Silver nanoparticles alter planktonic community structure and promote ecosystem respiration in freshwater mesocosms.

The widespread use of silver nanoparticles (AgNPs) has resulted in their release into the aquatic environment, which threatens the health of aquatic ecosystems. Although the ecotoxicological effects of AgNPs have been widely reported at individual and population levels, the impact of long-term exposure to AgNPs on community structure and ecosystem function in aquatic ecosystems remains poorly understood. Herein, the present study investigated the effects of long-term exposure (28 d) to environmentally relevant concentrations (1 µg/L and 10 µg/L) of AgNPs on the community structure and function of freshwater ecosystems by artificially constructed 28 mesocosms freshwater ecosystem in experimental greenhouses, using plastic water tanks and food web manipulation. The results showed that long-term exposure to AgNPs significantly altered the community structure of zooplankton, phytoplankton, and bacterioplankton in the aquatic ecosystem. Exposure to 10 µg/L AgNPs significantly reduced the zooplankton density (70.3%, p < 0.05) and increased the phytoplankton biomass and bacterial richness and diversity via a "top-down effect." With regards to ecosystem function, AgNPs exposure significantly increased the respiration in freshwater ecosystems but did not have a significant effect on decomposition. The partial least squares path modeling (PLS-PM) further revealed that AgNPs may have a negative impact on ecosystem functions by reducing zooplankton community density and thus increasing phytoplankton biomass. This study is the first to show that long-term exposure to environmentally relevant concentrations of AgNPs leads to alterations in plankton community structure and promotes respiration in freshwater ecosystems. It emphasizes the need for assessing the environmental risk of long-term exposure to AgNPs at the ecosystem level.

mTORC1 Coordinates Protein Synthesis and Immunoproteasome Formation via PRAS40 to Prevent Accumulation of Protein Stress.

Reduction of translational fidelity often occurs in cells with high rates of protein synthesis, generating defective ribosomal products. If not removed, such aberrant proteins can be a major source of cellular stress causing human diseases. Here, we demonstrate that mTORC1 promotes the formation of immunoproteasomes for efficient turnover of defective proteins and cell survival. mTORC1 sequesters precursors of immunoproteasome ß subunits via PRAS40. When activated, mTORC1 phosphorylates PRAS40 to enhance protein synthesis and simultaneously to facilitate the assembly of the ß subunits for forming immunoproteasomes. Consequently, the PRAS40 phosphorylations play crucial roles in clearing aberrant proteins that accumulate due to mTORC1 activation. Mutations of RAS, PTEN, and TSC1, which cause mTORC1 hyperactivation, enhance immunoproteasome formation in cells and tissues. Those mutations increase cellular dependence on immunoproteasomes for stress response and survival. These results define a mechanism by which mTORC1 couples elevated protein synthesis with immunoproteasome biogenesis to protect cells against protein stress.

Genome-Wide Association Analysis of Effective Tillers in Rice under Different Nitrogen Gradients.

Nitrogen is a crucial element that impacts rice yields, and effective tillering is a significant agronomic characteristic that can influence rice yields. The way that reduced nitrogen affects effective tillering is a complex quantitative trait that is controlled by multiple genes, and its genetic basis requires further exploration. In this study, 469 germplasm varieties were used for a genome-wide association analysis aiming to detect quantitative trait loci (QTL) associated with effective tillering at low (60 kg/hm2) and high (180 kg/hm2) nitrogen levels. QTLs detected over multiple years or under different treatments were scrutinized in this study, and candidate genes were identified through haplotype analysis and spatio-temporal expression patterns. A total of seven genes (NAL1, OsCKX9, Os01g0690800, Os02g0550300, Os02g0550700, Os04g0615700, and Os04g06163000) were pinpointed in these QTL regions, and were considered the most likely candidate genes. These results provide favorable information for the use of auxiliary marker selection in controlling effective tillering in rice for improved yields.

Cascade Delivery to Golgi Apparatus and On-Site Formation of Subcellular Drug Reservoir for Cancer Metastasis Suppression.

