glycoside that possesses various biological properties and has been discovered to demonstrate antioxidant and anti-inflammatory impacts in pathological processes, such as ischemia-reperfusion. The objective of this research was to investigate if AU treatment could mitigate myocardial inflammation and apoptosis caused by ischemia/reperfusion (I/R) in both laboratory and animal models, and to elucidate its underlying mechanism. By ligating the coronary artery on the left anterior descending side, a successful MI/RI rat model was created. Additionally, H9C2 cells were subjected to hypoxia/reoxygenation (H/R) in order to imitate the injury caused by ischemia/reperfusion (I/R). Furthermore, various concentrations of AU were administered to H9C2 cells or rats before H/R stimulation or myocardial I/R surgery, respectively. In vitro, the assessment was conducted on cardiac function, inflammatory markers, and myocardial pathology. In vivo, we examined the viability of cells, as well as factors related to apoptosis and oxidative stress. Furthermore, the presence of proteins belonging to the STAT3/NF-κB/HMGB1 signaling pathway was observed both in vivo and in vitro. AU effectively improved cardiomyocyte injury caused by H/R and myocardial injury caused by I/R. Furthermore, AU suppressed the production of reactive oxygen species and inflammatory molecules (TNF-alpha, IL-1β, and IL-6) and proteins associated with cell death (caspase-3 and Bax), while enhancing the levels of anti-inflammatory agents (IL-10) and the anti-apoptotic protein Bcl-2.AU mechanistically affected the phosphorylation of STAT3 at the Ser727 site and Tyr705 following H/R by modulating the signaling pathway involving signal transducer and activator of transcription 3 (STAT3)/nuclear factor-κB (NF-κB)/high mobility group box 1 (HMGB1), while also suppressing the nuclear translocation of NF-κB p65 and HMGB1 exonucleation. In conclusion, the use of AU treatment might offer protection against myocardial infarction and injury by reducing oxidative stress, suppressing apoptosis, and mitigating inflammation. The regulation of the STAT3/NF-κB/HMGB-1 pathway may contribute to this phenomenon by affecting STAT3 phosphorylation and controlling NF-κB and HMGB-1 translocation. Contributes to identifying possible objectives for myocardial ischemia/reperfusion damage. • Aucubin can alleviate myocardial ischemia-reperfusion injury by modulating the STAT3/NF-κB/HMGB-1 pathway. • Aucubin modulates the entry and exit of HMGB1 and NF-kB into the nucleus to exert anti-inflammatory effects. • Aucubin can regulate the phosphorylation of different sites of STAT3 and play different roles. [ABSTRACT FROM AUTHOR]

Cytosolic inflammasome complexes mediated by a pattern recognition receptor (PRR) defend against pathogen infection by activating caspase 1. Pyrin, a candidate PRR, can bind to the inflammasome adaptor ASC to form a caspase 1-activating complex. Mutations in the Pyrin-encoding gene, MEFV, cause a human autoinflammatory disease known as familial Mediterranean fever. Despite important roles in immunity and disease, the physiological function of Pyrin remains unknown. Here we show that Pyrin mediates caspase 1 inflammasome activation in response to Rho-glucosylation activity of cytotoxin TcdB, a major virulence factor of Clostridium difficile, which causes most cases of nosocomial diarrhoea. The glucosyltransferase-inactive TcdB mutant loses the inflammasome-stimulating activity. Other Rho-inactivating toxins, including FIC-domain adenylyltransferases (Vibrio parahaemolyticus VopS and Histophilus somni IbpA) and Clostridium botulinum ADP-ribosylating C3 toxin, can also biochemically activate the Pyrin inflammasome in their enzymatic activity-dependent manner. These toxins all target the Rho subfamily and modify a switch-I residue. We further demonstrate that Burkholderia cenocepacia inactivates RHOA by deamidating Asn 41, also in the switch-I region, and thereby triggers Pyrin inflammasome activation, both of which require the bacterial type VI secretion system (T6SS). Loss of the Pyrin inflammasome causes elevated intra-macrophage growth of B. cenocepacia and diminished lung inflammation in mice. Thus, Pyrin functions to sense pathogen modification and inactivation of Rho GTPases, representing a new paradigm in mammalian innate immunity. [ABSTRACT FROM AUTHOR]

