Molecular Choreography of Acute Exercise.

Acute physical activity leads to several changes in metabolic, cardiovascular, and immune pathways. Although studies have examined selected changes in these pathways, the system-wide molecular response to an acute bout of exercise has not been fully characterized. We performed longitudinal multi-omic profiling of plasma and peripheral blood mononuclear cells including metabolome, lipidome, immunome, proteome, and transcriptome from 36 well-characterized volunteers, before and after a controlled bout of symptom-limited exercise. Time-series analysis revealed thousands of molecular changes and an orchestrated choreography of biological processes involving energy metabolism, oxidative stress, inflammation, tissue repair, and growth factor response, as well as regulatory pathways. Most of these processes were dampened and some were reversed in insulin-resistant participants. Finally, we discovered biological pathways involved in cardiopulmonary exercise response and developed prediction models revealing potential resting blood-based biomarkers of peak oxygen consumption.

Broader anti-EBV TCR repertoire in multiple sclerosis: disease specificity and treatment modulation.

Epstein-Barr virus (EBV) infection has long been associated with the development of multiple sclerosis (MS). MS patients have elevated titers of EBV-specific antibodies in serum and show signs of CNS damage only after EBV infection. Regarding CD8+ T-cells, an elevated but ineffective response to EBV was suggested in MS patients, who present with a broader MHC-I-restricted EBV-specific T-cell receptor beta chain (TRB) repertoire compared to controls. It is not known whether this altered EBV response could be subject to dynamic changes, e.g., by approved MS therapies, and whether it is specific for MS. 1317 peripheral blood TRB repertoire samples of healthy donors (n=409), patients with MS (n=710) before and after treatment, patients with neuromyelitis optica spectrum disorder (n=87), myelin-oligodendrocyte-glycoprotein antibody-associated disease (n=64) and Susac's syndrome (n=47) were analyzed. Apart from MS, none of the evaluated diseases presented with a broader anti-EBV TRB repertoire. In MS patients undergoing autologous hematopoietic stem-cell transplantation, EBV reactivation coincided with elevated MHC-I-restricted EBV-specific TRB sequence matches. Therapy with ocrelizumab, teriflunomide or dimethyl fumarate reduced EBV-specific, but not CMV-specific MHC-I-restricted TRB sequence matches. Together, this data suggests that the aberrant MHC-I-restricted T-cell response directed against EBV is specific to MS with regard to NMO, MOGAD and Susac's Syndrome and that it is specifically modified by MS treatments interfering with EBV host cells or activated lymphocytes.

Longitudinal multi-omics of host-microbe dynamics in prediabetes.

Type 2 diabetes mellitus (T2D) is a growing health problem, but little is known about its early disease stages, its effects on biological processes or the transition to clinical T2D. To understand the earliest stages of T2D better, we obtained samples from 106 healthy individuals and individuals with prediabetes over approximately four years and performed deep profiling of transcriptomes, metabolomes, cytokines, and proteomes, as well as changes in the microbiome. This rich longitudinal data set revealed many insights: first, healthy profiles are distinct among individuals while displaying diverse patterns of intra- and/or inter-personal variability. Second, extensive host and microbial changes occur during respiratory viral infections and immunization, and immunization triggers potentially protective responses that are distinct from responses to respiratory viral infections. Moreover, during respiratory viral infections, insulin-resistant participants respond differently than insulin-sensitive participants. Third, global co-association analyses among the thousands of profiled molecules reveal specific host-microbe interactions that differ between insulin-resistant and insulin-sensitive individuals. Last, we identified early personal molecular signatures in one individual that preceded the onset of T2D, including the inflammation markers interleukin-1 receptor agonist (IL-1RA) and high-sensitivity C-reactive protein (CRP) paired with xenobiotic-induced immune signalling. Our study reveals insights into pathways and responses that differ between glucose-dysregulated and healthy individuals during health and disease and provides an open-access data resource to enable further research into healthy, prediabetic and T2D states.

Single-cell sequencing reveals distinct immune cell features in cutaneous lesions of pemphigus vulgaris and bullous pemphigoid.

