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1.
Cell ; 186(9): 1930-1949.e31, 2023 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-37071993

RESUMO

Cortical circuits are composed predominantly of pyramidal-to-pyramidal neuron connections, yet their assembly during embryonic development is not well understood. We show that mouse embryonic Rbp4-Cre cortical neurons, transcriptomically closest to layer 5 pyramidal neurons, display two phases of circuit assembly in vivo. At E14.5, they form a multi-layered circuit motif, composed of only embryonic near-projecting-type neurons. By E17.5, this transitions to a second motif involving all three embryonic types, analogous to the three adult layer 5 types. In vivo patch clamp recordings and two-photon calcium imaging of embryonic Rbp4-Cre neurons reveal active somas and neurites, tetrodotoxin-sensitive voltage-gated conductances, and functional glutamatergic synapses, from E14.5 onwards. Embryonic Rbp4-Cre neurons strongly express autism-associated genes and perturbing these genes interferes with the switch between the two motifs. Hence, pyramidal neurons form active, transient, multi-layered pyramidal-to-pyramidal circuits at the inception of neocortex, and studying these circuits could yield insights into the etiology of autism.


Assuntos
Transtorno Autístico , Neocórtex , Células Piramidais , Animais , Feminino , Camundongos , Gravidez , Transtorno Autístico/genética , Transtorno Autístico/patologia , Mutação , Neocórtex/fisiologia , Neurônios/fisiologia , Células Piramidais/fisiologia
2.
Plant J ; 117(2): 541-560, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37932864

RESUMO

Carotenoids are isoprenoid pigments indispensable for photosynthesis. Moreover, they are the precursor of apocarotenoids, which include the phytohormones abscisic acid (ABA) and strigolactones (SLs) as well as retrograde signaling molecules and growth regulators, such as ß-cyclocitral and zaxinone. Here, we show that the application of the volatile apocarotenoid ß-ionone (ß-I) to Arabidopsis plants at micromolar concentrations caused a global reprogramming of gene expression, affecting thousands of transcripts involved in stress tolerance, growth, hormone metabolism, pathogen defense, and photosynthesis. This transcriptional reprogramming changes, along with induced changes in the level of the phytohormones ABA, jasmonic acid, and salicylic acid, led to enhanced Arabidopsis resistance to the widespread necrotrophic fungus Botrytis cinerea (B.c.) that causes the gray mold disease in many crop species and spoilage of harvested fruits. Pre-treatment of tobacco and tomato plants with ß-I followed by inoculation with B.c. confirmed the effect of ß-I in increasing the resistance to this pathogen in crop plants. Moreover, we observed reduced susceptibility to B.c. in fruits of transgenic tomato plants overexpressing LYCOPENE ß-CYCLASE, which contains elevated levels of endogenous ß-I, providing a further evidence for its effect on B.c. infestation. Our work unraveled ß-I as a further carotenoid-derived regulatory metabolite and indicates the possibility of establishing this natural volatile as an environmentally friendly bio-fungicide to control B.c.


Assuntos
Arabidopsis , Norisoprenoides , Solanum lycopersicum , Reguladores de Crescimento de Plantas/metabolismo , Arabidopsis/metabolismo , Resistência à Doença/genética , Transcriptoma , Ácido Abscísico , Botrytis/metabolismo , Plantas Geneticamente Modificadas/genética , Doenças das Plantas/microbiologia , Regulação da Expressão Gênica de Plantas
3.
Plant J ; 117(5): 1305-1316, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38169533

RESUMO

Seeds of the root parasitic plant Striga hermonthica undergo a conditioning process under humid and warm environments before germinating in response to host-released stimulants, particularly strigolactones (SLs). The plant hormone abscisic acid (ABA) regulates different growth and developmental processes, and stress response; however, its role during Striga seed germination and early interactions with host plants is under-investigated. Here, we show that ABA inhibited Striga seed germination and that hindering its biosynthesis induced conditioning and germination in unconditioned seeds, which was significantly enhanced by treatment with the SL analog rac-GR24. However, the inhibitory effect of ABA remarkably decreased during conditioning, confirming the loss of sensitivity towards ABA in later developmental stages. ABA measurement showed a substantial reduction of its content during the early conditioning stage and a significant increase upon rac-GR24-triggered germination. We observed this increase also in released seed exudates, which was further confirmed by using the Arabidopsis ABA-reporter GUS marker line. Seed exudates of germinated seeds, containing elevated levels of ABA, impaired the germination of surrounding Striga seeds in vitro and promoted root growth of a rice host towards germinated Striga seeds. Application of ABA as a positive control caused similar effects, indicating its function in Striga/Striga and Striga/host communications. In summary, we show that ABA is an essential player during seed dormancy and germination processes in Striga and acts as a rhizospheric signal likely to support host infestation.