As the foremost cause of cancer-related death, metastasis consists of three steps: invasion, circulation, and colonization. Only targeting one single phase of the metastasis cascade may be insufficient since there are many alternative routes for tumor cells to disseminate. Here, to target the whole cascade of metastasis, hybrid erythrocyte and tumor cell membrane-coated nanoparticle (Hyb-NP) is designed with dual functions of increasing circulation time and recognizing primary, circulating, and colonized tumors. After loading with monensin, a recently reported metastasis inhibitor, the delivery system profoundly reduces spontaneous metastasis in an orthotopic breast cancer model. Underlying mechanism studies reveal that Hyb-NP can deliver monensin to its action site in the Golgi apparatus, and in return, monensin can block the exocytosis of Hyb-NP from the Golgi apparatus, forming a reservoir-like subcellular structure. Notably, the Golgi apparatus reservoir displays three vital functions for suppressing metastasis initialization, including enhanced subcellular drug retention, metastasis-related cytokine release inhibition, and directional migration inhibition. Collectively, based on metastasis cascade targeting at the tissue level, further formation of the Golgi apparatus drug reservoir at the subcellular level provides a potential therapeutic strategy for cancer metastasis suppression.

A recurrent SHANK1 mutation implicated in autism spectrum disorder causes autistic-like core behaviors in mice via downregulation of mGluR1-IP3R1-calcium signaling.

The genetic etiology and underlying mechanism of autism spectrum disorder (ASD) remain elusive. SHANK family genes (SHANK1/2/3) are well known ASD-related genes. However, little is known about how SHANK missense mutations contribute to ASD. Here, we aimed to clarify the molecular mechanism of and the multilevel neuropathological features induced by Shank1 mutations in knock-in (KI) mice. In this study, by sequencing the SHANK1 gene in a cohort of 615 ASD patients and 503 controls, we identified an ASD-specific recurrent missense mutation, c.2621 G > A (p.R874H). This mutation demonstrated strong pathogenic potential in in vitro experiments, and we generated the corresponding Shank1 R882H-KI mice. Shank1 R882H-KI mice displayed core symptoms of ASD, namely, social disability and repetitive behaviors, without confounding comorbidities of abnormal motor function and heightened anxiety. Brain structural changes in the frontal cortex, hippocampus and cerebellar cortex were observed in Shank1 R882H-KI mice via structural magnetic resonance imaging. These key brain regions also showed severe and consistent downregulation of mGluR1-IP3R1-calcium signaling, which subsequently affected the release of intracellular calcium. Corresponding cellular structural and functional changes were present in Shank1 R882H-KI mice, including decreased spine size, reduced spine density, abnormal morphology of postsynaptic densities, and impaired hippocampal long-term potentiation and basal excitatory transmission. These findings demonstrate the causative role of SHANK1 in ASD and elucidate the underlying biological mechanism of core symptoms of ASD. We also provide a reliable model of ASD with core symptoms for future studies, such as biomarker identification and therapeutic intervention studies.

Ecotoxicology of microplastics in Daphnia: A review focusing on microplastic properties and multiscale attributes of Daphnia.

The ubiquitous presence of microplastics in aquatic environments is considered a global threat to aquatic organisms. Species of the genus Daphnia provide an important link between aquatic primary producers and consumers of higher trophic levels; furthermore, these organisms exhibit high sensitivity to various environmental pollutants. Hence, the biological effects of microplastics on Daphnia species are well documented. This paper reviews the latest research regarding the ecotoxicological effects of microplastics on Daphnia, including the: 1) responses of individual, population, and community attributes of Daphnia to microplastics; 2) influence of the physical and chemical properties of microplastics; and 3) joint toxicity of microplastics and other pollutants on responses of Daphnia. Our literature review found that the published literature does not provide sufficient evidence to reveal the risks of microplastics at the population and community levels. Furthermore, we emphasized that high-level analysis has more general implications for understanding how individual-level research can reveal the ecological hazards of microplastics on Daphnia. Based on this review, we suggest avenues for future research, including microplastic toxicology studies based on both omics-based and community-level methods, especially the latter.

Comparison of antihypertensive drugs amlodipine and perindopril on blood pressure variability after long-term treatment of hypertension induced by apatinib and bevacizumab.

