RESUMO
Numerous studies have shown reduced performance in plants that are surrounded by neighbours of the same species1,2, a phenomenon known as conspecific negative density dependence (CNDD)3. A long-held ecological hypothesis posits that CNDD is more pronounced in tropical than in temperate forests4,5, which increases community stabilization, species coexistence and the diversity of local tree species6,7. Previous analyses supporting such a latitudinal gradient in CNDD8,9 have suffered from methodological limitations related to the use of static data10-12. Here we present a comprehensive assessment of latitudinal CNDD patterns using dynamic mortality data to estimate species-site-specific CNDD across 23 sites. Averaged across species, we found that stabilizing CNDD was present at all except one site, but that average stabilizing CNDD was not stronger toward the tropics. However, in tropical tree communities, rare and intermediate abundant species experienced stronger stabilizing CNDD than did common species. This pattern was absent in temperate forests, which suggests that CNDD influences species abundances more strongly in tropical forests than it does in temperate ones13. We also found that interspecific variation in CNDD, which might attenuate its stabilizing effect on species diversity14,15, was high but not significantly different across latitudes. Although the consequences of these patterns for latitudinal diversity gradients are difficult to evaluate, we speculate that a more effective regulation of population abundances could translate into greater stabilization of tropical tree communities and thus contribute to the high local diversity of tropical forests.
Assuntos
Biodiversidade , Florestas , Mapeamento Geográfico , Árvores , Modelos Biológicos , Especificidade da Espécie , Árvores/classificação , Árvores/fisiologia , Clima TropicalRESUMO
Elucidating gene function is a major goal in biology, especially among non-model organisms. However, doing so is complicated by the fact that molecular conservation does not always mirror functional conservation, and that complex relationships among genes are responsible for encoding pathways and higher-order biological processes. Co-expression, a promising approach for predicting gene function, relies on the general principal that genes with similar expression patterns across multiple conditions will likely be involved in the same biological process. For Cryptococcus neoformans, a prevalent human fungal pathogen greatly diverged from model yeasts, approximately 60% of the predicted genes in the genome lack functional annotations. Here, we leveraged a large amount of publicly available transcriptomic data to generate a C. neoformans Co-Expression Network (CryptoCEN), successfully recapitulating known protein networks, predicting gene function, and enabling insights into the principles influencing co-expression. With 100% predictive accuracy, we used CryptoCEN to identify 13 new DNA damage response genes, underscoring the utility of guilt-by-association for determining gene function. Overall, co-expression is a powerful tool for uncovering gene function, and decreases the experimental tests needed to identify functions for currently under-annotated genes.
Assuntos
Criptococose , Cryptococcus neoformans , Humanos , Cryptococcus neoformans/genética , Criptococose/genética , Criptococose/microbiologia , Reparo do DNA/genética , Fenótipo , Dano ao DNA/genética , Proteínas Fúngicas/genéticaRESUMO
Mitochondrial and synaptic dysfunction are pathological features of brain aging and cognitive decline. Synaptic mitochondria are vital for meeting the high energy demands of synaptic transmission. However, little is known about the link between age-related metabolic changes and the integrity of synaptic mitochondria. To this end, we investigate the mechanisms of advanced glycation endproducts (AGEs)-mediated mitochondrial and synaptic stress and evaluate the strategies to eliminate these toxic metabolites. Using aged brain and novel transgenic mice overexpressing neuronal glyoxalase 1 (GLO1), we comprehensively analyzed alterations in accumulation/buildup of AGEs and related metabolites in synaptic mitochondria and the association of AGE levels with mitochondrial function. We demonstrate for the first time that synaptic mitochondria are an early and major target of AGEs and the related toxic metabolite methylglyoxal (MG), a precursor of AGEs. MG/AGEs-insulted synaptic mitochondria exhibit deterioration of mitochondrial and synaptic function. Such accumulation of MG/AGEs positively correlated with mitochondrial perturbation and oxidative stress in aging brain. Importantly, clearance of AGEs-related metabolites by enhancing neuronal GLO1, a key enzyme for detoxification/of AGEs, reduces synaptic mitochondrial AGEs accumulation and improves mitochondrial and cognitive function in aging and AGE-challenged mice. Furthermore, we evaluated the direct effect of AGEs on synaptic function in hippocampal neurons in live brain slices as an ex-vivo model and in vitro cultured hippocampal neurons by recording long-term potentiation (LTP) and measuring spontaneously occurring miniature excitatory postsynaptic currents (mEPSCs). Neuronal GLO1 rescues deficits in AGEs-induced synaptic plasticity and transmission by fully recovery of decline in LTP or frequency of mEPSC. These studies explore crosstalk between synaptic mitochondrial dysfunction and age-related metabolic changes relevant to brain aging and cognitive decline. Synaptic mitochondria are particularly susceptible to AGEs-induced damage, highlighting the central importance of synaptic mitochondrial dysfunction in synaptic degeneration in age-related cognitive decline. Thus, augmenting GLO1 function to scavenge toxic metabolites represents a therapeutic approach to reduce age-related AGEs accumulation and to improve mitochondrial function and learning and memory.