Assuntos
Arabidopsis , Striga , Ácido Abscísico/farmacologia , Germinação , Striga/fisiologia , Reguladores de Crescimento de Plantas/farmacologia , Sementes
4.
EMBO J ; 40(15): e106800, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34156108

RESUMO

How organisms integrate metabolism with the external environment is a central question in biology. Here, we describe a novel regulatory small molecule, a proteogenic dipeptide Tyr-Asp, which improves plant tolerance to oxidative stress by directly interfering with glucose metabolism. Specifically, Tyr-Asp inhibits the activity of a key glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (GAPC), and redirects glucose toward pentose phosphate pathway (PPP) and NADPH production. In line with the metabolic data, Tyr-Asp supplementation improved the growth performance of both Arabidopsis and tobacco seedlings subjected to oxidative stress conditions. Moreover, inhibition of Arabidopsis phosphoenolpyruvate carboxykinase (PEPCK) activity by a group of branched-chain amino acid-containing dipeptides, but not by Tyr-Asp, points to a multisite regulation of glycolytic/gluconeogenic pathway by dipeptides. In summary, our results open the intriguing possibility that proteogenic dipeptides act as evolutionarily conserved small-molecule regulators at the nexus of stress, protein degradation, and metabolism.


Assuntos
Arabidopsis/efeitos dos fármacos , Dipeptídeos/farmacologia , Gliceraldeído-3-Fosfato Desidrogenases/antagonistas & inibidores , Nicotiana/efeitos dos fármacos , Proteínas de Plantas/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/metabolismo , Simulação por Computador , Dipeptídeos/química , Dipeptídeos/metabolismo , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/química , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , NADP/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Via de Pentose Fosfato/efeitos dos fármacos , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Proteínas de Plantas/antagonistas & inibidores , Plântula/efeitos dos fármacos , Plântula/metabolismo , Nicotiana/metabolismo
5.
Plant J ; 113(5): 986-1003, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36602437

RESUMO

The enzyme DWARF27 (D27) catalyzes the reversible isomerization of all-trans- into 9-cis-ß-carotene, initiating strigolactone (SL) biosynthesis. Genomes of higher plants encode two D27-homologs, D27-like1 and -like2, with unknown functions. Here, we investigated the enzymatic activity and biological function of the Arabidopsis D27-like1. In vitro enzymatic assays and expression in Synechocystis sp. PCC6803 revealed an unreported 13-cis/15-cis/9-cis- and a 9-cis/all-trans-ß-carotene isomerization. Although disruption of AtD27-like1 did not cause SL deficiency phenotypes, overexpression of AtD27-like1 in the d27 mutant restored the more-branching phenotype, indicating a contribution of AtD27-like1 to SL biosynthesis. Accordingly, generated d27 d27like1 double mutants showed a more pronounced branching phenotype compared to d27. The contribution of AtD27-like1 to SL biosynthesis is likely a result of its formation of 9-cis-ß-carotene that was present at higher levels in AtD27-like1 overexpressing lines. By contrast, AtD27-like1 expression correlated negatively with the content of 9-cis-violaxanthin, a precursor of ABA, in shoots. Consistently, ABA levels were higher in shoots and also in dry seeds of the d27like1 and d27 d27like1 mutants. Transgenic lines expressing GUS driven by the AtD27LIKE1 promoter and transcript analysis of hormone-treated Arabidopsis seedlings revealed that AtD27LIKE1 is expressed in different tissues and affects ABA and auxin. Taken together, our work reports a cis/cis-ß-carotene isomerase that affects the content of both cis-carotenoid-derived plant hormones, ABA and SLs.


