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Background: Alterations in levels of peripheral insulin-like growth factor-1 (IGF-1) in Alzheimer's disease (AD) have been reported in several studies, and results are inconsistent.Objective: We conducted a meta-analysis to investigate the relationship between peripheral and cerebrospinal fluid IGF-1 levels and AD or mild cognitive impairment (MCI).Methods: A systematic search in PubMed, Medline, Web of Science, Embase, and Cochrane Library was conducted and 18 studies were included.Results: Results of random-effects meta-analysis showed that there was no significant difference between AD patients and healthy control (17 studies; standard mean difference [SMD], -0.01; 95%CI, -0.35 to 0.32) and between MCI patients and healthy control (6 studies; SMD, -0.20; 95%CI, -0.52 to 0.13) in peripheral IGF-1 levels. Meta-regression analyses identified age difference might explain the heterogeneity (p = 0.017). However, peripheral IGF-1 levels were significantly decreased in AD subjects (9 studies; SMD, -0.44; 95%CI, -0.81 to -0.07) and MCI subjects exhibited a decreasing trend (4 studies; SMD, -0.31; 95%CI, -0.72 to 0.11) in studies with sample size≥80. Cerebrospinal fluid IGF-1 levels also significantly decreased in AD subjects (3 studies; SMD, -2.40; 95%CI, -4.36 to -0.43).Conclusion: These findings suggest that decreased peripheral and cerebrospinal fluid IGF-1 levels might be a potential marker for the cognitive decline and progression of AD. [ABSTRACT FROM AUTHOR]

Saving energy is essential for mitigating environmental harm, and convincing consumers to purchase energy-efficient products repeatedly represents a challenge for sustainable development. On the basis of motivation theory, this study developed a theoretical model to explore how the needs-based motivations (i.e., the need to feel unique and the need for social approval) of existing consumers of energy-efficient products affect their attitudes and repurchase intention of such products. People who had purchased energy-efficient products were asked to participate in a survey, and data were collected from 400 consumers. Structural equation modeling was employed for analysis. The results indicated that existing consumers of energy-efficient products who exhibited a greater need for uniqueness and social approval had a more positive attitude toward energy-efficient products. Existing consumers with a greater need for social approval exhibited an increased willingness to repurchase energy-efficient products. In addition, the attitudes of these consumers toward energy-efficient products positively influenced their repurchase intention. The aforementioned findings suggest that green marketers can encourage existing consumers to continue buying energy-efficient products by enhancing the uniqueness and social value of these products. [ABSTRACT FROM AUTHOR]

The extinct fern genus Coniopteris Brongniart represents a common component of the Mesozoic dicksoniaceous ferns. New materials of Coniopteris preserved with both sterile and fertile pinnae, are described from the Middle Jurassic Haifanggou Formation in Beipiao of western Liaoning, Northeast China. Totally two species, i.e., C. burejensis and C. bella , were recognized. The gross morphology of the present specimens indicates that both the species were hemidimorphic in frond type. A detailed investigation on the in - situ spores of C. burejensis and C. bella shows that they are morphologically similar to the dispersed spores Deltoidospora perpusilla and D. cf. turgidorimasa , respectively. Additionally, based on available data on fossil records, the fossil diversity and spatio-temporal distribution pattern of Chinese Coniopteris are systematically reviewed and summarized. The results show that over sixty Coniopteris species have been recorded in China, ranging from the Early Jurassic to Early Cretaceous in time, and particularly flourished in two geological time intervals, i.e., the Middle Jurassic and the Early Cretaceous. Palaeogeographically, Coniopteris fossils were found throughout China in the Early Jurassic; and they mostly occurred in northern China during the Middle Jurassic; thereafter, they were restricted in northeastern China in the Early Cretaceous. • Both Coniopteris burejensis and C. bella have hemidimorphic fronds. • In-situ spores of C. burejensis and C. bella are morphologically described. • The spatio-temporal distribution Chinese Coniopteris is summarized. [ABSTRACT FROM AUTHOR]

