Failure mechanisms of the Li(Ni0.6Co0.2Mn0.2)O2-Li4Ti5O12 lithium-ion batteries in long-time high-rate cycle.

With the ever-growing widespread use of lithium-ion batteries in heavy machinery and daily life, the demand for improved longevity and high-rate performance is escalating. While Li4Ti5O12 (LTO) batteries excel in safety and cycling performance, their full potential for long-term, high-rate cycling still yet remains unrealized. In this paper, we present an analysis of a pouch battery with an LTO anode system that was cycled for an extended period at high rates. We compared the performance changes and internal component properties between fresh and cycled batteries. Our results reveal that, after tens of thousands of high-rate cycles, microcracks emerged on the cathode electrode material (NCM622) particles of the battery, whereas the LTO remained largely unchanged. Additionally, we observed significant electrolyte reduction, characterized the separator surface, and measured its properties. Our findings indicate that the electrolyte reactions are the primary cause of battery failure, leading to capacity fading and impedance increase. This research provides valuable insights into the failure mechanisms of lithium-ion batteries at high rates, thus contributing to the improvement of high-rate lithium-ion batteries.

Development of a therapeutic monoclonal antibody against circulating adipocyte fatty acid binding protein to treat ischaemic stroke.

BACKGROUND AND PURPOSE: Adipocyte fatty acid-binding protein (A-FABP) exacerbates cerebral ischaemia injury by disrupting the blood-brain barrier (BBB) through inducing expression of MMP-9. Circulating A-FABP levels positively correlate with infarct size in stroke patients. We hypothesized that targeting circulating A-FABP by a neutralizing antibody would alleviate ischaemic stroke outcome. EXPERIMENTAL APPROACH: Monoclonal antibodies (mAbs) against A-FABP were generated using mouse hybridoma techniques. Binding affinities of a generated mAb named 6H2 towards various FABPs were determined using Biacore. Molecular docking studies were performed to characterize the 6H2-A-FABP complex structure and epitope. The therapeutic potential and safety of 6H2 were evaluated in mice with transient middle cerebral artery occlusion (MCAO) and healthy mice, respectively. KEY RESULTS: Replenishment of recombinant A-FABP exaggerated the stroke outcome in A-FABP-deficient mice. 6H2 exhibited nanomolar to picomolar affinities to human and mouse A-FABP, respectively, with minimal cross-reactivities with heart and epidermal FABPs. 6H2 effectively neutralized JNK/c-Jun activation elicited by A-FABP and reduced MMP-9 production in macrophages. Molecular docking suggested that 6H2 interacts with the "lid" of the fatty acid binding pocket of A-FABP, thus likely hindering the binding of its substrates. In mice with transient MCAO, 6H2 significantly attenuated BBB disruption, cerebral oedema, infarction, neurological deficits, and decreased mortality associated with reduced cytokine and MMP-9 production. Chronic 6H2 treatment showed no obvious adverse effects in healthy mice. CONCLUSION AND IMPLICATIONS: These results establish circulating A-FABP as a viable therapeutic target for ischaemic stroke, and provide a highly promising antibody drug candidate with high affinity and specificity.

Integrated transcriptomic and proteomic profiling reveals the key molecular signatures of brain endothelial reperfusion injury.

BACKGROUND: Reperfusion therapy after ischemic stroke often causes brain microvascular injury. However, the underlying mechanisms are unclear. METHODS: Transcriptomic and proteomic analyses were performed on human cerebral microvascular endothelial cells following oxygen-glucose deprivation (OGD) or OGD plus recovery (OGD/R) to identify molecules and signaling pathways dysregulated by reperfusion. Major findings were further validated in a mouse model of cerebral ischemia and reperfusion. RESULTS: Transcriptomic analysis identified 390 differentially expressed genes (DEGs) between the OGD/R and OGD group. Pathway analysis indicated that these genes were mostly associated with inflammation, including the TNF signaling pathway, TGF-ß signaling pathway, cytokine-cytokine receptor interaction, NOD-like receptor signaling pathway, and NF-κB signaling pathway. Proteomic analysis identified 201 differentially expressed proteins (DEPs), which were primarily associated with extracellular matrix destruction and remodeling, impairment of endothelial transport function, and inflammatory responses. Six genes (DUSP1, JUNB, NFKBIA, NR4A1, SERPINE1, and THBS1) were upregulated by OGD/R at both the mRNA and protein levels. In mice with cerebral ischemia and reperfusion, brain TNF signaling pathway was activated by reperfusion, and inhibiting TNF-α with adalimumab significantly attenuated reperfusion-induced brain endothelial inflammation. In addition, the protein level of THBS1 was substantially upregulated upon reperfusion in brain endothelial cells and the peri-endothelial area in mice receiving cerebral ischemia. CONCLUSION: Our study reveals the key molecular signatures of brain endothelial reperfusion injury and provides potential therapeutic targets for the treatment of brain microvascular injury after reperfusion therapy in ischemic stroke.

