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1.
Artigo em Inglês | MEDLINE | ID: mdl-36045654

RESUMO

Background: Shu Gan Jie Yu (SGJY) capsule has a good effect on relieving depressive symptoms in China. However, the mechanism of action is still unclear. Therefore, systemic pharmacology and molecular docking approaches were used to clarify its corresponding antidepressant mechanisms. Methods: Traditional Chinese Medicine Database and Analysis Platform (TCMSP), the Encyclopedia of Traditional Chinese Medicine (ETCM), and Swiss Target Prediction servers were used to screen and predict the bioactive components of the SGJY capsule and their antidepressive targets. Mild to moderate depression (MMD) related genes were obtained from GeneCards and DisGeNET databases. A network of bioactive components-therapeutic targets of the SGJY capsule was established by STRING 11.5 and Cytoscape 3.9.0 software. Gene function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed by utilizing Database for Annotation, Visualization, and Integrated Discovery (DAVID) platform. Active components were taken to dock with the hypothetical proteins by iGEMDOCK and SwissDock, and the docking details were visually displayed by UCSF Chimera software. Then, the related research literature of the SGJY capsule was reviewed, summarized, sorted, and analyzed, including experimental evidence and clinical experience. Results: Seven active components and 45 intersection targets were included in the study. PPI network had genuinely uncovered the potential therapeutic targets, such as AKT1, HSP90AA1, ESR1, EGFR, and PTGS2. KEGG pathway analysis showed that the mechanism of the SGJY capsule on MMD was mainly involved in the PI3K-Akt signaling pathway. Conclusions: In this study, we have successfully predicted the biochemically active constituents, potential therapeutic targets, and comprehensively predicted the related drug-gene interaction of the SGJY capsule for treating MMD and provided a basis for subsequent experiments.

2.
Annu Int Conf IEEE Eng Med Biol Soc ; 2022: 971-974, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36086164

RESUMO

Endoscopy serves as an indispensable minimally-invasive surgical procedure. Due to the limited view and non-intuitive operation of the instrument, the mastery of endoscopic manipulation requires deep medical knowledge as well as complex perception and motor skills of the surgeon. Intensive surgical training is required, and simulation-based training is of more and more importance over traditional animal- or cadaver-based approaches. Here, we developed a hybrid surgical simulator that consists of a realistic physical organ model and an artificial intelligence (AI)-driven cyber model. We built a physical model of the full urinary tract with soft materials and detailed blood vessel structures. Endourological procedures were performed to localize and treat renal calculi by a flexible endoscope. An AI algorithm detects the lesions automatically with high accuracy and provides quantitative feedback about an operator's endoscopic skills. The hybrid simulator system shows great potential as an interactive and personalized learning environment for endoscopic skills. Clinical Relevance- This work establishes a preliminary approach for realistic endoscopic training. The developed hybrid surgical simulator - with high-fidelity physical organ models and quantitative feedback - can deliver effective hands-on learning to surgeons to improve their endoscopic skills.


Assuntos
Treinamento por Simulação , Cirurgiões , Animais , Inteligência Artificial , Competência Clínica , Endoscopia , Humanos
3.
Med Oncol ; 39(12): 180, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071247

RESUMO

Breast cancer is the most common cancer among women worldwide. Researches show that Aurora kinase A (AURKA) is highly expressed in approximately 73% of breast cancer patients, which induces drug resistance in breast cancer patients and decreases the median survival time. AURKA regulates spindle assembly, centrosome maturation, and chromosome alignment. AURKA overexpression affects the occurrence and development of breast cancer. Besides AURKA overexpression, heat shock protein 90 (HSP90) maintains the survival and proliferation of tumor cells by stabilizing the structure of oncoproteins, including P53 mutants (mtP53). TP53 mutations accounted for approximately 13%, 40%, 80%, 33%, 71%, and 82% of luminal A, Luminal B, Luminal C, normal basal-like, HER2-amplified, and basal-like breast cancers, respectively. TP53 mutation can aggravate cell genome instability and enhance the invasion, migration, and resistance of cancer cell. This review describes the research status of AURKA and HSP90 in breast cancer, summarizes the structure, function, and the chaperone cycle of HSP90, elaborates the interrelation between HSP90, mtP53, P53, and AURKA, and proposes the combination of HSP90 inhibitor and AURKA inhibitor to treat breast cancer. Targeting AURKA and HSP90 to treat cancer with AURKA overexpression and TP53 mutations will help improve the specificity and efficiency of breast cancer treatment and solve the problem of drug resistance.


