Programmable Ferroelectricity in Hf0.5Zr0.5O2 Enabled by Oxygen Defect Engineering.

Ferroelectricity, especially the Si-compatible type recently observed in hafnia-based materials, is technologically useful for modern memory and logic applications, but it is challenging to differentiate intrinsic ferroelectric polarization from the polar phase and oxygen vacancy. Here, we report electrically controllable ferroelectricity in a Hf0.5Zr0.5O2-based heterostructure with Sr-doped LaMnO3, a mixed ionic-electronic conductor, as an electrode. Electrically reversible extraction and insertion of an oxygen vacancy into Hf0.5Zr0.5O2 are macroscopically characterized and atomically imaged in situ. Utilizing this reversible process, we achieved multilevel polarization states modulated by the electric field. Our study demonstrates the usefulness of the mixed conductor to repair, create, manipulate, and utilize advanced ferroelectric functionality. Furthermore, the programmed ferroelectric heterostructures with Si-compatible doped hafnia are desirable for the development of future ferroelectric electronics.

Susceptibility to Hepatotoxic Drug-Induced Liver Injury Increased After Traumatic Brain Injury in Mice.

The early stages of brain injury can induce acute liver injury, which can be recovered in the short term. Continued medication treatment during hospitalization for brain injury alleviates the prognosis and contributes to a high incidence of drug-induced liver injury (DILI). We hypothesize that there is an interaction between changes in the hepatic environment after brain injury and liver injury produced by intensive drug administration, leading to an upregulation of the organism's sensitivity to DILI. In this study, mice models of TBI were established by controlled cortical impact (CCI) and models of DILI were constructed by acetaminophen (APAP). All mice were divided into four groups: Sham, TBI, APAP, and TBI+APAP, and related liver injury indicators in liver and serum were detected by Western blot, Quantitative real-time PCR (qRT-PCR), and immunohistochemical staining. The results suggested that liver injury induced in the early stages of brain injury recovered in 3 days, but this state could still significantly aggravate DILI, represented by higher liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), oxidative stress (increase in malondialdehyde [MDA] concentration and deregulation of glutathione [GSH] and superoxide dismutase [SOD] activities), inflammatory response (activation of the HMGB1/TLR4/NF-κB signaling pathway, and increased messenger RNA [mRNA] and protein levels of pro-inflammatory cytokines including tumor necrosis factor alpha [TNF-α], interleukin [IL]-6, and IL-1ß), and apoptosis (TUNEL assay, upregulation of Bax protein and deregulation of Bcl-2 protein). In summary, our results suggested that TBI is a potential susceptibility factor for DILI and exacerbates DILI.

Landauer-QFLPS Model for Mixed Schottky-Ohmic Contact Two-Dimensional Transistors.

Two-dimensional material-based field-effect transistors (2DM-FETs) are playing a revolutionary role in electronic devices. However, before electronic design automation (EDA) for 2DM-FETs can be achieved, it remains necessary to determine how to incorporate contact transports into model. Reported methods compromise between physical intelligibility and model compactness due to the heterojunction nature. To address this, quasi-Fermi-level phase space theory (QFLPS) is generalized to incorporate contact transports using the Landauer formula. It turns out that the Landauer-QFLPS model effectively overcomes the issue of concern. The proposed new formula can describe 2DM-FETs with Schottky or Ohmic contacts with superior accuracy and efficiency over previous methods, especially when describing non-monotonic drain conductance characteristics. A three-bit threshold inverter quantizer (TIQ) circuit is fabricated using ambipolar black phosphorus and it is demonstrated that the model accurately predicts circuit performance. The model could be very effective and valuable in the development of 2DM-FET-based integrated circuits.

Advances in Genetic Tools and Their Application in Streptococcus thermophilus.