The purpose of this study was to elucidate the therapeutic effect of different antihypertensive drugs (amlodipine and perindopril) on hypertension induced by apatinib and bevacizumab. Sixty patients with hypertension treated with apatinib or bevacizumab were selected and divided into two groups: one group was treated with amlodipine and the other group was treated with perindopril. Before and after treatment, the dynamic blood pressure (BP) measurement (systolic BP [SBP] and diastolic BP [DBP]), echocardiography (left ventricular end-diastolic diameter, interventricular septal thickness [IVST], left ventricular posterior wall thickness [LVPWT], and left atrial diameter [LAD]), and detection of nitric oxide (NO) content in venous blood were performed. In the amlodipine group, the 24hSBP, 24hSSD, 24hSCV, daytime mean SBP (dSBP), daytime mean SSD (dSSD), daytime mean SBP CV, night mean SBP (nSBP), night mean SSD, 24hDBP, 24hDSD, 24 h DBP CV, daytime mean DBP (dDBP), daytime mean DSD (dDSD), daytime mean DBP CV, night mean DBP (nDBP), LAD, and LAD index (LADi) after treatment were all lower than before treatment, while NO was higher than before treatment (all P < 0.05). In the perindopril group, the 24hSBP, dSBP, nSBP, 24hDBP, dDBP, nDBP, LAD, LADi, IVST, LVPWT, and left ventricular mass index (LVMI) after treatment were lower than before treatment, and NO level after treatment was higher than before treatment (all P < 0.05). After treatment, the 24hSBP, 24hSSD, dSBP, dSSD, nSBP, 24hDBP, 24hDSD, dDBP, dDSD, nDBP, night mean DSD, and NO were all lower while the LAD, LADi, IVST, LVPWT, and LVMI were higher in the amlodipine group than those in the perindopril group (all P < 0.05). Our study suggests that the SBP and DBP variability of amlodipine in the treatment of hypertension induced by apatinib and bevacizumab is slightly better than that of perindopril, but the effect of perindopril in improving endothelial function indices NO and echocardiographic data is better than that of amlodipine.

A Quantitative Detection Algorithm for Multi-Test Line Lateral Flow Immunoassay Applied in Smartphones.

The traditional lateral flow immunoassay (LFIA) detection method suffers from issues such as unstable detection results and low quantitative accuracy. In this study, we propose a novel multi-test line lateral flow immunoassay quantitative detection method using smartphone-based SAA immunoassay strips. Following the utilization of image processing techniques to extract and analyze the pigments on the immunoassay strips, quantitative analysis of the detection results was conducted. Experimental setups with controlled lighting conditions in a dark box were designed to capture samples using smartphones with different specifications for analysis. The algorithm's sensitivity and robustness were validated by introducing noise to the samples, and the detection performance on immunoassay strips using different algorithms was determined. The experimental results demonstrate that the proposed lateral flow immunoassay quantitative detection method based on image processing techniques achieves an accuracy rate of 94.23% on 260 samples, which is comparable to the traditional methods but with higher stability and lower algorithm complexity.

5-((3-Amidobenzyl)oxy)nicotinamides as SIRT2 Inhibitors: A Study of Constrained Analogs.

SIRT2 is a member of NAD+-dependent sirtuins and its inhibition has been proposed as a promising therapeutic approach for treating human diseases, including neurodegenerative diseases, cancer, and infections. Expanding SIRT2 inhibitors based on the 3-aminobenzyloxy nicotinamide core structure, we have synthesized and evaluated constrained analogs and selected stereoisomers. Our structure-activity relationship (SAR) study has revealed that 2,3-constrained (S)-isomers possess enhanced in vitro enzymatic inhibitory activity against SIRT2 and retain excellent selectivity over SIRT1 and SIRT3, provided that a suitable ring A is used. This current study further explores SIRT2 inhibitors based on the 3-aminobenzyloxy nicotinamide scaffold and contributes to the discovery of potent, selective SIRT2 inhibitors that have been actively pursued for their potential therapeutic applications.

Cell Type-Specific Decrease of the Intrinsic Excitability of Motor Cortical Pyramidal Neurons in Parkinsonism.

