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The hippocampal CA3 region plays an important role in learning and memory. CA3 pyramidal neurons (PNs) receive two prominent excitatory inputs-mossy fibers (MFs) from dentate gyrus (DG) and recurrent collaterals (RCs) from CA3 PNs-that play opposing roles in pattern separation and pattern completion, respectively. Although the dorsoventral heterogeneity of the hippocampal anatomy, physiology, and behavior has been well established, nothing is known about the dorsoventral heterogeneity of synaptic connectivity in CA3 PNs. In this study, we performed Timm's sulfide silver staining, dendritic and spine morphological analyses, and ex vivo electrophysiology in mice of both sexes to investigate the heterogeneity of MF and RC pathways along the CA3 dorsoventral axis. Our morphological analyses demonstrate that ventral CA3 (vCA3) PNs possess greater dendritic lengths and more complex dendritic arborization, compared with dorsal CA3 (dCA3) PNs. Moreover, using ChannelRhodopsin2 (ChR2)-assisted patch-clamp recording, we found that the ratio of the RC-to-MF excitatory drive onto CA3 PNs increases substantially from dCA3 to vCA3, with vCA3 PNs receiving significantly weaker MFs, but stronger RCs, excitation than dCA3 PNs. Given the distinct roles of MF versus RC inputs in pattern separation versus completion, our findings of the significant dorsoventral variations of MF and RC excitation in CA3 PNs may have important functional implications for the contribution of CA3 circuit to the dorsoventral difference in hippocampal function.
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Região CA3 Hipocampal , Células Piramidais , Sinapses , Animais , Camundongos , Células Piramidais/fisiologia , Região CA3 Hipocampal/fisiologia , Região CA3 Hipocampal/citologia , Masculino , Feminino , Sinapses/fisiologia , Camundongos Endogâmicos C57BL , Fibras Musgosas Hipocampais/fisiologia , Dendritos/fisiologia , Vias Neurais/fisiologiaRESUMO
Late-stage functionalization (LSF) introduces functional group or structural modification at the final stage of the synthesis of natural products, drugs, and complex compounds. It is anticipated that late-stage functionalization would improve drug discovery's effectiveness and efficiency and hasten the creation of various chemical libraries. Consequently, late-stage functionalization of natural products is a productive technique to produce natural product derivatives, which significantly impacts chemical biology and drug development. Carbon-carbon bonds make up the fundamental framework of organic molecules. Compared with the carbon-carbon bond construction, the carbon-carbon bond activation can directly enable molecular editing (deletion, insertion, or modification of atoms or groups of atoms) and provide a more efficient and accurate synthetic strategy. However, the efficient and selective activation of unstrained carbon-carbon bonds is still one of the most challenging projects in organic synthesis. This review encompasses the strategies employed in recent years for carbon-carbon bond cleavage by explicitly focusing on their applicability in late-stage functionalization. This review expands the current discourse on carbon-carbon bond cleavage in late-stage functionalization reactions by providing a comprehensive overview of the selective cleavage of various types of carbon-carbon bonds. This includes C-C(sp), C-C(sp2), and C-C(sp3) single bonds; carbon-carbon double bonds; and carbon-carbon triple bonds, with a focus on catalysis by transition metals or organocatalysts. Additionally, specific topics, such as ring-opening processes involving carbon-carbon bond cleavage in three-, four-, five-, and six-membered rings, are discussed, and exemplar applications of these techniques are showcased in the context of complex bioactive molecules or drug discovery. This review aims to shed light on recent advancements in the field and propose potential avenues for future research in the realm of late-stage carbon-carbon bond functionalization.