Streptococcus thermophilus is a traditional starter. Nowadays, key aspects of S. thermophilus physiology have been revealed concerning the phenotypic traits relevant for industrial applications, including sugar metabolism, protein hydrolysis, and the production of important metabolites that affect the sensory properties of fermented foods as well as the original cooperation with Lactobacillus delbrueckii subsp. bulgaricus. Moreover, significant advances have been made in the synthetic biology toolbox of S. thermophilus based on technological advances in the genome and its sequencing and synthesis. In this review, we discuss the recently developed toolbox for S. thermophilus, including gene expression toolsets (promoters, terminators, plasmids, etc.) and genome editing tools. It can be used for both functionalized foods and therapeutic molecules for consumers. The availability of new molecular tools, including the genome editing toolbox, has facilitated the engineering of physiological studies of S. thermophilus and the generation of strains with improved technical and functional characteristics.

MicroRNA alteration in cerebrospinal fluid from comatose patients with traumatic brain injury after right median nerve stimulation.

Electrical stimulation of the right median nerve can aid coma arousal after traumatic brain injury (TBI). This study aimed to confirm the efficacy further and explore possible mechanisms of right median nerve electrical stimulation (RMNS). Five comatose patients after severe TBI from May to September 2020 in the Tianjin Medical University General Hospital received RMNS for 2 weeks besides standard management. After the 2-week treatment, the mean Glasgow Coma Scale (GCS) and neurophysiological examination were used. We then investigated the alterations in microRNA (miRNA) expression in cerebrospinal fluid (CSF) by high-throughput whole transcriptome sequencing, analyzed the data by Gene Ontology (GO) and pathway analysis, and constructed the miRNA-target gene network. Patient awareness and brain function showed a more rapid increase after treatment. We also found 38 differently expressed miRNAs, 34 of which were upregulated and 4 downregulated. GO analysis showed a relation of these differentially expressed miRNAs with neuronal growth, repair, and neural signal transmission. The most highly correlated pathways were primarily associated with the tumor necrosis factor (TNF) signaling pathway and dopaminergic synapse. The application of RMNS effectively promoted early awakening in comatose patients with severe TBI. Moreover, differentially expressed miRNAs might reduce neuronal apoptosis and increase dopamine levels by regulating target gene expression, thus participating in the specific biological process after arousal therapy. Our study provided novel targets for further research on the molecular mechanisms of RMNS arousal treatment and a new way to treat neurotraumatic diseases.

Alterations of microRNAs expression profiles in small extracellular vesicle after traumatic brain injury in mice.

Traumatic brain injury (TBI) is one of the leading causes of mortality and morbidity worldwide. Tools available for diagnosis and therapy are limited. Small extracellular vesicle (sEV) microRNAs (miRNAs) play an important role in TBI disease progression. This study aimed to investigate the alterations in sEV miRNAs expression in the mouse brain extracellular space after TBI. Twenty-four C57BL/6J mice were randomly divided into two groups (12/group). The TBI group was subjected to all surgical procedures and fluid percussion injury (FPI). The sham group only underwent surgery. Brain specimens were collected 3 h after TBI/sham. The brain sEV were isolated. Differentially expressed miRNAs were identified. A total of 50 miRNAs were observed to be differentially expressed (fold change ≥1.5 and P<0.05) after TBI, including 5 upregulated and 45 downregulated. The major enriched Gene Ontology terms were metabolic processes, cell, intracellular, organelle, cytoplasm, axon, binding, protein kinase activity, protein binding, and protein dimerization activity. The KEGG pathway analysis predicted that the pathways affected by the variation of miRNAs in sEVs after TBI included the Wnt signaling pathway and NF-κB signaling pathway. The changes in five miRNAs were confirmed by qRT-PCR. In conclusion, this study demonstrated the differential expression of a series of miRNAs in brain sEV after TBI, which might be correlated with post-TBI physiological and pathological processes. The findings might also provide novel targets for further investigating the molecular mechanisms underlying TBI and potential therapeutic interventions.

In vivo visualization of murine melanoma cells B16-derived exosomes through magnetic resonance imaging.