Bullous pemphigoid (BP) and pemphigus vulgaris (PV) are two common subtypes of autoimmune bullous disease (AIBD). The key role of circulating autoreactive immune cells contributing to skin damage of AIBD has been widely recognized. Nevertheless, the immune characteristics in cutaneous lesions remain unclear. Here, we performed single-cell RNA sequencing (scRNA-seq) and single-cell VDJ sequencing (scRNA-seq) to generate transcriptional profiles for cells and T/B cell clonetype in skin lesions of BP and PV. We found that the proportions of NK&T, macrophages/ dendritic cells, B cells, and mast cells increased in BP and PV lesions. Then, BP and PV cells constituted over 75% of all myeloid cell subtypes, CD4+ T cell subtypes and CD8+ T cell subtypes. Strikingly, CD8+ Trm was identified to be expanded in PV, and located in the intermediate state of the pseudotime trajectory from CD8+ Tm to CD8+ Tem. Interestingly, CD8+ Tem and CD4+ Treg highly expressed exhaustion-related genes, especially in BP lesions. Moreover, the enhanced cell communication between stromal cells and immune cells like B cells and macrophages/ dendritic cells was also identified in BP and PV lesions. Finally, clone expansion was observed in T cells of BP and PV compared with HC, while CD8+ Trm represented the highest ratio of hyperexpanded TCR clones among all T cell subtypes. Our study generally depicts a large and comprehensive single-cell landscape of cutaneous lesions and highlights immune cell features in BP and PV. This offers potential research targets for further investigation.

Longitudinal linked-read sequencing reveals ecological and evolutionary responses of a human gut microbiome during antibiotic treatment.

Gut microbial communities can respond to antibiotic perturbations by rapidly altering their taxonomic and functional composition. However, little is known about the strain-level processes that drive this collective response. Here, we characterize the gut microbiome of a single individual at high temporal and genetic resolution through a period of health, disease, antibiotic treatment, and recovery. We used deep, linked-read metagenomic sequencing to track the longitudinal trajectories of thousands of single nucleotide variants within 36 species, which allowed us to contrast these genetic dynamics with the ecological fluctuations at the species level. We found that antibiotics can drive rapid shifts in the genetic composition of individual species, often involving incomplete genome-wide sweeps of pre-existing variants. These genetic changes were frequently observed in species without obvious changes in species abundance, emphasizing the importance of monitoring diversity below the species level. We also found that many sweeping variants quickly reverted to their baseline levels once antibiotic treatment had concluded, demonstrating that the ecological resilience of the microbiota can sometimes extend all the way down to the genetic level. Our results provide new insights into the population genetic forces that shape individual microbiomes on therapeutically relevant timescales, with potential implications for personalized health and disease.

Ultrathin LayCoOx Nanosheets with High Porosity Featuring Boosted Catalytic Oxidation of Benzene: Mechanism Elucidation via an Experiment-Theory Combined Paradigm.

Designing transition-metal oxides for catalytically removing the highly toxic benzene holds significance in addressing indoor/outdoor environmental pollution issues. Herein, we successfully synthesized ultrathin LayCoOx nanosheets (thickness of ∼1.8 nm) with high porosity, using a straightforward coprecipitation method. Comprehensive characterization techniques were employed to analyze the synthesized LayCoOx catalysts, revealing their low crystallinity, high surface area, and abundant porosity. Catalytic benzene oxidation tests demonstrated that the La0.029CoOx-300 nanosheet exhibited the most optimal performance. This catalyst enabled complete benzene degradation at a relatively low temperature of 220 °C, even under a high space velocity (SV) of 20,000 h-1, and displayed remarkable durability throughout various catalytic assessments, including SV variations, exposure to water vapor, recycling, and long time-on-stream tests. Characterization analyses confirmed the enhanced interactions between Co and doped La, the presence of abundant adsorbed oxygen, and the extensive exposure of Co3+ species in La0.029CoOx-300 nanosheets. Theoretical calculations further revealed that La doping was beneficial for the formation of oxygen vacancies and the adsorption of more hydroxyl groups. These features strongly promoted the adsorption and activation of oxygen, thereby accelerating the benzene oxidation processes. This work underscores the advantages of doping rare-earth elements into transition-metal oxides as a cost-effective yet efficient strategy for purifying industrial exhausts.

