Drug use and relapse involve learned associations between drug-associated environmental cues and drug effects. Extinction procedures in the clinic can suppress conditioned responses to drug cues, but ...the extinguished responses typically reemerge after exposure to the drug itself (reinstatement), the drug-associated environment (renewal), or the passage of time (spontaneous recovery). We describe a memory retrieval-extinction procedure that decreases conditioned drug effects and drug seeking in rat models of relapse, and drug craving in abstinent heroin addicts. In rats, daily retrieval of drug-associated memories 10 minutes or 1 hour but not 6 hours before extinction sessions attenuated drug-induced reinstatement, spontaneous recovery, and renewal of conditioned drug effects and drug seeking. In heroin addicts, retrieval of drug-associated memories 10 minutes before extinction sessions attenuated cue-induced heroin craving 1, 30, and 180 days later. The memory retrieval-extinction procedure is a promising nonpharmacological method for decreasing drug craving and relapse during abstinence.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Abstract
Symbolic regression (SR) is an approach of interpretable machine learning for building mathematical formulas that best fit certain datasets. In this work, SR is used to guide the design of ...new oxide perovskite catalysts with improved oxygen evolution reaction (OER) activities. A simple descriptor,
μ
/
t
, where
μ
and
t
are the octahedral and tolerance factors, respectively, is identified, which accelerates the discovery of a series of new oxide perovskite catalysts with improved OER activity. We successfully synthesise five new oxide perovskites and characterise their OER activities. Remarkably, four of them, Cs
0.4
La
0.6
Mn
0.25
Co
0.75
O
3
, Cs
0.3
La
0.7
NiO
3
, SrNi
0.75
Co
0.25
O
3
, and Sr
0.25
Ba
0.75
NiO
3
, are among the oxide perovskite catalysts with the highest intrinsic activities. Our results demonstrate the potential of SR for accelerating the data-driven design and discovery of new materials with improved properties.
The frequently observed forest decline in water‐limited regions may be associated with impaired tree hydraulics, but the precise physiological mechanisms remain poorly understood. We compared ...hydraulic architecture of Mongolian pine (Pinus sylvestris var. mongolica) trees of different size classes from a plantation and a natural forest site to test whether greater hydraulic limitation with increasing size plays an important role in tree decline observed in the more water‐limited plantation site. We found that trees from plantations overall showed significantly lower stem hydraulic efficiency. More importantly, plantation‐grown trees showed significant declines in stem hydraulic conductivity and hydraulic safety margins as well as syndromes of stronger drought stress with increasing size, whereas no such trends were observed at the natural forest site. Most notably, the leaf to sapwood area ratio (LA/SA) showed a strong linear decline with increasing tree size at the plantation site. Although compensatory adjustments in LA/SA may mitigate the effect of increased water stress in larger trees, they may result in greater risk of carbon imbalance, eventually limiting tree growth at the plantation site. Our results provide a potential mechanistic explanation for the widespread decline of Mongolian pine trees in plantations of Northern China.
Hydraulic failure has been proposed as an important reason causing tree die‐off in vast areas of water‐limited land across the globe, especially under the influence of climate change, but the underlying mechanisms remain poorly understood. Decline has been more frequently observed in larger trees, and significant changes in hydraulic architecture are also commonly found with increasing tree size, suggesting a mechanistic linkage between tree decline and hydraulic limitations mediated by variation in tree size. Here, we compared hydraulic architecture of Pinus sylvestris var. mongolica trees between a plantation and a natural forest site across different tree size classes to test whether greater hydraulic limitation in larger trees is responsible for tree decline in the more water‐limited plantation site. We observed clear contrasts in hydraulic‐related characteristics between trees of the 2 sites and found clear trends of change in these traits with increasing tree size at the plantation site but not at the natural forest site, which provide a potential mechanistic explanation for the widespread decline of this species in plantations of Northern China.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Extensive research has reported that the tumor microenvironment components play crucial roles in tumor progression. Thus, blocking the supports of tumor microenvironment is a promising approach to ...prevent cancer progression. We aimed to determine whether blocking extracellular ATP-P2RY2 axis could be a potential therapeutic approach for PDAC treatment.
Expression of P2RY2 was determined in 264 human PDAC samples and correlated to patient survival. P2RY2 was inhibited in human PDAC cell lines by antagonist and shRNA, respectively, and cell viability, clonogenicity, and glycolysis were determined. RNA sequencing of PDAC cell line was applied to reveal underlying molecular mechanisms. Multiple PDAC mouse models were used to assess the effects of the P2RY2 inhibition on PDAC progression.