RESUMO
Glutamine is a critical amino acid that serves as an energy source, building block, and signaling molecule for the heart tissue and the immune system. However, the role of glutamine metabolism in regulating cardiac remodeling following myocardial infarction (MI) is unknown. In this study, we show in adult male mice that glutamine metabolism is altered both in the remote (contractile) area and in infiltrating macrophages in the infarct area after permanent left anterior descending artery occlusion. We found that metabolites related to glutamine metabolism were differentially altered in macrophages at days 1, 3, and 7 after MI using untargeted metabolomics. Glutamine metabolism in live cells was increased after MI relative to no MI controls. Gene expression in the remote area of the heart indicated a loss of glutamine metabolism. Glutamine administration improved LV function at days 1, 3, and 7 after MI, which was associated with improved contractile and metabolic gene expression. Conversely, administration of BPTES, a pharmacological inhibitor of glutaminase-1, worsened LV function after MI. Neither glutamine nor BPTES administration impacted gene expression or bioenergetics of macrophages isolated from the infarct area. Our results indicate that glutamine metabolism plays a critical role in maintaining LV contractile function following MI, and that glutamine administration improves LV function. Glutamine metabolism may also play a role in regulating macrophage function, but macrophages are not responsive to exogenous pharmacological manipulation of glutamine metabolism.
RESUMO
Diabetes (DM) and hypertension (HTN) are major risk factors for chronic kidney injury, together accounting for >70% of end-stage renal disease. The combination of DM and HTN significantly accelerates development of renal injury; however, the underlying mechanisms of this synergy are still poorly understood. This study assessed whether mitochondria (MT) dysfunction is essential in developing renal injury in a rat model with combined DM and HTN. Type 1 DM was induced in Wistar rats by streptozotocin (STZ). HTN was induced six weeks later by inter-renal aorta constriction between the renal arteries, so that right kidneys were exposed to HTN while left kidneys were exposed to normotension. Kidneys exposed to DM or HTN alone had only mild glomerular injury and urinary albumin excretion (UAE). In contrast, kidneys exposed to DM plus 8 weeks HTN had significantly increased UAE and glomerular structural damage with reduced glomerular filtration rate. Marked increases in MT-derived reactive oxygen species (ROS) were also observed in right kidneys exposed to HTN+DM. We further tested whether treatment with MT-targeted antioxidant (MitoTEMPO) after the onset of HTN attenuates renal injury in rats with DM+HTN. Results show that kidneys in DM+AC+MitoTEMPO rats had lower UAE, less glomerular damage, and preserved MT function compared to untreated DM+AC rats. Our studies indicate that MT-derived ROS play a major role in promoting kidney dysfunction when DM is combined with HTN. Preserving MT function might be a potential therapeutic approach to halt the development of renal injury when DM coexists with HTN.
