Bone mesenchymal stem cells improve cholestatic liver fibrosis by targeting ULK1 to regulate autophagy through PI3K/AKT/mTOR pathway.

Cholestatic liver disease (CLD) is a severe disease, which can progress to liver cirrhosis, even liver cancer. Hepatic stellate cells (HSCs) activation plays a crucial role in CLD development. Bone mesenchymal stem cells (BMSCs) treatment was demonstrated to be beneficial in liver diseases. However, the therapeutic effect and mechanism of BMSCs on CLD are poorly known. In the present study, we investigated the therapeutic effects and underlying mechanisms of BMSCs transplantation in mouse models of bile duct ligation-induced cholestatic liver fibrosis (CLF). The results revealed that BMSCs significantly improved liver function and reduced the formation of fibrosis after portal vein transplantation. Mechanistically, after coculturing BMSCs and HSCs, we identified that BMSCs alleviated starvation-induced HSCs activation. Further, BMSCs inhibited HSCs activation by decreasing autophagy, and PI3K/AKT/mTOR pathway was involved in the regulation. More importantly, ULK1 is identified as the main autophagy-related gene regulated by BMSCs in HSCs autophagy. Overexpression of ULK1 reversed the suppression of HSCs autophagy by BMSCs. Collectively, our results provide a theoretical basis for BMSCs targeting ULK1 to attenuate HSCs autophagy and activation and suggest that BMSCs or ULK1 may be an alternative therapeutic approach/target for the treatment of CLF.

Dual-stream EfficientNet with adversarial sample augmentation for COVID-19 computer aided diagnosis.

Though a series of computer aided measures have been taken for the rapid and definite diagnosis of 2019 coronavirus disease (COVID-19), they generally fail to achieve high enough accuracy, including the recently popular deep learning-based methods. The main reasons are that: (a) they generally focus on improving the model structures while ignoring important information contained in the medical image itself; (b) the existing small-scale datasets have difficulty in meeting the training requirements of deep learning. In this paper, a dual-stream network based on the EfficientNet is proposed for the COVID-19 diagnosis based on CT scans. The dual-stream network takes into account the important information in both spatial and frequency domains of CT scans. Besides, Adversarial Propagation (AdvProp) technology is used to address the insufficient training data usually faced by the deep learning-based computer aided diagnosis and also the overfitting issue. Feature Pyramid Network (FPN) is utilized to fuse the dual-stream features. Experimental results on the public dataset COVIDx CT-2A demonstrate that the proposed method outperforms the existing 12 deep learning-based methods for COVID-19 diagnosis, achieving an accuracy of 0.9870 for multi-class classification, and 0.9958 for binary classification. The source code is available at https://github.com/imagecbj/covid-efficientnet.

Locus coeruleus input-modulated reactivation of dentate gyrus opioid-withdrawal engrams promotes extinction.

Extinction training during the reconsolidation window following memory recall is an effective behavioral pattern for promoting the extinction of pathological memory. However, promoted extinction by recall-extinction procedure has not been universally replicated in different studies. One potential reason for this may relate to whether initially acquired memory is successfully activated. Thus, the methods for inducing the memory into an active or plastic condition may contribute to promoting its extinction. The aim of this study is to find and demonstrate a manipulatable neural circuit that engages in the memory recall process and where its activation improves the extinction process through recall-extinction procedure. Here, naloxone-precipitated conditioned place aversion (CPA) in morphine-dependent mice was mainly used as a pathological memory model. We found that the locus coeruleus (LC)-dentate gyrus (DG) circuit was necessary for CPA memory recall and that artificial activation of LC inputs to the DG just prior to initiating a recall-extinction procedure significantly promoted extinction learning. We also found that activating this circuit caused an increase in the ensemble size of DG engram cells activated during the extinction, which was confirmed by a cFos targeted strategy to label cells combined with immunohistochemical and in vivo calcium imaging techniques. Collectively, our data uncover that the recall experience is important for updating the memory during the reconsolidation window; they also suggest a promising neural circuit or target based on the recall-extinction procedure for weakening pathological aversion memory, such as opioid withdrawal memory and fear memory.