BACKGROUND: Numerous studies demonstrated that exosomes play a powerful role in mediating intercellular communication to induce a pro-tumoral environment to promote tumor progression, including pre-metastatic niche formation and metastasis. Noninvasive imaging could determine the in vivo kinetics of exosomes in real time to provide better understanding of the mechanisms of the tumor formation, progression and metastasis. Magnetic resonance imaging (MRI) is an ideal technique which provides excellent anatomical resolution, intrinsic soft tissue contrast, unlimited penetration depth and no radiation exposure. METHODS: A fusion protein composed of ferritin heavy chain (FTH1) and lactadherin was designed for visualizing exosomes through MRI. FTH1 was served as MRI reporter protein and lactadherin is a membrane-associated protein that is distributed on exosome surface. The characterizations of labeled exosomes were validated through transmission electron microscopy, western blot, nanoparticle tracking analysis and finally visualized in vitro and in vivo through MRI. RESULTS: MR imaging showed that the labeled exosomes are able to be visualized in vitro and in vivo. Verification of the characterizations of exosomes observed no significant difference between labeled and unlabeled exosomes. CONCLUSION: The proposed FTH1 labeling method was useful for visualizing exosomes through MRI. GENERAL SIGNIFICANCE: The present study first reported a novel self-label method for imaging labeled exosomes of tumor cells in vivo through MR with cell endogenous MRI reporter protein. It may be further used as a tool to enhance understanding the role of exosomes in various pathophysiological conditions.

Flexible Quasi-van der Waals Ferroelectric Hafnium-Based Oxide for Integrated High-Performance Nonvolatile Memory.

Ferroelectric memories with ultralow-power-consumption are attracting a great deal of interest with the ever-increasing demand for information storage in wearable electronics. However, sufficient scalability, semiconducting compatibility, and robust flexibility of the ferroelectric memories remain great challenges, e.g., owing to Pb-containing materials, oxide electrode, and limited thermal stability. Here, high-performance flexible nonvolatile memories based on ferroelectric Hf0.5Zr0.5O2 (HZO) via quasi-van der Waals heteroepitaxy are reported. The flexible ferroelectric HZO exhibits not only high remanent polarization up to 32.6 µC cm-2 without a wake-up effect during cycling, but also remarkably robust mechanical properties, degradation-free retention, and endurance performance under a series of bent deformations and cycling tests. Intriguingly, using HZO as a gate, flexible ferroelectric thin-film transistors with a low operating voltage of ±3 V, high on/off ratio of 6.5 × 105, and a small subthreshold slope of about 100 mV dec-1, which outperform reported flexible ferroelectric transistors, are demonstrated. The results make ferroelectric HZO a promising candidate for the next-generation of wearable, low-power, and nonvolatile memories with manufacturability and scalability.

In vivo quantification of mandibular bone remodeling and vascular changes in a Wistar rat model: A novel HR-MRI and micro-CT fusion technique.

PURPOSE: This study was performed to introduce an in vivo hybrid multimodality technique involving the coregistration of micro-computed tomography (micro-CT) and high-resolution magnetic resonance imaging (HR-MRI) to concomitantly visualize and quantify mineralization and vascularization at follow-up in a rat model. MATERIALS AND METHODS: Three adult female rats were randomly assigned as test subjects, with 1 rat serving as a control subject. For 20 weeks, the test rats received a weekly intravenous injection of 30 µg/kg zoledronic acid, and the control rat was administered a similar dose of normal saline. Bilateral extraction of the lower first and second molars was performed after 10 weeks. All rats were scanned once every 4 weeks with both micro-CT and HR-MRI. Micro-CT and HR-MRI images were registered and fused in the same 3-dimensional region to quantify blood flow velocity and trabecular bone thickness at T0 (baseline), T4 (4 weeks), T8 (8 weeks), T12 (12 weeks), T16 (16 weeks), and T20 (20 weeks). Histological assessment was the gold standard with which the findings were compared. RESULTS: The histomorphometric images at T20 aligned with the HR-MRI findings, with both test and control rats demonstrating reduced trabecular bone vasculature and blood vessel density. The micro-CT findings were also consistent with the histomorphometric changes, which revealed that the test rats had thicker trabecular bone and smaller marrow spaces than the control rat. CONCLUSION: The combination of micro-CT and HR-MRI may be considered a powerful non-invasive novel technique for the longitudinal quantification of localized mineralization and vascularization.

