Understanding the Neural Mechanisms of General Anesthesia from Interaction with Sleep-Wake State: A Decade of Discovery.

The development of cutting-edge techniques to study specific brain regions and neural circuits that regulate sleep-wake brain states and general anesthesia (GA), has increased our understanding of these states that exhibit similar neurophysiologic traits. This review summarizes current knowledge focusing on cell subtypes and neural circuits that control wakefulness, rapid eye movement (REM) sleep, non-REM sleep, and GA. We also review novel insights into their interactions and raise unresolved questions and challenges in this field. Comparisons of the overlapping neural substrates of sleep-wake and GA regulation will help us to understand sleep-wake transitions and how anesthetics cause reversible loss of consciousness. SIGNIFICANCE STATEMENT: General anesthesia (GA), sharing numerous neurophysiologic traits with the process of natural sleep, is administered to millions of surgical patients annually. In the past decade, studies exploring the neural mechanisms underlying sleep-wake and GA have advanced our understanding of their interactions and how anesthetics cause reversible loss of consciousness. Pharmacotherapies targeting the neural substrates associated with sleep-wake and GA regulations have significance for clinical practice in GA and sleep medicine.

Selective Activation of NAc D1R-VP/LH Circuits Promotes Reanimation From Sevoflurane Anesthesia in Mice.

BACKGROUND: Emerging evidence has uncovered a vital role of nucleus accumbens (NAc) neurons that express the dopamine D1 receptor (D1R) and its upstream neural circuit in general anesthesia (GA) regulation. However, the underlying downstream neural basis of the modulation of GA emergence by NAc D1R neurons remains unknown. In the present study, we explored the downstream neural mechanism of NAc D1R neurons in the modulation of emergence from sevoflurane GA. METHODS: We traced the axonal projections of NAc D1R neurons using a cell type-specific anterograde tracing method and immunohistochemical techniques in D1R-Cre mice. Optogenetic stimulations combined with electroencephalogram/electromyogram recordings and behavioral tests were used to determine the effects of optogenetic activation of the axonal terminals of NAc D1R neurons on sevoflurane emergence during sevoflurane-induced continuous, steady-state general anesthesia (CSSGA) or burst-suppression oscillations. RESULTS: Labeled efferent fibers of NAc D1R neurons were highly distributed in the ventral pallidum (VP), lateral hypothalamus (LH), and substantia nigra pars compacta. Optogenetic activation of the NAc D1R -VP circuit during CSSGA with sevoflurane induced cortical activation (mean ± standard deviation [SD]; delta power: prestimulation versus during stimulation, 48.7% ± 5.7% vs 35.1% ± 3.3%, P < .0001; beta power: 7.1% ± 2.7% vs 14.2% ± 3.3%, P = .0264) and behavioral emergence, and restored the righting reflex in 66.7% of ChR2 mice. Optogenetic stimulation of the NAc D1R -LH circuit also produced cortical activation (delta power: prestimulation versus during stimulation, 45.0% ± 6.5% vs 36.1% ± 4.6%, P = .0016) and behavioral emergence, and restored the righting reflex in 100% of the ChR2 mice during CSSGA with sevoflurane. Under a sevoflurane-induced burst-suppression state, NAc D1R -VP/LH circuit activation produced evidence of cortical activation (burst-suppression ratio [BSR]: NAc D1R -VP circuit, prestimulation versus during stimulation, 42.4% ± 4.0% vs 26.3% ± 6.0%, P = .0120; prestimulation versus poststimulation, 42.4% ± 4.0% vs 5.9% ± 5.6%, P = .0002; BSR: NAc D1R -LH circuit, prestimulation versus during stimulation, 33.3% ± 13.4% vs 5.1% ± 4.9%, P = .0177; prestimulation vs poststimulation, 33.3% ± 13.4% vs 3.2% ± 4.0%, P = .0105) and behavioral emergence. CONCLUSIONS: Both NAc D1R -VP and NAc D1R -LH circuits are sufficient to promote reanimation from sevoflurane GA by simultaneously inducing cortical and behavioral emergence.

Prevention of muscle atrophy in ICU patients without nerve injury by neuromuscular electrical stimulation: a randomized controlled study.