Assuntos
Antineoplásicos , Aurora Quinase A , Neoplasias da Mama , Antineoplásicos/farmacologia , Aurora Quinase A/antagonistas & inibidores , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Feminino , Humanos , Mutação , Proteína Supressora de Tumor p53/genética
4.
Polymers (Basel) ; 14(17)2022 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-36080744

RESUMO

Flexible electronic technology is one of the research hotspots, and numerous wearable devices have been widely used in our daily life. As an important part of wearable devices, flexible sensors can effectively detect various stimuli related to specific environments or biological species, having a very bright development prospect. Therefore, there has been lots of studies devoted to developing high-performance flexible pressure sensors. In addition to developing a variety of materials with excellent performances, the microstructure designs of materials can also effectively improve the performances of sensors, which has brought new ideas to scientists and attracted their attention increasingly. This paper will summarize the flexible pressure sensors based on material microstructure designs in recent years. The paper will mainly discuss the processing methods and characteristics of various sensors with different microstructures, and compare the advantages, disadvantages, and application scenarios of them. At the same time, the main application fields of flexible pressure sensors based on microstructure designs will be listed, and their future development and challenges will be discussed.

6.
Membranes (Basel) ; 12(7)2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35877844

RESUMO

Capacitors play an increasingly important role in hybrid integrated circuits, while the MIM capacitors with high capacitance density and small thickness can meet the needs of high integration. Generally speaking, the films prepared with a single metal oxide dielectric often achieve a breakthrough in one aspect of performance, but dielectric layers are required to be improved to get better performance in leakage current, capacitance density, and transmittance simultaneously in modern electronic devices. Therefore, we optimized the performance of the dielectric layers by using multiple metal oxides. We combined zirconia, yttria, magnesium oxide, alumina, and hafnium oxide with the solution method to find the best combination of these five metal oxides. The physical properties of the multi-component films were measured by atomic force microscopy (AFM), ultraviolet-visible spectrophotometer, and other instruments. The results show that the films prepared by multi-component metal oxides have good transmittance and low roughness. The thicknesses of all films in our experiment are less than 100 nm. Then, metal-insulator-metal (MIM) devices were fabricated. In addition, we characterized the electrical properties of MIM devices. We find that multi-component oxide films can achieve good performances in several aspects. The aluminum-magnesium-yttrium-zirconium-oxide (AMYZOx) group of 0.6 M has the lowest leakage current density, which is 5.03 × 10-8 A/cm2 @ 1.0 MV/cm. The hafnium-magnesium-yttrium-zirconium-oxide (HMYZOx) group of 0.8 M has a maximum capacitance density of 208 nF/cm2. The films with a small thickness and a high capacitance density are very conducive to high integration. Therefore, we believe that multi-component films have potential in the process of dielectric layers and great application prospects in highly integrated electronic devices.

7.
Pacing Clin Electrophysiol ; 45(9): 1075-1084, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35899803

RESUMO

BACKGROUND: Right ventricular (RV) dysfunction has been linked to a poor response to cardiac resynchronization therapy (CRT). We sought to determine whether cardiovascular magnetic resonance (CMR)-derived measures of RV function influence clinical outcomes after CRT. METHODS: In this retrospective study, we used CMR to assess pre-implant RV volumes and RV ejection fraction (RVEF) in relation to clinical outcomes after CRT implantation. RESULTS: Among 243 patients (age: 70.3 ± 10.8 years [mean ± SD]; 68.7% male; 121 [49.8%]) with ischemic cardiomyopathy and 122 (50.2%) with nonischemic cardiomyopathy, 141 (58%) after CRT-defibrillation (CRT-D) and 102 (42%) after CRT-pacing (CRT-P), 101 (41.6.0%) patients died, 61 (25.1%) from cardiac causes and 24 (9.88%) from noncardiac causes, over 5.87 years (median; interquartile range: 4.35-7.73). Two (0.82%) patients underwent cardiac transplantation and four (1.64%) had a left ventricular assist device (LVAD). A total of 41 (16.9%) met the composite endpoint of sudden cardiac death (SCD), ventricular tachycardia, or ventricular fibrillation. In univariate analyses, no measure of RV function was associated with total mortality or the arrhythmic endpoint. RVEF was associated with cardiac mortality on univariate analyses (HR per 10%: 0.82, 95% CI 0.70-0.96), but not on multivariate analyses that included left ventricular ejection fraction. CONCLUSIONS: There is no relationship between measures of RV function, such as RV volumes and RVEF, and the long-term clinical outcome of CRT. These findings indicate that such measures should not be considered in patient selection.


