High-Resolution Mass Spectrometry for Human Exposomics: Expanding Chemical Space Coverage.

In the modern "omics" era, measurement of the human exposome is a critical missing link between genetic drivers and disease outcomes. High-resolution mass spectrometry (HRMS), routinely used in proteomics and metabolomics, has emerged as a leading technology to broadly profile chemical exposure agents and related biomolecules for accurate mass measurement, high sensitivity, rapid data acquisition, and increased resolution of chemical space. Non-targeted approaches are increasingly accessible, supporting a shift from conventional hypothesis-driven, quantitation-centric targeted analyses toward data-driven, hypothesis-generating chemical exposome-wide profiling. However, HRMS-based exposomics encounters unique challenges. New analytical and computational infrastructures are needed to expand the analysis coverage through streamlined, scalable, and harmonized workflows and data pipelines that permit longitudinal chemical exposome tracking, retrospective validation, and multi-omics integration for meaningful health-oriented inferences. In this article, we survey the literature on state-of-the-art HRMS-based technologies, review current analytical workflows and informatic pipelines, and provide an up-to-date reference on exposomic approaches for chemists, toxicologists, epidemiologists, care providers, and stakeholders in health sciences and medicine. We propose efforts to benchmark fit-for-purpose platforms for expanding coverage of chemical space, including gas/liquid chromatography-HRMS (GC-HRMS and LC-HRMS), and discuss opportunities, challenges, and strategies to advance the burgeoning field of the exposome.

P/N-Type Conversion of 2D MoTe2 Controlled by Top Gate Engineering for Logic Circuits.

Two-dimensional (2D) transition-metal dichalcogenides (TMDCs) are regarded as promising materials for next-generation logic circuits. Top gate field-effect transistors (FETs) have independent gate control ability and can be fabricated directly on TMDC materials without a transfer process. Therefore, it has the merits of device reliability and complementary metal-oxide semiconductor (CMOS) process compatibility, which are demanded in practical circuit-level integration. However, the fabrication of the top gate FET involves depositing an insulating dielectric layer and a gate electrode in sequence on the TMDC channel material, which may affect the device performance. Insightfully investigating the influences of different top-gate-deposition methods on the electrical properties of the TMDC channel and further harnessing these influences to realize a homogeneous CMOS device on an identical 2D TMDC platform are with practice significance. In this work, p/n-type controllable top gate FET arrays based on 2H-MoTe2 are fabricated by using different top-gate-deposition methods. The electron-beam evaporation (EBE) of top metal gate exhibits an obvious n-doping effect on the 2H-MoTe2 channel and converts it from p-type to n-type, whereas the thermal evaporation of top gate affects little to the channel. High-resolution transmission electron microscopy (HR-TEM) analysis reveals that the high-energy metal atoms from the EBE process can penetrate through the 30 nm gate dielectric layers (including 10 nm Al2O3 seeding layer), leading to multiple atomic defects in both MoTe2 and the interface between MoTe2 and Al2O3. Furthermore, by utilizing the top gate engineering, a large-scale double-top-gate MoTe2 homogeneous CMOS inverter array is fabricated. The CMOS inverters exhibit clear logic swing, negligible hysteresis, and high device yield (∼93%), indicating high device reliability and stability. Notably, the fabrication process is facile, free from transfer procedure, and compatible with traditional silicon technology. This work promotes the application of 2D TMDCs in nanoelectronics integration.

African swine fever virus structural protein p17 inhibits IRF3 activation by recruiting host protein PR65A and inducing apoptotic degradation of STING.

African swine fever virus (ASFV) is notoriously known for evolving strategies to modulate IFN signaling. Despite lots of efforts, the underlying mechanisms have remained incompletely understood. This study concerns the regulatory role of viral inner membrane protein p17. We found that the ASFV p17 shows a preferential interaction with cGAS-STING-IRF3 pathway, but not the RIG-I-MAVS-NF-κB signaling, and can inhibit both poly(I:C)- and poly(A:T)-induced activation of IRF3, leading to attenuation of IFN-ß induction. Mechanistically, p17 interacts with STING and IRF3 and recruits host scaffold protein PR65A, a subunit of cellular phosphatase PP2A, to down-regulate the level of p-IRF3. Also, p17 targets STING for partial degradation via induction of cellular apoptosis that consequently inhibits activation of both p-TBK1 and p-IRF3. Thus, our findings reveal novel regulatory mechanisms for p17 modulation of IFN signaling and shed light on the intricate interplay between ASFV proteins and host immunity.

