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Background: There is evidence for dysregulated cholesterol homeostasis in Huntington's disease (HD). The brain-specific cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-OHC) is decreased in manifest HD. 24(S)-OHC is an endogenous positive allosteric modulator (PAM) of the N-methyl-D-aspartate (NMDA) receptor, suggesting lower 24(S)-OHC may contribute to NMDA receptor hypofunction in HD. We hypothesized changes in 24(S)-OHC would be associated with cognitive impairment in early HD. Objective: To determine the interactions between oxysterols (24(S)-OHC, 25-OHC, and 27-OHC) at the NMDA receptor, the plasma levels of these oxysterols, and how these levels relate to cognitive performance. Methods: An in vitro competition assay was used to evaluate interactions at the NMDA receptor, liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) was used to measure plasma 24(S)-OHC, 25-OHC, and 27-OHC levels, and correlation analyses investigated their relationship to performance on cognitive endpoints in TRACK and ENROLL-HD (NCT01574053). Results: In vitro, 25-OHC and 27-OHC attenuated the PAM activity of 24(S)-OHC on the NMDA receptor. Lower plasma 24(S)-OHC levels and 24(S)/25-OHC ratios were detected in participants with early HD. Moderate and consistent associations were detected between plasma 24(S)/25-OHC ratio and performance on Stroop color naming, symbol digit modality, Trails A/B, and emotion recognition. Little association was observed between the ratio and psychiatric or motor endpoints, suggesting specificity for the relationship to cognitive performance. Conclusions: Our findings support growing evidence for dysregulated CNS cholesterol homeostasis in HD, demonstrate a relationship between changes in oxysterols and cognitive performance in HD, and propose that NMDA receptor hypofunction may contribute to cognitive impairment in HD.
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Aging is an inevitable and irreversible biological process that gradually heightens the risks of various diseases and death. As a newly discovered endogenous gasotransmitter, hydrogen sulfide (H2S) has been identified to exert multiple beneficial impacts on the regulation of aging and age-related pathologies. This study was aimed at systematically exploring the relationship between asynchronous aging processes and H2S concentrations in various tissues of aging mice. Samples of plasma and thirteen tissues were collected from four cross-sectional age groups (3, 6, 12 and 18 months of age) covering the lifespan of male C57BL/6J mice. The H2S concentration was quantified by a reported liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with monobromobimane (MBB) derivatization. Additionally, the expressions of CSE, CBS and 3-MST in those tissues were analyzed by western blotting. We discovered that the H2S concentrations decreased asynchronously with the aging process in plasma, heart, liver, kidney, spleen, subcutaneous fat and brown fat and increased in brain and lung. At least one of the three H2S-generating enzymes expressions was compensatorily upregulated with the aging process in most tissues, among which the up-regulation of CSE was the most prominent.
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PURPOSE: The purpose of this study is to report the parameter characteristics of the femoral anteversion angle (FAA) and tibial tubercle-trochlear groove (TT-TG) distance in patients with patellar instability compared to healthy individuals and to evaluate their reliability in predicting patellar dislocation, providing potential indications for osteotomy. METHODS: A retrospective collection of consecutive patients with patellar instability constituted the study group, while individuals without patellofemoral disorder served as the control group. Measurement of the FAA and TT-TG distance were conducted by lower extremity computed tomography scans and knees with true patellar dislocation were recorded. The diagnostic capability of the FAA and TT-TG distance was assessed using receiver operating characteristic curves and area under the curve (AUC), determining the pathological values by sensitivity and specificity. RESULTS: The FAA (21.6 ± 9.0°) and TT-TG distance (20.1 ± 4.8 mm) in the study group were significantly greater than the control group (10.6 ± 7.9° and 15.6 ± 4.6 mm, respectively) (p < 0.001). The AUCs for patellar dislocation were 0.869 for FAA and 0.712 for TT-TG distance, with pathological cut-off values of 18.2° and 18.2 mm, respectively. The odds ratios for FAA and TT-TG distance were 1.185 and 1.125, respectively (p < 0.05). CONCLUSIONS: Patients with patellar instability exhibited significantly greater FAA and TT-TG distance compared to healthy individuals. The FAA demonstrated superior predictive capability for patellar dislocation compared to the TT-TG distance. The FAA (>18.2°) measured by surgical transepicondylar axis and TT-TG distance (>18.2 mm) were the potential pathological thresholds. Additionally, an increase of 1° in FAA and 1 mm in TT-TG distance was associated with a 18.5% and 12.5% increased risk of patellar dislocation, respectively. Surgeons should be aware of the risk of patellar dislocation associated with rotational malalignment. LEVEL OF EVIDENCE: Level III.