Exploring the bidirectional causal associations between pain and circulating inflammatory proteins: A Mendelian randomization study.

Multisite chronic pain (MCP) and site-specific chronic pain (SSCP) may be influenced by circulating inflammatory proteins, but the causal relationship remains unknown. To overcome this limitation, two-sample bidirectional Mendelian randomization (MR) analysis was used to analyse data for 91 circulating inflammatory proteins, MCP and SSCP encompassing headache, back pain, shoulder pain, hip pain, knee pain, stomach abdominal pain and facial pain. The primary MR method used was inverse variance weighting, sensitivity analyses included weighted median, MR pleiotropy residual sum and outlier and the Egger intercept method. Heterogeneity was also detected using Cochrane's Q test and leave-one-out analyses. Finally, a causal relationship between 29 circulating inflammatory proteins and chronic pain was identified. Among these proteins, 14 exhibited a protective effect, including MCP (T-cell surface glycoprotein cluster of differentiation 5), headache (4E-binding protein 1 [4EBP1], cluster of differentiation 40, cluster of differentiation 6 and C-X-C motif chemokine [CXCL] 11), back pain (leukaemia inhibitory factor), shoulder pain (fibroblast growth factor [FGF]-5 and interleukin [IL]-18R1), stomach abdominal pain (tumour necrosis factor [TNF]-α), hip pain (CXCL1, IL-20 and signalling lymphocytic activation molecule 1) and knee pain (IL-7 and TNF-ß). Additionally, 15 proteins were identified as risk factors for MCP and SSCP: MCP (colony-stimulating factor 1, human glial cell line-derived neurotrophic factor and IL-17C), headache (fms-related tyrosine kinase 3 ligand, IL-20 receptor subunit α [IL-20RA], neurotrophin-3 and tumour necrosis factor receptor superfamily member 9), facial pain (CXCL1), back pain (TNF), shoulder pain (IL-17C and matrix metalloproteinase-10), stomach abdominal pain (IL-20RA), hip pain (C-C motif chemokine 11/eotaxin-1 and tumour necrosis factor ligand superfamily member 12) and knee pain (4EBP1). Importantly, in the opposite direction, MCP and SSCP did not exhibit a significant causal impact on circulating inflammatory proteins. Our study identified potential causal influences of various circulating inflammatory proteins on MCP and SSCP and provided promising treatments for the clinical management of MCP and SSCP.

Melatonin Alleviates Acute Respiratory Distress Syndrome by Inhibiting Alveolar Macrophage NLRP3 Inflammasomes Through the ROS/HIF-1α/GLUT1 Pathway.

Sepsis-induced acute respiratory distress syndrome (ARDS) is a devastating clinically severe respiratory disorder, and no effective therapy is available. Melatonin (MEL), an endogenous neurohormone, has shown great promise in alleviating sepsis-induced ARDS, but the underlying molecular mechanism remains unclear. Using a lipopolysaccharide (LPS)-treated mouse alveolar macrophage cell line (MH-S) model, we found that MEL significantly inhibited NOD-like receptor protein 3 (NLRP3) inflammasome activation in LPS-treated macrophages, whereas this inhibitory effect of MEL was weakened in MH-S cells transfected with glucose transporter 1 (GLUT1) overexpressing lentivirus. Further experiments showed that MEL downregulated GLUT1 via inhibition of hypoxia-inducible factor 1 (HIF-1α). Notably, hydrogen peroxide (H2O2), a donor of reactive oxygen species (ROS), significantly increased the level of intracellular ROS and inhibited the regulatory effect of MEL on the HIF-1α/GLUT1 pathway. Interestingly, the protective effect of MEL was attenuated after the knockdown of melatonin receptor 1A (MT1) in MH-S cells. We also confirmed in vivo that MEL effectively downregulated the HIF-1α/GLUT1/NLRP3 pathway in the lung tissue of LPS-treated mice, as well as significantly ameliorated LPS-induced lung injury and improved survival in mice. Collectively, these findings revealed that MEL regulates the activation of the ROS/HIF-1α/GLUT1/NLRP3 pathway in alveolar macrophages via the MT1 receptor, further alleviating sepsis-induced ARDS.