Embryonic dexamethasone exposure exacerbates hepatic steatosis and APAP-mediated liver injury in zebrafish.

Dexamethasone (DXMS), a synthetic glucocorticoid, is known for its pharmacological effects on anti-inflammation, stress response enhancement and immune suppression, and has been widely used to treat potential premature delivery and related diseases. However, emerging evidence has shown that prenatal DXMS exposure leads to increased susceptibility to multiple diseases. In the present study, we used zebrafish as a model to study the effects of embryonic DXMS exposure on liver development and disease. We discovered that embryonic DXMS exposure upregulated the levels of total cholesterol and triglycerides in the liver, increased the glycolysis process and ultimately caused hepatic steatosis in zebrafish larvae. Furthermore, DXMS exposure exacerbated hepatic steatosis in a zebrafish model of fatty liver disease. In addition, we showed that embryonic DXMS exposure worsened liver injury induced by paracetamol (N-acetyl-p-aminophenol, APAP), increased the infiltration of macrophages and neutrophils, and promoted the expression of inflammatory factors, leading to impeded liver regeneration. Taken together, our results provide new evidence that embryonic DXMS exposure exacerbates hepatic steatosis by activating glycolytic pathway, aggravates APAP-induced liver damage and impeded regeneration under a persistent inflammation, calling attention to DXMS administration during pregnancy with probable clinical implications for offspring.

A cuproptosis-related gene DLAT as a novel prognostic marker and its relevance to immune infiltration in low-grade gliomas.

DLAT has been recognized as a cuproptosis-related gene that is crucial for cuproptosis in earlier research. The study is to look at how DLAT affects individuals with low-grade glioma's prognosis and immune infiltration. The Genotype-Tissue Expression (GTEx) database and the TCGA database were used in this work to download RNAseq data in TPM format. DLAT was found to be overexpressed in LGG by comparing DLAT expression levels between LGG and normal brain tissue, and the expression of DLAT was verified by immunohistochemistry and semi-quantitative analysis. Then, the functional enrichment analysis revealed that the biological functional pathways and possible signal transduction pathways involved were primarily focused on extracellular matrix organization, transmembrane transporter complex, ion channel complex, channel activity, neuroactive ligand-receptor interaction, complement and coagulation cascades, and channel activity. The level of immune cell infiltration by plasmacytoid dendritic cells and CD8 T cells was subsequently evaluated using single-sample gene set enrichment analysis, which showed that high DLAT expression was inversely connected with that level of infiltration. The link between the methylation and mRNA transcription of DLAT was then further investigated via the MethSurv database, and the results showed that DLAT's hypomethylation status was linked to a poor outcome. Finally, by evaluating the prognostic value of DLAT using the Cox regression analysis and Kaplan-Meier technique, a column line graph was created to forecast the overall survival (OS) rate at 1, 3, and 5 years after LGG identification. The aforementioned results demonstrated that high DLAT expression significantly decreased OS and DSS, and that overexpression of DLAT in LGG was significantly linked with WHO grade, IDH status, primary therapy outcome, overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) events. DLAT was discovered as a separate predictive sign of OS in the end. DLAT might thus represent a brand-new predictive biomarker.

Hsa_Circ_002144 Promotes Glycolysis and Immune Escape of Breast Cancer Through miR-326/PKM Axis.

Background: Breast cancer is a leading cause of cancer-related deaths in women worldwide, posing a significant threat to female health. Therefore, it is crucial to search for new therapeutic targets and prognostic biomarkers for breast cancer patients. Method: Bioinformatics analysis, quantitative real-time PCR (qRT-PCR), and fluorescence in situ hybridization (FISH) were employed to investigate the expression of hsa_circ_002144 in breast cancer. Transwell assay, Western blotting, and cell viability assay were utilized to assess the impact of hsa_circ_002144 on the proliferation, migration, and invasion of breast cancer cells. Additionally, a mouse model was established to validate its functionality. Flow cytometry, WB analysis, enzyme-linked immunosorbent assay (ELISA), qRT-PCR, exosomes isolation, and co-culture system were employed to elucidate the molecular mechanism underlying macrophage polarization. Result: we have discovered for the first time that hsa_circ_002144 is highly expressed in breast cancer. It affected tumor growth and metastasis and could influence macrophage polarization through the glycolytic pathway. Conclusion: This finding provides a new direction for breast cancer treatment and prognosis assessment.