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Objective: This meta-analysis examines the impact of different combinations of plyometric training (complexity, training volume, and rest intervals) on immediate vertical jump and sprint performance in athletes. Methods: A systematic search was conducted in four databases, and Cochrane guidelines were used to evaluate the quality of included studies. Review Manager 5.4 software was employed to analyze outcome measures. Nineteen randomized controlled trials involving 293 participants were included. Results: Single plyometric training-induced post-activation potentiation (PAP) had a slight positive effect on vertical jump performance [SMD = -0.24, 95% CI (-0.38, -0.1), P = 0.0009]. Optimal results were observed with rest intervals of 0.3-4 min (SMD = 0.30, P = 0.0008). Sprint performance showed slight improvement [SMD = 0.27, 95% CI (0.03, 0.52), P = 0.03]. Complex plyometric training had a moderate effect on vertical jump performance [SMD = 0.58, 95% CI (-0.86, -0.23), P = 0.002], with the best outcomes seen with rest intervals exceeding 8 min (SMD = 0.77). Sprint performance also improved significantly [SMD = 0.8, 95% CI (0.01, 1.59), P = 0.05]. Single-session plyometric training did not significantly enhance vertical jump performance [SMD = -0.19, 95% CI (-0.41, -0.02), P = 0.07], but had a notable effect on sprint performance [SMD = 0.8, 95% CI (0.01, 1.59), P = 0.05], particularly with rest intervals exceeding 8 min (SMD = 0.77). Multiple-session plyometric training improved vertical jump (SMD = 0.43, 95% CI [0.01, 1.59), P = 0.00001 < 0.05], with optimal effects observed at rest intervals of 5-7 min (SMD = 0.64). Sprint performance also improved [SMD = 0.46, 95% CI (0.01, 0.81), P = 0.01 < 0.05]. Conclusion: Plyometric training as an activation method has significant enhancing effects, depending on training complexity, volume, and rest intervals.
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Background: Effective glycemic control is crucial for hospitalized patients, leading to benefits such as shorter hospital stays and reduced postoperative infection rates. While previous studies have emphasized the effectiveness of multidisciplinary collaborative stewardship for hospital-wide hyperglycemia management, patient perspectives and preferences have not been adequately considered. Objective: To identify factors influencing treatment preferences of Chinese hospitalized diabetes patients using discrete choice experiments (DCEs) and provide practical insights for the construction of a hospital-wide glycemic control programme. Methods: A face-to-face survey was conducted among diabetes patients admitted to nonendocrine departments in a tertiary hospital in Nanjing, China. The attributes and levels were determined based on DCE principles, and a conditional logit model was used to quantify patients' preferences. Results: A total of 157 respondents were analyzed. Antihyperglycemic effectiveness, healthcare providers, treatment regimen, monitoring frequency, and adverse reactions were the five attributes that significantly influenced patient preference (p < 0.05). Notably, an 80% glycemic control rate (ß = 2.009) and a multidisciplinary management team involving clinical pharmacists (ß = 1.346) had the greatest impact. Negative effects were observed for hypoglycemia (ß = -1.008), insulin pump use (ß = -0.746), and frequent glucose monitoring (ß = -0.523). Female patients exhibited higher concern for healthcare providers (ß = 1.172) compared to males. Younger and shorter-course patients prioritized antihyperglycemic effectiveness (ß = 3.330, ß = 1.510), while older patients preferred multidisciplinary management (ß = 1.186) and opposed increased monitoring frequency (ß = -0.703). Patients with higher educational backgrounds showed greater acceptance of continuous glucose monitoring (ß = 1.983), and those with higher annual income placed more emphasis on glycemic control rate. Conclusion: Treatment preferences of hospitalized diabetes patients are mainly influenced by antihyperglycemic effectiveness, adverse reactions, healthcare providers, and individual characteristics. Comprehensive consideration and an individualized therapy strategy should be given when constructing a hospital-wide glycemic control programme.