BACKGROUND: Extensive muscle atrophy is a common occurrence in orthopaedics patients who are bedridden or immobilized. The incidence is higher in intensive care unit (ICU) inpatients. There is still controversy about how to use neuromuscular electrical stimulation (NMES) in ICU patients. We aim to compare the effectiveness and safety of NMES to prevent muscle atrophy in intensive care unit (ICU) patients without nerve injury. METHODS: ICU patients without central and peripheral nerve injury were randomized into experimental group I (Exp I: active and passive activity training (APAT) + NMES treatment on the gastrocnemius and tibialis anterior muscle), experimental group II (Exp II: APAT + NMES treatment on gastrocnemius alone), and control group (Ctl: APAT alone). Changes in the strength of gastrocnemius, the ankle range of motion, and the muscle cross-section area of the lower leg were evaluated before and after the intervention. Also, changes in prothrombin time, lactic acid, and C-reactive protein were monitored during the treatment. RESULTS: The gastrocnemius muscle strength, ankle joint range of motion, and cross-sectional muscle area of the lower leg in the three groups showed a downward trend, indicating that the overall trend of muscle atrophy in ICU patients was irreversible. The decrease in gastrocnemius muscle strength in Exp I and Exp II was smaller than that in the control group (P < 0.05), but there was no difference between Exp I and Exp II. The decrease in active ankle range of motion and cross-sectional area of the lower leg Exp I and Exp II was smaller than that in the control group (P < 0.05), and the decrease in Exp I was smaller than that of Exp II (all P < 0.05). The curative effect in Exp I was better than in Exp II. There were no significant differences in the dynamic changes of prothrombin time, lactic acid, and C-reactive protein during the three groups (P > 0.05). CONCLUSION: In addition to early exercise training, NMES should be applied to prevent muscle atrophy for patients without nerve injury in ICU. Also, simultaneous NMES treatment on agonist/antagonist muscle can enhance the effect of preventing muscle atrophy. TRIAL REGISTRATION: This study was prospectively registered in China Clinical Trial Registry ( www.chictr.org.cn ) on 16/05/2020 as ChiCTR2000032950.

Establishment and application of a CRISPR-Cas12a assisted genome-editing system in Zymomonas mobilis.

BACKGROUND: Efficient and convenient genome-editing toolkits can expedite genomic research and strain improvement for desirable phenotypes. Zymomonas mobilis is a highly efficient ethanol-producing bacterium with a small genome size and desirable industrial characteristics, which makes it a promising chassis for biorefinery and synthetic biology studies. While classical techniques for genetic manipulation are available for Z. mobilis, efficient genetic engineering toolkits enabling rapidly systematic and high-throughput genome editing in Z. mobilis are still lacking. RESULTS: Using Cas12a (Cpf1) from Francisella novicida, a recombinant strain with inducible cas12a expression for genome editing was constructed in Z. mobilis ZM4, which can be used to mediate RNA-guided DNA cleavage at targeted genomic loci. gRNAs were then designed targeting the replicons of native plasmids of ZM4 with about 100% curing efficiency for three native plasmids. In addition, CRISPR-Cas12a recombineering was used to promote gene deletion and insertion in one step efficiently and precisely with efficiency up to 90%. Combined with single-stranded DNA (ssDNA), CRISPR-Cas12a system was also applied to introduce minor nucleotide modification precisely into the genome with high fidelity. Furthermore, the CRISPR-Cas12a system was employed to introduce a heterologous lactate dehydrogenase into Z. mobilis with a recombinant lactate-producing strain constructed. CONCLUSIONS: This study applied CRISPR-Cas12a in Z. mobilis and established a genome editing tool for efficient and convenient genome engineering in Z. mobilis including plasmid curing, gene deletion and insertion, as well as nucleotide substitution, which can also be employed for metabolic engineering to help divert the carbon flux from ethanol production to other products such as lactate demonstrated in this work. The CRISPR-Cas12a system established in this study thus provides a versatile and powerful genome-editing tool in Z. mobilis for functional genomic research, strain improvement, as well as synthetic microbial chassis development for economic biochemical production.

Sodium salicylate modulates inflammatory responses through AMP-activated protein kinase activation in LPS-stimulated THP-1 cells.