The hypokinetic motor symptoms of Parkinson's disease (PD) are closely linked with a decreased motor cortical output as a consequence of elevated basal ganglia inhibition. However, whether and how the loss of dopamine (DA) alters the cellular properties of motor cortical neurons in PD remains undefined. We induced parkinsonism in adult C57BL/6 mice of both sexes by injecting neurotoxin, 6-hydroxydopamine (6-OHDA), into the medial forebrain bundle. By using ex vivo patch-clamp recording and retrograde tracing approach, we found that the intrinsic excitability of pyramidal tract neurons (PTNs) in the primary motor cortical (M1) layer (L)5b was greatly decreased in parkinsonism; but the intratelencephalic neurons (ITNs) were not affected. The cell type-specific intrinsic adaptations were associated with a depolarized threshold and broadened width of action potentials (APs) in PTNs. Moreover, the loss of midbrain dopaminergic neurons impaired the capability of M1 PTNs to sustain high-frequency firing, which could underlie their abnormal pattern of activity in the parkinsonian state. We also showed that the decreased excitability in parkinsonism was caused by an impaired function of both persistent sodium channels and the large conductance, Ca2+-activated K+ channels. Acute activation of dopaminergic receptors failed to rescue the impaired intrinsic excitability of M1 PTNs in parkinsonian mice. Altogether, our data demonstrated a cell type-specific decrease of the excitability of M1 pyramidal neurons in parkinsonism. Thus, intrinsic adaptations in the motor cortex provide novel insight in our understanding of the pathophysiology of motor deficits in PD.SIGNIFICANCE STATEMENT The degeneration of midbrain dopaminergic neurons in Parkinson's disease (PD) remodels the connectivity and function of cortico-basal ganglia-thalamocortical network. However, whether and how dopaminergic degeneration and the associated basal ganglia dysfunction alter motor cortical circuitry remain undefined. We found that pyramidal neurons in the layer (L)5b of the primary motor cortex (M1) exhibit distinct adaptations in response to the loss of midbrain dopaminergic neurons, depending on their long-range projections. Besides the decreased thalamocortical synaptic excitation as proposed by the classical model of Parkinson's pathophysiology, these results, for the first time, show novel cellular and molecular mechanisms underlying the abnormal motor cortical output in parkinsonism.

Redirecting Chemotherapeutics to the Endoplasmic Reticulum Increases Tumor Immunogenicity and Potentiates Anti-PD-L1 Therapy.

The endoplasmic reticulum (ER) in cancer cells has been considered as a pharmacological target. Still, the effects of a ER-targeted system remain less investigated, due to the fact that most chemo-drugs take actions in the nucleus. Here, it is demonstrated that ER-targeted delivery of doxorubicin (DOX), a typically nucleus-tropic-and-acting agent, attenuates its original effect on cytotoxicity while generating new functions favorable for immune activation. First, a library of DOX derivatives with variable ER-targeting abilities is synthesized. The results reveal that higher ER-targeting efficiency correlates with greater ER stress. As compared with naïve drug, ER-targeted DOX considerably alters the mode of action from nuclear DNA damage-associated cytotoxicity to ER stress-mediated calreticulin exposure. Consequently, ER-targeted DOX decreases cytotoxicity but increases the capability to induce immunogenic cell death (ICD). Therefore, a platform combining naïve and ER-targeted DOX is constructed for in vivo application. Conventional polymer-DOX conjugate inhibits tumor growth by exerting a direct killing effect, and ER-targeted polymer-DOX conjugate suppresses residual tumors by eliciting ICD-associated immunity, together resulting in considerable tumor regression. In addition, simultaneous inhibition of adaptive PD-L1 enrichment (due to negative-feedback to ICD induction) further leads to greater therapeutic outcome. Collectively, ER-targeted therapy can enhance anticancer efficacy by promoting ICD-associated immunotherapy, and potentiating chemotherapy and checkpoint blockade therapy.

Zika Virus Inhibitors Based on a 1,3-Disubstituted 1H-Pyrazolo[3,4-d]pyrimidine-amine Scaffold.

To search for Zika virus (ZIKV) antivirals, we have further explored previously reported 7H-pyrrolo[2,3-d]pyrimidines by examining an alternative substitution pattern of their central scaffold, leading to compound 5 with low micromolar antiviral activity. To circumvent the synthetic difficulties associated with compound 5, we have exploited a 1H-pyrazolo[3,4-d]pyrimidine scaffold and performed structure-activity relationship studies on its peripheral rings A and B. While ring B is less sensitive to structural modifications, an electron-withdrawing group at the para position of ring A is preferred for enhanced antiviral activity. Overall, we have not only discovered an alternative substitution pattern centered on a 1H-pyrazolo[3,4-d]pyrimidine scaffold but also generated anti-ZIKV compounds including 6 and 13, which possess low micromolar antiviral activity and relatively low cytotoxicity. These compounds represent new chemotypes that will be further optimized in our continued efforts to discover anti-ZIKV agents.

Microarray profile analysis identifies ETS1 as potential biomarker regulated by miR-23b and modulates TCF4 in gastric cancer.