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Glicemia , Diabetes Mellitus , Controle Glicêmico , Hospitalização , Hipoglicemiantes , Preferência do Paciente , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Hipoglicemiantes/uso terapêutico , China , Diabetes Mellitus/terapia , Diabetes Mellitus/sangue , Glicemia/metabolismo , Adulto , Comportamento de Escolha , Inquéritos e Questionários , HiperglicemiaRESUMO
The bacterium Pseudomonas aeruginosa is an exceptionally resilient opportunistic pathogen, presenting formidable challenges for treatment due to its proclivity for developing drug resistance. To address this predicament, we have devised a self-assembled supramolecular antibiotic known as dHTSN1@pHPplus, which can circumvent the drug resistance mechanism of Pseudomonas aeruginosa and effectively combat Pseudomonas aeruginosa infection by impeding the secretion of key virulence factors through the inhibition of the type III secretion system while simultaneously mobilizing immune cells to eradicate Pseudomonas aeruginosa. Furthermore, dHTSN1@pHPplus was ingeniously engineered with infection-targeting capabilities, enabling it to selectively concentrate precisely at the site of infection. As anticipated, the administration of dHTSN1@pHPplus exhibited a remarkable therapeutic efficacy in combating dual resistance to Meropenem and imipenem in a mouse model of P. aeruginosa lung infection. The results obtained from metagenomic detection further confirmed these findings, demonstrating a significant reduction in the proportion of Pseudomonas aeruginosa compared to untreated mice with Pseudomonas aeruginosa-infected lungs. Additionally, no notable acute toxicity was observed in the acute toxicity experiments. The present study concludes that the remarkable efficacy of dHTSN1@pHPplus in treating drug-resistant P. aeruginosa infection confirms its immense potential as a groundbreaking antibiotic agent for combating drug-resistant P. aeruginosa.
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Antibacterianos , Infecções por Pseudomonas , Pseudomonas aeruginosa , Fatores de Virulência , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/patogenicidade , Animais , Antibacterianos/farmacologia , Antibacterianos/química , Camundongos , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/microbiologia , Imunidade Adaptativa/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Humanos , Farmacorresistência Bacteriana/efeitos dos fármacos , Camundongos Endogâmicos BALB C , FemininoRESUMO
Human space activities have been continuously increasing. Astronauts experiencing spaceflight are faced with health problems caused by special space environments such as microgravity, and the investigation of cell injury is fundamental. The development of a platform capable of cell culture and injury detection is the prerequisite for the investigation. Constructing a platform suitable for special conditions in space life science research is the key issue. The ground-based investigation is an indispensable part of the research. Accordingly, a simulated microgravity (SMG)-oriented integrated chip platform capable of 3D cell culture and in situ visual detection of superoxide anion radical (O2â¢-) is developed. SMG can cause oxidative stress in human cells, and O2â¢- is one of the signaling molecules. Thus, a O2â¢--responsive aggregation-induced emission (AIE) probe is designed, which shows high selectivity and sensitivity to O2â¢-. Moreover, the probe exhibits abilities of long-term and wash-free staining to cells due to the AIE behavior, which is precious for space cell imaging. Meanwhile, a chip with a high-aspect-ratio chamber for adequate medium storage for the lack of the perfusion system during the SMG experiment and a cell culture chamber which can integrate the extracellular matrix (ECM) hydrogel for the bioinspired 3D cell culture is fabricated. In addition, a porous membrane is introduced between the chambers to prevent the hydrogel from separating during the SMG experiment. The afforded AIE probe-ECM hydrogel-integrated chip can achieve 3D culturing of U87-MG cells and in situ fluorescent detection of endogenous O2â¢- in the cells after long-term staining under SMG. The chip provides a powerful and potential platform for ground-based investigation in space life science and biomedical research.