Sodium salicylate (NaSal) is a nonsteroidal anti-inflammatory drug. The putative mechanisms for NaSal's pharmacologic actions include the inhibition of cyclooxygenases, platelet-derived thromboxane A2, and NF-κB signaling. Recent studies demonstrated that salicylate could activate AMP-activated protein kinase (AMPK), an energy sensor that maintains the balance between ATP production and consumption. The anti-inflammatory action of AMPK has been reported to be mediated by promoting mitochondrial biogenesis and fatty acid oxidation. However, the exact signals responsible for salicylate-mediated inflammation through AMPK are not well-understood. In the current study, we examined the potential effects of NaSal on inflammation-like responses of THP-1 monocytes to lipopolysaccharide (LPS) challenge. THP-1 cells were stimulated with or without 10 ug/mL LPS for 24 h in the presence or absence of 5 mM NaSal. Apoptosis was measured by flow cytometry using Annexin V/PI staining and by Western blotting for the Bcl-2 anti-apoptotic protein. Cell proliferation was detected by EdU incorporation and by Western blot analysis for proliferating cell nuclear antigen (PCNA). Secretion of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6) was determined by enzyme-linked immunosorbent assay (ELISA). We observed that the activation of AMPK by NaSal was accompanied by induction of apoptosis, inhibition of cell proliferation, and increasing secretion of TNF-α and IL-1ß. These effects were reversed by Compound C, an inhibitor of AMPK. In addition, NaSal/AMPK activation inhibited LPS-induced STAT3 phosphorylation, which was reversed by Compound C treatment. We conclude that AMPK activation is important for NaSal-mediated inflammation by inducing apoptosis, reducing cell proliferation, inhibiting STAT3 activity, and producing TNF-α and IL-1ß.

Centrosymmetric Thiophenemethyleneoxindole-Based Donor-Acceptor Copolymers for Organic Field-Effect Transistors.

Two novel, donor-acceptor-type π-conjugated polymers (P1 and P2) with 3'-(thieno[3,2-b]thiophene-2,5-diylbis(methan-1-yl-1-ylidene))bis-(indolin-2-one) (ITTI) as the acceptor and thiophene/bithiophene as the donor are designed and synthesized by palladium-catalyzed Stille coupling. The optical and electrochemical properties of these polymers are characterized and further implemented into organic field-effect transistors (OFET). Both polymers exhibit excellent thermal stability, broad UV-vis absorption, and high highest occupied molecular orbital energy levels. Thermal annealing induces a well-ordered structure, a highly planar π-system (oxygen-sulfur interaction), and a bathochromic shift in the polymers; furthermore, significant enhancement of the long wavelength intensity is also observed. Both polymers exhibit p-type charge transport behavior, with hole mobilities up to 0.51 cm2 V-1 s-1 for P1 and 0.65 cm2 V-1 s-1 for P2. This work demonstrates that ITTI can be a promising building block for the construction of donor-acceptor polymers with high-performance OFETs.

A novel oxaliplatin derivative, Ht-2, triggers mitochondrion-dependent apoptosis in human colon cancer cells.

Ht-2 is a novel oxaliplatin derivative previously identified in a compound screen performed by our laboratory. In the present study, we evaluated the antitumor effects of Ht-2 and investigated its underlying mechanism of action. Ht-2 exhibited anti-tumor activity and demonstrated low cytotoxicity in normal cells in vitro. The IC50 of Ht-2 was 2-10-fold lower than oxaliplatin in all of the cancer cell lines tested except MCF-7 cells, whereas, the value was threefold higher than cisplatin or oxaliplatin in normal HUVEC cells. Further studies indicated that Ht-2 caused S-phase arrest and led to apoptosis in HCT-116 cells through the activation of the caspase cascade. Moreover, Ht-2 treatment contributed to increased mitochondrial permeability by altering the Bax/Bcl-2 ratio and consequently induced mitochondrial dysfunction, mitochondrial membrane potential depletion, reactive oxygen species (ROS) elevation and cytochrome C release in HCT-116 cells. The cellular antioxidative superoxide dismutase 1 protein was also downregulated. We demonstrated that the cytotoxicity was almost completely recovered by antioxidant treatment, indicating a crucial role of ROS for Ht-2-induced apoptosis. Collectively, our data suggest that Ht-2 can target tumor cells by inducing mitochondrion-dependent apoptosis.

Biosensor-assisted CRISPRi high-throughput screening to identify genetic targets in Zymomonas mobilis for high d-lactate production.