Assuntos
Terapia de Ressincronização Cardíaca , Cardiomiopatias , Insuficiência Cardíaca , Disfunção Ventricular Direita , Idoso , Idoso de 80 Anos ou mais , Cardiomiopatias/complicações , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/terapia , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Volume Sistólico , Resultado do Tratamento , Disfunção Ventricular Direita/terapia , Função Ventricular Esquerda , Função Ventricular Direita
8.
ACS Chem Biol ; 17(8): 2018-2023, 2022 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-35816339

RESUMO

As the "writer" enzymes of protein S-acylation, a dynamic and functionally significant post-translational modification (PTM), DHHC family proteins have emerged in the past decade as both key modulators of cellular homeostasis and as drivers of neoplastic, autoimmune, metabolic, and neurological pathologies. Currently, biological and clinical discovery is hampered by the limitations of existing DHHC family inhibitors, which possess poor physicochemical properties and off-target profiles. However, progress in identifying new inhibitory scaffolds has been meager, in part due to a lack of robust in vitro assays suitable for high-throughput screening (HTS). Here, we report the development of palmitoyl transferase probes (PTPs), a novel family of turn-on pro-fluorescent molecules that mimic the palmitoyl-CoA substrate of DHHC proteins. We use the PTPs to develop and validate an assay with an excellent Z'-factor for HTS. We then perform a pilot screen of 1687 acrylamide-based molecules against zDHHC20, establishing the PTP-based HTS assay as a platform for the discovery of improved DHHC family inhibitors.


Assuntos
Aciltransferases , Ensaios de Triagem em Larga Escala , Aciltransferases/metabolismo , Processamento de Proteína Pós-Traducional
9.
Artigo em Inglês | MEDLINE | ID: mdl-35908438

RESUMO

Co-exposure to tobacco and marijuana has become common in areas where recreational marijuana use is legal. To assist in the determination of the combined health risks of this co-exposure, an analytical method capable of simultaneously measuring tobacco and marijuana metabolites is needed to reduce laboratory costs and the required sample volume. So far, no such analytical method exists. Thus, we developed and validated a method to simultaneously quantify urinary levels of trans-3'-hydroxycotinine (3OH-COT), cotinine (COT), and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (COOH-THC) to assess co-exposure to tobacco and marijuana. Urine (200 µL) was spiked with labelled internal standards and enzymatically hydrolyzed to liberate the conjugated analytes before extraction using solid-supported liquid-liquid extraction (SLE) with ethyl acetate serving as an eluent. The target analytes were separated on a C18 (4.6 × 100 mm, 5 µm) analytical column with a gradient mobile phase elution and analyzed using tandem mass spectrometry with multiple reaction monitoring of target ion transitions. Positive electrospray ionization (ESI) was used for 3OH-COT and COT, while negative ESI was used for COOH-THC. The total run time was 13 min. The extraction recoveries were 18.4-23.9 % (3OH-COT), 65.1-96.8 % (COT), and 80.6-95.4 % (COOH-THC). The method limits of quantification were 5.0 ng/mL (3OH-COT) and 2.5 ng/mL (COT and COOH-THC). The method showed good accuracy (82.5-98.5 %) and precision (1.22-6.21 % within-day precision and 1.42-6.26 % between-day precision). The target analytes were stable for at least 144 h inside the autosampler (10 °C). The analyses of reference materials and 146 urine samples demonstrated good method performance. The use of a 96-well plate for preparation makes the method useful for the analysis of large numbers of samples.


Assuntos
Cannabis , Alucinógenos , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Dronabinol , Extração Líquido-Líquido , Espectrometria de Massas em Tandem/métodos , Tabaco
10.
FASEB J ; 36(8): e22446, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35816159