Assuntos
Arabidopsis , Arabidopsis/genética , Arabidopsis/metabolismo , beta Caroteno/metabolismo , cis-trans-Isomerases/genética , cis-trans-Isomerases/metabolismo , Regulação da Expressão Gênica de Plantas , Isomerases/genética , Isomerases/metabolismo
6.
Plant J ; 115(5): 1214-1230, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37219088

RESUMO

Identification of protein interactors is ideally suited for the functional characterization of small molecules. 3',5'-cAMP is an evolutionary ancient signaling metabolite largely uncharacterized in plants. To tap into the physiological roles of 3',5'-cAMP, we used a chemo-proteomics approach, thermal proteome profiling (TPP), for the unbiased identification of 3',5'-cAMP protein targets. TPP measures shifts in the protein thermal stability upon ligand binding. Comprehensive proteomics analysis yielded a list of 51 proteins significantly altered in their thermal stability upon incubation with 3',5'-cAMP. The list contained metabolic enzymes, ribosomal subunits, translation initiation factors, and proteins associated with the regulation of plant growth such as CELL DIVISION CYCLE 48. To functionally validate obtained results, we focused on the role of 3',5'-cAMP in regulating the actin cytoskeleton suggested by the presence of actin among the 51 identified proteins. 3',5'-cAMP supplementation affected actin organization by inducing actin-bundling. Consistent with these results, the increase in 3',5'-cAMP levels, obtained either by feeding or by chemical modulation of 3',5'-cAMP metabolism, was sufficient to partially rescue the short hypocotyl phenotype of the actin2 actin7 mutant, severely compromised in actin level. The observed rescue was specific to 3',5'-cAMP, as demonstrated using a positional isomer 2',3'-cAMP, and true for the nanomolar 3',5'-cAMP concentrations reported for plant cells. In vitro characterization of the 3',5'-cAMP-actin pairing argues against a direct interaction between actin and 3',5'-cAMP. Alternative mechanisms by which 3',5'-cAMP would affect actin dynamics, such as by interfering with calcium signaling, are discussed. In summary, our work provides a specific resource, 3',5'-cAMP interactome, as well as functional insight into 3',5'-cAMP-mediated regulation in plants.


Assuntos
Citoesqueleto de Actina , Actinas , Actinas/metabolismo , Citoesqueleto de Actina/metabolismo , Plantas/metabolismo , Sinalização do Cálcio
7.
Neuroimage ; 296: 120686, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38871037

RESUMO

Centromedian nucleus (CM) is one of several intralaminar nuclei of the thalamus and is thought to be involved in consciousness, arousal, and attention. CM has been suggested to play a key role in the control of attention, by regulating the flow of information to different brain regions such as the ascending reticular system, basal ganglia, and cortex. While the neurophysiology of attention in visual and auditory systems has been studied in animal models, combined single unit and LFP recordings in human have not, to our knowledge, been reported. Here, we recorded neuronal activity in the CM nucleus in 11 patients prior to insertion of deep brain stimulation electrodes for the treatment of epilepsy while subjects performed an auditory attention task. Patients were requested to attend and count the infrequent (p = 0.2) odd or "deviant" tones, ignore the frequent standard tones and report the total number of deviant tones at trial completion. Spikes were discriminated, and LFPs were band pass filtered (5-45 Hz). Average peri­stimulus time histograms and spectra were constructed by aligning on tone onsets and statistically compared. The firing rate of CM neurons showed selective, multi-phasic responses to deviant tones in 81% of the tested neurons. Local field potential analysis showed selective beta and low gamma (13-45 Hz) modulations in response to deviant tones, also in a multi-phasic pattern. The current study demonstrates that CM neurons are under top-down control and participate in the selective processing during auditory attention and working memory. These results, taken together, implicate the CM in selective auditory attention and working memory and support a role of beta and low gamma oscillatory activity in cognitive processes. It also has potential implications for DBS therapy for epilepsy and non-motor symptoms of PD, such as apathy and other disorders of attention.