Levofloxacin alleviates blood-brain barrier disruption following cerebral ischemia and reperfusion via directly inhibiting A-FABP.

Reperfusion therapy is currently the most effective treatment for acute ischemic stroke, but often results in secondary brain injury. Adipocyte fatty acid-binding protein (A-FABP, FABP4, or aP2) was shown to critically mediate cerebral ischemia/reperfusion (I/R) injury by exacerbating blood-brain barrier (BBB) disruption. However, no A-FABP inhibitors have been approved for clinical use due to safety issues. Here, we identified the therapeutic effect of levofloxacin, a widely used antibiotic displaying A-FABP inhibitory activity in vitro, on cerebral I/R injury and determined its target specificity and action mechanism in vivo. Using molecular docking and site-directed mutagenesis, we showed that levofloxacin inhibited A-FABP activity through interacting with the amino acid residue Asp76, Gln95, Arg126 of A-FABP. Accordingly, levofloxacin significantly inhibited A-FABP-induced JNK phosphorylation and expressions of proinflammatory factors and matrix metalloproteinase 9 (MMP-9) in mouse primary macrophages. In wild-type mice with transient middle cerebral artery occlusion, levofloxacin substantially mitigated BBB disruption and neuroinflammation, leading to reduced cerebral infarction, alleviated neurological outcomes, and improved survival. Mechanistically, levofloxacin decreased MMP-9 expression and activity, and thus reduced degradation of extracellular matrix and endothelial tight junction proteins. Importantly, the BBB- and neuro-protective effects of levofloxacin were abolished in A-FABP or MMP-9 knockout mice, suggesting that the therapeutic effects of levofloxacin highly depended on specific targeting of the A-FABP-MMP-9 axis. Overall, our study demonstrates that levofloxacin alleviates A-FABP-induced BBB disruption and neural tissue injury following cerebral I/R, and unveils its therapeutic potential for the treatment of ischemic stroke.

Integrative multi-omic profiling of adult mouse brain endothelial cells and potential implications in Alzheimer's disease.

The blood-brain barrier (BBB) is primarily manifested by a variety of physiological properties of brain endothelial cells (ECs), but the molecular foundation for these properties remains incompletely clear. Here, we generate a comprehensive molecular atlas of adult brain ECs using acutely purified mouse ECs and integrated multi-omics. Using RNA sequencing (RNA-seq) and proteomics, we identify the transcripts and proteins selectively enriched in brain ECs and demonstrate that they are partially correlated. Using single-cell RNA-seq, we dissect the molecular basis of functional heterogeneity of brain ECs. Using integrative epigenomics and transcriptomics, we determine that TCF/LEF, SOX, and ETS families are top-ranked transcription factors regulating the BBB. We then validate the identified brain-EC-enriched proteins and transcription factors in normal mouse and human brain tissue and assess their expression changes in mice with Alzheimer's disease. Overall, we present a valuable resource with broad implications for regulation of the BBB and treatment of neurological disorders.

Discovery of Cobimetinib as a novel A-FABP inhibitor using machine learning and molecular docking-based virtual screening.