Aims: This study investigated the relationship between plasma Wnt2b levels and Alzheimer's disease (AD), and explored the effect of Wnt2b on mitochondrial dysfunction in AD. Methods: Healthy and AD subjects, AD transgenic mice, and in vitro models were used to investigate the roles of Wnt2b in abnormalities in canonical Wnt signaling and mitochondria in AD. RT‐qPCR, immunoblotting, and immunofluorescence analysis were performed to assay canonical Wnt signaling. Mitochondrial structure was analyzed by electron microscopy. Flow cytometry was used to examine the intracellular calcium and neuronal apoptosis. Results: Plasma Wnt2b levels were lower in AD patients and positively correlated with cognitive performance. Similarly, Wnt2b was reduced in the hippocampus of AD mice and in vitro models. Next, Wnt2b overexpression and recombinant Wnt2b were used to endogenously and exogenously upregulate Wnt2b levels. Upregulation of Wnt2b could effectively prevent downregulation of canonical Wnt signaling, mitochondrial dysfunction in in vitro AD models. Subsequently, intracellular calcium overload and neuronal damage were ameliorated. Conclusions: Our study highlights that Wnt2b decline is associated with cognitive impairment in AD, and upregulation of Wnt2b can exert neuroprotective effects in AD, particularly in ameliorating mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Exact solutions of the Einstein-Maxwell equations for spherically symmetric charged perfect fluid have been broadly studied so far. However, the cases with a nonzero cosmological constant are seldom focused. In the present paper, the Tolman-Oppenheimer-Volkoff (TOV) equations have been generalized from the neutral case of hydrostatic equilibrium to the charged case of hydroelectrostatic equilibrium, and base on it, for the first time we find a series of new exact solutions of Einstein-Maxwell's equations with a nonzero cosmological constant for static charged perfect fluid spheres. Moreover, two special TOV equations and two classical constant density interior solutions are also given. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common form of neurodegenerative dementia among the elderly. Excitotoxicity has been implicated as playing a dominant role in AD, especially related to the hyperactivation of excitatory neurons. Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin-dependent kinase and involved in the pathogenesis of AD, but the roles and mechanisms of DAPK1 in excitotoxicity in AD are still uncertain. Objective: We mainly explored the underlying mechanisms of DAPK1 involved in the excitotoxicity of AD and its clinical relevance. Methods: Differentiated SH-SY5Y human neuroblastoma cells, PS1 V97 L transgenic mice, and human plasma samples were used. Protein expression was assayed by immunoblotting, and intracellular calcium and neuronal damage were analyzed by flow cytometry. Plasma DAPK1 was measured by ELISA. Results: We found that DAPK1 was activated after amyloid-β oligomers (AβOs) exposure in differentiated SH-SY5Y cells. Besides, we found the phosphorylation of GluN2B subunit at Ser1303 was increased, which contributing to excitotoxicity and Ca2+ overload in SH-SY5Y cells. Inhibiting DAPK1 activity, knockdown of DAPK1 expression, and antagonizing GluN2B subunits could effectively prevent AβOs-induced activation of GluN2B subunit, Ca2+ overload, and neuronal apoptosis. Additionally, we found that DAPK1 was elevated in the brain of AD transgenic mouse and in the plasma of AD patients. Conclusion: Our finding will help to understand the mechanism of DAPK1 in the excitotoxicity in AD and provide a reference for the diagnosis and therapy of AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common form of neurodegenerative dementia among the elderly. Excitotoxicity has been implicated as playing a dominant role in AD, especially related to the hyperactivation of excitatory neurons. Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin-dependent kinase and involved in the pathogenesis of AD, but the roles and mechanisms of DAPK1 in excitotoxicity in AD are still uncertain. Objective: We mainly explored the underlying mechanisms of DAPK1 involved in the excitotoxicity of AD and its clinical relevance. Methods: Differentiated SH-SY5Y human neuroblastoma cells, PS1 V97 L transgenic mice, and human plasma samples were used. Protein expression was assayed by immunoblotting, and intracellular calcium and neuronal damage were analyzed by flow cytometry. Plasma DAPK1 was measured by ELISA. Results: We found that DAPK1 was activated after amyloid-β oligomers (AβOs) exposure in differentiated SH-SY5Y cells. Besides, we found the phosphorylation of GluN2B subunit at Ser1303 was increased, which contributing to excitotoxicity and Ca2+ overload in SH-SY5Y cells. Inhibiting DAPK1 activity, knockdown of DAPK1 expression, and antagonizing GluN2B subunits could effectively prevent AβOs-induced activation of GluN2B subunit, Ca2+ overload, and neuronal apoptosis. Additionally, we found that DAPK1 was elevated in the brain of AD transgenic mouse and in the plasma of AD patients. Conclusion: Our finding will help to understand the mechanism of DAPK1 in the excitotoxicity in AD and provide a reference for the diagnosis and therapy of AD. [ABSTRACT FROM AUTHOR]