A high-performance standalone planar field asymmetric waveform ion mobility spectrometry (p-FAIMS) system with a deconvolution algorithm (two-step particle swarm optimization algorithm, TSPSO) for overlapping peaks was developed to effectively detect chemical warfare agents (CWAs). Four CWA simulants were applied in this study to systemically evaluate the performance of the standalone p-FAIMS system. The experimental results showed that each CWA simulant in the mixture can be positively identified by carefully comparing the compensation voltage (CV) value of each peak in the FAIMS spectra for the mixture to the ones in the spectra acquired by using the same FAIMS system for the pure CWA simulant standards. The FAIMS spectrum of the CWA simulant mixture might consist of multiple overlapping peaks, which would be difficult to accurately determine the CV value for each CWA simulant peak. This problem has been effectively resolved in this study by deconvoluting the overlapping peaks via the TSPSO algorithm. As the effective peak deconvolution via TSPSO requires the degree of overlap between each FAIMS peak to be lower than a specific value, the flow rate of FAIMS carrier gas was decreased to further improve the resolution of the p-FAIMS system. After the accurate deconvolution, the resolution of original FAIMS spectrum can also be enhanced to achieve baseline separation by using TSPSO algorithm to narrow the peak width of each peak. The experimental results in this study demonstrated the possibility of using TSPSO algorithm to achieve high-resolution on a typically low-resolution standalone FAIMS. The concept in this study can potentially be applied to any low-resolution instruments to achieve high-resolution results. [Display omitted] • A high-performance standalone FAIMS system was developed in this study. • The chemical warfare agent mixtures were effectively analyzed by using FAIMS. • The overlaid peaks in FAIMS spectra can be effectively deconvoluted via TSPSO algorithm. • The FAIMS spectra can be enhanced to achieve baseline separation using TSPSO algorithm. [ABSTRACT FROM AUTHOR]

Previous research has demonstrated that glycyrrhizic acid (GA) exhibits antioxidant, anti-inflammatory, and antiapoptotic characteristics. Using myocardial ischemia/reperfusion injury as a case study, this study aims to clarify the functional significance of GA and to elucidate the mechanisms involved. In this study, an MI/R injury model was established both in vivo and in vitro to investigate the impact of GA on MI/R injury. The viability of H9c2 cells was evaluated using the Cell Counting Kit-8. Myocardial damage was assessed through the measurement of creatine kinase myocardial band (CK-MB) levels and lactate dehydrogenase (LDH), HE staining, and MASSON staining. Inflammatory cytokine levels (IL-6, IL-1β, IL-10, and TNF-α) were measured to determine the presence of inflammation. Cellular oxidative stress was evaluated by measuring ROS and MMP levels, while cardiac function was assessed using cardiac color Doppler ultrasound. Immunofluorescence staining to determine the nuclear translocation of YAP, TUNEL to determine apoptosis, and western blotting to determine gene expression. GA treatment effectively alleviated myocardial injury induced by MI/R, as evidenced by reduced levels of inflammatory cytokines (IL-1β, IL-6, IL-10, and TNF-α) and cardiac biomarkers (CK-MB, LDH) in MI/R rats. Moreover, There was a significant increase in cell viability in vitro after GA treatment and inhibited reactive oxygen species (ROS) during oxidative stress, while also increasing mitochondrial membrane potential (MMP) in vitro. The Western blot findings indicate that GA treatment effectively suppressed apoptosis in both in vivo and in vitro settings. Additionally, GA demonstrated inhibitory effects on the activation of the Hippo/YAP signaling pathway triggered by MI/R and facilitated YAP nuclear translocation both in vitro and in vivo. It has been found, however, in vitro, that silencing the YAP gene negates GA's protective effect against hypoxia/reoxygenation-induced myocardial injury. This study suggests that GA regulates YAP nuclear translocation by inhibiting the Hippo/YAP signaling pathway, which protects ists against MI/R injury. This finding may present a novel therapeutic approach for the treatment of MI/R. • Glycyrrhizic acid alleviates myocardial ischemia-reperfusion injury by reducing oxidative stress and apoptosis. • The mechanism of the protective effect of Glycyrrhizic acid on myocardial ischemia-reperfusion injury is related to the inhibition of Hippo/YAP signaling and nuclear translocation of YAP. • Through molecular docking and molecular dynamics simulation techniques, Glycyrrhizic acid specifically targets MST1 molecules in the HIPPO/YAP signaling pathway, thereby promoting downstream pathway molecules. [ABSTRACT FROM AUTHOR]