BACKGROUND: Gastric cancer (GC), a common malignancy of the human digestive system, represents the second leading cause of cancer-related deaths worldwide. Early detection of GC has a significant impact on clinical outcomes. The aim of this study was to identify potential GC biomarkers. METHODS: In this study, we conducted a multi-step analysis of expression profiles in GC clinical samples downloaded from TCGA database to identify differentially expressed miRNAs (DEMs) and differentially expressed mRNAs (DEGs). Potential prognostic biomarkers from the available DEMs were then established using the Cox regression method. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to investigate the biological role of the predicted target genes of the miRNA biomarkers. Then, the prognostic DEM-mediated regulatory network was constructed based on transcription factor (TF)-miRNA-target interaction. Subsequently, the consensus genes were further determined based on the overlap between DEGs and these target genes of DEMs. Besides, expression profile, co-expression analysis, immunity, and prognostic values of these prognostic genes were also investigated to further explore the roles in the mechanism of GC tumorigenesis. RESULTS: We got five miRNAs, including miR-23b, miR-100, miR-143, miR-145, and miR-409, which are associated with the overall survival of GC patients. Subsequently, enrichment analysis of the target genes of the miRNA biomarkers shown that the GO biological process terms were mainly enriched in mRNA catabolic process, nuclear chromatin, and RNA binding. In addition, the KEGG pathways were significantly enriched in fatty acid metabolism, extracellular matrix (ECM) receptor interaction, and proteoglycans in cancer pathways. The transcriptional regulatory network consisting of 68 TFs, 4 DEMs, and 58 targets was constructed based on the interaction of TFs, miRNAs, and targets. The downstream gene ETS1 of miR-23b and TCF4 regulated by ETS1 were obtained by the regulatory network construction and co-expression analysis. High expression of ETS1 and TCF4 indicated poor prognosis in GC patients, particularly in the advanced stages. The expression of ETS1 and TCF4 was correlated with CD4+ T cells, CD8+ T cells, and B cells. CONCLUSIONS: miR-23b, ETS1, and TCF4 were identified as the prognostic biomarkers. ETS1 and TCF4 had potential immune function in GC, which provided a theoretical basis for molecular-targeted combined immunotherapy in the future.

Metabolic profiling of nanosilver toxicity in the gills of common carp.

Studies have shown silver nanoparticles (AgNPs) exposure can result in a series of toxic effects in fish gills. However, it is still unclear how AgNPs affect metabolite expression and their related molecular metabolic pathways in fish gills. In this study, we employed untargeted metabolomics to study the effects of AgNPs and silver supernatant ions on fish gill metabolites. The results showed that AgNPs can induce significant changes in 96 differentially expressed metabolites, which mainly affect amino acid metabolism and energy metabolism in fish gills. Among these metabolites, AgNPs specifically induce significant changes in 72 differentially expressed metabolites, including L-histidine, L-isoleucine, L-phenylalanine, and citric acid. These metabolites were significantly enriched in the pathways of aminoacyl-tRNA biosynthesis, ABC transporters, and the citrate cycle. In contrast, Ag+ supernatant exposure can specifically induce significant changes in 14 differentially expressed metabolites that mainly interfere with sphingolipid metabolism in fish gills. These specifically regulated fish gill metabolites include sphinganine, sphingosine, and phytosphingosine, which were significantly enriched in the sphingolipid metabolism pathway. Our results clearly reveal the effects and potential toxicity mechanisms of AgNPs on fish gill metabolites. Furthermore, our study further determined the unique functions of released silver ions in AgNPs toxicity in fish gills.

Formal or informal recycling sectors? Household solid waste recycling behavior based on multi-agent simulation.

Urban household solid waste recycling and management are complex adaptive systems with multiple agents, stages, and elements. Previous studies neglected the impact of municipal residents' behavioral decisions on recycling sectors. In this study, the degree of regret-joy and personality characteristics were introduced into a multi-agent-based model to simulate the action decision-making of agents under different strategies. The results demonstrate that, without the government's role, nearly 60% of municipal residents preferred the informal recycling sector (IFRS). Meanwhile, the formal recycling sectors (FRS) find it difficult to attract urban residents because of their low income levels. Regarding a single policy, the subsidy policy is more beneficial than the regulation policy for increasing the income of the FRS from 20 to 250 Yuan. However, neither of the two single policies can weaken the market competitiveness of the IFRS. Moreover, a comprehensive policy combining both subsidies and regulations has enabled more than 60% of urban residents to choose the FRS, thereby increasing its profit and market share to 270 yuan and 500 kg, respectively. These results provide policy suggestions for optimizing the waste recycling management systems.