RESUMO
Although obesity is recognized as a risk factor for cardiorenal and metabolic diseases, the impact of parental obesity on the susceptibility of their offspring to renal injury at adulthood is unknown. We examined the impact of parental obesity on offspring kidney function, morphology, and markers of kidney damage after acute kidney injury (AKI). Offspring from normal (N) diet-fed C57BL/6J parents were fed either N (NN) or a high-fat (H) diet (NH) from weaning until adulthood. Offspring from obese H diet-fed parents were fed N (HN) or H diet (HH) after weaning. All offspring groups were submitted to bilateral AKI by clamping the left and right renal pedicles for 30 min. Compared with male NH and NN offspring from lean parents, male HH and HN offspring from obese parents exhibited higher kidney injury markers such as urinary, renal osteopontin, plasma creatinine, urinary albumin excretion, and neutrophil gelatinase-associated lipocalin (NGAL) levels, and worse histological injury score at 22 wk of age. Only albumin excretion and NGAL were elevated in female HH offspring from obese parents compared with lean and obese offspring from lean parents. We also found an increased mortality rate and worse kidney injury scores after AKI in male offspring from obese parents, regardless of the diet consumed after weaning. Female offspring were protected from major kidney injury after AKI. These results indicate that parental obesity leads to increased kidney injury in their offspring after ischemia-reperfusion in a sex-dependent manner, even when their offspring remain lean.NEW & NOTEWORTHY Offspring from obese parents are more susceptible to kidney injury and worse outcomes following an acute ischemia-reperfusion insult. Male, but not female, offspring from obese parents exhibit increased blood pressure early in life. Female offspring are partially protected against major kidney injury induced by ischemia-reperfusion.
Assuntos
Injúria Renal Aguda , Rim , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão , Animais , Masculino , Feminino , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/fisiopatologia , Injúria Renal Aguda/patologia , Rim/fisiopatologia , Rim/patologia , Rim/metabolismo , Fatores Sexuais , Obesidade/complicações , Obesidade/fisiopatologia , Dieta Hiperlipídica , Gravidez , Lipocalina-2/metabolismo , Obesidade Materna/metabolismo , Obesidade Materna/complicações , Obesidade Materna/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal , Camundongos , Fatores de Risco , Modelos Animais de Doenças , Biomarcadores/sangueRESUMO
Childhood adversity is an important risk factor for adverse health across the life course. Epigenetic modifications, such as DNA methylation (DNAm), are one hypothesized mechanism linking adversity to disease susceptibility. Yet, few studies have determined whether adversity-related DNAm alterations are causally related to future health outcomes or if their developmental timing plays a role in these relationships. Here, we used two-sample Mendelian Randomization to obtain stronger causal inferences about the association between adversity-associated DNAm loci across development (i.e., birth; childhood; adolescence; young adulthood) and 24 mental, physical, and behavioral health outcomes. We identified particularly strong associations between adversity-associated DNAm and ADHD, depression, obsessive-compulsive disorder, suicide attempts, asthma, coronary artery disease, and chronic kidney disease. A greater number of associations were identified for birth and childhood DNAm, while adolescent and young adulthood DNAm were more closely linked to mental health. Childhood DNAm loci also showed primarily risk suppressing relationships with health outcomes, suggesting that DNAm might reflect compensatory or buffering mechanisms against childhood adversity, rather than acting solely as an indicator of disease risk. Together, our results suggest adversity-related DNAm alterations are linked to both physical and mental health outcomes, with particularly strong impacts of DNAm differences emerging earlier in development.
RESUMO
Along with mass spectrometry (MS), ion mobility separations (IMS) are advancing to ever larger biomolecules. The emergence of electrospray ionization (ESI) and native MS enabled the IMS/MS analyses of proteins up to â¼100 kDa in the 1990s and whole protein complexes and viruses up to â¼10 MDa since the 2000s. Differential IMS (FAIMS) is substantially orthogonal to linear IMS based on absolute mobility K and offers exceptional resolution, unique selectivity, and steady filtering readily compatible with slower analytical methods such as electron capture or transfer dissociation (ECD/ETD). However, the associated MS stages had limited FAIMS to ions with m/z < 8000 and masses under â¼300 kDa. Here, we integrate high-definition FAIMS with the Q-Exactive Orbitrap UHMR mass spectrometer that can handle m/z up to 80,000 and MDa-size ions in the native ESI regime. In the initial evaluation, the oligomers of monoclonal antibody adalimumab (148 kDa) are size-selected up to at least the nonamers (1.34 MDa) with m/z values up to â¼17,000. This demonstrates the survival and efficient separation of noncovalent MDa assemblies in the FAIMS process, opening the door to novel analyses of the heaviest macromolecules.