Adipocyte fatty acid-binding protein (A-FABP, also called FABP4, aP2) is an adipokine identified as a critical regulator of metabolic function due to its dual functions of fatty acid transport and pro-inflammation. Because of the high therapeutic potential of A-FABP inhibition for the treatment of metabolic diseases and related vascular complications, numerous inhibitors have been developed against A-FABP. However, none of these inhibitors have been approved for use in patients due to severe side effects. Here, we used a virtual screening (VS) strategy to identify potential inhibitors of A-FABP in the latest FDA-approved drug library (∼2600 compounds), aiming to explore the existing drugs with proven safety profiles. We firstly combined ligand-based machine learning and structure-based molecular docking to develop a screening pipeline for identifying A-FABP inhibitors. The screening of FDA-approved drugs identified four compounds (Cobimetinib, Larotrectinib, Pantoprazole, and Vildagliptin) with the highest scores, whose inhibitory effects on A-FABP were further assessed in cellular assays. Among the selected compounds, Cobimetinib significantly inhibited the activation of the JNK/c-Jun signaling pathway by A-FABP in mouse macrophages without causing obvious cytotoxicity. In summary, we present an integrated VS pipeline for A-FABP inhibitor screening, and identified Cobimetinib as a novel A-FABP inhibitor that may be repurposed for the treatment of metabolic diseases and associated vascular complications.

The tissue origin of human mesenchymal stem cells dictates their therapeutic efficacy on glucose and lipid metabolic disorders in type II diabetic mice.

BACKGROUND: The therapeutic efficacy of mesenchymal stem cells (MSCs) of different tissue origins on metabolic disorders can be varied in many ways but remains poorly defined. Here we report a comprehensive comparison of human MSCs derived from umbilical cord Wharton's jelly (UC-MSCs), dental pulp (PU-MSCs), and adipose tissue (AD-MSCs) on the treatment of glucose and lipid metabolic disorders in type II diabetic mice. METHODS: Fourteen-to-fifteen-week-old male C57BL/6 db/db mice were intravenously administered with human UC-MSCs, PU-MSCs, and AD-MSCs at various doses or vehicle control once every 2 weeks for 6 weeks. Metformin (MET) was given orally to animals in a separate group once a day at weeks 4 to 6 as a positive control. Body weight, blood glucose, and insulin levels were measured every week. Glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were performed every 2 weeks. All the animals were sacrificed at week 6 and the blood and liver tissues were collected for biochemical and histological examinations. RESULTS: UC-MSCs showed the strongest efficacy in reducing fasting glucose levels, increasing fasting insulin levels, and improving GTT and ITT in a dose-dependent manner, whereas PU-MSCs showed an intermediate efficacy and AD-MSCs showed the least efficacy on these parameters. Moreover, UC-MSCs also reduced the serum low-density lipoprotein cholesterol (LDL-C) levels with the most prominent potency and AD-MSCs had only very weak effect on LDL-C. In contrast, AD-MSCs substantially reduced the lipid content and histological lesion of liver and accompanying biomarkers of liver injury such as serum aspartate transaminase (AST) and alanine aminotransferase (ALT) levels, whereas UC-MSCs and PU-MSCs displayed no or modest effects on these parameters, respectively. CONCLUSIONS: Taken together, our results demonstrated that MSCs of different tissue origins can confer substantially different therapeutic efficacy in ameliorating glucose and lipid metabolic disorders in type II diabetes. MSCs with different therapeutic characteristics could be selected according to the purpose of the treatment in the future clinical practice.

The Role of Immune Cells in Post-Stroke Angiogenesis and Neuronal Remodeling: The Known and the Unknown.

Following a cerebral ischemic event, substantial alterations in both cellular and molecular activities occur due to ischemia-induced cerebral pathology. Mounting evidence indicates that the robust recruitment of immune cells plays a central role in the acute stage of stroke. Infiltrating peripheral immune cells and resident microglia mediate neuronal cell death and blood-brain barrier disruption by releasing inflammation-associated molecules. Nevertheless, profound immunological effects in the context of the subacute and chronic recovery phase of stroke have received little attention. Early attempts to curtail the infiltration of immune cells were effective in mitigating brain injury in experimental stroke studies but failed to exert beneficial effects in clinical trials. Neural tissue damage repair processes include angiogenesis, neurogenesis, and synaptic remodeling, etc. Post-stroke inflammatory cells can adopt divergent phenotypes that influence the aforementioned biological processes in both endothelial and neural stem cells by either alleviating acute inflammatory responses or secreting a variety of growth factors, which are substantially involved in the process of angiogenesis and neurogenesis. To better understand the multiple roles of immune cells in neural tissue repair processes post stroke, we review what is known and unknown regarding the role of immune cells in angiogenesis, neurogenesis, and neuronal remodeling. A comprehensive understanding of these inflammatory mechanisms may help identify potential targets for the development of novel immunoregulatory therapeutic strategies that ameliorate complications and improve functional rehabilitation after stroke.