Assuntos
Atenção , Percepção Auditiva , Núcleos Intralaminares do Tálamo , Memória de Curto Prazo , Neurônios , Humanos , Atenção/fisiologia , Masculino , Feminino , Memória de Curto Prazo/fisiologia , Adulto , Percepção Auditiva/fisiologia , Núcleos Intralaminares do Tálamo/fisiologia , Pessoa de Meia-Idade , Neurônios/fisiologia , Adulto Jovem , Estimulação Acústica , Estimulação Encefálica Profunda/métodos
8.
J Med Virol ; 96(2): e29431, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38293752

RESUMO

The aim of the study was to determine the presence of human papillomavirus (HPV) in patients with intractable plantar keratosis (IPK) by comparing the histopathological findings of biopsies. A prospective, observational, and concordance study was carried out. Three different specimens were taken from each IPK. A first punch was sent for histopathological examination, and a second punch and a superficial skin scraping were both sent for HPV  polymerase chain reaction (PCR) and type determination. A total of 51 patients were included. From the histopathological examination, it was determined that 35 (68.6%) samples were diagnosed as warts and 16 (31.3%) as keratosis. However, the presence of HPV was confirmed by PCR in 49 (96.1%) and in 42 (82.4%) samples obtained by punch and superficial scraping, respectively. In the 49 PCR-positive samples, the most common HPV types were HPV1, HPV2, HPV27, HPV57, and HPV65, accounting for 81.6% of the samples. In conclusion, this study demonstrates that HPV infection and IPK lesions are very closely related. Although we cannot confirm that HPV is the cause of the development of IPK, the high prevalence of HPV observed in these lesions calls for a change to the procedures for managing IPK.


Assuntos
Ceratose , Infecções por Papillomavirus , Verrugas , Humanos , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/epidemiologia , Papillomavirus Humano , Estudos Prospectivos , Verrugas/epidemiologia , Papillomaviridae/genética , DNA Viral/genética , DNA Viral/análise
9.
J Pathol ; 261(2): 169-183, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37555366

RESUMO

Intravascular hemolysis is a common feature of different clinical entities, including sickle cell disease and malaria. Chronic hemolytic disorders are associated with hepatic damage; however, it is unknown whether heme disturbs lipid metabolism and promotes liver steatosis, thereby favoring the progression to nonalcoholic fatty liver disease (NAFLD). Using an experimental model of acute intravascular hemolysis, we report here the presence of liver injury in association with microvesicular lipid droplet deposition. Hemolysis promoted serum hyperlipidemia and altered intrahepatic triglyceride fatty acid composition, with increments in oleic, palmitoleic, and palmitic acids. These findings were related to augmented expression of transporters involved in fatty acid uptake (CD36 and MSR1) and deregulation of LDL transport, as demonstrated by decreased levels of LDL receptor and increased PCSK9 expression. Hemolysis also upregulated hepatic enzymes associated with cholesterol biosynthesis (SREBP2, HMGC1, LCAT, SOAT1) and transcription factors regulating lipid metabolism (SREBP1). Increased LC3II/LC3I ratio and p62/SQSTM1 protein levels were reported in mice with intravascular hemolysis and hepatocytes stimulated with heme, indicating a blockade of lipophagy. In cultured hepatocytes, cell pretreatment with the autophagy inductor rapamycin diminished heme-mediated toxicity and accumulation of lipid droplets. In conclusion, intravascular hemolysis enhances liver damage by exacerbating lipid accumulation and blocking the lipophagy pathway, thereby promoting NAFLD. These new findings have a high translational potential as a novel NAFLD-promoting mechanism in individuals suffering from severe hemolysis episodes. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Hepatopatia Gordurosa não Alcoólica/patologia , Pró-Proteína Convertase 9/metabolismo , Metabolismo dos Lipídeos , Hemólise , Fígado/patologia , Hepatócitos/patologia , Ácidos Graxos/metabolismo , Autofagia , Heme/metabolismo , Camundongos Endogâmicos C57BL
10.
Cell Mol Life Sci ; 80(7): 185, 2023 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-37340282