Depression, a common neurological condition, is one of the leading causes of disability and suicide worldwide. Standard treatment, targeting monoamine transporters selective for the neurotransmitters serotonin and noradrenaline, is not able to help many patients that are poor responders. This study advances the development of sazetidine-A analogues that interact with α4β2 nicotinic acetylcholine receptors (nAChRs) as partial agonists and that possess favorable antidepressant profiles. The resulting compounds that are highly selective for the α4β2 subtype of nAChR over α3β4-nAChRs are partial agonists at the α4β2 subtype and have excellent antidepressant behavioral profiles as measured by the mouse forced swim test. Preliminary absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies for one promising ligand revealed an excellent plasma protein binding (PPB) profile, low CYP450-related metabolism, and low cardiovascular toxicity, suggesting it is a promising lead as well as a drug candidate to be advanced through the drug discovery pipeline. [ABSTRACT FROM AUTHOR]

The first total synthesis of lathyranoic acid A (1) was accomplished stereoselectively in a linear sequence of 20 steps and an overall yield of 1.4%. This modular synthesis featured a cyclic, stereocontrolled Cu-catalyzed intramolecular cyclopropanation to construct the cis-cyclopropane unit, a Grubbs metathesis to construct the γ-substituted cyclopentenone moiety, and an anion-mediated conjugate addition. [ABSTRACT FROM AUTHOR]

Neural stem cell differentiation and the determination of lineage decision between neuronal and glial fates have important implications in the study of developmental, pathological, and regenerative processes. Although small molecule chemicals with the ability to control neural stem cell fate are considered extremely useful tools in this field, few were reported. AICAR is an adenosine analog and extensively used to activate AMP-activated protein kinase (AMPK), a metabolic "fuel gauge" of the biological system. In the present study, we found an unrecognized astrogliogenic activity of AICAR on not only immortalized neural stem cell line C17.2 (C17.2-NSC), but also primary neural stem cells (NSCs) derived from post-natal (P0) rat hippocampus (P0-NSC) and embryonic day 14 (E14) rat embryonic cortex (E14-NSC). However, another AMPK activator, Metformin, did not alter either the C17.2-NSC or E14-NSC undifferentiated state although both Metformin and AICAR can activate the AMPK pathway in NSC. Furthermore, overexpression of dominant-negative mutants of AMPK in C17.2-NSC was unable to block the gliogenic effects of AICAR. We also found AICAR could activate the Janus kinase (JAK) STAT3 pathway in both C17.2-NSC and E14-NSC but Metformin fails. JAK inhibitor I abolished the gliogenic effects of AICAR. Taken together, these results suggest that the astroglial differentiation effect of AICAR on neural stem cells was acting independently of AMPK and that the JAK-STAT3 pathway is essential for the gliogenic effect of AICAR. [ABSTRACT FROM AUTHOR]

The growing number of industrial carbon emissions have resulted in a significant increase in the greenhouse gas carbon dioxide (CO 2), which, in turn, will have a major impact on climate change. Therefore, the reduction, storage, and reuse of CO 2 is an important concern in modern society. Calcium oxide (CaO) is known to be an excellent adsorbent of CO 2 in a high-temperature environment. However, since deterioration of the adsorbent is likely to occur after repeated cycles of adsorption under high temperature conditions, it would be desirable to mitigate this phenomenon, in order to maintain the stability of CaO. In the present study, common eggshell waste was used as the starting material. The main component of eggshell waste is calcium carbonate (CaCO 3), which was purified to produce CaO. Different surfactants and amino-containing polymers were added to synthesize CaO-based adsorbents with different configurations and pore sizes. The amount of CO 2 adsorbed was determined using a thermogravimetric analyzer (TGA). The results showed that the CO 2 adsorption capacity of the synthetic CaO recovered from purified eggshell waste could reach 0.6 g-CO 2 /g-sorbent, indicating a good adsorption capacity. CaO modified with a dopamine-containing polymer was shown to have an adsorption capacity of 0.62 g-CO 2 /g-sorbent. Moreover, it showed an excellent adsorption capacity of 0.40 g-CO 2 /g-sorbent, even after 10 cycles of CO 2 adsorption. The present study suggests that using eggshell waste to synthesize CaO-based adsorbents for effective CO 2 adsorption can not only reduce environmental waste, but also have the potential to capture greenhouse gas CO 2 emissions, which conforms to the principles of green chemistry. [Display omitted] • CaO prepared from eggshell was applied for CO 2 gas adsorption. • Pore size and volume of CaO were varied by using surfactants and amino containing polymers. • Through thermogravimetry analysis amount of CO 2 adsorbed were analyzed. • CaO prepare from dopamine containing polymer showed excellent adsorption capacity. [ABSTRACT FROM AUTHOR]