Apoptosis-Promoting Effects on A375 Human Melanoma Cells Induced by Exposure to 35.2-GHz Millimeter Wave.

Malignant tumors pose a major problem in the medical field. Millimeter wave (MMW) exposure have potential apoptosis-promoting effects on several types of tumors. Considering that the penetration depth of millimeter wave is usually several millimeters, we study the apoptosis-promoting effects of millimeter wave exposure on A375 human melanoma tumor cells in vitro, and this topic has not been explored in the previous literature. In this study, we use the A375 human melanoma cell line as an experimental model exposed to 35.2 GHz millimeter wave in vitro to determine any positive effect and further explore the underlying mechanisms. In this study, 2 groups namely, exposed and sham groups, were set. The exposed groups included 4 exposure time periods of 15, 30, 60, and 90 minutes. The cells in the sham group did not receive millimeter wave exposure. After millimeter wave exposure, the A375 cells in the exposed and sham groups were collected for further experimental procedures. The cell viability after exposure was determined using a cell counting kit, and the apoptosis of A375 cells was assessed by Annexin V/propidium iodide. Changes in the expression of apoptosis-related proteins, including cleaved-caspase-3, and -8, were examined by Western blot. We observed that the millimeter wave exposure could inhibit the viability and induce apoptosis in A375 cells, and the expression of cleaved caspase-3 and -8 were upregulated (P < .05). The results indicated that the millimeter wave at 35.2 GHz exerted apoptosis-promoting effects on the A375 cells via a pathway by activating of caspase-8 and -3.

Visualization of exosomes from mesenchymal stem cells in vivo by magnetic resonance imaging.

BACKGROUND AND PURPOSE: We develop a method of imaging exosomes in vivo according to the vital role of exosomes in intercellular communication. This study aims to design a new label method that allows the visualization of labeled exosomes with magnetic resonance imaging (MRI). METHODS: We designed a fusion protein consisting of two parts, namely, ferritin heavy chain (FTH1) and a truncated lactadherin. FTH1 is used as an MRI reporter. Lactadherin is a trans-membrane protein. The lactadherin protein are mostly located on the outer surface of exosomes. We replaced the outer membrane part of lactadherin with FTH1, infected mesenchymal stem cells with lentivirus carrying the fusion protein, and isolated exosomes from the labeled cells by ultracentrifugation. Labeled exosomes were validated by transmission electron microscopy images, Western blot, nanosight particle tracking, and visualized in vitro and in vivo by MRI. RESULTS: FTH1 expression would suppress mesenchymal stem cell proliferation, whereas the characterization of labeled exosomes remains comparable with unlabeled exosomes. MR imaging shows that exosomes labeled with FTH1 can be visualized in vitro and in vivo. CONCLUSION: This innovative reporter-imaging approach to track and visualize exosomes with MRI can be utilized as a tool for the study of the role of exosomes under different conditions.

[Millimeter wave exposure induces apoptosis in human melanoma A375 cells in vitro].

OBJECTIVE: To investigate the effects of millimeter wave (MMW) exposure on apoptosis of human melanoma A375 cells and explore the mechanisms. METHODS: Through electromagnetic field calculation we simulated MMW exposure in cells and calculated the specific absorption rate (SAR). The optimal irradiation parameters were determined according to the uniformity and intensity of the SAR. A375 cells were then exposed to MMV for 15, 30, 60, or 90 min, with or without pretreatment with the caspase-3 inhibitor AC-DEVD-fmk (10 µmol/L) for 1 h at 90 min before the exposure. CCK-8 assay was used to assess the changes in the viability and Annexin-V/ PI staining was used to detect the apoptosis of the cells following the exposures; Western blotting was used to detect the expression of caspase-3 in the cells. RESULTS: The results of electromagnetic field calculation showed that for optimal MMV exposure, the incident field needed to be perpendicular to the bottom of the plastic Petri dish with the antenna placed below the dish. CCk-8 assay showed that MMW exposure significantly inhibited the cell viability in a time-dependent manner (P < 0.05); exposures for 15, 30, 60, and 90 min all resulted in significantly increased apoptosis of the cells (P < 0.05). The cells with MMW exposure showed significantly increased expression of caspase-3. The inhibitory effect of MMW on the cell viability was antagonized significantly by pretreatment of the cells with AC-DEVD-fmk (P < 0.05), which increased the cell viability rate from (36.7±0.09)% to (59.8±0.06)% (P < 0.05). CONCLUSIONS: 35.2 GHz millimeter wave irradiation induces apoptosis in A375 cells by activating the caspase-3 protein.