Evaluation and Identification of the Neuroprotective Compounds of Xiaoxuming Decoction by Machine Learning: A Novel Mode to Explore the Combination Rules in Traditional Chinese Medicine Prescription.

Xiaoxuming decoction (XXMD), a classic traditional Chinese medicine (TCM) prescription, has been used as a therapeutic in the treatment of stroke in clinical practice for over 1200 years. However, the pharmacological mechanisms of XXMD have not yet been elucidated. The purpose of this study was to develop neuroprotective models for identifying neuroprotective compounds in XXMD against hypoxia-induced and H2O2-induced brain cell damage. In this study, a phenotype-based classification method was designed by machine learning to identify neuroprotective compounds and to clarify the compatibility of XXMD components. Four different single classifiers (AB, kNN, CT, and RF) and molecular fingerprint descriptors were used to construct stacked naïve Bayesian models. Among them, the RF algorithm had a better performance with an average MCC value of 0.725±0.014 and 0.774±0.042 from 5-fold cross-validation and test set, respectively. The probability values calculated by four models were then integrated into a stacked Bayesian model. In total, two optimal models, s-NB-1-LPFP6 and s-NB-2-LPFP6, were obtained. The two validated optimal models revealed Matthews correlation coefficients (MCC) of 0.968 and 0.993 for 5-fold cross-validation and of 0.874 and 0.959 for the test set, respectively. Furthermore, the two models were used for virtual screening experiments to identify neuroprotective compounds in XXMD. Ten representative compounds with potential therapeutic effects against the two phenotypes were selected for further cell-based assays. Among the selected compounds, two compounds significantly inhibited H2O2-induced and Na2S2O4-induced neurotoxicity simultaneously. Together, our findings suggested that machine learning algorithms such as combination Bayesian models were feasible to predict neuroprotective compounds and to preliminarily demonstrate the pharmacological mechanisms of TCM.

Baicalein administered in the subacute phase ameliorates ischemia-reperfusion-induced brain injury by reducing neuroinflammation and neuronal damage.

Ischemic stroke is a cerebrovascular disease with high morbidity, high mortality, and high disability, representing a serious threat to human life and health. Clinically, the extensive injury caused by ischemic stroke results from ischemia-reperfusion (I/R) injury thrombolytic treatment. However, there are few reports on the use of medications in the subacute stage of cerebral I/R. Baicalein (5,6,7-trihydroxyflavone) is a biologically active ingredient extracted from the root of Scutellaria baicalensis Georgi. In the present study, we investigated the therapeutic effect of baicalein administered in the subacute phase of cerebral I/R injury in a rat model of ischemia induced by occlusion of the middle cerebral artery (MCA). Rats were treated daily with baicalein (200 mg/kg, i.g.) in the subacute phase (24 h after reperfusion) for 7 days. The results showed that baicalein significantly reduced neurobehavioral deficits and decreased brain infarct volume from 18.99% to 7.41%. Immunofluorescence analysis of the ischemic penumbra showed that baicalein significantly reduced expression of the M1 marker, cluster of differentiation (CD) 16 and CD86, and increased expression of the M2 marker, CD 163 and CD206, indicating that baicalein inhibited M1 transformation and promoted M2 transformation of microglia/macrophage to inhibit neuroinflammation. Moreover, baicalein suppressed NF-κB signaling by reducing IκBα phosphorylation and nuclear translocation of NF-κB/p65, which decreased the release of the pro-inflammatory factors IL-6, IL-18, and TNF-α. In addition, baicalein reduced phosphorylation of JNK, ERK and p38, which are involved modulation of microglia/macrophage M1/M2 polarization. Western blot analysis of apoptosis- and autophagy-related proteins showed that baicalein increased the Bcl-2/Bax ratio and reduced caspase-3 expression to decrease neuronal apoptosis and ameliorate neuronal loss. Baicalein also decreased the LC3-II/LC3-I ratio and promoted phosphorylation of the PI3K/Akt/mTOR signaling pathway which implied inhibition of autophagy. These observations suggest that baicalein exerts neuroprotective effects by reducing neuroinflammation, apoptosis and autophagy, and protects against cerebral I/R injury in the subacute phase in vivo.