Lactate is an important monomer for the synthesis of poly-lactate (PLA), which is a substitute for the petrochemical plastics. To achieve the goal of high lactate titer, rate, and yield for commercial production, efficient lactate production pathway is needed as well as genetic targets that affect high lactate production and tolerance. In this study, an LldR-based d-lactate biosensor with a broad dynamic range was first applied into Zymomonas mobilis to select mutant strains with strong GFP fluorescence, which could be the mutant strains with increased d-lactate production. Then, LldR-based d-lactate biosensor was combined with a genome-wide CRISPR interference (CRISPRi) library targeting the entire genome to generate thousands of mutants with gRNA targeting different genetic targets across the whole genome. Specifically, two mutant libraries were selected containing 105 and 104 mutants with different interference sites from two rounds of fluorescence-activated cell sorting (FACS), respectively. Two genetic targets of ZMO1323 and ZMO1530 were characterized and confirmed to be associated with the increased d-lactate production, further knockout of ZMO1323 and ZMO1530 resulted in a 15% and 21% increase of d-lactate production, respectively. This work thus not only established a high-throughput approach that combines genome-scale CRISPRi and biosensor-assisted screening to identify genetic targets associated with d-lactate production in Z. mobilis, but also provided a feasible high-throughput screening approach for rapid identification of genetic targets associated with strain performance for other industrial microorganisms.

Molybdenum/selenium based heterostructure catalyst for efficient hydrogen evolution: Effects of ionic dissolution and repolymerization on catalytic performance.

Transition metal chalcogenides (TMCs) are recognized as highly efficient electrocatalysts and have wide applications in the field of hydrogen production by electrolysis of water, but the real catalytic substances and catalytic processes of these catalysts are not clear. The species evolution of Mo and Se during alkaline hydrogen evolution was investigated by constructing MoSe2@CoSe2 heterostructure. The real-time evolution of Mo and Se in MoSe2@CoSe2 was monitored using in situ Raman spectroscopy to determine the origin of the activity. Mo and Se in MoSe2@CoSe2 were dissolved in the form of MoO42- and SeO32-, respectively, and subsequently re-adsorbed and polymerized on the electrode surface to form new species Mo2O72- and SeO42-. Theoretical calculations show that adsorption of Mo2O72- and SeO42- can significantly enhance the HER catalytic activity of Co(OH)2. The addition of additional MoO42- and SeO32- to the electrolyte with Co(OH)2 electrodes both enhances its HER activity and promotes its durability. This study helps to deepen our insight into mechanisms involved in the structural changes of catalyst surfaces and offers a logical basis for revealing the mechanism of the influence of species evolution on catalytic performance.

In situ self-reconstructed hierarchical bimetallic oxyhydroxide nanosheets of metallic sulfides for high-efficiency electrochemical water splitting.

The advancement of economically efficient electrocatalysts for alkaline water oxidation based on transition metals is essential for hydrogen production through water electrolysis. In this investigation, a straightforward one-step solvent method was utilized to spontaneously cultivate bimetallic sulfide S-FeCo1 : 1/NIF on the surface of a nickel-iron foam (NIF). Capitalizing on the synergistic impact between the bimetallic constituents and the highly active species formed through electrochemical restructuring, S-FeCo1 : 1/NIF exhibited remarkable oxygen evolution reaction (OER) performance, requiring only a 310 mV overpotential based on 500 mA cm-2 current density. Furthermore, it exhibited stable operation at 200 mA cm-2 for 275 h. Simultaneously, the catalyst demonstrated excellent hydrogen evolution reaction (HER) and overall water-splitting capabilities. It only requires an overpotential of 191 mV and a potential of 1.81 V to drive current densities of 100 and 50 mA cm-2. Density functional theory (DFT) calculations were also employed to validate the impact of the bimetallic synergistic effect on the catalytic activity of sulfides. The results indicate that the coupling between bimetallic components effectively reduces the energy barrier required for the rate-determining step in water oxidation, enhancing the stability and activity of bimetallic sulfides. The exploration of bimetallic coupling to improve the OER performance holds theoretical significance in the rational design of advanced electrocatalysts.

A Novel Air-Cooled Nd:YAG Laser for the Treatment of the Venous Lakes of the Lips.