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A key mode of neuronal communication between distant brain regions is through excitatory synaptic transmission mediated by long-range glutamatergic projections emitted from principal neurons. The long-range glutamatergic projection normally forms numerous en passant excitatory synapses onto both principal neurons and interneurons along its path. Under physiological conditions, the monosynaptic excitatory drive onto postsynaptic principal neurons outweighs disynaptic feedforward inhibition, with the net effect of depolarizing principal neurons. In contrast with this conventional doctrine, here we report that a glutamatergic projection from the hypothalamic supramammillary nucleus (SuM) largely evades postsynaptic pyramidal neurons (PNs), but preferentially target interneurons in the hippocampal CA3 region to predominantly provide feedforward inhibition. Using viral-based retrograde and anterograde tracing and ChannelRhodopsin2 (ChR2)-assisted patch-clamp recording in mice of either sex, we show that SuM projects sparsely to CA3 and provides minimal excitation onto CA3 PNs. Surprisingly, despite its sparse innervation, the SuM input inhibits all CA3 PNs along the transverse axis. Further, we find that SuM provides strong monosynaptic excitation onto CA3 parvalbumin-expressing interneurons evenly along the transverse axis, which likely mediates the SuM-driven feedforward inhibition. Together, our results demonstrate that a novel long-range glutamatergic pathway largely evades principal neurons, but rather preferentially innervates interneurons in a distant brain region to suppress principal neuron activity. Moreover, our findings reveal a new means by which SuM regulates hippocampal activity through SuM-to-CA3 circuit, independent of the previously focused projections from SuM to CA2 or dentate gyrus.SIGNIFICANCE STATEMENT The dominant mode of neuronal communication between brain regions is the excitatory synaptic transmission mediated by long-range glutamatergic projections, which form en passant excitatory synapses onto both pyramidal neurons and interneurons along its path. Under normal conditions, the excitation onto postsynaptic neurons outweighs feedforward inhibition, with the net effect of depolarization. In contrast with this conventional doctrine, here we report that a glutamatergic input from hypothalamic supramammillary nucleus (SuM) largely evades PNs but selectively targets interneurons to almost exclusively provide disynaptic feedforward inhibition onto hippocampal CA3 PNs. Thus, our findings reveal a novel subcortical-hippocampal circuit that enables SuM to regulate hippocampal activity via SuM-CA3 circuit, independent of its projections to CA2 or dentate gyrus.
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Interneurônios , Células Piramidais , Camundongos , Animais , Células Piramidais/fisiologia , Interneurônios/fisiologia , Neurônios/fisiologia , Hipocampo/fisiologia , Hipotálamo PosteriorRESUMO
BACKGROUND: Daptomycin is widely used in critically ill patients for Gram-positive bacterial infections. Extracorporeal membrane oxygenation (ECMO) is increasingly used in this population and can potentially alter the pharmacokinetic (PK) behaviour of antibiotics. However, the effect of ECMO has not been evaluated in daptomycin. Our study aims to explore the effect of ECMO on daptomycin in critically ill patients through population pharmacokinetic (PopPK) analysis and to determine optimal dosage regimens based on both efficacy and safety considerations. METHODS: A prospective, open-label PK study was carried out in critically ill patients with or without ECMO. The total concentration of daptomycin was determined by UPLC-MS/MS. NONMEM was used for PopPK analysis and Monte Carlo simulations. RESULTS: Two hundred and ninety-three plasma samples were collected from 36 critically ill patients, 24 of whom received ECMO support. A two-compartment model with first-order elimination can best describe the PK of daptomycin. Creatinine clearance (CLCR) significantly affects the clearance of daptomycin while ECMO has no significant effect on the PK parameters. Monte Carlo simulations showed that, when the MICs for bacteria are â≥1â mg/L, the currently recommended dosage regimen is insufficient for critically ill patients with CLCRâ>â30â mL/min. Our simulations suggest 10â mg/kg for patients with CLCR between 30 and 90â mL/min, and 12â mg/kg for patients with CLCR higher than 90â mL/min. CONCLUSIONS: This is the first PopPK model of daptomycin in ECMO patients. Optimal dosage regimens considering efficacy, safety, and pathogens were provided for critical patients based on pharmacokinetic-pharmacodynamic analysis.