Robust identification of temporal biomarkers in longitudinal omics studies.

MOTIVATION: Longitudinal studies increasingly collect rich 'omics' data sampled frequently over time and across large cohorts to capture dynamic health fluctuations and disease transitions. However, the generation of longitudinal omics data has preceded the development of analysis tools that can efficiently extract insights from such data. In particular, there is a need for statistical frameworks that can identify not only which omics features are differentially regulated between groups but also over what time intervals. Additionally, longitudinal omics data may have inconsistencies, including non-uniform sampling intervals, missing data points, subject dropout and differing numbers of samples per subject. RESULTS: In this work, we developed OmicsLonDA, a statistical method that provides robust identification of time intervals of temporal omics biomarkers. OmicsLonDA is based on a semi-parametric approach, in which we use smoothing splines to model longitudinal data and infer significant time intervals of omics features based on an empirical distribution constructed through a permutation procedure. We benchmarked OmicsLonDA on five simulated datasets with diverse temporal patterns, and the method showed specificity greater than 0.99 and sensitivity greater than 0.87. Applying OmicsLonDA to the iPOP cohort revealed temporal patterns of genes, proteins, metabolites and microbes that are differentially regulated in male versus female subjects following a respiratory infection. In addition, we applied OmicsLonDA to a longitudinal multi-omics dataset of pregnant women with and without preeclampsia, and OmicsLonDA identified potential lipid markers that are temporally significantly different between the two groups. AVAILABILITY AND IMPLEMENTATION: We provide an open-source R package (https://bioconductor.org/packages/OmicsLonDA), to enable widespread use. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Alterations of fecal microbiome and metabolome in pemphigus patients.

The role of gut microbiome and metabolic substances in the development of autoimmune diseases has gradually been revealed. However, the relevant gut features in pemphigus have not been well clarified. We collected stool samples from pemphigus patients and healthy controls (HCs). Metagenomic sequencing and liquid chromatography-mass spectrometry (LC/MS) metabolome sequencing were performed to analyze the compositional and metabolic alternations of the gut microbiome in pemphigus patients and HCs. We observed the reduced richness and diversity and greater heterogeneity in pemphigus patients, which was characterized by a significant decrease in Firmicutes and an increase in Proteobacteria. At the species level, Intestinal pathogenic bacteria such as Escherichia coli and Bacteroides fragilis were significantly enriched, while anti-inflammatory bacteria and butyric acid-producing bacteria were significantly reduced, which were related to clinical indicators (Dsg1/3 and PDAI). 4 species were selected by the machine learning algorithm to better distinguish pemphigus patients from healthy people. Metabolomic analysis showed that the composition of pemphigus patients was different from that of HCs. PE (18:3 (6Z,9Z, 12Z)/14:1 (9Z)) was the main metabolic substance in pemphigus and involved in a variety of metabolic pathways. While Retinol, flavonoid compounds and various amino acids decreased significantly compared with HCs. Furthermore, we found that differences in the levels of these metabolites correlated with changes in the abundance of specific species. Our study provides a comprehensive picture of gut microbiota and metabolites in pemphigus patients and suggests a potential mechanism of the aberrant gut microbiota and metabolites in the pathogenesis of pemphigus.

Sensitivity of late ERP old/new effects in source memory to self-referential encoding focus and stimulus emotionality.

In episodic memory, the old/new effect, the contrast of the waveforms elicited by the correctly recognized studied items and the correctly rejected novel items, has been broadly concerned. However, the contribution of self-referential encoding to the old/new effect in source memory (i.e., source-SRE), is far from clarification; further, it remains unclear whether the contribution is susceptible to the factor of stimulus emotionality. To address these issues, adopting the event-related potential (ERP) technique, this study applied words of three types of emotional valences (positive, neutral, vs. negative) in the self-focus vs. external-focus encoding tasks. In the course of the test, four ERP old/new effects were identified: (a) the familiarity- and recollection-reflected mid-frontal effect (FN400) and late positive component (LPC) were both independent of source-SRE and stimulus emotionality; (b) the reconstruction-driven late posterior negativity (LPN) exhibited an adverse pattern of source-SRE and was susceptible to the emotional valence by encoding focus; and (c) the right frontal old/new effect (RFE), reflecting post-retrieval process, exhibited a source-SRE in emotional words. These effects provide compelling evidence for the influences of both stimulus valence and encoding focus on SRE in source memory, especially during the late processes. Further directions considering more perspectives are put forward.