Background. Young patients with type 2 diabetes mellitus (DM) and acute myocardial infarction (AMI) have high long-term all-cause and cardiovascular mortality rates. We aimed to investigate the differentially expressed genes (DEGs) that might be potential targets for DM patients with AMI. Methods. Gene datasets GSE775, GSE19322, and GSE97494 were meta-analyzed to obtain DEGs of the left ventricle myocardium in infarcted mice. Gene datasets including GSE3313, GSE10617, and GSE136948 were meta-analyzed to identify DEGs in diabetes mice. A Venn diagram was used to obtain the overlapping DEGs. KEGG and GO pathway analyses were performed, and hub genes were obtained. Pivotal miRNAs were predicted and validated using the miRNA dataset in GSE114695. To investigate the cardiac function of the screened genes, a MI mouse model was constructed; echocardiogram, qPCR, and ELISA of hub genes were performed; ELISA of hub genes in human blood samples was also utilized. Results. A total of 67 DEGs were identified, which may be potential biomarkers for patients with DM and AMI. GO and KEGG pathway analyses were performed, which were mainly enriched in response to organic cyclic compound and PI3K-Akt signaling pathway. The expression of PIK3R1 and SPNB2 increased in the MI group and was negatively correlated to left ventricular ejection fraction (LVEF), whereas that of CRYAB decreased and was positively correlated to LVEF. Patients with high CRYAB expression demonstrated a short hospital stay and the area under the curves of the three protein levels before and after treatment were 0.964, 0.982, and 0.918, suggesting that PIK3R1, SPNB2, and CRYAB may be diagnostic and prognostic biomarkers for the diabetes patients with AMI. Conclusion. The screened hub genes, PIK3R1, SPNB2, and CRYAB, were validated as credible molecular biomarkers and may provide a novel therapy for diabetic cardiac diseases with increased proteotoxic stress. [ABSTRACT FROM AUTHOR]

Near fatal asthma is a life-threatening disorder that requires mechanical ventilation. Near fatal asthma and COPD with sudden cardiac arrest can worsen the outcomes. Previous studies demonstrated that ECMO is a live-saving measure for near fatal asthma that does not respond to traditional treatment. A patient with near fatal asthma (NFA) and COPD presented with high airway resistance, life-threatening acidemia and severe hypoxemia that failed to respond to conventional therapy. His hospital course was complicated by sudden cardiac arrest when preparing to initiate V-V mode extracorporeal membrane oxygenation (ECMO). The mode immediately changed from V-V to V-A, then to V-AV and finally to V-V mode in order to improve cardiac function and promote recovery of lung function. On the sixth day, ECMO was removed and on the ninth day, he was extubated and transferred to the ward. Finally, the patient was discharged home on the nineteenth day after admission to be followed up in the pulmonary clinic. The early application of ECMO and mode changing plausibly resulted in dramatic improvement in gas exchange and restoration of cardiac function. This case illustrates the critical role of ECMO mode changing as salvage therapy in NFA and COPD with sudden cardiac arrest. [ABSTRACT FROM AUTHOR]

Background and Purpose: Gut microbiota plays an important role in type 2 diabetes mellitus (T2DM) progression. From our previous work N‐(4‐Hydroxyphenethyl)‐3‐mercapto‐2‐methylpropanamide (HMPA) is a potential T2DM drug. We evaluated the effect of HMPA on gut microbiota and studied the molecular mechanism underlying HMPA's regulation of gut microbiota. Experimental Approach The pseudo germ‐free (PGF) T2DM model and faecal microbiota transplantation method were used to study whether gut microbiota mediates the actions of HMPA. The composition of gut microbiota was detected by using 16S rRNA sequence. Short‐chain fatty acids (SCFAs) content was detected by gas chromatography. The HMPA probe was synthesised for finding and identifying the target protein of HMPA. The effect of HMPA on the utilisation of carbon sources in Bifidobacterium was evaluated. Key Results: HMPA has a slight effect on the PGF T2DM model. The gut microbiota changed by HMPA can also alleviate the symptoms of T2DM. HMPA can regulate gut microbiota structure, increase SCFAs production and reduce nitrate content in the intestinal tissues. The thickness of the mucus on colon tissues increases after HMPA treatment. The target protein of HMPA in gut microbiota is the nitrogen metabolism global transcriptional regulator (GlnR). HMPA promotes the utilisation of less preferred carbon source in the gut microbiota and increases the fermentation product of SCFAs. Conclusion and Implications: HMPA plays a hypoglycaemic role through the gut microbiota. HMPA improves the carbon catabolite repression effect of gut microbiota and increases SCFAs production by targeting GlnR. GlnR may be a target for gut microbiota regulation. [ABSTRACT FROM AUTHOR]