Assuntos
Espectrometria de Mobilidade Iônica , Proteínas , Espectrometria de Massas/métodos , Proteínas/química , ÍonsRESUMO
Ion mobility spectrometry (IMS) coupled to mass spectrometry (MS) has become a versatile tool to fractionate complex mixtures, distinguish structural isomers, and elucidate molecular geometries. Along with the whole MS field, IMS/MS advances to ever larger species. A topical proteomic problem is the discovery and characterization of d-amino acid-containing peptides (DAACPs) that are critical to neurotransmission and toxicology. Both linear IMS and FAIMS previously disentangled d/l epimers with up to â¼30 residues. In the first study using all three most powerful IMS methodologiesâtrapped IMS, cyclic IMS, and FAIMSâwe demonstrate baseline resolution of the largest known d/l peptides (CHH from Homarus americanus with 72 residues) with a dynamic range up to 100. This expands FAIMS analyses of isomeric modified peptides, especially using hydrogen-rich buffers, to the â¼50-100 residue range of small proteins. The spectra for d and l are unprecedentedly strikingly similar except for a uniform shift of the separation parameter, indicating the conserved epimer-specific structural elements across multiple charge states and conformers. As the interepimer resolution tracks the average for smaller DAACPs, the IMS approaches could help search for yet larger DAACPs. The a priori method to calibrate cyclic (including multipass) IMS developed here may be broadly useful.
Assuntos
Peptídeos , Proteômica , Peptídeos/química , Espectrometria de Massas/métodos , Proteínas , Espectrometria de Mobilidade Iônica , Aminoácidos/químicaRESUMO
The Irati Formation (Paraná Basin) is a mixed carbonate and organic-rich shale sequence intruded by Jurassic-Cretaceous basic rocks, featuring Brazil's most important oil shale deposits with different maturity levels. For the first time, the distribution of oil shale biomarkers from an outcrop section (quarry) of the Irati Formation in the northernmost Paraná Basin was analyzed by GC-MS and GC-MS/MS to determine the thermal evolution, organic matter origin and the depositional paleoenvironment. The organic-rich shale at the northernmost border of the basin has high similarity with the central and southernmost areas, indicating a primary control able to induce cyclic sedimentation in a broad (106 km2) and restricted environment. PCA and HCA analysis of bulk and molecular parameters showed changes in the organic matter composition and paleoenvironmental conditions throughout the stratigraphic column. Nonetheless, there are significant differences compared to the central-eastern and southern areas of the basin. Contrasting with the southern region, the north, predominates biphytane, low and medium gammacerane index. Pr/n-C17, Ph/n-C18, HI and OI values suggest type II/III kerogen from marine organic matter with freshwater input. Among the steranes, those of stereochemistry ααα 20R predominate over ααα 20S, and the presence of ßTm indicates the shales are less thermally evolved.
Assuntos
Biomarcadores , Sedimentos Geológicos , Brasil , Sedimentos Geológicos/química , Sedimentos Geológicos/análise , Biomarcadores/análise , Cromatografia Gasosa-Espectrometria de Massas , Lipídeos/análise , FósseisRESUMO
Green manure (GM) may reduce the use of chemical fertilizers, been an ecologically appropriate strategy to cultivation of medicinal plants. Crotalaria juncea, is one of the most used because it adapts to different climatic and high nitrogen content. Origanum vulgare. is widely used in cooking, pharmaceutical, cosmetic industries and food products. The objectives of this study were to evaluate the GM on biomass, essential oil (EO), phenolic and antioxidant. The experiment consisted: control; 150, 300, 450, and 600 g (Sh= leaves+steam) more 200 g roots (R); 600 g aerial part; 200 g roots; and soil with 300 g cattle manure per pot. The highest dry weights were observed in the presence of GM and cattle manure (90 days). The control had an EO production 75% lower in relation to the dose of 450 g GM (Sh+R). Principal component analysis showed that GM and cattle manure positively influenced the dry weight, content, yield, and EO constituents, and total flavonoids. The GM contributed to the accumulation of the major EO compounds (trans-sabinene hydrate, thymol, terpinen-4-ol). The GM management may be beneficial for cultivating, because it can increase the production of biomass and the active components, in addition to being an inexpensive resource.