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Técnicas Biossensoriais , Hidrogéis , Superóxidos , Humanos , Superóxidos/análise , Técnicas Biossensoriais/instrumentação , Técnicas Biossensoriais/métodos , Hidrogéis/química , Matriz Extracelular/química , Técnicas de Cultura de Células/instrumentação , Simulação de Ausência de Peso , Desenho de Equipamento , Corantes Fluorescentes/química , Dispositivos Lab-On-A-Chip , Ausência de Peso , Estresse OxidativoRESUMO
INTRODUCTION: Hereditary Hemorrhagic Telangiectasia (HHT) is charactered by telangiectasia and arteriovenous malformations (AVMs). Recurrent visceral and mucocutaneous bleeding is frequently reported among HHT patients, while data on the prevalence of thrombosis remains limited. This study aims to describe the clinical manifestations and molecular biological characteristics of HHT patients. METHODS: We conducted a retrospective study at Ruijin Hospital, affiliated with Shanghai Jiao Tong University School of Medicine. A total of 24 HHT patients, observed between January 2019 and December 2023, were included. We recorded the biological, clinical, and therapeutic events, with particular attention to bleeding and thrombotic events. Gene mutation analysis and blood constituent measurements were performed. RESULTS: The prevalence of bleeding among all HHT patients was 100 %, while thrombotic events were noted in 41.70 % of cases. Hepatic arteriovenous malformations (HAVMs) were identified in six patients, pulmonary arteriovenous malformations (PAVMs) in five patients, and cerebral arteriovenous malformations (CAVMs) in one patient. For patients with thrombosis, the discontinuation rates were 23.08 % for antiplatelet therapy and 33.33 % for anticoagulant therapy due to the increased risk of bleeding. Genetic mutations related to HHT were present in 16 patients, with ACVRL1 (activin A receptor-like type 1) mutations being the most frequent at 41.67 %, followed by ENG (endoglin) mutations at 20.83 %, and GDF2 (growth differentiation factor 2) mutations at 4.17 %. The incidence of PAVMs was 75.00 % in HHT1 patients with ENG mutations and 20 % in HHT2 patients with ACVRL1 mutations, while HAVMs occurred in 0 % and 40.00 % of these groups, respectively. Patients were divided into non-AVMs and AVMs groups. Compared to normal controls, von Willebrand factor (vWF) activity was significantly increased in all HHT patients (149.10 % vs. 90.65 %, P < 0.001). In the non-AVMs group, the median level of stromal cell-derived factor-1 (SDF-1) was significantly elevated (124.31 pg/mL vs. 2413.57 pg/mL, P < 0.05), while vWF antigen levels were markedly higher in the AVMs group (165.30 % vs. 130.60 %, P = 0.021). Further grouping of HHT patients based on bleeding and thrombosis phenotypes revealed that those with thrombosis had significantly higher median percentages of schistocytes (3.50 % vs. 0 %, P = 0.002), ferritin concentrations (318.50 µg/L vs. 115.50 µg/L, P = 0.001), and lactate dehydrogenase (LDH) levels (437 U/L vs. 105 U/L, P < 0.001). There were no significant differences in the activity of vWF, protein C (PC), protein S (PS), and factor VIII (FVIII) between the two groups. CONCLUSION: This study highlighted the complex relationship between arteriovenous malformations and genetic mutations in HHT patients. A comprehensive assessment of bleeding and thrombosis risks should be conducted for each HHT patient, additionally, further clinical studies are needed to explore the risk factors for thrombosis and anticoagulant-related bleeding in HHT.
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Telangiectasia Hemorrágica Hereditária , Humanos , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/genética , Telangiectasia Hemorrágica Hereditária/epidemiologia , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Adulto , Mutação , Idoso , Adulto Jovem , Trombose/genética , Trombose/etiologia , Malformações Arteriovenosas/genética , Malformações Arteriovenosas/complicações , AdolescenteRESUMO
BACKGROUND: Both autoregulatory progressive resistance exercise (APRE) and velocity-based resistance training (VBRT) utilize real-time monitoring of athlete physical performance to adjust training loads to provide appropriate training stimuli. However, the monitoring and adjustment approaches differ between both methods. This study aimed to compare the effects of APRE and VBRT on the muscle strength, power, and agility of college taekwondo athletes. HYPOTHESIS: Eight weeks of APRE and VBRT will promote similar results to strength gains in regards maximal strength, but VBRT will be superior to APRE in explosive power and agility. STUDY DESIGN: Clinical trial. LEVEL OF EVIDENCE: Level 3. METHODS: Thirty taekwondo athletes were divided randomly into 2 groups (VBRT/APRE), and all participants completed an 8-week APRE/VBRT intervention. Maximum strength, explosive power, and agility performance were assessed during the squat 1-repetition maximum (1RM), countermovement jump (CMJ), drop jump (DJ), kicking strength test (KST), taekwondo-specific agility test (TSAT), and hexagon test (HT). RESULTS: Highly significant time effects (P < 0.01) were observed for squat 1RM, CMJ, and TSAT in both the APRE and VBRT groups. However, there were no significant group-by-time differences for any of the measured outcomes to intergroup (P > 0.05), but APRE had a small effect size (ES) over VBRT for CMJ (ES = 0.48, η2p = 0.06), TSAT (ES = 0.26, η2p = 0.02), and HT (ES = 0.42, η2p = 0.05). CONCLUSION: An 8-week autoregulatory APRE and VBRT can both effectively improve both the maximal strength, explosive power, and agility performance of taekwondo athletes, with APRE exhibiting potential advantages in improving CMJ, TSAT, and HT. CLINICAL RELEVANCE: These results provide important insights into the selection of suitable resistance training programs by professional coaches, taking into account athlete needs, training efficiency, and safety considerations.