Evaluation of Novel Dual Acetyl- and Butyrylcholinesterase Inhibitors as Potential Anti-Alzheimer's Disease Agents Using Pharmacophore, 3D-QSAR, and Molecular Docking Approaches.

DL0410, containing biphenyl and piperidine skeletons, was identified as an acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitor through high-throughput screening assays, and further studies affirmed its efficacy and safety for Alzheimer's disease treatment. In our study, a series of novel DL0410 derivatives were evaluated for inhibitory activities towards AChE and BuChE. Among these derivatives, compounds 6-1 and 7-6 showed stronger AChE and BuChE inhibitory activities than DL0410. Then, pharmacophore modeling and three-dimensional quantitative structure activity relationship (3D-QSAR) models were performed. The R² of AChE and BuChE 3D-QSAR models for training set were found to be 0.925 and 0.883, while that of the test set were 0.850 and 0.881, respectively. Next, molecular docking methods were utilized to explore the putative binding modes. Compounds 6-1 and 7-6 could interact with the amino acid residues in the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE/BuChE, which was similar with DL0410. Kinetics studies also suggested that the three compounds were all mixed-types of inhibitors. In addition, compound 6-1 showed better absorption and blood brain barrier permeability. These studies provide better insight into the inhibitory behaviors of DL0410 derivatives, which is beneficial for rational design of AChE and BuChE inhibitors in the future.

[Spatial distribution and contamination evaluation of heavy metals in the intertidal surface sediments of Eastern Chongming].

Using the ArcGIS geostatistical analysis module, this work investigated the spatial distribution pattern of heavy metals (Cu, Pb, Zn, Cr, Cd) and their deposition fluxes in the intertidal surface sediments of Eastern Chongming based on the analysis of grain size, heavy metal concentrations and organic carbon content. The spatial interpolation (Kriging) was performed to estimate the deposition fluxes, and the contamination status of heavy metals was evaluated using geoaccumulation index and potential ecological risk index. The results showed that the average contents of Cu, Pb, Zn, Cr and Cd were 42, 27, 69, 71 and 0.23 microg x g(-1), respectively, all of which exceeded the background value in the Shanghai tidal flat. The contents of heavy metals showed a landward as well as northward increasing trend due to the influences of sediment grain size and organic carbon content. The annual deposition of Cu, Pb, Zn, Cr and Cd in Eastern Chongming were 187, 121, 395, 312 and 1.04 t, respectively; the total deposition flux of these heavy metals was 11 g x (m2 x a)-1. Although the overall contamination level of heavy metals in Eastern Chongming was relatively low, Cd, Pb and Cu had a potential pollution threat to the sediment environment.

Estimation of plant water content by spectral absorption features centered at 1,450 nm and 1,940 nm regions.

Vegetation water content could possibly provide widespread utility in agriculture, forestry and hydrology. In this article, three species leaves were measured radiometrically in order to determine a relationship between leaf water status and the spectral feature centered at 1,450 and 1,940 nm where there are strong water absorptions. The first step of our research is to measure leaf spectra with a FieldSpec-FR. After the spectral analysis using the continuum removal technique, the spectral absorption feature parameters: absorption band depth (D (1450), D (1940)), the normalized band depth of absorption in 1,450 and 1,940 nm (BNA(1450), BNA(1940)), the ratio of the two reflectance of continuum line (R (1450i )/R (1940i )), the ratio of the two band depth (D (1450)/D (1940)) and the ratio of the two absorption areas (A (1450)/A (1940)) in the two wavebands were extracted from each leaf spectrum. The fuel moisture content (FMC), specific leaf weight (SLW), equivalent water thickness (EWT) were measured for each leaf sample. A correlation analysis was conducted between the spectral absorption feature parameters and corresponding FMC, SLW and EWT. In addition, some existing indices for assessing water status such as WI (water index), WI/NDVI (water index/normalized difference vegetation index), MSI (moisture stress index), NDWI (normalized difference water index)were calculated and the correlation between them and water status were analyzed too. The results by comparing the correlations indicated that the spectral absorption feature indices we proposed were better. The indexes BNA(1940), D (1450)/D (1940), and A (1450)/A (1940) were well correlated with FMC, and the correlation between the indexes D (1450,) D (1940), R (1450i )/R (1940i ) and EWT were strong. The index A (1450)/A (1940) was tested to be a good indictor for evaluating plant water content, because there was strongest positive correlation between it and FMC than other indices.