Assuntos
Crotalaria , Óleos Voláteis , Origanum , Bovinos , Animais , Óleos Voláteis/química , Origanum/química , Esterco , Biomassa , Compostos FitoquímicosRESUMO
The green synthesis of zinc oxide nanoparticles (ZnO NPs) using plants has grown in significance in recent years. ZnO NPs were synthesized in this work via a chemical precipitation method with Jasminum sambac (JS) leaf extract serving as a capping agent. These NPs were characterized using UV-vis spectroscopy, FT-IR, XRD, SEM, TEM, TGA, and DTA. The results from UV-vis and FT-IR confirmed the band gap energies (3.37 eV and 3.50 eV) and the presence of the following functional groups: CN, OH, C=O, and NH. A spherical structure and an average grain size of 26 nm were confirmed via XRD. The size and surface morphology of the ZnO NPs were confirmed through the use of SEM analysis. According to the TEM images, the ZnO NPs had an average mean size of 26 nm and were spherical in shape. The TGA curve indicated that the weight loss starts at 100 °C, rising to 900 °C, as a result of the evaporation of water molecules. An exothermic peak was seen during the DTA analysis at 480 °C. Effective antibacterial activity was found at 7.32 ± 0.44 mm in Gram-positive bacteria (S. aureus) and at 15.54 ± 0.031 mm in Gram-negative (E. coli) bacteria against the ZnO NPs. Antispasmodic activity: the 0.3 mL/mL sample solution demonstrated significant reductions in stimulant effects induced by histamine (at a concentration of 1 µg/mL) by (78.19%), acetylcholine (at a concentration of 1 µM) by (67.57%), and nicotine (at a concentration of 2 µg/mL) by (84.35%). The antipyretic activity was identified using the specific Shodhan vidhi method, and their anti-inflammatory properties were effectively evaluated with a denaturation test. A 0.3 mL/mL sample solution demonstrated significant reductions in stimulant effects induced by histamine (at a concentration of 1 µg/mL) by 78.19%, acetylcholine (at a concentration of 1 µM) by 67.57%, and nicotine (at a concentration of 2 µg/mL) by 84.35%. These results underscore the sample solution's potential as an effective therapeutic agent, showcasing its notable antispasmodic activity. Among the administered doses, the 150 mg/kg sample dose exhibited the most potent antipyretic effects. The anti-inflammatory activity of the synthesized NPs showed a remarkable inhibition percentage of (97.14 ± 0.005) at higher concentrations (250 µg/mL). Furthermore, a cytotoxic effect was noted when the biologically synthesized ZnO NPs were introduced to treated cells.
Assuntos
Antipiréticos , Jasminum , Nanopartículas , Óxido de Zinco , Óxido de Zinco/farmacologia , Parassimpatolíticos , Acetilcolina , Escherichia coli , Histamina , Nicotina , Espectroscopia de Infravermelho com Transformada de Fourier , Staphylococcus aureus , Anti-Inflamatórios/farmacologia , Antibacterianos/farmacologia , Extratos Vegetais/farmacologiaRESUMO
Chronic subdural hematoma (cSDH) is defined as a subdural collection of blood on CT imaging that tends to persist and gradually increase in volume over time, with components that are hypodense or isodense compared to the brain. There are no proven guidelines for the management of patients with cSDH. Surgical approaches included burr hole, twist drill hole, and craniotomy-based evacuations. Outcomes after surgical removal is generally favorable, but cSDH tends to recur after the initial evacuation.Middle meningeal artery (MMA) embolization has been gaining increasing popularity among the treatments of cSDH. This is largely due to a growing population of patients with cSDH who are refractory to other treatments or in patients who present with multiple comorbidities or who are taking antiplatelet and anticoagulant medications. The goal of middle meningeal artery (MMA) embolization is to devascularize subdural membranes associated with SDH so that the balance between continued leakage and reabsorption is shifted toward reabsorption.We discuss our clinical and technical approach to cSDH treated with perioperative embolization of the MMA.