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Helicases, which utilize ATP hydrolysis to separate nucleic acid duplexes, play crucial roles in DNA and RNA replication, repair, recombination, and transcription. Categorized into the major groups superfamily 1 (SF1) and superfamily 2 (SF2), alongside four minor groups, these proteins exhibit a conserved catalytic core indicative of a shared evolutionary origin while displaying functional diversity through interactions with various substrates. This review summarizes the structures, functions and mechanisms of SF1 and SF2 helicases, with an emphasis on conserved ATPase sites and RecA-like domains essential for their enzymatic and nucleic acid binding capabilities. It highlights the unique 1B and 2B domains in SF1 helicases and their impact on enzymatic activity. The DNA unwinding process is detailed, covering substrate recognition, ATP hydrolysis, and conformational changes, while addressing debates over the active form of UvrD helicase and post-unwinding dissociation. More importantly, this review discusses the biotechnological potential of helicases in emerging technologies such as nanopore sequencing, protein sequencing, and isothermal amplification, focusing on their use in pathogen detection, biosensor enhancement, and cancer treatment. As understanding deepens, innovative applications in genome editing, DNA sequencing, and synthetic biology are anticipated.
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The misuse of antibiotics has caused serious impacts on food safety and human health, making it crucial to develop rapidly and highly sensitive methods for detecting trace nitrofuran antibiotics (NFs). In this study, phosphorus, nitride-doped carbon nanosheets (PN/CNs) were synthesized using a simple hydrothermal method based on graphitic carbon nitride. This prepared material showed excellent water solubility and stable optical properties. A new fluorescence sensing platform based on PN/CNs was constructed for the highly sensitive detection of four NFs. This sensitivity was mainly attributed to the fluorescence resonance energy transfer (FRET) mechanism. The limits of detection for nitrofurazone, nitrofurantoin, furazolidone and furaltadone were determined to be 13.41, 15.24, 16.37 and 19.94 nM, respectively. The high sensitivity and selectivity of PN/CNs for these four NFs were thoroughly evaluated by the Stern-Volmer equation and FRET quenching efficiency. This proposed method exhibited high sensitivity and can be successfully applied to detect NFs in fish.
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Antibacterianos , Peixes , Transferência Ressonante de Energia de Fluorescência , Contaminação de Alimentos , Nanoestruturas , Nitrofuranos , Nitrofuranos/análise , Antibacterianos/análise , Antibacterianos/química , Animais , Nanoestruturas/química , Contaminação de Alimentos/análise , Carbono/química , Limite de Detecção , Fluorescência , Fósforo/química , Fósforo/análise , Alimentos Marinhos/análiseRESUMO
In brief: PLCZ1 mutations are related to total fertilisation failure (TFF) after intracytoplasmic sperm injection (ICSI), characterised by abnormal oocyte oscillations. The novel PLCZ1 compound heterozygous mutations reported by this study were associated with TFF after ICSI, with one of the mutations indicating a gene dosage effect. Abstract: Oocyte activation failure is thought to be one of the main factors for total fertilisation failure (TFF) after intracytoplasmic sperm injection (ICSI), which could be induced by abnormal calcium oscillations. Phospholipase C zeta (PLCZ), a sperm factor, is associated with Ca2+ oscillations in mammalian oocytes. To date, some mutations in PLCZ1 (the gene that encodes PLCZ) have been linked to TFF, as demonstrated by the observed reduction in protein levels or activity to induce Ca2+ oscillations. In this study, normozoospermic males whose sperms exhibited TFF after ICSI and their families were recruited. First, mutations in the PLCZ1 sequence were identified by whole exome sequencing and validated using Sanger sequencing. Then, the locations of PLCZ1/PLCZ and the transcript and protein levels in the sperm of the patients were studied. Subsequently, in vitro function analysis and in silico analysis were performed to investigate the function-structure correlation of mutations identified in PLCZ1 using western blotting, immunofluorescence, RT-qPCR, and molecular simulation. Ca2+ oscillations were detected after cRNA microinjection into MII mouse oocytes to investigate calcium oscillations induced by abnormal PLCZ. Five variants with compound heterozygosity were identified, consisting of five new mutations and three previously reported mutations distributed across the main domains of PLCZ, except the EF hands domain. The transcript and protein levels decreased to varying degrees among all detected mutations in PLCZ1 when transfected in HEK293T cells. Among these, mutations in M138V and R391* of PLCZ were unable to trigger typical Ca2+ oscillations. In case 5, aberrant localisation of PLCZ in the sperm head and an increased expression of PLCZ in the sperm were observed. In conclusion, this study enhances the potential for genetic diagnosis of TFF in clinics and elucidates the possible relationship between the function and structure of PLCZ in novel mutations.