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Antibacterianos , Estado Terminal , Daptomicina , Oxigenação por Membrana Extracorpórea , Método de Monte Carlo , Humanos , Daptomicina/farmacocinética , Daptomicina/administração & dosagem , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto , Idoso , Testes de Sensibilidade Microbiana , Espectrometria de Massas em Tandem , Infecções por Bactérias Gram-Positivas/tratamento farmacológicoRESUMO
Glial activation and dysregulation of adenosine triphosphate (ATP)/adenosine are involved in the neuropathology of several neuropsychiatric illnesses. The ventral hippocampus (vHPC) has attracted considerable attention in relation to its role in emotional regulation. However, it is not yet clear how vHPC glia and their derived adenosine regulate the anxiodepressive-like consequences of chronic pain. Here, we report that chronic cheek pain elevates vHPC extracellular ATP/adenosine in a mouse model resembling trigeminal neuralgia (rTN), which mediates pain-related anxiodepression, through a mechanism that involves synergistic effects of astrocytes and microglia. We found that rTN resulted in robust activation of astrocytes and microglia in the CA1 area of the vHPC (vCA1). Genetic or pharmacological inhibition of astrocytes and connexin 43, a hemichannel mainly distributed in astrocytes, completely attenuated rTN-induced extracellular ATP/adenosine elevation and anxiodepressive-like behaviors. Moreover, inhibiting microglia and CD39, an enzyme primarily expressed in microglia that degrades ATP into adenosine, significantly suppressed the increase in extracellular adenosine and anxiodepressive-like behaviors. Blockade of the adenosine A2A receptor (A2AR) alleviated rTN-induced anxiodepressive-like behaviors. Furthermore, interleukin (IL)-17A, a pro-inflammatory cytokine probably released by activated microglia, markedly increased intracellular calcium in vCA1 astrocytes and triggered ATP/adenosine release. The astrocytic metabolic inhibitor fluorocitrate and the CD39 inhibitor ARL 67156, attenuated IL-17A-induced increases in extracellular ATP and adenosine, respectively. In addition, astrocytes, microglia, CD39, and A2AR inhibitors all reversed rTN-induced hyperexcitability of pyramidal neurons in the vCA1. Taken together, these findings suggest that activation of astrocytes and microglia in the vCA1 increases extracellular adenosine, which leads to pain-related anxiodepression via A2AR activation. Approaches targeting astrocytes, microglia, and adenosine signaling may serve as novel therapies for pain-related anxiety and depression.
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Dor Crônica , Neuralgia do Trigêmeo , Animais , Camundongos , Adenosina/farmacologia , Trifosfato de Adenosina/farmacologia , Modelos Animais de Doenças , Hipocampo , MicrogliaRESUMO
N-Alkoxyphthalimides, one kind of phthalimide derivative, have great importance in synthesis, mainly used as free radical precursors. While the phthalimide unit, for a long time, was treated as part of the waste stream. Construction of C-N bonds has always been a hot spot, especially in reductive cross-coupling. Herein, a nickel-catalyzed reductive cross-coupling reaction of N-methoxyphthalimides with alkyl halides is described, where N-methoxyphthalimides serve as nitrogen electrophiles. This tactic provides a new approach to construct C-N bonds under mild neutral conditions. Alkyl chlorides, bromides, iodides, and sulfonates are all fit to this transformation. Moreover, the reaction could tolerate a broad substrate scope, especially base-sensitive functional groups (boron or silicon groups), as well as competitive nucleophilic groups (phenols and amides), which are incompatible with traditional Gabriel synthesis under basic conditions, demonstrating a complementary role of this work to Gabriel synthesis.
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Aluminum-doped Ga2O3(AGO) thin films were prepared by plasma-enhanced atomic layer deposition (PE-ALD). The growth mechanism, surface morphology, chemical composition, and optical properties of AGO films were systematically investigated. The bandgap of AGO films can be theoretically set between 4.65 and 6.8 eV. Based on typical AGO films, metal-semiconductor-metal photodetectors (PDs) were created, and their photoelectric response was examined. The preliminary results show that PE-ALD grown AGO films have high quality and tunable bandgap, and AGO PDs possess superior characterizations to undoped films. The AGO realized using PE-ALD is expected to be an important route for the development of a new generation of gallium oxide-based photodetectors into the deep-ultraviolet.