RESUMO

DIS3L2 degrades different types of RNAs in an exosome-independent manner including mRNAs and several types of non-coding RNAs. DIS3L2-mediated degradation is preceded by the addition of nontemplated uridines at the 3'end of its targets by the terminal uridylyl transferases 4 and 7. Most of the literature that concerns DIS3L2 characterizes its involvement in several RNA degradation pathways, however, there is some evidence that its dysregulated activity may contribute to cancer development. In the present study, we characterize the role of DIS3L2 in human colorectal cancer (CRC). Using the public RNA datasets from The Cancer Genome Atlas (TCGA), we found higher DIS3L2 mRNA levels in CRC tissues versus normal colonic samples as well as worse prognosis in patients with high DIS3L2 expression. In addition, our RNA deep-sequencing data revealed that knockdown (KD) of DIS3L2 induces a strong transcriptomic disturbance in SW480 CRC cells. Moreover, gene ontology (GO) analysis of significant upregulated transcripts displays enrichment in mRNAs encoding proteins involved in cell cycle regulation and cancer-related pathways, which guided us to evaluate which specific hallmarks of cancer are differentially regulated by DIS3L2. To do so, we employed four CRC cell lines (HCT116, SW480, Caco-2 and HT-29) differing in their mutational background and oncogenicity. We demonstrate that depletion of DIS3L2 results in reduced cell viability of highly oncogenic SW480 and HCT116 CRC cells, but had little or no impact in the more differentiated Caco-2 and HT-29 cells. Remarkably, the mTOR signaling pathway, crucial for cell survival and growth, is downregulated after DIS3L2 KD, whereas AZGP1, an mTOR pathway inhibitor, is upregulated. Furthermore, our results indicate that depletion of DIS3L2 disturbs metastasis-associated properties, such as cell migration and invasion, only in highly oncogenic CRC cells. Our work reveals for the first time a role for DIS3L2 in sustaining CRC cell proliferation and provides evidence that this ribonuclease is required to support the viability and invasive behavior of dedifferentiated CRC cells.


Assuntos
Neoplasias Colorretais , Humanos , Células CACO-2 , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Células HCT116 , Proliferação de Células/genética , RNA Mensageiro , Movimento Celular/genética , Ribonucleases/genética , Regulação Neoplásica da Expressão Gênica , Exorribonucleases/genética , Exorribonucleases/metabolismo
11.
Neurol Sci ; 45(6): 2859-2867, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38261153

RESUMO

BACKGROUND: Variant transthyretin amyloidosis (ATTRv) can cause sensorimotor and autonomic neuropathy. Objective quantification of sudomotor function may be essential for early diagnosis and early initiation of treatment. The aim of this study is to evaluate the diagnostic value of the Sudoscan® in ATTRv. METHODS: Electrochemical skin conductance (ESC) was measured in V30M ATTRv patients, asymtomatic V30M carriers and healthy controls. Comparisons between the three groups were made using the Kruskal-Wallis test, and ROC curves were used to estimate the discriminatory power of ESC values between groups. RESULTS: ESC was measured in 52 ATTRv patients, 107 asymptomatic carriers and 40 healthy controls. ESC was significantly lower in ATTRv patients compared to asymptomatic carriers and healthy controls in both feet and hands; median values are as follows: 40 µS, 78 µS and 81 µS, respectively (p < 0.001), and 53 µS, 69 µS and 74 µS, respectively (p < 0.001). ESC in feet < 70.5 µS had a sensitivity of 89.7% and specificity of 84.6% to discriminate asymptomatic carriers from patients with ATTRv. CONCLUSION: The determination of ESC by Sudoscan® is a rapid, noninvasive and easily reproducible technique capable of discriminating patients with ATTRv from asymptomatic carriers and healthy controls with adequate sensitivity and specificity.


Assuntos
Neuropatias Amiloides Familiares , Resposta Galvânica da Pele , Humanos , Masculino , Feminino , Neuropatias Amiloides Familiares/diagnóstico , Pessoa de Meia-Idade , Idoso , Resposta Galvânica da Pele/fisiologia , Sensibilidade e Especificidade , Adulto , Pré-Albumina , Mãos/fisiopatologia , Pé/fisiopatologia
12.
J Neuroeng Rehabil ; 21(1): 30, 2024 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-38419069