Gravitational waves (GWs) from extra dimensions, very early universe, and some high-energy astrophysical processes might have at most six polarization states: tensor- and nontensor-mode gravitons. The peak regions or partial peak regions (of the amplitudes or energy densities) of some of such GWs are just distributed in the GHz or higher frequency band, which would be an optimal frequency band for the electromagnetic (EM) response to such high-frequency GWs (HFGWs). In this paper we investigate the EM response to the HFGWs, and for the first time we obtain the concrete form of analytic solutions of the perturbative EM fields caused by all six possible polarizations of the HFGWs in the background stable EM fields and in the proposed three dimensional synchro-resonance system (3DSR system), respectively. It is found that all such six polarizations may in principle show separability and detectability. Moreover, the detection frequency band ( ∼ 10 8 to 10 12 Hz or higher) of the signal photon fluxes by the 3DSR system and the observation frequency range ( ∼ 7 × 10 7 to 3 × 10 9 Hz) of the signals by the FAST (Five-hundred-meter Aperture Spherical Telescope, China) have a certain overlapping property, and thus their coincidence experiments in the future for observations will have high complementarity. [ABSTRACT FROM AUTHOR]

Interaction between the gravitational waves (GWs) and the strong magnetic fields would lead to the perturbed electromagnetic waves (EMWs). Magnetars can have ultra-strong surface magnetic fields ∼ 10 11 Tesla, and meanwhile, they would generate the thermal high-frequency GWs (HFGWs) caused by the Fermi liquid phonons and the gravitational bremsstrahlung inside. Here, we for the first time address the perturbed EMWs caused by such thermal-HFGWs interacting with the ultra-strong surface magnetic fields of the magnetars. It is expected that the perturbed EMWs would distribute in very characteristic patterns that have never been predicted before, which may deliver and reflect the crucial information of the polarizations (tensorial and possible nontensorial) of the thermal-HFGWs and the particular features of the structures of magnetars. The estimated power density of such perturbed EMWs would reach ∼ 10 6 –108 W/m2 in the area around the surface of magnetar, and the strengths of perturbed EMWs in the observational direction would appear in characteristic pulse-like envelopes. Obtained results may suggest the novel effect of potential evidences of the possible nontensorial GWs, the thermal-HFGWs from magnetars, the mechanism of EM response to the GWs, and the models of magnetars and their magnetic fields. [ABSTRACT FROM AUTHOR]

Aluminium‐based metal–organic framework (MOF) coatings on polystyrene bead surfaces were easily synthesized by reacting an intermediate metal hydroxide coating with an organic linker. Several different sizes of polystyrene beads were coated with aluminium metal hydroxide to construct Al@PS core–shell bead materials. The activated Al@PS core–shell beads were involved to make a homogenous MOF‐based layer in the presence of the organic linker. By using different sizes of the PS support the size of MOFs on the PS composites could be fine‐tuned under specific reaction conditions. MOF‐coated core–shell bead materials (Al‐1,4‐NDC@PS and MIL‐53(Al)@PS) were characterized using various analytical techniques. Al‐1,4‐NDC@PS and MIL‐53(Al)@PS were evaluated for solid‐phase microextraction (SPME) of hydrophobic polycyclic aromatic hydrocarbons (PAHs) and hydrophilic non‐steroidal anti‐inflammatory drugs (NSAIDs), respectively. Al‐1,4‐NDC@PS‐1000 displayed high extraction recoveries ranging from 79.2 % to 99.8 % in the SPME of PAHs. Meanwhile, MIL‐53(Al)@PS‐1000 showed 85.9–99.0 % extraction recoveries in the SPME of NSAIDs. These results show that the proposed approach holds potential to extract organic analytes on an industrial scale. [ABSTRACT FROM AUTHOR]