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Molybdenum sulfide (MoS2) as an emerging optoelectronic material, shows great potential for phototransistors owing to its atomic thickness, adjustable band gap, and low cost. However, the phototransistors based on MoS2have been shown to have some issues such as large gate leakage current, and interfacial scattering, resulting in suboptimal optoelectronic performance. Thus, Al-doped hafnium oxide (Hf1-xAlx) is proposed to be a dielectric layer of the MoS2-based phototransistor to solve this problem because of the relatively higher crystallization temperature and dielectric constant. Here, a high-performance MoS2phototransistor with Hf1-xAlxO gate dielectric layer grown by plasma-enhanced atomic layer deposition has been fabricated and studied. The results show that the phototransistor exhibits a high responsivity of 2.2 × 104A W-1, a large detectivity of 1.7 × 1017Jones, a great photo-to-dark current ratio of 2.2 × 106%, and a high external quantum efficiency of 4.4 × 106%. The energy band alignment and operating mechanism were further used to clarify the reason for the enhanced MoS2phototransistor. The suggested MoS2phototransistors could provide promising strategies in further optoelectronic applications.
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OBJECTIVE: To present the prenatal sonographic features and genomic spectrum of pregnancies with fetal Bardet-Biedl syndrome (BBS). METHODS: This was a retrospective study of 11 cases with BBS diagnosed by prenatal ultrasound and confirmed by genetic testing. Clinical and laboratory data were collected and reviewed for these cases, including maternal demographics, prenatal sonographic findings, molecular testing sequencing results, and pregnancy outcomes. RESULTS: All cases had unremarkable first-trimester ultrasound scans without reporting limb malformations. All had second-trimester abnormal ultrasounds: postaxial polydactyly in nine cases (9/11), renal abnormalities in seven (7/11), reduced amniotic fluid volume in two (2/11), central nervous system anomalies in two (2/11), and ascites in three (3/11). Ten fetuses presented with at least two-system anomalies, and one (Case 11) presented with only postaxial polydactyly. Variants were detected in five genes, including BBS2, ARL6/BBS3, BBS7, CEP290/BBS14 and IFT74/BBS22. Ten pregnancies were terminated in the second trimester, while one continued to term. CONCLUSION: Enlarged hyperechogenic kidneys and postaxial polydactyly are the two most common sonographic features of fetal BBS. Prenatal diagnosis of BBS can be done with ultrasound and genetic testing although the diagnosis may be made in the second trimester.
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Síndrome de Bardet-Biedl , Fenótipo , Ultrassonografia Pré-Natal , Humanos , Síndrome de Bardet-Biedl/genética , Síndrome de Bardet-Biedl/diagnóstico , Feminino , Gravidez , Estudos Retrospectivos , Adulto , Polidactilia/genética , Polidactilia/diagnóstico por imagem , Polidactilia/diagnóstico , Genótipo , Segundo Trimestre da Gravidez , Testes Genéticos/métodosRESUMO
The brown planthopper (Nilaparvata lugens) is a major destructive rice pest in Asia. High levels of insecticide resistance have been frequently reported, and the G932C mutation in the chitin synthase 1 (CHS1) gene has been found to mediate buprofezin resistance. However, there has been no direct evidence to confirm the functional significance of the single G932C substitution mutation leading to buprofezin resistance in N. lugens. Here, we successfully constructed a knock-in homozygous strain (Nl-G932C) of N. lugens using CRISPR/Cas9 coupled with homology-directed repair (HDR). Compared with the background strain susceptible to buprofezin (Nl-SS), the knock-in strain (Nl-G932C) showed a 94.9-fold resistance to buprofezin. Furthermore, resistant strains (Nl-932C) isolated from the field exhibited a 2078.8-fold resistance to buprofezin, indicating that there are other mechanisms contributing to buprofezin resistance in the field. Inheritance analysis showed that the resistance trait is incomplete dominance. In addition, the Nl-G932C strain had a relative fitness of 0.33 with a substantially decreased survival rate, emergence rate, and fecundity. This study provided in vivo functional evidence for the causality of G932C substitution mutation of CHS1 with buprofezin resistance and valuable information for facilitating the development of resistance management strategies in N. lugens. This is the first example of using CRISPR/Cas9 gene-editing technology in a hemipteran insect to directly confirm the role of a candidate target site mutation in insecticide resistance.