Assuntos
Embolização Terapêutica , Hematoma Subdural Crônico , Humanos , Hematoma Subdural Crônico/diagnóstico por imagem , Hematoma Subdural Crônico/terapia , Artérias Meníngeas/diagnóstico por imagem , Encéfalo , AnticoagulantesRESUMO
ABSTRACT: There is evidence to suggest that the hypothermia observed in the most severe cases of systemic inflammation or sepsis is a regulated response with potential adaptive value, but the mechanisms involved are poorly understood. Here, we investigated the interplay between brain oxygenation (assessed by tissue P o2 ) and the development of hypothermia in unanesthetized rats challenged with a hypotension-inducing dose of bacterial LPS (1 mg/kg i.v.). At an ambient temperature of 22°C, oxygen consumption (VÌO 2 ) began to fall only a few minutes after the LPS injection, and this suppression in metabolic rate preceded the decrease in core temperature. No reduction in brain P o2 was observed prior to the development of the hypometabolic, hypothermic response, ruling out the possibility that brain hypoxia served as a trigger for hypothermia in this model. Brain P o2 was even increased. Such an improvement in brain oxygenation could reflect either an increased O 2 delivery or a decreased O 2 consumption. The former explanation seems unlikely because blood flow (cardiac output) was being progressively decreased during the recording period. On the other hand, the decrease in VÌO 2 usually preceded the rise in P o2 , and an inverse correlation between VÌO 2 and brain P o2 was consistently observed. These findings do not support the existence of a closed-loop feedback relationship between brain oxygenation and hypothermia in systemic inflammation. The data are consistent with a feedforward mechanism in which hypothermia is triggered (possibly by cryogenic inflammatory mediators) in anticipation of changes in brain oxygenation to prevent the development of tissue hypoxia.
Assuntos
Encéfalo , Hipotermia , Consumo de Oxigênio , Oxigênio , Choque Séptico , Animais , Encéfalo/metabolismo , Ratos , Masculino , Choque Séptico/metabolismo , Choque Séptico/fisiopatologia , Consumo de Oxigênio/fisiologia , Oxigênio/metabolismo , Hipotermia/metabolismo , Hipotermia/fisiopatologia , Lipopolissacarídeos , Ratos WistarRESUMO
Chiral ligands are important components in asymmetric homogeneous catalysis, but their synthesis and screening can be both time-consuming and resource-intensive. Data-driven approaches, in contrast to screening procedures based on intuition, have the potential to reduce the time and resources needed for reaction optimization by more rapidly identifying an ideal catalyst. These approaches, however, are often nontransferable and cannot be applied across different reactions. To overcome this drawback, we introduce a general featurization strategy for bidentate ligands that is coupled with an automated feature selection pipeline and Bayesian ridge regression to perform multivariate linear regression modeling. This approach, which is applicable to any reaction, incorporates electronic, steric, and topological features (rigidity/flexibility, branching, geometry, and constitution) and is well-suited for early stage ligand optimization. Using only small data sets, our workflow capably predicts the enantioselectivity of four metal-catalyzed asymmetric reactions. Uncertainty estimates provided by Bayesian ridge regression permit the use of Bayesian optimization to efficiently explore pools of prospective ligands. Finally, we constructed the BDL-Cu-2023 data set, composed of 312 bidentate ligands extracted from the Cambridge Structural Database, and screened it with this procedure to identify ligand candidates for a challenging asymmetric oxy-alkynylation reaction.