Hydroxyl-Decorated Pt as a Robust Water-Resistant Catalyst for Catalytic Benzene Oxidation.

In catalytic oxidation reactions, the presence of environmental water poses challenges to the performance of Pt catalysts. This study aims to overcome this challenge by introducing hydroxyl groups onto the surface of Pt catalysts using the pyrolysis reduction method. Two silica supports were employed to investigate the impact of hydroxyl groups: SiO2-OH with hydroxyl groups and SiO2-C without hydroxyl groups. Structural characterization confirmed the presence of Pt-Ox, Pt-OHx, and Pt0 species in the Pt/SiO2-OH catalysts, while only Pt-Ox and Pt0 species were observed in the Pt/SiO2-C catalysts. Catalytic performance tests demonstrated the remarkable capacity of the 0.5 wt % Pt/SiO2-OH catalyst, achieving complete conversion of benzene at 160 °C under a high space velocity of 60,000 h-1. Notably, the catalytic oxidation capacity of the Pt/SiO2-OH catalyst remained largely unaffected even in the presence of 10 vol % water vapor. Moreover, the catalyst exhibited exceptional recyclability and stability, maintaining its performance over 16 repeated cycles and a continuous operation time of 70 h. Theoretical calculations revealed that the construction of Pt-OHx sites on the catalyst surface was beneficial for modulating the d-band structure, which in turn enhanced the adsorption and activation of reactants. This finding highlights the efficacy of decorating the Pt surface with hydroxyl groups as an effective strategy for improving the water resistance, catalytic activity, and long-term stability of Pt catalysts.

Molecular modelling of shockwave-mediated delivery of paclitaxel aggregates across the neuronal plasma membrane.

Shock-assisted paclitaxel (PTX) transport across the blood-brain barrier offers a promising treatment strategy for brain tumors. Here, based on a realistically complex human brain plasma membrane (PM) model, we investigated the dynamic transmembrane behavior of a PTX cluster by shock induced bubble collapse, focusing on the effect of impulse (I), bubble diameter (D) and arrays. The results show that all three factors can control the transport depth (ΔDPM) of PTX. For a fixed D, the ΔDPM grows exponentially with I, ΔDPM ∼ exp (I), and eventually reaches a critical depth. But the depth, ΔDPM, can be adjusted linearly in a wider range of D. This mainly depends on the size of jets from bubble collapse. For bubble arrays, the bubbles in series can transport PTX deeper than a single bubble, while the parallel does the opposite. In addition, only PTX clusters in the range of jet action can be successfully transported. Finally, the absorption of PTX clusters was examined via recovery simulation. Not all PTX clusters across the membrane can be effectively absorbed by cells. The shallow PTX clusters are quickly attracted by the membrane and embedded into it. The critical depth at which PTX clusters can be effectively absorbed is about 20 nm. These molecular-level mechanisms and dynamic processes of PTX clusters crossing the PM membrane may be helpful in optimizing the application of shock-induced bubble collapse for the delivery of PTX to tumor cells.

iNetModels 2.0: an interactive visualization and database of multi-omics data.

It is essential to reveal the associations between various omics data for a comprehensive understanding of the altered biological process in human wellness and disease. To date, very few studies have focused on collecting and exhibiting multi-omics associations in a single database. Here, we present iNetModels, an interactive database and visualization platform of Multi-Omics Biological Networks (MOBNs). This platform describes the associations between the clinical chemistry, anthropometric parameters, plasma proteomics, plasma metabolomics, as well as metagenomics for oral and gut microbiome obtained from the same individuals. Moreover, iNetModels includes tissue- and cancer-specific Gene Co-expression Networks (GCNs) for exploring the connections between the specific genes. This platform allows the user to interactively explore a single feature's association with other omics data and customize its particular context (e.g. male/female specific). The users can also register their data for sharing and visualization of the MOBNs and GCNs. Moreover, iNetModels allows users who do not have a bioinformatics background to facilitate human wellness and disease research. iNetModels can be accessed freely at https://inetmodels.com without any limitation.