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Sistemas CRISPR-Cas , Quitina Sintase , Hemípteros , Resistência a Inseticidas , Inseticidas , Tiadiazinas , Animais , Hemípteros/genética , Resistência a Inseticidas/genética , Tiadiazinas/farmacologia , Quitina Sintase/genética , Inseticidas/farmacologia , Mutação , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Técnicas de Introdução de Genes , Feminino , MasculinoRESUMO
INTRODUCTION: CHARGE syndrome is an autosomal dominant genetic disorder with known pattern of features. The aim of the study was to present the fetal features of CHARGE syndrome to gain awareness that the antenatal characteristics can be very nonspecific. CASE PRESENTATION: This was a retrospective study of 13 cases with CHARGE syndrome diagnosed by prenatal or postnatal genetic testing and physical examination. Two (15.4%; 2/13) had normal ultrasound scans during pregnancy. One (7.7%; 1/13) with first-trimester cystic hygroma presented intrauterine fetal demise at 16 weeks gestation. The remaining 10 (76.9%; 10/13) cases had abnormal ultrasound features in utero; among these, 1 had an increased nuchal translucency in the first trimester, 5 had second-trimester abnormal ultrasounds including micrognathia, cardiac defects, and facial defects, and 4 third-trimester abnormal ultrasounds including micrognathia, isolated fetal growth restriction, and polyhydramnios. Among the 11 cases with abnormal prenatal ultrasound scans, no fetus could reach the diagnostic criteria of CHARGE syndrome if only based on the results of ultrasound. However, the diagnosis was made in all cases when CHD7 defects were detected. DISCUSSION/CONCLUSION: The CHARGE syndrome presents non-specific abnormal ultrasound markers in utero. Exome sequencing in the genetic workup will aid in prenatal diagnosis of this syndrome.
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Síndrome CHARGE , Fenótipo , Ultrassonografia Pré-Natal , Humanos , Síndrome CHARGE/genética , Síndrome CHARGE/diagnóstico , Feminino , Gravidez , Estudos Retrospectivos , Adulto , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Medição da Translucência Nucal , Testes GenéticosRESUMO
BACKGROUND AND OBJECTIVES: This study aimed to find the optimal intervention available to both control blood glucose and improve physical function in the geriatric population with T2DM. METHODS AND STUDY DESIGN: A systemic review and network meta-analysis (NMA) was conducted to assess and rank the comparative efficacy of different interventions on glycosylated hemoglobin A1c (HbAc1), fasting blood glucose (FBG), muscle mass, grip strength, gait speed, lower body muscle strength, and dynamic balance. A total of eight databases were searched for eligible randomized controlled trials (RCTs) that the elderly aged more than 60 years or with mean age ≥ 55 years, the minimal duration of the RCT intervention was 6 weeks, and those lacking data about glycemic level and at least one indicator of physical performance were excluded. The Cochrane risk of bias tool was used to assess the bias of each study included. Bayesian NMA was performed as the main results, the Bayesian meta regression and the frequentist NMA as sensitivity analysis. RESULTS: Of the 2266 literature retrieved, 27 RCTs with a total of 2289 older adults were included. Health management provided by health workers exerts beneficial effects that is superior to other interventions at achieving glycemic control, but less marked improvement in physical performance. Exercise combined with cognitive training showed more pronounced improvement in muscle strength, gait speed, and dynamic balance, but ranked behind in decreasing the HbAc1 and FBG. CONCLUSIONS: Personalized health management combined with physical and cognitive training might be the optimal intervention to both accomplish glycemic control and improvement of physical performance. Further RCTs are needed to validate and assess the confidence of our results from this NMA.