Rapid and convenient detection of SARS-CoV-2 using a colorimetric triple-target reverse transcription loop-mediated isothermal amplification method.

Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV-2 poses a significant threat to global public health. Early detection with reliable, fast, and simple assays is crucial to contain the spread of SARS-CoV-2. The real-time reverse transcription-polymerase chain reaction (RT-PCR) assay is currently the gold standard for SARS-CoV-2 detection; however, the reverse transcription loop-mediated isothermal amplification method (RT-LAMP) assay may allow for faster, simpler and cheaper screening of SARS-CoV-2. In this study, the triple-target RT-LAMP assay was first established to simultaneously detect three different target regions (ORF1ab, N and E genes) of SARS-CoV-2. The results revealed that the developed triplex RT-LAMP assay was able to detect down to 11 copies of SARS-CoV-2 RNA per 25 µL reaction, with greater sensitivity than singleplex or duplex RT-LAMP assays. Moreover, two different indicators, hydroxy naphthol blue (HNB) and cresol red, were studied in the colorimetric RT-LAMP assay; our results suggest that both indicators are suitable for RT-LAMP reactions with an obvious color change. In conclusion, our developed triplex colorimetric RT-LAMP assay may be useful for the screening of COVID-19 cases in limited-resource areas.

Corticotropin-releasing factor receptor 1 in infralimbic cortex modulates social stress-altered decision-making.

Chronic stress could lead to a bias in behavioral strategies toward habits. However, it remains unclear which neuronal system modulates stress-induced behavioral abnormality during decision making. The corticotropin-releasing factor (CRF) system in the medial prefrontal cortex (mPFC), which has been implicated in governing strategy choice, is involved in the response to stress. The present study aimed to clarify whether altered function in cortical CRF receptors is linked to abnormal behaviors after chronic stress. In results, mice subjected to a 10-day social defeat preferred to use a habitual strategy. The infralimbic cortex (IL), but not the prelimbic cortex (PL) or anterior cingulate cortex (ACC), showed higher cFos expression in stress-subjected mice than in control mice, which may be associated with habitual behavior choice. Furthermore, CRF receptor 1 (CRFR1) agonist and antagonist infusion in IL during behavioral training mimicked and rescued stress-caused behavioral change in the decision-making assessment, respectively. An electrophysiological approach showed that the frequencies of both spontaneous IPSC and spontaneous EPSC, but not their amplitude, increased after stress and were modulated by CRFR1 agents. Further recordings revealed that an increased ratio of excitation to inhibition (E/I ratio) of IL by stress was rescued under conditions with CRFR1 antagonist. Collectively, these data indicate that CRFR1 plays a critical role in stress-permitted or enhanced glutamatergic and GABAergic presynaptic transmission in direct or indirect ways, as well as the modulation for E/I ratio in the IL. Thus, CRFR1 in the mPFC may be a proper target for treating cases of chronic stress-altered behavior.

The role of hippocampus in memory reactivation: an implication for a therapeutic target against opioid use disorder.

Purpose of the review: The abuse of opioids induces many terrible problems in human health and social stability. For opioid-dependent individuals, withdrawal memory can be reactivated by context, which is then associated with extremely unpleasant physical and emotional feelings during opioid withdrawal. The reactivation of withdrawal memory is considered one of the most important reasons for opioid relapse, and it also allows for memory modulation based on the reconsolidation phenomenon. However, studies exploring withdrawal memory modulation during the reconsolidation window are lacking. By summarizing the previous findings about the reactivation of negative emotional memories, we are going to suggest potential neural regions and systems for modulating opioid withdrawal memory. Recent findings: Here, we first present the role of memory reactivation in its modification, discuss how the hippocampus participates in memory reactivation, and discuss the importance of noradrenergic signaling in the hippocampus for memory reactivation. Then, we review the engagement of other limbic regions receiving noradrenergic signaling in memory reactivation. We suggest that noradrenergic signaling targeting hippocampus neurons might play a potential role in strengthening the disruptive effect of withdrawal memory extinction by facilitating the degree of memory reactivation. Summary: This review will contribute to a better understanding of the mechanisms underlying reactivation-dependent memory malleability and will provide new therapeutic avenues for treating opioid use disorders.