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Heterozigoto , Mutação , Fosfoinositídeo Fosfolipase C , Injeções de Esperma Intracitoplásmicas , Masculino , Humanos , Fosfoinositídeo Fosfolipase C/genética , Fosfoinositídeo Fosfolipase C/metabolismo , Feminino , Oócitos/metabolismo , Animais , Espermatozoides/metabolismo , Espermatozoides/patologia , Adulto , Camundongos , Sinalização do Cálcio/genética , Infertilidade Masculina/genéticaRESUMO
Plants are often exposed to biotic or abiotic stress, which can seriously impede their growth and development. In recent years, researchers have focused especially on the study of plant responses to biotic and abiotic stress. As one of the most widely planted grapevine rootstocks, 'Beta' has been extensively proven to be highly resistant to stress. However, further research is needed to understand the mechanisms of abiotic stress in 'Beta' rootstocks. In this study, we isolated and cloned a novel WRKY transcription factor, VhWRKY44, from the 'Beta' rootstock. Subcellular localization analysis revealed that VhWRKY44 was a nuclear-localized protein. Tissue-specific expression analysis indicated that VhWRKY44 had higher expression levels in grape roots and mature leaves. Further research demonstrated that the expression level of VhWRKY44 in grape roots and mature leaves was highly induced by salt and cold treatment. Compared with the control, Arabidopsis plants overexpressing VhWRKY44 showed stronger resistance to salt and cold stress. The activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) were significantly increased, and the contents of proline, malondialdehyde (MDA) and chlorophyll were changed considerably. In addition, significantly higher levels of stress-related genes were detected in the transgenic lines. The results indicated that VhWRKY44 was an important transcription factor in 'Beta' with excellent salt and cold tolerance, providing a new foundation for abiotic stress research.
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Arabidopsis , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas , Plantas Geneticamente Modificadas , Fatores de Transcrição , Vitis , Arabidopsis/genética , Arabidopsis/metabolismo , Vitis/genética , Vitis/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/genética , Estresse Fisiológico/genética , Temperatura Baixa , Raízes de Plantas/genética , Raízes de Plantas/metabolismo , Tolerância ao Sal/genética , Folhas de Planta/metabolismo , Folhas de Planta/genéticaRESUMO
N-methyl-D-aspartate receptor (NMDAR)-positive allosteric modulators (PAMs) represent a potential therapeutic strategy for cognitive impairment in disorders associated with NMDAR hypofunction, including Huntington's disease (HD) and Alzheimer's disease. Dalzanemdor (SAGE-718) is a novel, investigational NMDAR PAM being evaluated for the potential treatment of cognitive impairment in these disorders. We report first-in-human, phase I, double-blind, dose-finding studies to assess the safety, tolerability, and clinical pharmacology of dalzanemdor. A single-ascending dose study (dalzanemdor 0.35, 0.75, 1.5, or 3.0 mg vs. placebo) was conducted in healthy participants and included food effects. A multiple-ascending dose study (14 days) was conducted in healthy participants (dalzanemdor 0.5 or 1.0 mg vs. placebo) and HD participants (open-label dalzanemdor 1.0 mg) and included exploratory pharmacodynamics on cognitive performance. Dalzanemdor was generally well tolerated with no adverse events leading to discontinuation. Dalzanemdor exhibited pharmacokinetic parameters appropriate for once-daily dosing. Following single and multiple doses in healthy participants, median terminal half-life was 8-118 h, and the median time to reach maximum plasma concentration was 4-7 h. Exposures were dose-proportional after single dose (6-46 ng/mL) and more than dose-proportional after multiple doses (6-41 ng/mL). With multiple dosing, a steady state was achieved after 11 days in healthy participants and 13 days in HD participants. Dalzanemdor exposure decreased slightly with food. In HD participants, results suggest that dalzanemdor may improve cognitive performance on tests of executive function. These results support continued clinical development of dalzanemdor for the potential treatment of cognitive impairment in disorders of NMDAR hypofunction.