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Glicemia , Diabetes Mellitus Tipo 2 , Desempenho Físico Funcional , Humanos , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/sangue , Idoso , Metanálise em Rede , Hemoglobinas Glicadas/análise , Força Muscular/fisiologia , Controle Glicêmico/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Exercício Físico/fisiologiaRESUMO
OBJECTIVE: The impact of selenium (Se) on human thyroid function remains unclear, with inconsistent results from recent epidemiological studies. Moreover, the observed associations are prone to bias due to potential confounding and reverse causation. Mendelian randomization (MR) analysis facilitates the large minimization of biases produced by environmental and lifestyle influences, providing unconfounded estimates of causal effects using instrumental variables. We aim to examine the association between Se concentrations and human thyroid function using a two-sample MR analysis. DESIGN AND METHODS: Genetic instruments for Se concentrations, including toenail and blood (TAB) and blood Se concentrations, were identified from a genome-wide association study (GWAS) of blood Se (n = 5477) and toenail Se levels (n = 4162). GWAS summary statistics on thyroid phenotypes were downloaded from the ThyroidOmics consortium, including thyroid-stimulating hormone (TSH) (n = 54,288), free thyroxin (FT4) (n = 49,269), hypo (n = 53,423), and hyperthyroidism (n = 51,823). The MR study was conducted using the inverse-variance weighted (IVW) method, supplemented with the weighted median and the mode-based method. RESULTS: Genetically determined TAB Se was negatively associated with FT4 (ß = -.067; 95% confidence interval [CI] = -0.106, -0.028; p = 0.001) using the IVW analyses, as well in the additional analyses using the weighted median and weighted-mode methods. No evidence in heterogeneity, pleiotropy or outlier single-nucleotide polymorphisms was detected (all p > 0.05). Suggestive casual association between increased genetically determined TAB Se concentrations and decreased hypothyroidism risk was found by the IVW method (odds ratio [OR] = 0.847; 95% CI = 0.728, 0.985; p = 0.031). The causal effect of TAB Se on FT4 was observed in women (ß = -.076; 95% CI = -0.129, -0.024; p = 0.004). However, the influence of genetically determined higher Se concentrations on TSH levels and hyperthyroidism revealed insignificance in the primary and sensitivity analyses. CONCLUSIONS: The present MR study indicated that high Se concentration enable the decreasing of FT4 levels, and the effects of Se concentrations on FT4 remain sex-specific.
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Hipertireoidismo , Selênio , Masculino , Humanos , Feminino , Análise da Randomização Mendeliana/métodos , Estudo de Associação Genômica Ampla , Tireotropina , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
A facile and dual fluorescent chemosensor (named 7-IDF) based on a phenylalanine derivative with an indole group was designed and synthesized. 7-IDF can selectively and sensitively detect Zn2+ via obvious fluorescence enhancement in an aqueous solution. Remarkably, the 7-IDF-Zn complex with blue luminescence has higher selectivity toward cysteine (Cys) and histidine (His) than for other amino acids. Intriguingly, 7-IDF can also be used as an excellent probe to detect Zn2+ in real water samples. Moreover, 7-IDF and 7-IDF-Zn possess excellent biocompatibility and cell permeability, and 7-IDF can consecutively detect Zn2+ and Cys/His in Hela cells through fluorescence imaging experiments. This study suggests that the phenylalanine-based chemosensor possesses great potential applications for the sequential detection of Zn2+ and Cys/His in biosystems.
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Cisteína , Corantes Fluorescentes , Humanos , Corantes Fluorescentes/química , Cisteína/química , Células HeLa , Histidina , Fenilalanina , Espectrometria de Fluorescência , ZincoRESUMO
Social adversity not only causes severe psychological diseases but also may improve people's ability to learn and grow. However, the beneficial effects of social adversity are often ignored. In this study, we investigated whether and how social adversity affects learning and memory in a mouse social defeat stress (SDS) model. A total of 652 mice were placed in experimental groups of six to 23 mice each. SDS enhanced spatial, novelty, and fear memory with increased synaptosome associated protein 25 (SNAP-25) level and dendritic spine density in hippocampal neurons among young but not middle-aged mice. Chemogenetic inhibition of hippocampal CaMK2A+ neurons blocked SDS-induced enhancement of learning or memory. Knockdown of SNAP-25 or blockade of N-methyl-D-aspartate (NMDA) receptor subunit GluN2B in the hippocampus prevented SDS-induced learning memory enhancement in an emotion-independent manner. These findings suggest that social adversity promotes learning and memory ability in youths and provide a neurobiological foundation for biopsychological antifragility.