Systemic versus local adipokine expression differs in a combined obesity and osteoarthritis mouse model.

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage loss and reduced joint function. OA risk factors are age and obesity. Many adipokines are altered by obesity but also OA although systemic adipokine regulation in OA is not always clear. Therefore, metabolic effects of diet-induced obesity on OA development as well as the influence of obesity and OA progression on systemic vs. local adipokine expression in joints were compared. C57Bl/6-mice fed with HFD (high fat diet) or normal diet prior to destabilization of the medial meniscus (DMM) were sacrificed 4/6/8 weeks after surgery. Sera were evaluated for adiponectin, leptin, visfatin, cytokines. Liver grading and staging for non-alcoholic steatohepatitis (NASH) was performed and crown-like structures (CLS) in adipose tissue measured. OA progression was scored histologically. Adipokine-expressing cells and types were evaluated by immunohistochemistry. Time-dependent changes in DMM-progression were reflected by increased systemic adiponectin levels in DMM especially combined with HFD. While HFD increased serum leptin, DMM reduced systemic leptin significantly. OA scores correlated with bodyweight, leptin and hepatic scoring. Locally, increased numbers of adiponectin- and leptin-producing fibroblasts were observed in damaged menisci but visfatin was not changed. Local adipokine expression was independent from systemic levels, suggesting different mechanisms of action.

Dopamine induces in vitro migration of synovial fibroblast from patients with rheumatoid arthritis.

Preventing synovial fibroblast (SF) migration into the adjacent cartilage is a desirable therapeutic target in rheumatoid arthritis (RA). As previous studies demonstrated that RASF and SF from osteoarthritis (OA) patients express dopamine receptors (DR), aim of the present study was to investigate the impact of dopamine on mobility of fibroblasts from patients with chronic arthritides. Synovial tissue and fibroblasts were obtained from RA and OA patients. Immunohistochemistry was performed for all DR-subtypes in the invasion zone. Migration- and motility-assays were performed under DR-stimulation. Cytokines were evaluated using ELISA. Expression of DRs was evaluated by flow cytometry, and DR activation was measured by xCELLigence real-time analysis. All DRs were expressed in RA invasion zone. Migration and motility of RASF and OASF were increased after DR stimulation in patients ≤ 75 years old. Synovial fibroblasts from older RA patients (> 75 years old) expressed lower levels of D1-, D2- and D4-DR than patients ≤ 75 years old. DR activation was not altered in older patients. Our results suggest a possible involvement of dopamine on migration of fibroblasts from arthritis patients. Therefore, the synovial dopaminergic pathway might represent a potential therapeutic target to interfere with progressive joint damage in RA patients.

Realizing small-flake graphene oxide membranes for ultrafast size-dependent organic solvent nanofiltration.

Membranes for organic solvent nanofiltration (OSN) or solvent-resistant nanofiltration (SRNF) offer unprecedented opportunities for highly efficient and cost-competitive solvent recovery in the pharmaceutical industry. Here, we describe small-flake graphene oxide (SFGO) membranes for high-performance OSN applications. Our strategy exploits lateral dimension control to engineer shorter and less tortuous transport pathways for solvent molecules. By using La3+ as a cross-linker and spacer for intercalation, the SFGO membrane selective layer was stabilized, and size-dependent ultrafast selective molecular transport was achieved. The methanol permeance was up to 2.9-fold higher than its large-flake GO (LFGO) counterpart, with high selectivity toward three organic dyes. More importantly, the SFGO-La3+ membrane demonstrated robust stability for at least 24 hours under hydrodynamic stresses that are representative of realistic OSN operating conditions. These desirable attributes stem from the La3+ cross-linking, which forms uniquely strong coordination bonds with oxygen-containing functional groups of SFGO. Other cations were found to be ineffective.

Tunable low-dimensional self-assembly of H-shaped bichromophoric perylenediimide Gemini in solution.