P2RY2 was upregulated and associated with poor prognosis in PDAC. Activated P2RY2 by increased extracellular ATP in tumor microenvironment promoted PDAC growth and glycolysis. Further studies showed that the agonist-activated P2RY2 triggered PI3K/AKT-mTOR signaling by crosstalk with PDGFR mediated by Yes1, resulting in elevated expression of c-Myc and HIF1α, which subsequently enhanced cancer cell glycolysis. Genetic and pharmacologic inhibition of P2RY2 impaired tumor cell growth in subcutaneous and orthotopic xenograft model, as well as delayed tumor progression in inflammation-driven PDAC model. In addition, synergy was observed when AR-C118925XX, the selective antagonist of P2RY2 receptor, and gemcitabine were combined, resulting in prolonged survival of xenografted PDAC mice.
These findings reveal the roles of the P2RY2 in PDAC metabolic reprogramming, suggesting that P2RY2 might be a potential metabolic therapeutic target for PDAC.
The tea-like beverage
Bertoni (
) is popular in China because it reduces blood glucose and has a sweet taste. In this work, a comprehensive quality assessment of
led to the discovery of five ...phenylethanoid glycosides, namely steviophethanoside (
), cuchiloside (
), salidroside (
), icariside D (
), and tyrosol (
). Of them, compound
is a novel compound. Mass spectrometry and NMR spectroscopy were employed to confirm the absolute configuration. A hydrolytic step with 4 N TFA at 95 °C for 4 h was used to confirm the monosaccharides. In addition, Discovery Studio 4.0 was used to predict the ADME and toxicity activity of compound
. The results suggested that compound
was biocompatible and had poor toxicity, which was verified by rat INS-1 islet β cells through an MTT assay. Meanwhile, a significant stimulatory effect on INS-1 cells was observed, which indicated a hypoglycemic effect of compound
. This is the first report that describes a natural, novel, and hypoglycemic phenylethanoid glycoside in
.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The safety and health benefits of Tai Chi mind-body exercise has been documented in a large number of clinical studies focused on specific diseases and health conditions. The objective of this ...systematic review is to more comprehensively summarize the evidence base of clinical studies of Tai Chi for healthcare.
We searched for all types of clinical studies on Tai chi in PubMed, the Cochrane Library and four major Chinese electronic databases from their inception to July 2013. Data were analyzed using SPSS17.0 software. A total of 507 studies published between 1958 and 2013 were identified, including 43 (8.3%) systematic reviews of clinical studies, 255 (50.3%) randomized clinical trials, 90 (17.8%) non-randomized controlled clinical studies, 115 (22.7%) case series and 4 (0.8%) case reports. The top 10 diseases/conditions was hypertension, diabetes, osteoarthritis, osteoporosis or osteopenia, breast cancer, heart failure, chronic obstructive pulmonary disease, coronary heart disease, schizophrenia, and depression. Many healthy participants practiced Tai Chi for the purpose of health promotion or preservation. Yang style Tai Chi was the most popular, and Tai Chi was frequently practiced two to three 1-hour sessions per week for 12 weeks. Tai Chi was used alone in more than half of the studies (58.6%), while in other studies Tai Chi was applied in combination with other therapies including medications, health education and other physical therapies. The majority of studies (94.1%) reported positive effects of Tai Chi, 5.1% studies reported uncertain effects and 0.8% studies reported negative effects. No serious adverse events related to Tai Chi were reported.
The quantity and evidence base of clinical studies on Tai Chi is substantial. However, there is a wide variation in Tai Chi intervention studied and the reporting of Tai Chi intervention needs to be improved. Further well-designed and reported studies are recommended to confirm the effects of Tai Chi for the frequently reported diseases/conditions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Layered oxides have become the research focus of cathode materials for sodium‐ion batteries (SIBs) due to the low cost, simple synthesis process, and high specific capacity. However, the poor air ...stability, unstable phase structure under high voltage, and slow anionic redox kinetics hinder their commercial application. In recent years, the concept of manipulating orbital hybridization has been proposed to simultaneously regulate the microelectronic structure and modify the surface chemistry environment intrinsically. In this review, the hybridization modes between atoms in 3d/4d transition metal (TM) orbitals and O 2p orbitals near the region of the Fermi energy level (EF) are summarized based on orbital hybridization theory and first‐principles calculations as well as various sophisticated characterizations. Furthermore, the underlying mechanisms are explored from macro‐scale to micro‐scale, including enhancing air stability, modulating high working voltage, and stabilizing anionic redox chemistry. Meanwhile, the origin, formation conditions, and different types of orbital hybridization, as well as its application in layered oxide cathodes are presented, which provide insights into the design and preparation of cathode materials. Ultimately, the main challenges in the development of orbital hybridization and its potential for the production application are also discussed, pointing out the route for high‐performance practical sodium layered oxide cathodes.