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Derrota Social , Sinaptossomos , Animais , Camundongos , Hipocampo , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Estresse PsicológicoRESUMO
It is difficult to subject simple reaction starting materials to a "one-pot" in situ tandem reaction without post-treatment under mild reaction conditions to obtain multimers with complex structural linkages. In organic synthesis, acetal reactions are often used to protect derivatives containing carbonyl functional groups. Therefore, acetal products tend to have very low stability, and performing multi-step condensation to obtain complex multimeric products is difficult. Herein, we achieved the first efficient multiple condensation of o-vanillin derivatives using Dy(OAc)3·6H2O undergoing a "one-pot" in situ tandem reaction under mild solvothermal conditions to obtain a series of dimers (I and II, clusters 1 and 2) and trimers (I and II, clusters 3 and 4). When methanol or ethanol is used as the solvent, the alcoholic solvent participates in acetal and dehydration reactions to obtain dimers (I and II). Surprisingly, when using acetonitrile as the reaction solvent, the o-vanillin derivatives undergo acetal and dehydration reactions to obtain trimers (I and II). In addition, clusters 1-4 all showed distinct single-molecule magnetic behaviors under zero-field conditions. To the best of our knowledge, this is the first time that multiple acetal reactions catalyzed by coordination-directed catalysis under "one-pot" conditions have been realized, opening a new horizon for the development of fast, facile, green, and efficient synthetic methods for complex compounds.
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A.D. is a common disease among other neurodegenerative disorders primarily developing due to amyloid-ß (Aß) neurotoxicity derived from the amyloid-ß protein precursor (AßPP). The amyloid precursor-like proteins 1 and 2 (APP1 and APLP2) biochemically behave similarly in many aspects to AßPP. We, therefore, proposed to test WGX-50 and Alpha-M for their interaction mechanism with APLP1 and APLP2 because both these drug candidate compounds previously showed inhibition of Aß aggregation. We employed a comparative atomic investigation on Alpha-M and WGX-50 in complex with novel targets, i.e., APLP1 and APLP2, using biophysical and molecular simulation methods. The docking score was -6.83 kcal mol-1 for Alpha-M-APLP1, -8.41 kcal mol-1 for WGX-50-APLP1, -7.02 kcal mol-1 for Alpha-M-APLP2 and -8.25 kcal mol-1 for the WGX-50-APLP2 complex. Our results also elaborate that in the case of their interaction with both APLP1 and APLP2, the WGX-50 complex exhibits better stability than the APLP1/2-Alpha-M complexes during simulation. Furthermore, WGX50 in both APLP1 and APLP2 stabilized the internal flexibility upon binding in contrast to the Alpha-M complexes. The data showed that the BFE for Alpha-M-APLP1 was calculated to be -27.38 ± 0.93 kcal mol-1, for WGX-50-APLP1 -39.65 ± 0.95 kcal mol-1, for Alpha-M-APLP2 -24.80 ± 0.63 kcal mol-1 while for WGX-50-APLP2 the BFE was -57.16 ± 1.03 kcal mol-1 respectively. These results highlight that APLP2-WGX50 has greater binding energies in all four systems. PCA and FEL analysis further revealed variations in the dynamic behavior of these complexes. Overall, our findings demonstrate that WGX50 potentially acts as a more potent inhibitor for APLP1 and APLP2 than Alpha-M and thus shows the diverse pharmacological potential of WGX50. Due to its stable binding interaction, WGX50 might be a suitable candidate drug compound for targeting these precursors under pathological conditions.