Oxygenation membranes operate as indirectly contacting barriers between blood and gas in extracorporeal membrane oxygenation (ECMO), improving oxygenation and removing carbon dioxide from blood. However, the low gas exchange efficiency of the current poly (4-methyl-1-pentene) (PMP) artificial lung membrane results in a high prime volume. Facilitated transport membrane is a fascinating strategy to construct high-performance membranes for blood-gas exchange. This study put forward hybrid strategy by using metal-covalent organic frameworks (MCOFs) to construct facilitated transport membrane of PMP flat membranes and hollow fiber membranes (HFMs) via thermally induced phase separation (TIPS) to achieve facilitated blood-gas exchange. Cu-TAPB-COF nanosheets (CuCON) with framework structure and abundant active metal sites were synthetized and introduced into PMP to construct hybrid oxygenation membranes, reducing the resistance of gas exchange channels and ensuring the high affinity toward CO 2 and O 2. Cu+ and benzene rings existed in aromatic skeleton as well as the tunable structure, that could ensure the stability of MCOF and the uniform distribution of facilitated transport sites. The prepared PMP-CuCON-1 HFMs exhibited O 2 and CO 2 exchange rate of ∼467.5 ml min−1 m−2 and ∼309.1 ml min−1 m−2 in blood gas exchange process, which was 143.1% and 261.3% higher than the commercial PMP HFM, respectively. Asymmetric structure ensured resistance to plasma leakage for more than two weeks, and Cu+ kept stable in CuCON and hybrid membranes. The hybrid membrane exhibited superior blood-gas exchange performance and good hemocompatibility, possessing great potential for application. [Display omitted] • PMP-CuCON membranes were fabricated for facilitated blood-gas transport. • PMP-CuCON hollow fiber oxygenation membranes with superior performance were prepared. • Multiple facilitated transport sites and mass transfer channels were introduced via CuCON. • The membrane shows enhancing gas permeance and long-term stability. [ABSTRACT FROM AUTHOR]

Electrospray image and spray electric current measurement were used to experimentally characterize the optimum operating condition of the electrospray ionization process under different operating conditions, including electrospray flow rate (Q), solution electric conductivity (k) and the organic solvent content in the sample solution (R o). It was first observed that a special cone-jet mode electrospray with extremely high stability could be obtained when the electrospray voltage was operated in a specific range (the optimum voltage range). In this mode, the spray current remains independent of spray voltage and the angle of electrospray (the optimum spray angle) was much larger than the ones in other modes of electrospray. The experimental results also showed that the optimum voltage range was dependent on multiple factors. The average value of the optimum voltage range (the optimum voltage) increased slightly as Q was increased and decreased significantly as R o was increased. In addition, the optimum voltage would increase initially with the increase of k and become essentially independent of k at a sufficiently high solution electric conductivity. In contrast to a rather complicated parametric dependence of the optimum voltage range, the optimum spray angle was found to only depend on Q. It would increase initially as the increase of Q and remain to be constant when Q was higher than a specific value. The experimental results in this study allow one to maintain an optimum electrospray ionization under different operating conditions as required by the actual method of mass spectrometry analysis. [Display omitted] • A high performance ESI image and spray electric current measurement system was developed. • The optimum ESI voltage was explored systemically under different spray operating conditions. • It was proved that the maximum spray angle measured from the ESI image can be used to positively identify the cone-jet electrospray mode. • The factors affacting the optimum voltage and the spray angle of cone-jet mode electrospray were systemically explored. [ABSTRACT FROM AUTHOR]