Objective: To evaluate the therapeutic effect of a novel air-cooled Nd:YAG laser in the venous lakes of the lips (VLL). Background: The thermal injury is one of the most important issues during laser therapy for venous lakes. Methods: Six pieces of fresh pork livers were used to provide 30 regions with a diameter of 6 mm for experiment in vitro, among which 15 regions were treated by Nd:YAG laser with air cooling until the tissue turned gray-white, whereas the rest were treated without air cooling as control. The operation time of laser irradiation, the degree of temperature increase, and the depth of coagulation tissue were compared between two groups. Then, 60 VLL patients were selected for Nd:YAG laser treatment with or without air cooling. The operation time of laser irradiation, the degree of temperature increase, the postoperative pain visual analog scale (VAS) score, and the percentage of lesions removed within 1 month were compared. Results: In tissue studies, the treated group showed a longer operation time of laser irradiation (p < 0.01), a lower degree of temperature increase (p < 0.01), and there was no significant statistical difference in the depth of coagulation tissue (p = 0.624). In clinical studies, the treated group showed a longer operation time of laser irradiation (p < 0.01), a lower degree of temperature increase (p < 0.01), and a lower VAS score on the 1st and 2nd day, compared with the control group (p < 0.01). Conclusions: Air cooling during Nd:YAG laser for the treatment of VLL can prolong the surgical time, but lowered tissue temperature and reduced patient pain within 2 days under the premise of ensuring the treatment effect.

Ursolic acid inhibits epithelial-mesenchymal transition by suppressing the expression of astrocyte-elevated gene-1 in human nonsmall cell lung cancer A549 cells.

Lung cancer is one of the most death-related cancers worldwide. Ursolic acid (UA), a pentacyclic triterpene acid, has a wide range of anticancer functions such as proapoptosis, antiangiogenesis, and antimetastasis. This study was carried out to explore the inhibition mechanism of UA on metastasis of lung cancer A549 cells. First, we found that UA inhibited the metastasis of lung cancer cells in a concentration-dependent manner through an adhesion assay, a cell wound healing assay, and a transwell migration assay in vitro. In addition, after treatment with UA, the A549 cells showed decreased expression of astrocyte-elevated gene-1 (AEG-1) accompanied by upregulation of E-cadherin and downregulation of N-cadherin and vimentin, which have been reported to characterize the epithelial-mesenchymal transition (EMT). Further results also confirmed that the expression of vimentin was decreased by the siRNA technique to directly knock down AEG-1 expression, indicating that AEG-1 was involved in UA-mediated EMT inhibition. Furthermore, our results showed that UA suppressed the expression level of AEG-1 by repressing nuclear factor-κB signaling. Altogether, UA inhibited the EMT by suppressing the expression of AEG-1, correlating with inhibition of nuclear factor-κB in A549 cells. These findings suggested that UA was a potent anti-lung cancer agent, and it may be able to prevent invasion and metastasis of lung cancer cells.

Synergistic Effect of P Doping and Mo-Ni-Based Heterostructure Electrocatalyst for Overall Water Splitting.

Heterostructure construction and heteroatom doping are powerful strategies for enhancing the electrolytic efficiency of electrocatalysts for overall water splitting. Herein, we present a P-doped MoS2/Ni3S2 electrocatalyst on nickel foam (NF) prepared using a one-step hydrothermal method. The optimized P[0.9mM]-MoS2/Ni3S2@NF exhibits a cluster nanoflower-like morphology, which promotes the synergistic electrocatalytic effect of the heterostructures with abundant active centers, resulting in high catalytic activity for the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) in alkaline electrolyte. The electrode exhibits low overpotentials and Tafel slopes for the HER and OER. In addition, the catalyst electrode used in a two-electrode system for overall water splitting requires an ultralow voltage of 1.42 V at 10 mA·cm-2 and shows no obvious increase in current within 35 h, indicating excellent stability. Therefore, the combination of P doping and the heterostructure suggests a novel path to formulate high-performance electrocatalysts for overall water splitting.

Clinical and Molecular Characteristics of Carbapenemase-Producing E. coli Strains from Patients with Biliary System Diseases and Hematological Malignancies.