RESUMO
Evidence suggests that MDMA-assisted psychotherapy (MDMA-AP) has therapeutic potential for treatment of psychiatric illness. We conducted the first comprehensive systematic review and meta-analysis of the side effects of MDMA-AP across indications. We also assessed the quality of side effects-reporting in published trials of MDMA-AP. PubMed, EMBASE, PsycINFO, MEDLINE and Cochrane Central Register of Controlled Trials (CENTRAL) were systematically searched. Phase 2 and 3 MDMA-AP studies were included; Phase 1 studies, which assessed MDMA without psychotherapy, were not. Quality of side effects-reporting was assessed against the CONSORT Harms 2022 guidelines. We also compared numbers of adverse events reported in publications to those recorded in ClinicalTrial.gov registers. Thirteen studies were included, with eight contributing to the meta-analysis. In Phase 2 studies, MDMA-AP was associated with increased odds of any side effect during medication sessions (OR = 1.67, 95%CI (1.12, 2.49)) and in the 7 days following (OR = 1.59, 95%CI (1.12, 2.24)) relative to control conditions. In Phase 3 studies, MDMA-AP was associated with increased odds of any adverse event during the treatment period relative to placebo-assisted psychotherapy (OR = 3.51, 95%CI (2.76, 4.46)). The majority of RCTs were rated as having high risk of bias. Certainty of the evidence was rated as very low to moderate according to the GRADE framework. No included RCT had adequate adherence to the CONSORT Harms 2022 recommendations and reporting rates were also low. Compared to placebo, MDMA-AP was associated with increased odds of side effects, which were largely transient and mild or moderate in severity. However, identified limitations in existing evidence indicate that further investigation is needed to better characterize the safety profile of MDMA-AP and guide implementation.
Assuntos
N-Metil-3,4-Metilenodioxianfetamina , Psicoterapia , Humanos , N-Metil-3,4-Metilenodioxianfetamina/efeitos adversos , N-Metil-3,4-Metilenodioxianfetamina/administração & dosagem , Psicoterapia/métodos , Alucinógenos/efeitos adversos , Alucinógenos/uso terapêutico , Transtornos Mentais/terapia , Transtornos Mentais/tratamento farmacológico , Terapia Combinada/métodosRESUMO
Biobased plastics provide a sustainable alternative to conventional food packaging materials, thereby reducing the environmental impact. The present study investigated the effectiveness of chitosan with varying levels of Moringa oleifera seed powder (MOSP) and tannic acid (TA). Chitosan (CS) biocomposite films with tannic acid acted as a cross-linker, and Moringa oleifera seed powder served as reinforcement. To enhance food packaging and film performance, Moringa oleifera seed powder was introduced at various loadings of 1.0, 3.0, 5.0, and 10.0 wt.%. Fourier-transform infrared spectroscopy, X-ray diffraction, and scanning electron microscopy analyses were performed to study the structure and morphology of the CS/TA/MOSP films. The scanning electron microscopy results confirmed that chitosan/TA with 10.0 wt.% of MOSP produced a lightly miscible droplet/matrix structure. Furthermore, mechanical properties, swelling, water solubility, optical barrier, and water contact angle properties of the film were also calculated. With increasing Moringa oleifera seed powder contents, the biocomposite films' antimicrobial and antifungal activity increased at the 10.0 wt.% MOSP level; all of the observed bacteria [Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), Aspergillus niger (A. niger), and Candida albicans (C. albicans)] had a notably increased percentage of growth. The film, with 10.0 wt.% MOSP content, effectively preserves strawberries' freshness, making it an ideal food packaging material.