RESUMO

BACKGROUND: Despite technical advances in the field of wearable robotic devices (WRD), there is still limited user acceptance of these technologies. While usability often comes as a key factor influencing acceptance, there is a scattered landscape of definitions and scopes for the term. To advance usability evaluation, and to integrate usability features as design requirements during technology development, there is a need for benchmarks and shared terminology. These should be easily accessible and implementable by developers. METHODS: An initial set of usability attributes (UA) was extracted from a literature survey on usability evaluation in WRD. The initial set of attributes was enriched and locally validated with seven developers of WRD through an online survey and a focus group. The locally validated glossary was then externally validated through a globally distributed online survey. RESULTS: The result is the Robotics Usability Glossary (RUG), a comprehensive glossary of 41 UA validated by 70 WRD developers from 17 countries, ensuring its generalizability. 31 of the UA had high agreement scores among respondents and 27 were considered highly relevant in the field, but only 11 of them had been included as design criteria by the respondents. CONCLUSIONS: Multiple UA ought to be considered for a comprehensive usability assessment. Usability remains inadequately incorporated into device development, indicating a need for increased awareness and end-user perspective. The RUG can be readily accessed through an online platform, the Interactive Usability Toolbox (IUT), developed to provide context-specific outcome measures and usability evaluation methods. Overall, this effort is an important step towards improving and promoting usability evaluation practices within WRD. It has the potential to pave the way for establishing usability evaluation benchmarks that further endorse the acceptance of WRD.


Assuntos
Robótica , Dispositivos Eletrônicos Vestíveis , Humanos , Interface Usuário-Computador , Inquéritos e Questionários , Grupos Focais
13.
Sensors (Basel) ; 24(2)2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38257492

RESUMO

E-scooter vibrations are a problem recently studied. Theoretical models based on dynamic simulations and also real measurements have confirmed the high impact of e-scooter vibrations on driver comfort and health. Some authors recommend improving e-scooter damping systems, including tyres. However, it has not been suggested nor has any research been published studying how to improve e-scooter frame design for reducing driver vibrations and improving comfort. In this paper, we have modelled a real e-scooter to have a reference. Then, we have developed a multibody dynamic model for running dynamic simulations studying the influence of mass geometry parameters of the e-scooter frame (mass, centre of gravity and inertia moment). Acceleration results have been analysed based on the UNE-2631 standard for obtaining comfort values. Based on results, a qualitative e-scooter frame design guide for mitigating vibrations and increasing the comfort of e-scooter driver has been developed. Some application cases have been running on the multibody dynamic simulation model, finding improvements of comfort levels higher than 9% in comparison with the e-scooter reference model. The dynamic model has been qualitatively validated from real measurements. In addition, a basic sensor proposal and comfort colour scale is proposed for giving feedback to e-scooter drivers.

14.
J Vet Pharmacol Ther ; 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38655611

RESUMO

Pharmacokinetics studies of anesthetic agents are important for understanding of the pharmacology and metabolism of anesthetic agents in reptilians. This study was designed to examine the pharmacokinetic and pharmacodynamic properties of intravenous dextroketamine alone or combined with midazolam in Caiman crocodilus. Eight caimans were anesthetized with dextroketamine (10 mg/kg; group D) or dextroketamine and midazolam (10 and 0.5 mg/kg respectively; group DM) into the occipital venous sinus. The pharmacokinetic parameters were calculated by HPLC using a non-compartmental modeling. Serial blood samples were collected at baseline and within 15 and 30 min, and 11.5, 2, 4, 8, 12, 24 and 48 h of drug administration. Sedation status over time differed between groups. All animals in group D (8/8; 100%) showed signs of light sedation at t10. Half (4/8; 50%) of these caimans did not progress to deeper levels of sedation. In spite of light sedation at t10, animals in group DM were deeply sedated within 13.13 ± 7.04 min of anesthetic agent injection. The area under the plasma concentration-time curve (AUC0-48) and half-life of dextroketamine changed significantly after combination with midazolam. Even without significant changes in clearance, the almost two-fold increase in the half-life of dextroketamine suggests a slower rate of elimination.