First-principles study of sulfur vacancy concentration effect on the electronic structures and hydrogen evolution reaction of MoS2.

Defect engineering has been widely used in experiments to modulate the electrocatalytic properties of molybdenum disulfide (MoS2). However, the effect of vacancy concentration on the vacancy distribution, electronic properties, and hydrogen evolution reaction (HER) activity remains elusive. Herein, we perform density functional theory (DFT) studies to investigate defective MoS2 with different numbers of sulfur vacancies. In the case of low S-vacancy concentration, the vacancies prefer to agglomerate rather than being dispersed, while at the higher-vacancy concentration, the combination of local point defect and clustered vacancy chain is preferred. The coupling between S-vacancies leads to decreased band gap and increased Mo-H adsorption strength with increasing vacancy concentration. The optimal HER activity is identified to occur below vacancy concentration of 12.50%. Our work provides an atomic-level understanding about the role of S-vacancies in the HER performance of MoS2, and offers useful guidelines for the design of defective MoS2 and other TMDs electrocatalysts.

DIAlignR Provides Precise Retention Time Alignment Across Distant Runs in DIA and Targeted Proteomics.

Sequential Windowed Acquisition of All Theoretical Fragment Ion Mass Spectra (SWATH-MS) is widely used for proteomics analysis given its high throughput and reproducibility, but ensuring consistent quantification of analytes across large-scale studies of heterogeneous samples such as human plasma remains challenging. Heterogeneity in large-scale studies can be caused by large time intervals between data acquisition, acquisition by different operators or instruments, and intermittent repair or replacement of parts, such as the liquid chromatography column, all of which affect retention time (RT) reproducibility and, successively, performance of SWATH-MS data analysis. Here, we present a novel algorithm for RT alignment of SWATH-MS data based on direct alignment of raw MS2 chromatograms using a hybrid dynamic programming approach. The algorithm does not impose a chronological order of elution and allows for alignment of elution-order-swapped peaks. Furthermore, allowing RT mapping in a certain window around a coarse global fit makes it robust against noise. On a manually validated dataset, this strategy outperformed the current state-of-the-art approaches. In addition, on real-world clinical data, our approach outperformed global alignment methods by mapping 98% of peaks compared with 67% cumulatively. DIAlignR reduced alignment error up to 30-fold for extremely distant runs. The robustness of technical parameters used in this pairwise alignment strategy is also demonstrated. The source code is released under the BSD license at https://github.com/Roestlab/DIAlignR.

Digital Health: Tracking Physiomes and Activity Using Wearable Biosensors Reveals Useful Health-Related Information.

A new wave of portable biosensors allows frequent measurement of health-related physiology. We investigated the use of these devices to monitor human physiological changes during various activities and their role in managing health and diagnosing and analyzing disease. By recording over 250,000 daily measurements for up to 43 individuals, we found personalized circadian differences in physiological parameters, replicating previous physiological findings. Interestingly, we found striking changes in particular environments, such as airline flights (decreased peripheral capillary oxygen saturation [SpO2] and increased radiation exposure). These events are associated with physiological macro-phenotypes such as fatigue, providing a strong association between reduced pressure/oxygen and fatigue on high-altitude flights. Importantly, we combined biosensor information with frequent medical measurements and made two important observations: First, wearable devices were useful in identification of early signs of Lyme disease and inflammatory responses; we used this information to develop a personalized, activity-based normalization framework to identify abnormal physiological signals from longitudinal data for facile disease detection. Second, wearables distinguish physiological differences between insulin-sensitive and -resistant individuals. Overall, these results indicate that portable biosensors provide useful information for monitoring personal activities and physiology and are likely to play an important role in managing health and enabling affordable health care access to groups traditionally limited by socioeconomic class or remote geography.

Assessment of Elemental Components in Atmospheric Particulate Matter from a Typical Mining City, Central China: Size Distribution, Source Characterization and Health Risk.