RESUMO
The structural and electro-thermophysical characteristics of organosilicon elastomers modified with multilayer carbon nanotubes (MWCNTs) synthesized on Co-Mo/Al2O3-MgO and metallic (Cu or Ni) microparticles have been studied. The structures were analyzed with scanning electron microscopy (SEM), transmission electron microscopy (TEM), Raman spectroscopy, and energy-dispersive X-ray spectroscopy (EDX). The main focus of this study was the influence of metallic dispersed fillers on the resistance of a modified elastomer with Cu and Ni to the degradation of electrophysical parameters under the action of applied electrical voltage. The distribution of the temperature field on the surface of a modified polymer composite with metallic micro-dimensional structures has been recorded. The collected data demonstrate the possibility of controlling the degradation caused by electrical voltage. It has been found that repeated on/off turns of the elastomer with an MWCNTs on 50 and 100 cycles leads to a deterioration in the properties of the conductive elastomer from the available power of 1.1 kW/m2 (-40 °C) and, as a consequence, a decrease in the power to 0.3 kW/m2 (-40 °C) after 100 on/off cycles. At the same time, the Ni additive allows increasing the power by 1.4 kW/m2 (-40 °C) and reducing the intensity of the degradation of the conductive structures (after 100 on/off cycles up to 1.2 kW/m2 (-40 °C). When Ni is replaced by Cu, the power of the modified composite in the heating mode increases to 1.6 kW/m2 (-40 °C) and, at the same time, the degradation of the conductive structures in the composite decreases in the mode of cyclic offensives (50 and 100 cycles) (1.5 kW/m2 (-40 °C)). It was found that the best result in terms of heat removal is typical for an elastomer sample with an MWCNTs and Cu (temperature reaches 93.9 °C), which indicates an intensification of the heat removal from the most overheated places of the composite structure. At the same time, the maximum temperature for the Ni additives reaches 86.7 °C. A sample without the addition of a micro-sized metal is characterized by the local unevenness of the temperature field distribution, which causes undesirable internal overheating and destruction of the current-conducting structures based on the MWCNTs. The maximum temperature at the same time reaches a value of 49.8 °C. The conducted studies of the distribution of the micro-sizes of Ni and Cu show that Cu, due to its larger particles, improves internal heat exchange and intensifies heat release to the surface of the heater sample, which improves the temperature regime of the MWCNTs and, accordingly, increases resistance to electrophysical degradation.
RESUMO
Understanding the complex relationships between enzyme sequence, folding stability and catalytic activity is crucial for applications in industry and biomedicine. However, current enzyme assay technologies are limited by an inability to simultaneously resolve both stability and activity phenotypes and to couple these to gene sequences at large scale. Here we present the development of enzyme proximity sequencing, a deep mutational scanning method that leverages peroxidase-mediated radical labeling with single cell fidelity to dissect the effects of thousands of mutations on stability and catalytic activity of oxidoreductase enzymes in a single experiment. We use enzyme proximity sequencing to analyze how 6399 missense mutations influence folding stability and catalytic activity in a D-amino acid oxidase from Rhodotorula gracilis. The resulting datasets demonstrate activity-based constraints that limit folding stability during natural evolution, and identify hotspots distant from the active site as candidates for mutations that improve catalytic activity without sacrificing stability. Enzyme proximity sequencing can be extended to other enzyme classes and provides valuable insights into biophysical principles governing enzyme structure and function.
Assuntos
Mutação de Sentido Incorreto , Mutação , Estabilidade EnzimáticaRESUMO
To address the global problem of bacterial antibiotic resistance, antimicrobial peptides (AMPs) are considered promising therapeutic candidates due to their broad-spectrum and membrane-lytic activity. As preferential interactions with bacteria are crucial, it is equally important to investigate and understand their impact on eukaryotic cells. In this study, we employed 19F solid-state nuclear magnetic resonance (ssNMR) as a novel approach to examine the interaction of AMPs with whole red blood cells (RBCs). We used RBC ghosts (devoid of hemoglobin) and developed a protocol to label their lipid membranes with palmitic acid (PA) monofluorinated at carbon positions 4, 8, or 14 on the acyl chain, allowing us to probe different locations in model and intact RBC ghost membranes. Our work revealed that changes in the 19F chemical shift anisotropy, monitored through a CF bond order parameter (SCF), can provide insights into lipid bilayer dynamics. This information was also obtained using magic-angle spinning 19F ssNMR spectra with and without 1H decoupling, by studying alterations in the second spectral moment (M2) as well as the 19F isotropic chemical shift, linewidth, T1, and T2 relaxation times. The appearance of an additional isotropic peak with a smaller chemical shift anisotropy, a narrower linewidth, and a shorter T1, induced by the AMP caerin 1.1, supports the presence of high-curvature regions in RBCs indicative of pore formation, analogous to its antimicrobial mechanism. In summary, the straightforward incorporation of monofluorinated FAs and rapid signal acquisition offer promising avenues for the study of whole cells using 19F ssNMR.