Purpose: This study aims to investigate the clinical and molecular characteristics of carbapenemase-producing E. coli strains (CPECO). Patients and Methods: We collected 38 non-repetitive CPECO strains, identified them using MALDI-TOF, and assessed their antimicrobial susceptibility via the VITEK-Compact II system. We gathered demographic and clinical patient data. Phenotypic assays were employed to detect carbapenemase types. Polymerase chain reaction (PCR) was utilized to identify the carbapenemase genes. Seven housekeeping genes were amplified and sequenced to determine the multilocus sequence typings (MLSTs). Results: These CPECO strains, primarily isolated from aseptic site and stool screening specimens, exhibited significant resistance to most clinical antibiotics, except for tigecycline and amikacin. Most patients had underlying medical conditions and underwent invasive procedures. There were significant differences among patients concerning the presence of malignancies, digestive system disorders, endoscopic retrograde cholangiopancreatography (ERCP) surgeries and abdominal drainage tubes. However, no significant differences were observed among patients regarding conditions, including hypertension, diabetes, respiratory diseases, urinary diseases and cardiovascular diseases, as well as invasive procedures such as deep venous catheterization, endotracheal intubation and gastrointestinal catheterization. Metallo-ß-lactamase was primarily responsible for carbapenem resistance, including blaNDM-5(24/38), blaNDM-1(5/38), blaNDM-9(1/38) and blaIMP-4(1/38). Additionally, 7 CPECO strains carried blaKPC-2. The distribution of CPECO sequence types (STs) was diverse, with seven strains being ST131, six strains being ST410, three strains each of ST1196 and ST10, although most STs were represented by only one strain. Conclusion: CPECO infections in patients with biliary system diseases may result from intestinal CPECO translocation, with ERCP surgery potentially facilitating this. Meanwhile, malignant tumor was found to be a significant factor affecting CPECO infections in patients with hematological diseases. blaNDM-5, blaNDM-1 and blaNDM-9 were primarily responsible for carbapenem resistance in CPECO strains. The emergence of carbapenem-resistant ST131 and ST410 strains should be alert to prevent the spread of carbapenem-resistant genes within high-risk epidemic clones.

Metabolic engineering of Zymomonas mobilis for co-production of D-lactic acid and ethanol using waste feedstocks of molasses and corncob residue hydrolysate.

Lactate is the precursor for polylactide. In this study, a lactate producer of Z. mobilis was constructed by replacing ZMO0038 with LmldhA gene driven by a strong promoter PadhB, replacing ZMO1650 with native pdc gene driven by Ptet, and replacing native pdc with another copy of LmldhA driven by PadhB to divert carbon from ethanol to D-lactate. The resultant strain ZML-pdc-ldh produced 13.8 ± 0.2 g/L lactate and 16.9 ± 0.3 g/L ethanol using 48 g/L glucose. Lactate production of ZML-pdc-ldh was further investigated after fermentation optimization in pH-controlled fermenters. ZML-pdc-ldh produced 24.2 ± 0.6 g/L lactate and 12.9 ± 0.8 g/L ethanol as well as 36.2 ± 1.0 g/L lactate and 40.3 ± 0.3 g/L ethanol, resulting in total carbon conversion rate of 98.3% ± 2.5% and 96.2% ± 0.1% with final product productivity of 1.9 ± 0.0 g/L/h and 2.2 ± 0.0 g/L/h in RMG5 and RMG12, respectively. Moreover, ZML-pdc-ldh produced 32.9 ± 0.1 g/L D-lactate and 27.7 ± 0.2 g/L ethanol as well as 42.8 ± 0.0 g/L D-lactate and 53.1 ± 0.7 g/L ethanol with 97.1% ± 0.0% and 99.1% ± 0.8% carbon conversion rate using 20% molasses or corncob residue hydrolysate, respectively. Our study thus demonstrated that it is effective for lactate production by fermentation condition optimization and metabolic engineering to strengthen heterologous ldh expression while reducing the native ethanol production pathway. The capability of recombinant lactate-producer of Z. mobilis for efficient waste feedstock conversion makes it a promising biorefinery platform for carbon-neutral biochemical production.

MiR-19b-1 inhibits angiogenesis by blocking cell cycle progression of endothelial cells.