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Relação Dose-Resposta a Droga , Doença de Huntington , Receptores de N-Metil-D-Aspartato , Humanos , Masculino , Adulto , Doença de Huntington/tratamento farmacológico , Feminino , Pessoa de Meia-Idade , Método Duplo-Cego , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Adulto Jovem , Voluntários Saudáveis , Adolescente , Cognição/efeitos dos fármacos , IdosoRESUMO
Improving the nutrient content of red soils in southern China is a priority for efficient rice production there. To assess the effectiveness of oilseed rape as green manure for the improvement of soil phosphorus nutrient supply and rice yield in red soil areas, a long-term field plot experiment was conducted comparing two species of rape, Brassica napus (BN) and Brassica juncea (BJ). The effects of returning oilseed rape on soil phosphorus availability, phosphorus absorption, and yield of subsequent rice under rice-green manure rotation mode were analyzed, using data from the seasons of 2020 to 2021. The study found that compared with winter fallow treatment (WT) and no-tillage treatment (NT), the soil available phosphorus content of BN was increased, and that of BJ was significantly increased. The content of water-soluble inorganic phosphorus of BJ increased, and that of BN increased substantially. Compared with the WT, the soil organic matter content and soil total phosphorus content of BN significantly increased, as did the soil available potassium content of BJ, and the soil total phosphorus content of BJ was significantly increased compared with NT. The soil particulate phosphorus content of BJ and BN was significantly increased by 14.00% and 16.00%, respectively. Compared with the WT, the phosphorus activation coefficient of BJ was significantly increased by 11.41%. The rice plant tiller number under the green manure returning treatment was significantly increased by 43.16% compared with the winter fallow treatment. The green manure returning measures increased rice grain yield by promoting rice tiller numbers; BN increased rice grain yield by 9.91% and BJ by 11.68%. Based on these results, returning oilseed rape green manure could augment the phosphorus nutrients of red soil and promote phosphorus availability. Rice-oilseed rape green manure rotation could increase rice grain yield.
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Chiral molecules have similar physicochemical properties, which are different in terms of physiological activities and toxicities, rendering their differentiation and recognition highly significant. Nanozymes, which are nanomaterials with inherent enzyme-like activities, have garnered significant interest owing to their high cost-effectiveness, enhanced stability, and straightforward synthesis. However, constructing nanozymes with high activity and enantioselectivity remains a significant challenge. This review briefly introduces the synthesis methods of chiral nanozymes and systematically summarizes the latest research progress in enantioselective recognition of chiral molecules based on electrochemical methods and ultraviolet-visible absorption spectroscopy. Moreover, the challenges and development trends in developing enantioselective nanozymes are discussed. It is expected that this review will provide new ideas for the design of multifunctional chiral nanozymes and broaden the application field of nanozymes.
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Técnicas Eletroquímicas , Nanoestruturas , Espectrofotometria Ultravioleta , Estereoisomerismo , Nanoestruturas/químicaRESUMO
Intestinal pathogenic Escherichia coli (InPEC) is one of the most common causes of bacterial diarrhea in farm animals, including profuse neonatal diarrhea and post weaning diarrhea (PWD) in piglets. In this study, we investigated the prevalence of InPEC and associated primary virulence factors among 543 non-duplicate E. coli isolates from diarrheal pigs from 15 swine farms in southern China. Six major virulence genes associated with InPEC were identified among 69 (12.71â¯%) E. coli isolates and included est (6.62â¯%), K88 (4.79â¯%), elt (3.68â¯%), eae (1.47â¯%), stx2 (0.92â¯%) and F18 (0.55â¯%). Three pathotypes of InPEC were identified including ETEC (8.10â¯%), EPEC (1.29â¯%) and STEC/ETEC (0.92â¯%). In particular, K88 was only found in ETEC from breeding farms, whereas F18 was only present in STEC/ETEC hybrid from finishing farms. Whole genome sequence analysis of 37 E. coli isolates revealed that InPEC strains frequently co-carried multiple antibiotic resistance gene (ARG). est, elt and F18 were also found to co-locate with ARGs on a single IncFIB/IncFII plasmid. InPEC isolates from different pathotypes also possessed different profiles of virulence genes and antimicrobial resistance genes. Population structure analysis demonstrated that InPEC isolates from different pathotypes were highly heterogeneous whereas those of the same pathotype were extremely similar. Plasmid analysis revealed that K88 and/or est/elt were found on pGX18-2-like/pGX203-2-like and pGX203-1-like IncFII plasmids, while F18 and elt/est, as well as diverse ARGs were found to co-locate on IncFII/IncFIB plasmids with a non-typical backbone. Moreover, these key virulence genes were flanked by or adjacent to IS elements. Our findings indicated that both clonal expansion and horizontal spread of epidemic IncFII plasmids contributed to the prevalence of InPEC and the specific virulence genes (F4, F18, elt and est) in the tested swine farms.