A material with diverse self-assembled morphologies is extremely important and highly desirable because such samples can provide tunable optical and electronic properties, which are critical in applications such as organic photovoltaics, microelectronics and bio-imaging. Moreover, the synthesis and controllable self-assembly of H-shaped bichromophoric perylenediimides (PDIs) are needed to advance these materials in organic photovoltaics, microelectronics and bio-imaging; however, this has remained a great challenge thus far. Here, we successfully synthesize a novel H-shaped bichromophoric PDI Gemini through the palladium-catalyzed coupling reaction. The as-prepared PDI Gemini exhibited unprecedented tunable self-assembly behavior in solution, yielding diverse low-dimensional superstructures, such as one-dimensional (1D) helices, two-dimensional (2D) rectangular nanocrystals, pyramid-shaped parallelograms, ultralarge micro-sheets, and uniform nanospheres, under different self-assembly conditions. Of particular interest, the 2D hierarchical superstructures along with their formation mechanisms represent the first finding in the self-assembly of PDI-based molecules. This study opens a new avenue for tunable self-assembly of conjugated molecules and affords opportunities for the fabrication of novel self-assembled optical and electronic materials based on PDI molecules.

Serotonin 5-HT2A and 5-HT2C receptors regulate rat maternal behavior through distinct behavioral and neural mechanisms.

Serotonin 5-HT2A and 5-HT2C receptors play important yet distinctive roles in the regulation of rat maternal behavior. The present study investigated their neural substrates and explored the possible behavioral mechanisms (i.e., behavioral organization or maternal motivation). Sprague-Dawley postpartum females were microinjected with either a selective 5-HT2A agonist (TCB-2, 0.4 or 4.0 µg/side) or a 5-HT2C agonist (MK212, 2.5 or 5.0 µg/side) into the medial prefrontal cortex (mPFC) or ventral tegmental area (VTA). Ten and 60 min later, their maternal activities were observed in the home cage; and their motivational responses towards pups were examined in a pup preference test and pup retrieval test throughout the first week of postpartum. In the mPFC, TCB-2 microinjection disrupted major components of maternal behavior (e.g., pup retrieval, pup crouching), as well as the sequential pup retrieval score (a measure of behavioral organization). In contrast, MK212 microinjection had a minimal disruption of maternal behavior. In the VTA, TCB-2 microinjection impaired pup retrieval, nest building, and pup crouching, whereas MK212 microinjection severely impaired pup retrieval, nest building and pup crouching. Moreover, only intra-VTA injection of MK212 significantly suppressed pup preference. Together, our data suggest that 5-HT2A receptors in the mPFC and VTA may play an important role in the behavioral organization or executive control of maternal activities, but not in the motivational processing of the rewarding value of pups (maternal motivation). In contrast, 5-HT2C receptors in the VTA play a critical role in maternal motivation, but not in the organization of maternal responses.

Blockade of serotonin 5-HT2A receptors potentiates dopamine D2 activation-induced disruption of pup retrieval on an elevated plus maze, but has no effect on D2 blockade-induced one.

Appetitive aspect of rat maternal behavior, such as pup retrieval, is motivationally driven and sensitive to dopamine disturbances. Activation or blockade of dopamine D2 receptors causes a similar disruption of pup retrieval, which may also reflect an increase in maternal anxiety and/or a disruption of executive function. Recent work indicates that serotonin 5-HT2A receptors also play an important role in rat maternal behavior. Given the well-known modulation of 5-HT2A on the mesolimbic and mesocortical dopamine functions, the present study examined the extent to which blockade of 5-HT2A receptors on dopamine D2-mediated maternal effects using a pup retrieval on the elevated plus maze (EPM) test. Sprague-Dawley postpartum female rats were acutely injected with quinpirole (a D2 agonist, 0.10 and 0.25 mg/kg, sc), or haloperidol (a D2 antagonist, 0.1 or 0.2 mg/kg, sc), in combination of MDL100907 (a 5-HT2A receptor antagonist, 1.0 mg/kg, sc, 30 min before quinpirole or haloperidol injection) or saline and tested at 30, 90 and 240 min after quinpirole or haloperidol injection on postpartum days 3 and 7. Quinpirole and haloperidol decreased the number of pup retrieved (an index of maternal motivation) and sequential retrieval score (an index of executive function), prolonged the pup retrieval latencies, reduced the percentage of time spent on the open arms (an index of maternal anxiety), and decreased the distance travelled on the maze in a dose-dependent and time-dependent fashion. MDL100907 treatment by itself had no effect on pup retrieval, but it exacerbated the quinpirole-induced disruption of pup retrieval, but had no effect on the haloperidol-induced one. These findings suggest a complex interactive effect between 5-HT2A and D2 receptors on one or several maternal processes (maternal motivation, anxiety and executive function), and support the idea that one molecular mechanism by which 5-HT2A receptors mediate maternal behavior is through its modulation of D2 receptors.