MicroRNAs are endogenously expressed small, non-coding RNAs that modulate biological processes by recognizing specific gene transcripts, leading to translational repression or degradation. Previous work showed that the miR-17-92 cluster is highly expressed in human endothelial cells that participate in angiogenesis. In this study we showed that miR-19b-1, a component of this cluster, controls the intrinsic angiogenic activity of human umbilical vein endothelial cells (HUVECs) in vitro. In silico and in vitro analyses have suggested that miR-19b-1 targets mRNA corresponding to the pro-angiogenic protein, FGFR2, and blocks the cell cycle from the S phase to the G(2)/M phase transition by controlling the expression of cyclin D1. Thus, miR-19b-1 may serve as a valuable therapeutic agent in the context of tumor angiogenesis.

Chromium-Modified Ultrathin CoFe LDH as High-Efficiency Electrode for Hydrogen Evolution Reaction.

Hydrogen evolution reaction (HER) has a dominant function in energy conversion and storage because it supplies a most effective way for converting electricity into sustainable high-purity hydrogen. Layered double hydroxides (LDHs) have shown promising performance in the process of electrochemical water oxidation (a half-reaction for water splitting). Nevertheless, HER properties have not been well released due to the structural characteristics of related materials. Herein, a simple and scalable tactics is developed to synthesize chromium-doped CoFe LDH (CoFeCr LDH). Thanks to oxygen vacancy, optimized electronic structure and interconnected array hierarchical structure, our developed ternary CoFeCr-based layered double hydroxide catalysts can provide 10 mA cm-2 current density at -0.201 V vs. RHE with superior long-term stability in alkaline electrolyte. We anticipate that the simple but feasible polymetallic electronic modulation strategy can strengthen the electrocatalytic property of the layered double hydroxides established in the present study, based on a carbon neutral and hydrogen economy.

The Impact of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and highly fatal neurodegenerative disease. Although the pathogenesis of ALS remains unclear, increasing evidence suggests that a key contributing factor is mitochondrial dysfunction. Mitochondria are organelles in eukaryotic cells responsible for bioenergy production, cellular metabolism, signal transduction, calcium homeostasis, and immune responses and the stability of their function plays a crucial role in neurons. A single disorder or defect in mitochondrial function can lead to pathological changes in cells, such as an impaired calcium buffer period, excessive generation of free radicals, increased mitochondrial membrane permeability, and oxidative stress (OS). Recent research has also shown that these mitochondrial dysfunctions are also associated with pathological changes in ALS and are believed to be commonly involved in the pathogenesis of the disease. This article reviews the latest research on mitochondrial dysfunction and its impact on the progression of ALS, with specific attention to the potential of novel therapeutic strategies targeting mitochondrial dysfunction.

The Biogenesis of miRNAs and Their Role in the Development of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects upper and lower motor neurons. As there is no effective treatment for ALS, it is particularly important to screen key gene therapy targets. The identifications of microRNAs (miRNAs) have completely changed the traditional view of gene regulation. miRNAs are small noncoding single-stranded RNA molecules involved in the regulation of post-transcriptional gene expression. Recent advances also indicate that miRNAs are biomarkers in many diseases, including neurodegenerative diseases. In this review, we summarize recent advances regarding the mechanisms underlying the role of miRNAs in ALS pathogenesis and its application to gene therapy for ALS. The potential of miRNAs to target diverse pathways opens a new avenue for ALS therapy.

Hydrogen-Bonded Conjugated Materials and Their Application in Organic Field-Effect Transistors.

Recent research on organic semiconductors has revealed that the composition of the constituent organic material, as well as the subtle changes in its structure (the stacking order of molecules), can noticeably affect its bulk properties. One of the reasons for this is that the charge transport in conjugated materials is strongly affected by their structure. Further, the charge mobility increases significantly when the conjugated materials exhibit self-assembly, resulting in the formation of ordered structures. However, well-organized nanostructures are difficult to obtain using classical solution processing methods, owing to their disordered state. A simple strategy for obtaining well-ordered material films involves synthesizing new conjugated materials that can self-organize. Introducing hydrogen bonding in the materials to yield hydrogen-bonded material superstructures can be a suitable method to fulfill these critical requirements. The formed hydrogen bonds will facilitate the assembly of the molecules into a highly ordered structure and bridge the distance between the adjacent molecules, thus enhancing the intermolecular charge transfer. In this minireview, hydrogen-bonded small molecules and polymers as well as the relationship between their chemical structures and performances in organic field-effect transistors are discussed.