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Diarreia , Infecções por Escherichia coli , Escherichia coli , Doenças dos Suínos , Fatores de Virulência , Animais , Suínos , Doenças dos Suínos/microbiologia , Doenças dos Suínos/epidemiologia , China/epidemiologia , Infecções por Escherichia coli/veterinária , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/epidemiologia , Diarreia/microbiologia , Diarreia/veterinária , Diarreia/epidemiologia , Prevalência , Fatores de Virulência/genética , Escherichia coli/genética , Escherichia coli/patogenicidade , Escherichia coli/isolamento & purificação , Escherichia coli/classificação , Virulência/genética , Intestinos/microbiologia , Sequenciamento Completo do Genoma , Escherichia coli Enterotoxigênica/genética , Escherichia coli Enterotoxigênica/patogenicidade , Escherichia coli Enterotoxigênica/isolamento & purificação , Proteínas de Escherichia coli/genéticaRESUMO
[This retracts the article DOI: 10.3892/ol.2019.9978.].
RESUMO
This study aims to understand the influence of nitrogen accumulation, fungal endophyte, yield, nitrogen use efficiency, and grain nutritional quality parameters on the yield of quinoa in some areas of China. The endophytic microbial community in plants plays a crucial role in plant growth, development, and health, especially in quinoa plants under different nitrogen fertilizer levels. The results from the present study indicated that appropriate nitrogen application significantly enhanced the nitrogen accumulation and yield of quinoa grains during maturity, increasing by 34.54-42.18% and 14.59-30.71%, respectively. Concurrently, protein content, amylose, total starch, ash, and fat content also increased, with respective growth rates of 1.15-18.18%, 30.74-42.53%, 6.40-12.40%, 1.94-21.94%, and 5.32-22.22%. Our constructed interaction network of bacterial and fungal communities revealed that bacteria outnumbered fungi significantly, and most of them exhibited synergistic interactions. The moderate increase in N150 was beneficial for increasing quinoa yield, achieving nitrogen use efficiency (NUE) of over 20%. The N210 was increased, and both the yield and NUE significantly decreased. This study provides novel insights into the impact of nitrogen fertilizer on quinoa growth and microbial communities, which are crucial for achieving agricultural sustainable development.
RESUMO
PURPOSE: To investigate the effect of Morinda officinalis polysaccharides(MOP) on the expression of fibronectin(FN) and fibronectin containing extra domain A(FN-EDA) in inflammatory periodontal ligament fibroblasts. METHODS: Thirty six rats were randomly divided into a control group(n=12) and a model group (n=24). The model group used orthodontic wire ligation to establish periodontitis. After three weeks, 6 rats from each group were selected and confirmed by Micro-CT to complete the modeling. The remaining rats in the model group were randomly divided into periodontitis group, normal saline(NS) group, and MOP group. In the MOP group, MOP (200 mg/kg for 3 d, 50 µL for 4 weeks) was injected into the palatal side of the left maxillary first molar of the rats. In the NS group, same volume of NS was injected, and no treatment was performed in the periodontitis group. The left maxillary tissue of rats were taken and the pathological changes of periodontal tissue were observed by H-E staining. The expression of FN and FN-EDA was detected by immunohistochemistry. Periodontal ligament fibroblasts were cultured in vitro, the effect of MOP on cell activity detected by CCK-8. The fourth generation cells were divided into control group, inflammation group (10 mg/mL lipopolysaccharide), and experimental group (12.5 µg/mL MOP, 12.5 µg/mL MOP+10 mg/mL lipopolysaccharide). The expression of FN and FN-EDA was detected by qRT-PCR and Western blot. The data were statistically analyzed using Prism 8.0 software package. RESULTS: In vivo experiments, the expression of FN-EDA in the MOP group was significantly lower than that in the periodontitis group and NS group(Pï¼0.05), and the infiltration of inflammatory cells was reduced. However, there was no significant difference in the expression of FN in each group. In vitro experiments, compared with the control group, the expression of FN-EDA mRNA and protein in the inflammation group was significantly increased(Pï¼0.000 1). MOP significantly reduced the expression of FN-EDA in inflammatory cells, but had no significant effect on FN expression. CONCLUSIONS: With increased expression of FN-EDA in inflammatory periodontal ligament tissues and cells, MOP may play a role in inhibiting inflammation by down-regulating FN-EDA.