15.
Int J Mol Sci ; 25(5)2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38474208

RESUMO

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a prevalent clinical condition associated with elevated morbidity and mortality rates. Patients with MASLD treated with semaglutide, a glucagon-like peptide-1 receptor agonist, demonstrate improvement in terms of liver damage. However, the mechanisms underlaying this beneficial effect are not yet fully elucidated. We investigated the efficacy of semaglutide in halting MASLD progression using a genetic mouse model of diabesity. Leptin-receptor-deficient mice with obesity and diabetes (BKS db/db) were either untreated or administered with semaglutide for 11 weeks. Changes in food and water intake, body weight and glycemia were monitored throughout the study. Body fat composition was assessed by dual-energy X-ray absorptiometry. Upon sacrifice, serum biochemical parameters, liver morphology, lipidomic profile and liver-lipid-related pathways were evaluated. The semaglutide-treated mice exhibited lower levels of glycemia, body weight, serum markers of liver dysfunction and total and percentage of fat mass compared to untreated db/db mice without a significant reduction in food intake. Histologically, semaglutide reduced hepatic steatosis, hepatocellular ballooning and intrahepatic triglycerides. Furthermore, the treatment ameliorated the hepatic expression of de novo lipogenesis markers and modified lipid composition by increasing the amount of polyunsaturated fatty acids. The administration of semaglutide to leptin-receptor-deficient, hyperphagic and diabetic mice resulted in the amelioration of MASLD, likely independently of daily caloric intake, suggesting a direct effect of semaglutide on the liver through modulation of the lipid profile.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Fígado Gorduroso , Peptídeos Semelhantes ao Glucagon , Hepatopatia Gordurosa não Alcoólica , Humanos , Animais , Camundongos , Lipogênese , Leptina/metabolismo , Diabetes Mellitus Experimental/metabolismo , Fígado Gorduroso/metabolismo , Obesidade/metabolismo , Fígado/metabolismo , Peso Corporal , Triglicerídeos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Camundongos Obesos
16.
Int J Mol Sci ; 25(9)2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38732094

RESUMO

This article reviews the role of fibroblast growth factor 23 (FGF23) protein in phosphate metabolism, highlighting its regulation of vitamin D, parathyroid hormone, and bone metabolism. Although it was traditionally thought that phosphate-calcium homeostasis was controlled exclusively by parathyroid hormone (PTH) and calcitriol, pathophysiological studies revealed the influence of FGF23. This protein, expressed mainly in bone, inhibits the renal reabsorption of phosphate and calcitriol formation, mediated by the α-klotho co-receptor. In addition to its role in phosphate metabolism, FGF23 exhibits pleiotropic effects in non-renal systems such as the cardiovascular, immune, and metabolic systems, including the regulation of gene expression and cardiac fibrosis. Although it has been proposed as a biomarker and therapeutic target, the inhibition of FGF23 poses challenges due to its potential side effects. However, the approval of drugs such as burosumab represents a milestone in the treatment of FGF23-related diseases.


Assuntos
Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos , Fosfatos , Humanos , Fator de Crescimento de Fibroblastos 23/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Animais , Fosfatos/metabolismo , Hormônio Paratireóideo/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Vitamina D/metabolismo , Osso e Ossos/metabolismo , Proteínas Klotho
17.
J Environ Manage ; 363: 121315, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38850910

RESUMO

The rising generation of waste activated sludge (WAS) demands a fundamental shift towards resource reuse and recovery. The conventional methodologies used to manage this by-product derived from wastewater treatment plants are increasingly constrained due to stringent regulatory measures aimed at mitigating its adverse impacts on the environment and public health. Therefore, this work evaluated a promising strategy for the efficient management of WAS, transforming it into a valuable renewable source to produce high-value-added compounds, such as lipids and a slow-release fertilizer (struvite). Wet oxidation (WO) was identified as a suitable technique for solubilising WAS while generating short-chain fatty acids (primarily acetic acid). It was found that conducting WO at 200 °C for 120 min resulted in a 65% reduction of the total suspended solids (TSS) content and 87% of the volatile suspended solids (VSS) content. Additionally, under these conditions, 4440 ± 105 mg/L and 593 ± 21 mg/L of acetic and propionic acid were obtained, respectively, which were assimilated by Yarrowia lipolytica to produce biolipids. Furthermore, the rupture of WAS flocs also led to the solubilisation of 980 ± 8 mg/L of ammonium. During the struvite precipitation stage, a NH4:PO4:Mg ratio of 1:1.5:1.5 was found to be the most effective for removing soluble ammonium (97.4 ± 0.8%), resulting in a high-purity struvite formation, and enhancing the carbon/nitrogen (C/N) ratio of the oxidised WAS from 3 to 105. This improvement in the C/N ratio raised the lipid content from 36 ± 1% to 49 ± 1% during the cultivation of Y. lipolytica. The application of the sequencing batch culture strategy further increased lipid content to 59 ± 1%, with 6.0 ± 0.3 g/L as the final concentration after the fifth cycle. The lipids produced, mainly monounsaturated fatty acids with 40% of oleic acid, offer potential as biodiesel feedstock. This lipid composition led to biodiesel properties, including cetane number, iodine value, kinematic viscosity and density that met international standards. Therefore, this research presents a promising alternative not only for WAS management but also for harnessing valuable resources, thereby establishing a basis for large-scale studies.