Interfacial epitaxy of multilayer rhombohedral transition-metal dichalcogenide single crystals.

Rhombohedral-stacked transition-metal dichalcogenides (3R-TMDs), which are distinct from their hexagonal counterparts, exhibit higher carrier mobility, sliding ferroelectricity, and coherently enhanced nonlinear optical responses. However, surface epitaxial growth of large multilayer 3R-TMD single crystals is difficult. We report an interfacial epitaxy methodology for their growth of several compositions, including molybdenum disulfide (MoS2), molybdenum diselenide, tungsten disulfide, tungsten diselenide, niobium disulfide, niobium diselenide, and molybdenum sulfoselenide. Feeding of metals and chalcogens continuously to the interface between a single-crystal Ni substrate and grown layers ensured consistent 3R stacking sequence and controlled thickness from a few to 15,000 layers. Comprehensive characterizations confirmed the large-scale uniformity, high crystallinity, and phase purity of these films. The as-grown 3R-MoS2 exhibited room-temperature mobilities up to 155 and 190 square centimeters per volt second for bi- and trilayers, respectively. Optical difference frequency generation with thick 3R-MoS2 showed markedly enhanced nonlinear response under a quasi-phase matching condition (five orders of magnitude greater than monolayers).

Simple and low-cost microscopy setup for 3D particle field measurement using incoherent illumination and open-source hardware.

The quantification of 3D particle field is of interest for a vast range of fields. While in-line particle holography (PH) can provide high-resolution measurements of particles, it suffers from speckle noise. Plenoptic imaging (PI) is less susceptible to speckle noises, but it involves a trade-off between spatial and angular resolution, rendering images with low resolution. Here, we report a simple microscopy setup with the goals of getting the strengths of both techniques. It is built with off-the-shelf and cost-effective components including a photographic lens, a diaphragm, and a CCD camera. The cost of the microscopy setup is affordable to small labs and individual researchers. The pupil plane of the proposed setup can be mechanically accessible, allowing us to implement pupil plane modulation and increase the depth of field (DOF) without requiring any additional relay lenses. It also allows us to understand the working principle of pupil plane modulation clearly, benefiting microscopy education. It illuminates the sample (particles) using diffuse white light, and thus avoids the problem of speckle noise. It captures multiple perspective images via pupil plane modulation, without requiring trading off angular and spatial resolution. We validate the setup with 2D and 3D particle samples. RESEARCH HIGHLIGHTS: We report a simple and cost-effective microscopy setup with the goals of getting the strengths of plenoptic imaging and in-line particle holography. It is built with off-the-shelf and cost-effective components. The cost of the microscopy setup is affordable to small labs and individual researchers. The pupil plane of the proposed setup can be mechanically accessible, allowing us to implement pupil plane modulation and increase the DOF without requiring any additional relay lenses. It also allows us to understand the working principle of pupil plane modulation clearly, benefiting microscopy education. It illuminates the sample (particles) using diffuse white light, and thus avoids the problem of speckle noise. It captures multiple perspective images via pupil plane modulation, without requiring trading off angular and spatial resolution. We validate the setup with 2D and 3D particle samples.

CALCR exacerbates renal cell carcinoma progression via stabilizing CD44.

The calcitonin receptor (CALCR) is an essential protein for maintaining calcium homeostasis and has been reported to be upregulated in numerous cancers. However, the molecular role of CALCR in renal cell carcinoma (RCC) is not well understood. In this study, we identified the overexpression of CALCR in RCC using human tissue chip by immunohistochemical (IHC) staining, which was associated with a poor prognosis. Functionally, CALCR depletion inhibited RCC cell proliferation and migration, and induced cell apoptosis and cycle arrest. CALCR is also essential for in vivo tumor formation. Mechanistically, we demonstrated that CALCR could directly bind to CD44, preventing CD44 protein degradation and thereby upregulating CD44 expression. Moreover, a deficiency in CD44 significantly attenuated the promoting role of CALCR on RCC cell proliferation, migration and anti-apoptosis capacities. Collectively, CALCR exacerbates RCC progression via stabilizing CD44, offering a fundamental basis for considering CALCR as a potential therapeutic target for RCC patients.