Atmospheric particulate matters in nine size fractions were sampled at Huangshi city, Hubei province. Elemental concentrations occurred unimodal size distribution for Zn, Pb and Ni, dimodal distribution for Ca, S, Fe and Ti, and trimodal distribution for Cl, K, Mn, Cu and Cr. Enrichment factor and principal component analysis identified the main sources from crustal material, biomass burning, waste incineration, vehicular and industrial emission. As for the non-carcinogenic health risk through inhalation, there were certain potential risks for Mn and Sb for children, and Pb for children and adults in PM2.5. It showed certain potential risks for Mn, Sb and Pb for children and adults in PM10. As for the carcinogenic health risk through inhalation, Cr in PM2.5 and Ni, Co and Cr in PM10 indicated unacceptable risk for children and adults. Meanwhile, Co and Ni in PM2.5 represented acceptable risk for children.

Azoreductase-Responsive Nanoprobe for Hypoxia-Induced Mitophagy Imaging.

Mitophagy, as a crucial metabolic process, plays an essential role in maintaining cellular and tissue homeostasis. Various stresses especially hypoxia could improve intracellular reactive oxygen species (ROS) level to induce mitophagy. However, high-specific fluorescence imaging of mitophagy in living cells under hypoxia is still a challenge. Based on this, we report an azoreductase-responsive nanoprobe (termed Micelle@Mito-rHP@TATp, MCM@TATp) by encapsulating cationic spiropyrane derivative (Mito-rHP) to realize specific imaging of mitophagy in living cells under hypoxia. An azoreductase-responsive amphiphilic polymer, 1,2-distearoyl- sn-glycero-3-phosphoethanolamine-azo- N-[maleimide(polyethylene glycol-2000) (Mal-PEG2000-Azo-DSPE), was first self-assembled into a micelle in aqueous solution. Meanwhile, the synthetic Mito-rHP encapsulated into this formed micelle to construct MCM. By modifying the surface of MCM with cell-penetrating peptide (TATp) to form MCM@TATp, the nanoprobe could avoid endolysosomal trapping. Under hypoxic conditions, the azobenzene moiety-contained MCM@TATp would be disrupted by the highly expressed azoreductase, then the encapsulated Mito-rHP would be released. Since Mito-rHP is a mitochondria-targeted and pH-sensitive probe, thus it could target into mitochondria and displayed a desirable "off-on" fluorescence response to mitophagy during which mitochondria were regarded to undergo acidification. The results indicated that the MCM@TATp in our design could image mitophagy under hypoxia in high-specificity. As further application, we have also demonstrated that this MCM@TATp can perform well to realize mitophagy imaging under the photodynamic therapy (PDT) which can induce hypoxia in treatment of cancer. We expect this new strategy would be a powerful tool for hypoxia-related fundamental and clinical research.

Influence of Deviated Centers of Rotation on Kinematics and Kinetics of a Lumbar Functional Spinal Unit: An In Vitro Study.

BACKGROUND Center of rotation (COR) has been used for assessing spinal motion quality. However, the biomechanical influence of COR deviation towards different directions during flexion-extension (FE) remains largely unknown. This study aimed to investigate the alteration in the range of motion (ROM), compressive force, shear force, and neutral zone size (NZ) in a lumbar functional spinal unit (FSU), caused by the deviated COR in different directions during FE. MATERIAL AND METHODS Twelve human cadaveric lumbar FSUs (6 for L2-L3, 6 for L4-L5) were tested in a 6-degree-of-freedom servo-hydraulic load frame. These FSUs were firstly applied a 7.5 Nm pure moment to perform FE to obtain their natural COR during FE. Subsequently, they were subjected to FE around 9 established deviated CORs with 6 Nm cyclical loading. RESULTS It was found that the ROM and NZ increased significantly when the COR moved from the superior plane to the inferior plane for the L2-L3 unit and when the COR located in the superior plane compared with the inferior plane for the L4-L5 unit. The compressive forces for both FSUs demonstrated significant changes caused by COR shift in the same horizontal plane, while the shear forces demonstrated significant changes caused by COR shift in the same vertical plane. CONCLUSIONS The ROM, NZ, and shear force of FSU are sensitive to the vertical COR shift, while the compressive force of FSU is highly sensitive to the horizontal COR shift. Additionally, the kinematics and kinetics of the L2-L3 unit are more sensitive to COR location than those of the L4-L5 unit.