Organic-Dye-Modified Upconversion Nanoparticle as a Multichannel Probe To Detect Cu2+ in Living Cells.

The development of an inorganic-organic hybrid probe to more accurately detect ions in living systems is very challenging but highly desirable. Here we combined upconversion nanoparticles with the electrically active ferrocene group to detect Cu2+ in living cells. The as-prepared probe displays three different signal changes in absorption, emission, and electrochemical behavior, respectively, during Cu2+ ion detection. Moreover, this new probe has been demonstrated to show high stability and adaptability. In addition, bioimaging testing reveals that this probe is suitable for detecting and visualizing Cu2+ in A549 cells with low cytotoxicity.

Simultaneous crystallization of an in situ formed conjugated polymer and inorganic matrix for structure solving.

Here, we have, for the first time, reported the crystal structure of a conjugated polymer-inorganic composite by encapsulating conjugated polymer chains into a porous bromoplumbate matrix. The photoelectrochemical studies indicate that the as-obtained hybrid displays a p-type semiconductor behavior under visible-light illumination.

Surfactant 1-Hexadecyl-3-methylimidazolium Chloride Can Convert One-Dimensional Viologen Bromoplumbate into Zero-Dimensional.

A zero-dimensional N,N'-dibutyl-4,4'-dipyridinium bromoplumbate, [BV]6[Pb9Br30], with unusual discrete [Pb9Br30]12- anionic clusters was prepared via a facile surfactant-mediated solvothermal process. This bromoplumbate exhibits a narrower optical band gap relative to the congeneric one-dimensional viologen bromoplumbates.

Self-Healing Behavior in a Thermo-Mechanically Responsive Cocrystal during a Reversible Phase Transition.

The molecular-level motions of a coronene-based supramolecular rotator are amplified into macroscopic changes of crystals by co-assembly of coronene and TCNB (1,2,4,5-tetracyanobenzene) into a charge-transfer complex. The as-prepared cocrystals show remarkable self-healing behavior and thermo-mechanical responses during thermally-induced reversible single-crystal-to-single-crystal (SCSC) phase transitions. Comprehensive analysis of the microscopic observations as well as differential scanning calorimetry (DSC) measurements and crystal habits reveal that a thermally-reduced-rate-dependent dynamic character exists in the phase transition. The crystallographic studies show that the global similarity of the packing patterns of both phases with local differences, such as molecular stacking sequence and orientations, should be the origin of the self-healing behavior of these crystals.

Improving the Performance of Lithium-Sulfur Batteries by Employing Polyimide Particles as Hosting Matrixes.

Sulfur cathodes with four polyimide (PI) compounds as hosting matrixes have been prepared through a simple one-step approach. These four PIs-S composites exhibited higher sulfur utilization and better cycling stability than pure sulfur. At a current rate of 300 mA g(-1), the initial discharge capacities of PI-1S, PI-2S, PI-3S, and BBLS reached 1120, 1100, 1150, and 1040 mAh g(-1), respectively. After the 30th cycle, PI-1S, PI-2S, PI-3S, BBLS and pristine sulfur powder still remained discharge capacities of 715, 673, 729, 643, and 550 mAh g(-1). Especially, PI-1S and PI-3S cathodes exhibit excellent cycling stability with the discharge capacities of 522 and 574 mAh g(-1) at the 450th cycle, respectively.

Surfactant-thermal syntheses, structures, and magnetic properties of Mn-Ge-sulfides/selenides.