4,7-Disubstituted 7H-Pyrrolo[2,3-d]pyrimidines and Their Analogs as Antiviral Agents against Zika Virus.

Discovery of compound 1 as a Zika virus (ZIKV) inhibitor has prompted us to investigate its 7H-pyrrolo[2,3-d]pyrimidine scaffold, revealing structural features that elicit antiviral activity. Furthermore, we have demonstrated that 9H-purine or 1H-pyrazolo[3,4-d]pyrimidine can serve as an alternative core structure. Overall, we have identified 4,7-disubstituted 7H-pyrrolo[2,3-d]pyrimidines and their analogs including compounds 1, 8 and 11 as promising antiviral agents against flaviviruses ZIKV and dengue virus (DENV). While the molecular target of these compounds is yet to be elucidated, 4,7-disubstituted 7H-pyrrolo[2,3-d]pyrimidines and their analogs are new chemotypes in the design of small molecules against flaviviruses, an important group of human pathogens.

Anti-HCMV activity by an irreversible p97 inhibitor LC-1310.

The AAA+ (ATPase associated with various cellular activities) protein p97, also called valosin-containing protein, is a hexameric ring ATPase and uses ATP hydrolysis to unfold or extract proteins from biological complexes. Many cellular processes are affected by p97 including ER-associated degradation, DNA damage response, cell signaling (NF-κB), cell cycle progression, autophagy, and others. Not surprisingly, with its role in many fundamental cellular processes, p97 function is important for the replication of many viruses. We tested irreversible p97-targeting compounds for their ability to inhibit the replication of multiple viruses compared to the known p97 inhibitors NMS-873 and CB-5083. Our results indicate that overall cellular toxicity for p97 compounds provides a challenge for antivirals targeting p97. However, we identified one compound with sub-micromolar activity against human cytomegalovirus and improved cell viability to provide evidence for the potential of irreversible p97 inhibitors as antivirals.

Distinct Function of Estrogen Receptors in the Rodent Anterior Cingulate Cortex in Pain-related Aversion.

BACKGROUND: Brain-derived estrogen is implicated in pain-related aversion; however, which estrogen receptors mediate this effect remains unclear. This study hypothesized that the different estrogen receptors in the rostral anterior cingulate cortex play distinct roles in pain-related aversion. METHODS: Formalin-induced conditioned place avoidance and place escape/avoidance paradigms were used to evaluate pain-related aversion in rodents. Immunohistochemistry and Western blotting were used to detect estrogen receptor expression. Patch-clamp recordings were used to examine N-methyl-D-aspartate-mediated excitatory postsynaptic currents in rostral anterior cingulate cortex slices. RESULTS: The administration of the estrogen receptor-ß antagonist 4-(2-phenyl-5,7-bis [trifluoromethyl] pyrazolo [1,5-a] pyrimidin-3-yl) phenol (PHTPP) or the G protein-coupled estrogen receptor-1 antagonist (3aS*,4R*,9bR*)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta [c] quinolone (G15) but not the estrogen receptor-α antagonist 1,3-bis (4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy) phenol]-1H-pyrazole dihydrochloride (MPP) into the rostral anterior cingulate cortex blocked pain-related aversion in rats (avoidance score, mean ± SD: 1,3-bis [4-hydroxyphenyl]-4-methyl-5-(4-[2-piperidinylethoxy] phenol)-1H-pyrazole dihydrochloride (MPP): 47.0 ± 18.9%, 4-(2-phenyl-5,7-bis [trifluoromethyl] pyrazolo [1,5-a] pyrimidin-3-yl) phenol (PHTPP): -7.4 ± 20.6%, and [3aS*,4R*,9bR*]-4-[6-bromo-1,3-benzodioxol-5-yl]-3a,4,5,9b-3H-cyclopenta [c] quinolone (G15): -4.6 ± 17.0% vs. vehicle: 46.5 ± 12.2%; n = 7 to 9; P < 0.0001). Consistently, estrogen receptor-ß knockdown but not estrogen receptor-α knockdown by short-hairpin RNA also inhibited pain-related aversion in mice (avoidance score, mean ± SD: estrogen receptor-α-short-hairpin RNA: 26.0 ± 7.1% and estrogen receptor-ß-short-hairpin RNA: 6.3 ± 13.4% vs. control short-hairpin RNA: 29.1 ± 9.1%; n = 7 to 10; P < 0.0001). Furthermore, the direct administration of the estrogen receptor-ß agonist 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN) or the G protein-coupled estrogen receptor-1 agonist (±)-1-([3aR*,4S*,9bS*]-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta [c]quinolin-8-yl)-ethanone (G1) into the rostral anterior cingulate cortex resulted in conditioned place avoidance (avoidance score, mean ± SD: 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN): 35.3 ± 9.5% and (±)-1-([3aR*,4S*,9bS*]-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta [c]quinolin-8-yl)-ethanone (G1): 43.5 ± 22.8% vs. vehicle: 0.3 ± 14.9%; n = 8; P < 0.0001) but did not affect mechanical or thermal sensitivity. The activation of the estrogen receptor-ß/protein kinase A or G protein-coupled estrogen receptor-1/protein kinase B pathway elicited the long-term potentiation of N-methyl-D-aspartate-mediated excitatory postsynaptic currents. CONCLUSIONS: These findings indicate that estrogen receptor-ß and G protein-coupled estrogen receptor-1 but not estrogen receptor-α in the rostral anterior cingulate cortex contribute to pain-related aversion by modulating N-methyl-D-aspartate receptor-mediated excitatory synaptic transmission.