Formation and retention of aroma compounds in pigeons roasted by circulating non-fried roast technique by means of UHPLC-HRMS and GC-O-MS.

Lipids are key aroma contributors in meat products. However, the role of different lipids in the presence of aroma compounds in roasted pigeons has not been studied. The formation of aroma compounds and lipids during the circulating non-fried roasting of pigeons was investigated. The results presented that 18 aroma compounds, including 5-methy-2,3-diethylpyrazine, were identified as key aroma compounds. A total of 6324 lipids were classed into 47 categories, such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), and triglyceride (TG). Nine lipids, containing PA(P-20:0/22:4(7Z,10Z,13Z,16Z)) and LPC 16:0-SN1, showed promise as potential biomarkers for discriminating differential pigeons using OPLS-DA. PC (13.76%), TG (13.58%), and their products were major lipids, among which TG 16:0 16:0 18:2, LPC 18:2-SN1, and PC 18:1_18:1 played a crucial role in the presence of aroma compounds. Interestingly, the linoleic acid, an important aroma contributor, was predominantly bonded to the sn-2 position of phospholipid and sn-3 position of neutral lipids.

Multi-omic profiling reveals potential biomarkers of hepatocellular carcinoma prognosis and therapy response among mitochondria-associated cell death genes in the context of 3P medicine.

Background: Cancer cell growth, metastasis, and drug resistance are major challenges in treating liver hepatocellular carcinoma (LIHC). However, the lack of comprehensive and reliable models hamper the effectiveness of the predictive, preventive, and personalized medicine (PPPM/3PM) strategy in managing LIHC. Methods: Leveraging seven distinct patterns of mitochondrial cell death (MCD), we conducted a multi-omic screening of MCD-related genes. A novel machine learning framework was developed, integrating 10 machine learning algorithms with 67 different combinations to establish a consensus mitochondrial cell death index (MCDI). This index underwent rigorous evaluation across training, validation, and in-house clinical cohorts. A comprehensive multi-omics analysis encompassing bulk, single-cell, and spatial transcriptomics was employed to achieve a deeper insight into the constructed signature. The response of risk subgroups to immunotherapy and targeted therapy was evaluated and validated. RT-qPCR, western blotting, and immunohistochemical staining were utilized for findings validation. Results: Nine critical differentially expressed MCD-related genes were identified in LIHC. A consensus MCDI was constructed based on a 67-combination machine learning computational framework, demonstrating outstanding performance in predicting prognosis and clinical translation. MCDI correlated with immune infiltration, Tumor Immune Dysfunction and Exclusion (TIDE) score and sorafenib sensitivity. Findings were validated experimentally. Moreover, we identified PAK1IP1 as the most important gene for predicting LIHC prognosis and validated its potential as an indicator of prognosis and sorafenib response in our in-house clinical cohorts. Conclusion: This study developed a novel predictive model for LIHC, namely MCDI. Incorporating MCDI into the PPPM framework will enhance clinical decision-making processes and optimize individualized treatment strategies for LIHC patients. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00362-8.

Photoaffinity probe-based antimalarial target identification of artemisinin in the intraerythrocytic developmental cycle of Plasmodium falciparum.