Although either surfactants or amines have been investigated to direct the crystal growth of metal chalcogenides, the synergic effect of organic amines and surfactants to control the crystal growth has not been explored. In this report, several organic bases (hydrazine monohydrate, ethylenediamine (en), 1,2-propanediamine (1,2-dap), and 1,3-propanediamine (1,3-dap)) have been employed as structure-directing agents (SDAs) to prepare four novel chalcogenides (Mn3Ge2S7(NH3)4 (1), [Mn(en)2(H2O)][Mn(en)2MnGe3Se9] (2), (1,2-dapH)2{[Mn(1,2-dap)2]Ge2Se7} (3), and (1,3-dapH)(puH)MnGeSe4(4) (pu = propyleneurea) under surfactant media (PEG-400). These as-prepared new crystalline materials provide diverse metal coordination geometries, including MnS3N tetrahedra, MnGe2Se7 trimer, and MnGe3Se10 T2 cluster. Compounds 1-3 have been fully characterized by single-crystal X-ray diffraction (XRD), powder XRD, UV-vis spectra, Fourier transform infrared spectroscopy, and thermogravimetric analysis. Moreover, magnetic measurements for compound 1 showed an obvious antiferromagnetic transition at ~9 K. Our research not only enriches the structural chemistry of the transitional-metal/14/16 chalcogenides but also allows us to better understand the synergic effect of organic amines and surfactants on the crystallization of metal chalcogenides.

Characterization of the TaAIDFa gene encoding a CRT/DRE-binding factor responsive to drought, high-salt, and cold stress in wheat.

Dehydration responsive element-binding factors (DBFs) belong to the AP2/ERF superfamily and play vital regulatory roles in abiotic stress responses in plants. In this study, we isolated three novel homologs of the DBF gene family in wheat (Triticum aestivum L.) by screening a drought-induced cDNA library and designated them as TaAIDFs (T. aestivum abiotic stress-induced DBFs). Compared to TaAIDFb and TaAIDFc, TaAIDFa lacks a short Ser/Thr-rich region, a putative phosphorylation site, following the AP2/ERF domain. The TaAIDFa gene, located on chromosome 3BS, is interrupted by a single intron at the 17th Arg (R) in the N-terminal domain. The N-terminal region of the TaAIDFa protein modulates nuclear localization. The TaAIDFa protein is capable of binding to CRT/DRE elements in vitro and in vivo, and of trans-activating reporter gene expression in yeast cells. The TaAIDFa promoter, with various stress-related cis-acting elements, drives expression of the GUS reporter gene in wheat calli under stress conditions. This was further confirmed by responses of TaAIDFa transcripts to drought, salinity, low-temperature, and exogenous ABA. Furthermore, overexpression of TaAIDFa activated CRT/DRE-containing genes under normal growth conditions, and improved drought and osmotic stress tolerances in transgenic Arabidopsis plants. These results suggested that TaAIDFa encodes a CRT/DRE element-binding factor that might be involved in multiple abiotic stress signal transduction pathways.

A novel paradigm of fatty acid beta-oxidation exemplified by the thioesterase-dependent partial degradation of conjugated linoleic acid that fully supports growth of Escherichia coli.

An alternative pathway of beta-oxidation for unsaturated fatty acids was studied in Escherichia coli. 9- cis,11- trans-Octadecadienoic acid (conjugated linoleic acid), a potential substrate of this pathway, was shown to support growth of E. coli in the absence of any other carbon source. The identification of 3,5-dodecadienoic acid in the growth medium revealed the partial beta-oxidation of conjugated linoleic acid to 3,5-dodecadienoyl-CoA, which was hydrolyzed to 3,5-dodecadienoic acid and released from cells. The involvement of acyl-CoA thioesterases in this process was evaluated by determining the substrate specificity of thioesterase II and comparing it with that of a novel thioesterase (thioesterase III) and by assessing mutant strains devoid of one or both of these thioesterases for growth on conjugated linoleic acid. Both thioesterases were highly active with 3,5-dodecadienoyl-CoA as substrate. A deficiency of either thioesterase decreased the growth rate of cells on conjugated linoleic acid but not on palmitic acid. The absence of both thioesterases reduced the cellular growth in a cumulative manner but did not abolish it. It is concluded that thioesterases II and III and at least one other thioesterase function in the partial degradation of conjugated linoleic acid via the thioesterase-dependent pathway of beta-oxidation, which provides all energy and carbon precursors required for the growth of E. coli.