An Integrated Analysis of the Rice Transcriptome and Metabolome Reveals Root Growth Regulation Mechanisms in Response to Nitrogen Availability.

Nitrogen is an essential nutrient for plant growth and basic metabolic processes. Root systems play an important role in the ability of plants to obtain nutrients from the soil, and are closely related to the growth and development of above-ground plants. Root morphology analysis showed that root growth was induced under low-nitrogen conditions and inhibited under high-nitrogen conditions. To better understand the molecular mechanisms and metabolic basis underlying the rice root response to nitrogen availability, an integrated analysis of the rice root transcriptome and metabolome under three environmental conditions (low-, control, and high-nitrogen conditions) was conducted. A total of 262 and 262 differentially level metabolites were identified under low- and high-nitrogen conditions, respectively. A total of 696 and 808 differentially expressed genes were identified under low- and high-nitrogen conditions, respectively. For both the differentially expressed genes and metabolites, KEGG pathway analysis indicated that amino acid metabolism, carbon and nitrogen metabolism, phenylpropanoid metabolism, and phytohormones' signal transduction were significantly affected by nitrogen availability. Additionally, variable levels of 65 transcription factors (TFs) were identified in rice leaves exposed to high and low nitrogen, covering 22 TF families. These results also indicate that there is a significant difference in the transcriptional regulation mechanisms of rice roots between low and high nitrogen. In summary, our study provides new information for a further understanding of the response of rice roots to low-nitrogen and high-nitrogen conditions.

Modulation of PTEN by hexarelin attenuates coronary artery ligation-induced heart failure in rats

Background/aim: Hexarelin is a synthetic growth hormone-releasing peptide that exerts cardioprotective effects. However, its cardioprotective effect against heart failure (HF) is yet to be explained. This study investigated the therapeutic role of hexarelin and the mechanisms underlying its cardioprotective effects against coronary artery ligation (CAL)-induced HF in rats. Materials and methods: Rats with four weeks of permanent CAL, induced myocardial infarction, and HF were randomly separated into four groups: the control group (Ctrl), sham group (Sham), hexarelin treatment group (HF + Hx), and heart failure group (HF). The rats were treated with subcutaneous injection of hexarelin (100 µg/kg) in the treatment group or saline in the other groups twice a day for 30 days. Left ventricular (LV) function, oxidative stress, apoptosis, molecular analyses, and cardiac structural and pathological changes in rats were assessed. Results: The treatment of HF rats with hexarelin significantly induced the upregulation of phosphatase and tensin homologue (PTEN) expression and inhibited the phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR) to significantly improve LV function, ameliorate myocardial remodeling, and reduce oxidative stress. Conclusion: These findings indicate that hexarelin attenuates CAL-induced HF in rats by ameliorating myocardial remodeling, LV dysfunction, and oxidative stress via the upmodulation of PTEN signaling and downregulation of the Akt/mTOR signaling pathway.