Malaria continues to pose a serious global health threat, and artemisinin remains the core drug for global malaria control. However, the situation of malaria resistance has become increasingly severe due to the emergence and spread of artemisinin resistance. In recent years, significant progress has been made in understanding the mechanism of action (MoA) of artemisinin. Prior research on the MoA of artemisinin mainly focused on covalently bound targets that are alkylated by artemisinin-free radicals. However, less attention has been given to the reversible noncovalent binding targets, and there is a paucity of information regarding artemisinin targets at different life cycle stages of the parasite. In this study, we identified the protein targets of artemisinin at different stages of the parasite's intraerythrocytic developmental cycle using a photoaffinity probe. Our findings demonstrate that artemisinin interacts with parasite proteins in vivo through both covalent and noncovalent modes. Extensive mechanistic studies were then conducted by integrating target validation, phenotypic studies, and untargeted metabolomics. The results suggest that protein synthesis, glycolysis, and oxidative homeostasis are critically involved in the antimalarial activities of artemisinin. In summary, this study provides fresh insights into the mechanisms underlying artemisinin's antimalarial effects and its protein targets.

Detection of the novel HLA-DRB5*01:01:01:07 allele by Pacific Biosciences HiFi sequencing in a Chinese individual.

HLA-DRB5*01:01:01:07 differs from HLA-DRB5*01:01:01:01 by two nucleotide changes in intron 1 and intron 2.

Design of vilazodone-donepezil chimeric derivatives as acetylcholinesterase inhibitors by QSAR, molecular docking and molecular dynamics simulations.

Alzheimer's disease (AD) is a disease that affects the cognitive abilities of older adults, and it is one of the biggest global medical challenges of the 21st century. Acetylcholinesterase (AChE) can increase acetylcholine concentrations and improve cognitive function in patients, and is a potential target to develop small molecule inhibitors for the treatment of Alzheimer's disease (AD). In this study, 29 vilazodone-donepezil chimeric derivatives are systematically studied using 3D-QSAR modeling, and a robust and reliable Topomer CoMFA model was obtained with: q2 = 0.720, r2 = 0.991, F = 287.234, N = 6, and SEE = 0.098. Based on the established model and combined with the ZINC20 database, 33 new compounds with ideal inhibitory activity are successfully designed. Molecular docking and ADMET property prediction also show that these newly designed compounds have a good binding ability to the target protein and can meet the medicinal conditions. Subsequently, four new compounds with good comprehensive ability are selected for molecular dynamics simulation, and the simulation results confirm that the newly designed compounds have a certain degree of reliability and stability. This study provides guidance for vilazodone-donepezil chimeric derivatives as a potential AChE inhibitor and has certain theoretical value.

Controlled NiOx Defect Engineering to Harnessing Redox Reactions in Perovskite Photovoltaic Cells via Atomic Layer Deposition.

Albeit the undesirable attributes of NiOx, such as low conductivity, unmanageable defects, and redox reactions occurring at the perovskite/NiOx interface, which impede the progress in inverted perovskite solar cells (i-PSCs), it is the most favorable choice of technology for industrialization of PSCs. In this study, we propose a novel Ni vacancy defect modulate approach to leverage the conformal growth and surface self-limiting reaction characteristics of the atomic layer deposition (ALD)-fabricated NiOx by varying the O2 plasma injection time (tOE) to induce self-doping. Consequently, NiOx thin films with enhanced conductivity, an appropriate Ni3+/Ni2+ ratio, stable surface states, and ultrathinness are realized as hole-transporting layers (HTLs) in p-i-n PSCs. As a result of these improvements, ALD-NiOx-based devices exhibit the highest power conversion efficiency (PCE) of 19.86% and a fill factor (FF) of 81.86%. Notably, the optimal interfacial defects effectively suppressed the severe reaction between the perovskite and NiOx. This suppression is evidenced by the lowest decay rate observed in a harsh environment, lasting for 500 consecutive hours. The proposed approach introduces the possibility of a hierarchical distribution of defects and offers feasibility for the fabrication of large-area, uniform, and high-quality films.

Macrophage GIT1 promotes oligodendrocyte precursor cell differentiation and remyelination after spinal cord injury.