Based on orbital hybridization theory, the challenges of layered oxide cathodes in terms of air stability, high voltage, anion redox chemistry, and improving the intrinsic characteristics through interactions between the 3d/4d transition metal and the O 2p atomic orbitals are summarized. This strategy of modulating orbitals hybridization will promote the development of sodium layered oxide cathodes and its commercialization process.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Genomic landscapes of 92 adult and 111 pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) were investigated using next-generation sequencing and copy number alteration analysis. ...Recurrent gene mutations and fusions were tested in an additional 87 adult and 93 pediatric patients. Among the 29 newly identified in-frame gene fusions, those involving MEF2D and ZNF384 were clinically relevant and were demonstrated to perturb B-cell differentiation, with EP300-ZNF384 inducing leukemia in mice. Eight gene expression subgroups associated with characteristic genetic abnormalities were identified, including leukemia with MEF2D and ZNF384 fusions in two distinct clusters. In subgroup G4 which was characterized by ERG deletion, DUX4-IGH fusion was detected in most cases. This comprehensive dataset allowed us to compare the features of molecular pathogenesis between adult and pediatric B-ALL and to identify signatures possibly related to the inferior outcome of adults to that of children. We found that, besides the known discrepancies in frequencies of prognostic markers, adult patients had more cooperative mutations and greater enrichment for alterations of epigenetic modifiers and genes linked to B-cell development, suggesting difference in the target cells of transformation between adult and pediatric patients and may explain in part the disparity in their responses to treatment.
•The genomic landscapes of adult and pediatric B-ALL were defined by next-generation sequencing of patient samples.•MEF2D and ZNF384 fusions could perturb B-cell differentiation or induce leukemia in mice and exhibited clinical relevance.•Adult patients showed greater enrichment for alterations of genes linked to epigenetic modification and B-cell development.
This study comprehensively addressed the genomic signatures of adult versus pediatric B-ALL. The identification of distinct MEF2D and ZNF384 fusions expands the existing knowledge about molecular subtypes of B-ALL in both age groups. RNA-seq data allowed most of the B-ALL cases to be clustered into 8 subgroups related to genetic abnormalities. Notably, adult patients have more cooperative sequence variation mutations than pediatric patients, especially in genes involved in epigenetic regulation and B-cell development. These findings may improve our understanding of leukemogenesis in B-ALL, leading to a more precise genetic classification and the further development of targeted therapy in this disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Threat and extinction memories are crucial for organisms’ survival in changing environments. These memories are believed to be encoded by separate ensembles of neurons in the brain, but ...their whereabouts remain elusive. Using an auditory fear-conditioning and extinction paradigm in male mice, here we discovered that two distinct projection neuron subpopulations in physical proximity within the insular cortex (IC), targeting the central amygdala (CeA) and nucleus accumbens (NAc), respectively, to encode fear and extinction memories. Reciprocal intracortical inhibition of these two IC subpopulations gates the emergence of either fear or extinction memory. Using rabies-virus-assisted tracing, we found IC-NAc projection neurons to be preferentially innervated by intercortical inputs from the orbitofrontal cortex (OFC), specifically enhancing extinction to override fear memory. These results demonstrate that IC serves as an operation node harboring distinct projection neurons that decipher fear or extinction memory under the top-down executive control from OFC.
Huperzine A (HupA), derived from Huperzia Serrata, has exhibited a variety of biological actions, in particular neuroprotective effect. However, the protective activities of HupA on murine embryonic ...fibroblast NIH3T3 cells after X‐rays radiation have not been fully elucidated. Herein, HupA treatment dramatically promoted cell viability, abated a G0/G1 peak accumulation, and ameliorated increase of cell apoptosis in NIH3T3 cells after X‐rays radiation. Simultaneously, HupA notably enhanced activities of anti‐oxidant enzymes, inhibited activity of lipid peroxide, and efficiently eliminated production of reactive oxygen species in NIH3T3 cells after X‐rays radiation. Dose‐dependent increase of antioxidant genes by HupA were associated with up‐regulated Nrf2 and down‐regulated Keap‐1 expression, which was confirmed by increasing nuclear accumulation, and inhibiting of degradation of Nrf2. Notably, augmented luciferase activity of ARE may explained Nrf2/ARE‐mediated signaling pathways behind HupA protective properties. Moreover, expression of Nrf2 HupA‐mediated was significant attenuated by AKT inhibitor (LY294002), p38 MAPK inhibitor (SB202190) and ERK inhibitor (PD98059). Besides, HupA‐mediated cell viability, and ROS production were dramatically bated by LY294002, SB202190, and PD98059. Taken together, HupA effectively ameliorated X‐rays radiation‐induced damage Nrf2‐ARE‐mediated transcriptional response via activation AKT, p38, and ERK signaling in NIH3T3 cells.
1. HupA notably enhanced activities of anti‐oxidant enzymes, inhibited activity of lipid peroxide, and efficiently eliminated production of reactive oxygen species in NIH3T3 cells X‐rays radiation‐induced. 2. HupA effectively ameliorated X‐rays radiation‐induced damage Nrf2‐ARE‐mediated transcriptional response via activation AKT, p38, and ERK signaling in NIH3T3 cells.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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