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Acrilamidas , Proteínas do Tecido Nervoso , Proteínas do Tecido Nervoso/metabolismoRESUMO
BACKGROUND: Timely and systematic professional treatment is crucial in schizophrenia prognosis, but the global rate of mental health service, now, use or help-seeking behavior is low. METHODS: In-depth semi-structured interviews were conducted with 13 participants with the diagnosis of schizophrenia between October to December 2021. The participants were purposively sampled from a psychiatric hospital's. Interviews were recorded and transcribed verbatim into NVivo 12.0. RESULTS: The findings were summarized under 3 themes and 12 subthemes: (1) capability (lack of knowledge due to insufficient mental health literacy or lack of insight, inability to access disease information due to a lack of mental health literacy, and symptoms-related barriers); (2) opportunity (lack of disease information sources, inability to balance work and study during prolonged hospitalization, accessibility and convenience of medical resources, and the acquisition and utilization of social support); and (3) motivation (awareness of the disease and professional treatment, negative experiences of disease episodes, past medical experience, confidence in tcuring the disease, and the fulfillment of daily life and self-worth). CONCLUSION: The medical help-seeking behavior of people with the diagnosis of schizophrenia is the result of the interaction of many barriers and facilitators, and challenges persist today. Interventions can be implemented with the BCW framework and our results to precisely eliminate delays in the diagnosis and treatment of mental problems.
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Comportamento de Busca de Ajuda , Serviços de Saúde Mental , Esquizofrenia , Humanos , Esquizofrenia/diagnóstico , Esquizofrenia/terapia , Pesquisa Qualitativa , Saúde MentalRESUMO
BACKGROUND: Sexual health is one of the main areas of health and basic human rights which has been paid less attention in schizophrenia. Most studies have focused on sexual dysfunction rather than the sexual needs of people with schizophrenia. This study explores the sexual needs of people with schizophrenia and identify factors hindering sexual activities. METHODS: We carried out a qualitative study using a descriptive phenomenological approach. Data were collected at a psychiatric hospital in China. In total, 20 patients with schizophrenia were recruited through purposive sampling. Face to face semi-structured in-depth interviews were conducted with them. Interview recordings were transcribed by the research team, and transcripts were analyzed by two independent coders with Colaizzi's descriptive analysis framework by using NVivo 11 software. The consolidated criteria for reporting qualitative research checklist was used for reporting. RESULTS: The data analysis revealed 10 subthemes categorized into 3 macro themes: (1) multiple barriers hinder sexual activity; (2) significance of sex; and (3) conditions for fulfilling sexual needs. CONCLUSION: A poor sexual quality of life may be found in patients with schizophrenia. Furthermore, people with schizophrenia did not lose interest in maintaining an active sex life. Mental health services should address this issue in three areas: sexual knowledge, sexual space, and sexual objects.
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Serviços de Saúde Mental , Esquizofrenia , Humanos , Qualidade de Vida , Pesquisa Qualitativa , Comportamento SexualRESUMO
BACKGROUND: Patients suffering from schizophrenia are at a higher risk of relapse. The perception of the risk of relapse in patients is critical for relapse prevention. In the field of psychiatry, the study of risk perception of relapse has been neglected. METHODS: We carried out a qualitative study using a descriptive phenomenological approach. Data were collected at two psychiatric hospitals in China. In total, 22 patients with schizophrenia were recruited through purposive sampling. Face to face semi-structured in-depth interviews were conducted. Interview recordings were transcribed by the research team, and transcripts were analysed by two independent coders with Colaizzi's descriptive analysis framework. The consolidated criteria for reporting qualitative research checklist were used for reporting. RESULTS: The data of first-episode patients yielded three themes: (i) lack of knowledge about disease recognition and medical treatment; (ii) overoptimistic estimation of the risk of relapse; (iii) perceived importance of treatment. For first-relapse patients : (i) initial awareness of relapse warning signs; (ii) lack of systematic and accurate assessment of disease information; (iii) the perception that drug withdrawal is related to relapse. Patients with multiple relapses: (i) susceptibility to relapse: confusion and powerlessness; (ii) the severity of relapse: suicidal thoughts and behavior; (iii) effects of perceived benefits and barriers of medication behaviour. CONCLUSIONS: In schizophrenic patients with first-episode, first-relapse, and multiple relapses, there were dynamic changes in the perception of disease relapse risk and medication behaviour. Medical workers must improve risk awareness education. They should provide patients with scientific, accurate, and timely communication channels, and dynamically assess and manage the risk of relapse in various patients.