Spinal cord injury (SCI) can result in severe motor and sensory deficits, for which currently no effective cure exists. The pathological process underlying this injury is extremely complex and involves many cell types in the central nervous system. In this study, we have uncovered a novel function for macrophage G protein-coupled receptor kinase-interactor 1 (GIT1) in promoting remyelination and functional repair after SCI. Using GIT1flox/flox Lyz2-Cre (GIT1 CKO) mice, we identified that GIT1 deficiency in macrophages led to an increased generation of tumor necrosis factor-alpha (TNFα), reduced proportion of mature oligodendrocytes (mOLs), impaired remyelination, and compromised functional recovery in vivo. These effects in GIT1 CKO mice were reversed with the administration of soluble TNF inhibitor. Moreover, bone marrow transplantation from GIT1 CWT mice reversed adverse outcomes in GIT1 CKO mice, further indicating the role of macrophage GIT1 in modulating spinal cord injury repair. Our in vitro experiments showed that macrophage GIT1 plays a critical role in secreting TNFα and influences the differentiation of oligodendrocyte precursor cells (OPCs) after stimulation with myelin debris. Collectively, our data uncovered a new role of macrophage GIT1 in regulating the transformation of OPCs into mOLs, essential for functional remyelination after SCI, suggesting that macrophage GIT1 could be a promising treatment target of SCI.

WS2 ribbon arrays with defined chirality and coherent polarity.

One-dimensional transition metal dichalcogenides exhibiting an enhanced bulk photovoltaic effect have the potential to exceed the Shockley-Queisser limit efficiency in solar energy harvest within p-n junction architectures. However, the collective output of these prototype devices remains a challenge. We report on the synthesis of single-crystalline WS2 ribbon arrays with defined chirality and coherent polarity through an atomic manufacturing strategy. The chirality of WS2 ribbon was defined by substrate couplings into tunable armchair, zigzag, and chiral species, and the polarity direction was determined by the ribbon-precursor interfacial energy along a coherent direction. A single armchair ribbon showed strong bulk photovoltaic effect and the further integration of ~1000 aligned ribbons with coherent polarity enabled upscaling of the photocurrent.

Strong chiroptical nonlinearity in coherently stacked boron nitride nanotubes.

Nanomaterials with a large chiroptical response and high structural stability are desirable for advanced miniaturized optical and optoelectronic applications. One-dimensional (1D) nanotubes are robust crystals with inherent and continuously tunable chiral geometries. However, their chiroptical response is typically weak and hard to control, due to the diverse structures of the coaxial tubes. Here we demonstrate that as-grown multiwalled boron nitride nanotubes (BNNTs), featuring coherent-stacking structures including near monochirality, homo-handedness and unipolarity among the component tubes, exhibit a scalable nonlinear chiroptical response. This intrinsic architecture produces a strong nonlinear optical response in individual multiwalled BNNTs, enabling second-harmonic generation (SHG) with a conversion efficiency up to 0.01% and output power at the microwatt level-both excellent figures of merit in the 1D nanomaterials family. We further show that the rich chirality of the nanotubes introduces a controllable nonlinear geometric phase, producing a chirality-dependent SHG circular dichroism with values of -0.7 to +0.7. We envision that our 1D chiral platform will enable novel functions in compact nonlinear light sources and modulators.

Is Smoking Associated with the Risk of Acute Mountain Sickness? A Systematic Review and Meta-Analysis.

Background: Controversy remains in the association between smoking and the risk of acute mountain sickness (AMS). Therefore, a systematic review of the existing literature may help clarify this association. Methods: We conducted a systematic search of PubMed, Embase, and Cochrane Library from database inception up to October 19, 2021. Both unadjusted and adjusted relative risks (RRs) and 95% confidence intervals (CIs) were calculated to compare the risk of AMS in the smoking and nonsmoking groups. Meta-regression was conducted to explore the factors causing heterogeneity of the studies, and subsequent stratified analysis was performed to present the pooled RR in different subgroups. Publication bias was assessed using funnel plots. Results: A total of 28 eligible articles (31 studies) were included. The pooled unadjusted and adjusted RRs were 0.88 (95% CI: 0.78-1.01) and 0.87 (95% CI: 0.77-0.99), respectively, using random-effect models. Publication bias was observed owing to restrictions on the sample size. The ascending altitude and sex composition of the study population were likely sources of heterogeneity according to meta-regression. Studies on participants with an ascending altitude of over 3,500 m or composed of both males and females reported a slight but not significant protective effect of smoking on the risk of AMS, with high heterogeneity. Conclusions: Smoking had no significant effect on AMS risk in this meta-analysis. Current studies showed high heterogeneity and included little information on quantitative exposure to smoking (i.e., dose and frequency); thus, the results require careful explanation.