Broad network (BN) is commonly used as an efficient and computationally inexpensive machine learning method. The flat structure of BN ensures the efficiency of model learning, but in the mean time the structural characteristics also affect the network performances, such as generalization. However, it is challenging to improve the BN's generalization performance via adjusting its structure based on certain specific criteria. In this paper, to get the required network structure, a self-organizing BN based on the information evaluation method (IE-SOBN) is designed. First, a capability evaluation metric (CEM) is introduced into BN, which can evaluate the ability of hidden neurons to express and transmit data information. Then, the evaluation metric obtained by CEM is used as the basis for structure adjustment. Second, a structure adjustment mechanism (SAM) based on CEM is proposed to dynamically optimize the BN structure, leading to an improved generalization performance. Third, the convergence of the suggested IE-SOBN is theoretically analyzed to ensure its effectiveness. Finally, the advantages of IE-SOBN are verified by three real applications. The generalization performance and test accuracy of the proposed IE-SOBN are satisfactory in the experiments. [ABSTRACT FROM AUTHOR]

Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure-activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form coumestans that are shown to be active in SIT. Whole genome deep sequencing of the coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of this target for the development of new antitubercular agents. [ABSTRACT FROM AUTHOR]

Selective CB2 agonists represent an attractive therapeutic strategy for the treatment of a variety of diseases without psychiatric side effects mediated by the CB1 receptor. We carried out a rational optimization of a black market designer drug SDB-001 that led to the identification of potent and selective CB2 agonists. A 7-methoxy or 7-methylthio substitution at the 3-amidoalkylindoles resulted in potent CB2 antagonists (27 or 28, IC50 = 16-28 nM). Replacement of the amidoalkyls from 3-position to the 2-position of the indole ring dramatically increased the agonist selectivity on the CB2 over CB1 receptor. Particularly, compound 57 displayed a potent agonist activity on the CB2 receptor (EC50 = 114-142 nM) without observable agonist or antagonist activity on the CB1 receptor. Furthermore, 57 significantly alleviated the clinical symptoms and protected the murine central nervous system from immune damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. [ABSTRACT FROM AUTHOR]

A novel series of sigma (σ) receptor ligands based on an alkoxyisoxazole scaffold has been designed and synthesized. Preliminary receptor binding assays identified highly potent (Ki < 1 nM) and selective σ1 ligands devoid of binding interactions with the monoamine transporters DAT, NET, and SERT. In particular, compound 53 was shown to possess significant antinociceptive activity in the mouse formalin-induced inflammation pain model when administered intraperitoneally at 40 and 80 mg/kg. Initial pharmacokinetics evaluation indicated an excellent brain exposure following oral dosing in mice, suggesting that further investigation into the use of alkoxyisoxazoles as σ1 ligands for antinociception is warranted. This study supports the notion that selective σ1 antagonism could be a useful strategy in the development of novel antipain therapy. [ABSTRACT FROM AUTHOR]

AMP-activated protein kinase (AMPK) serves as an energy sensor and is considered a promising drug target for treatment of type II diabetes and obesity. A previous report has shown that mammalian AMPK al catalytic subunit including autoinhibitory domain was inactive. To test the hypothesis that small molecules can activate AMPK through antagonizing the autoinhibition in a subunits, we screened a chemical library with inactive human a1394 (αl, residues 1-394) and found a novel small-molecule activator, PT1, which dose-dependently activated AMPK α1394, α1335, α2398, and even heterotrimer α1β1γ1. Based on PT1-docked AMPK α1 subunit structure model and different mutations, we found PT1 might interact with Glu-96 and Lys156 residues near the autoinhibitory domain and directly relieve autoinhibition. Further studies using L6 myotubes showed that the phosphorylation of AMPK and its downstream substrate, acetyl-CoA carboxylase, were dose-dependently and time-dependently increased by PT1 without an increase in cellular AMP:ATP ratio. Moreover, in HeLa cells deficient in LKB1, PT1 enhanced AMPK phosphorylation, which can be inhibited by the calcium/calmodulin-dependent protein kinase kinases inhibitor STO-609 and AMPK inhibitor compound C. PT1 also lowered hepatic lipid content in a dose-dependent manner through AMPK activation in HepG2 cells, and this effect was diminished by compound C. Taken together, these data indicate that this small-molecule activator may directly activate AMPK via antagonizing the autoinhibition in vitro and in cells. This compound highlights the effort to discover novel AMPK activators and can be a useful tool for elucidating the mechanism responsible for conformational change and autoinhibitory regulation of AMPK. [ABSTRACT FROM AUTHOR]