Assuntos
Lipídeos , Esgotos , Yarrowia , Yarrowia/metabolismo , Lipídeos/química , Eliminação de Resíduos Líquidos/métodos , Nutrientes/metabolismo , Fertilizantes/análise
18.
Int J Paediatr Dent ; 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-38200627

RESUMO

BACKGROUND: The aetiology of Sleep bruxism includes specific personality traits, related to perfectionism. AIM: To investigate the relationship between probable sleep bruxism (PSB) and personality traits in children and their parents, determining whether children with PSB and their parents are more perfectionists. DESIGN: This case-control study included 104 children aged 8-9 years, 52 cases and 52 controls. A clinical examination was performed on the children who completed the Big Five Personality Questionnaire (BFQ-NA) and the Child Perfectionism Inventory. Parents completed a bruxism diagnostic questionnaire according to the AASM criteria, BFQ and Frost multidimensional perfectionism scale questionnaires. t-Tests for independent samples and multivariate logistic regression models were used for statistical analysis. RESULTS: A significant relationship between PSB and a self-demanding personality (OR = 1.11, p = .01), restless sleep (OR = 4.41, p = .004), and a family history of clenching and grinding teeth (OR = 3.07, p = .0006) was found in a binary logistic regression model. When adjusted, only restless sleep showed a significant relationship with PSB (p = .03, OR 3.32, 95% CI 1.13-9.81). CONCLUSION: Children whose parents reported as clenching or grinding their teeth while asleep in the previous 6 months, and who were found to have abnormal dental wear, had significantly more nightmares, sleep disruption, daytime sleepiness, family history of bruxism, and tended to be more perfectionist.

19.
Actas Esp Psiquiatr ; 52(3): 375-377, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38863053

RESUMO

A case of Kloos syndrome is presented, a rare psychopathological manifestation in psychiatry characterized by the experience of "time paralysis" related to an epileptic focus in the left temporoparietal areas. This syndrome was identified through a detailed psychopathological analysis and detected by an electroencephalographic record. The patient's symptoms disappeared after receiving antiepileptic treatment with Carbamazepine. In this case report we highlight the detailed phenomenological and clinical analysis, as well as the importance of carrying out complementary tests when we are faced with unusual or sudden-onset symptoms without any trigger, as took place in the case exposed.


Assuntos
Eletroencefalografia , Humanos , Síndrome , Masculino , Carbamazepina/uso terapêutico , Adulto , Anticonvulsivantes/uso terapêutico
20.
Plant Physiol ; 188(4): 1966-1978, 2022 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-35043968

RESUMO

The role of the RNA degradation product 2',3'-cyclic adenosine monophosphate (2',3'-cAMP) is poorly understood. Recent studies have identified 2',3'-cAMP in plant material and determined its role in stress signaling. The level of 2',3'-cAMP increases upon wounding, in the dark, and under heat, and 2',3'-cAMP binding to an RNA-binding protein, Rbp47b, promotes stress granule (SG) assembly. To gain further mechanistic insights into the function of 2',3'-cAMP, we used a multi-omics approach by combining transcriptomics, metabolomics, and proteomics to dissect the response of Arabidopsis (Arabidopsis thaliana) to 2',3'-cAMP treatment. We demonstrated that 2',3'-cAMP is metabolized into adenosine, suggesting that the well-known cyclic nucleotide-adenosine pathway of human cells might also exist in plants. Transcriptomics analysis revealed only minor overlap between 2',3'-cAMP- and adenosine-treated plants, suggesting that these molecules act through independent mechanisms. Treatment with 2',3'-cAMP changed the levels of hundreds of transcripts, proteins, and metabolites, many previously associated with plant stress responses, including protein and RNA degradation products, glucosinolates, chaperones, and SG components. Finally, we demonstrated that 2',3'-cAMP treatment influences the movement of processing bodies, confirming the role of 2',3'-cAMP in the formation and motility of membraneless organelles.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , AMP Cíclico/metabolismo , Perfilação da Expressão Gênica , Glucosinolatos/metabolismo , Humanos
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