Circular Ribonucleic Acid Expression Alteration in Exosomes from the Brain Extracellular Space after Traumatic Brain Injury in Mice.

Traumatic brain injury (TBI) has high morbidity and mortality rates. The mechanisms underlying TBI are unclear and may include the change in biological material in exosomes. Circular ribonucleic acids (circRNAs) are enriched and stable in exosomes, which can function as microRNA (miRNA) sponges to regulate gene expression levels. Therefore, we speculated that circRNAs in exosomes might play an important role in regulating gene expression after TBI and then regulate specific signaling pathways, which may protect the brain. We first isolated exosomes from the brain extracellular space in mice with TBI by digestion. We then investigated the alterations in circRNA expression in exosomes by high-throughput whole transcriptome sequencing, analyzed the data by gene ontology (GO) and pathway analysis, and constructed the circRNA-miRNA network. In this study, we identified 231 significantly and differentially expressed circRNAs, including 155 that were upregulated and 76 that were downregulated. GO analysis showed that these differentially expressed circRNAs might be related to the growth and repair of neurons, the development of the nervous system, and the transmission of nerve signals. The most highly correlated pathways that we identified were involved primarily with glutamatergic synapse and the cyclic guanosine monophosphate-protein kinase G signaling pathway. The circRNA-miRNA network predicted the potential roles of these differentially expressed circRNAs and the interaction of circRNAs with miRNAs. Our study broadens the horizon of research on gene regulation in exosomes from the brain extracellular space after TBI and provides novel targets for further research on both the molecular mechanisms of TBI and the potential intervention therapy targets.

Paraburkholderia caffeinitolerans sp. nov., a caffeine degrading species isolated from a tea plantation soil sample.

A Gram-stain negative, facultatively anaerobic, non-sporulating, non-motile and rod-shaped bacterium, designated CF3T, was isolated from a tea plantation soil sample and its taxonomic position was determined using polyphasic taxonomy. Strain CF3T displayed optimum growth at 25 °C, pH 5.0 and in the presence of 0-1 % NaCl. Comparative phylogenetic analysis of the 16S rRNA, recA and gyrB gene sequences showed that the isolate belongs to the genus Paraburkholderia, showing high levels of similarity with respect to Paraburkholderia oxyphila OX-01T (98.3, 95 and 93 %, respectively) and Paraburkholderia sacchari IPT101T (98.2, 95 and 95 %, respectively). The predominant ubiquinone was determined to be Q-8, and the polar lipids are phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, one unidentified amino-phospholipid, three unidentified amino-lipids and three unidentified polar lipids. The major fatty acids were found to be C16:0, C17:0 cyclo, summed feature 8 (C18:1 ω7c and/or C18:1 ω6c) and summed feature 3 (C16:1 ω7c and/or C16:1 ω6c). The DNA G+C content was found to be 63.8 mol% and the DNA-DNA relatedness values between strain CF3T and its two close relatives P. oxyphila OX-01T and P. sacchari IPT101T was 41 and 40 %, respectively. Based on phylogenetic analysis, phenotypic and genotypic data, it is concluded that the isolate represents a novel species of the genus Paraburkholderia, for which the name Paraburkholderia caffeinitolerans sp. nov. is proposed. The type strain is CF3T (= LMG 28688T = CGMCC 1.15105T).