RESUMO

d-alanine (d-Ala) and several other d-amino acids (d-AAs) act as hormones and neuromodulators in nervous and endocrine systems. Unlike the endogenously synthesized d-serine in animals, d-Ala may be from exogenous sources, e.g., diet and intestinal microorganisms. However, it is unclear if the capability to produce d-Ala and other d-AAs varies among different microbial strains in the gut. We isolated individual microorganisms of rat gut microbiota and profiled their d-AA production in vitro, focusing on d-Ala. Serial dilutions of intestinal contents from adult male rats were plated on agar to obtain clonal cultures. Using MALDI-TOF MS for rapid strain typing, we identified 38 unique isolates, grouped into 11 species based on 16S rRNA gene sequences. We then used two-tier screening to profile bacterial d-AA production, combining a d-amino acid oxidase-based enzymatic assay for rapid assessment of non-acidic d-AA amount and chiral LC-MS/MS to quantify individual d-AAs, revealing 19 out of the 38 isolated strains as d-AA producers. LC-MS/MS analysis of the eight top d-AA producers showed high levels of d-Ala in all strains tested, with substantial inter- and intra-species variations. Though results from the enzymatic assay and LC-MS/MS analysis aligned well, LC-MS/MS further revealed the existence of d-glutamate and d-aspartate, which are poor substrates for this enzymatic assay. We observed large inter- and intra-species variation of d-AA production profiles from rat gut microbiome species, demonstrating the importance of chemical profiling of gut microbiota in addition to sequencing, furthering the idea that microbial metabolites modulate host physiology.


Assuntos
Microbioma Gastrointestinal , Alanina , Aminoácidos/metabolismo , Animais , Cromatografia Líquida , Microbioma Gastrointestinal/fisiologia , Masculino , RNA Ribossômico 16S/genética , Ratos , Espectrometria de Massas em Tandem
11.
BMC Infect Dis ; 22(1): 579, 2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35764948

RESUMO

BACKGROUND: The G8 rotavirus genotype has been detected frequently in children in many countries and even became the predominant strain in sub-Saharan African countries, while there are currently no reports from China. In this study we described the genetic characteristics and evolutionary relationship between rotavirus strains from Guangzhou in China and the epidemic rotavirus strains derived from GenBank, 2020-2021. METHODS: Virus isolation and subsequent next-generation sequencing were performed for confirmed G8P[8] specimens. The genetic characteristics and evolutionary relationship were analyzed in comparison with epidemic rotavirus sequences obtained from GenBank. RESULTS: The two Guangzhou G8 strains were DS-1-like with the closest genetic distance to strains circulating in Southeast Asia. The VP7 genes of the two strains were derived from a human, not an animal G8 rotavirus. Large genetic distances in several genes suggested that the Guangzhou strains may not have been transmitted directly from Southeast Asian countries, but have emerged following reassortment events. CONCLUSIONS: We report the whole genome sequence information of G8P[8] rotaviruses recently detected in China; their clinical and epidemiological significance remains to be explored further.


Assuntos
Infecções por Rotavirus , Rotavirus , Animais , Genoma Viral , Genótipo , Filogenia , Rotavirus/genética , Infecções por Rotavirus/epidemiologia
12.
J Chem Phys ; 156(23): 234107, 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35732536

RESUMO

We show that the Berry force as computed by an approximate, mean-field electronic structure can be meaningful if properly interpreted. In particular, for a model Hamiltonian representing a molecular system with an even number of electrons interacting via a two-body (Hubbard) interaction and a spin-orbit coupling, we show that a meaningful nonzero Berry force emerges whenever there is spin unrestriction-even though the Hamiltonian is real-valued and formally the on-diagonal single-surface Berry force must be zero. Moreover, if properly applied, this mean-field Berry force yields roughly the correct asymptotic motion for scattering through an avoided crossing. That being said, within the context of a ground-state calculation, several nuances do arise as far interpreting the Berry force correctly, and as a practical matter, the Berry force diverges near the Coulson-Fischer point (which can lead to numerical instabilities). We do not address magnetic fields here.

13.
Proc Natl Acad Sci U S A ; 119(26): e2121513119, 2022 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-35737832

RESUMO

Both chronic obstructive pulmonary disease (COPD) and asthma are severe respiratory diseases. Bitter receptor-mediated bronchodilation is a potential therapy for asthma, but the mechanism underlying the agonistic relaxation of airway smooth muscle (ASM) is not well defined. By exploring the ASM relaxation mechanism of bitter substances, we observed that pretreatment with the bitter substances nearly abolished the methacholine (MCh)-induced increase in the ASM cell (ASMC) calcium concentration, thereby suppressing the calcium-induced contraction release. The ASM relaxation was significantly inhibited by simultaneous deletion of three Gαt proteins, suggesting an interaction between Tas2R and AChR signaling cascades in the relaxation process. Biochemically, the Gαt released by Tas2R activation complexes with AChR and blocks the Gαq cycling of AChR signal transduction. More importantly, a bitter substance, kudinoside A, not only attenuates airway constriction but also significantly inhibits pulmonary inflammation and tissue remodeling in COPD rats, indicating its modulation of additional Gαq-associated pathological processes. Thus, our results suggest that Tas2R activation may be an ideal strategy for halting multiple pathological processes of COPD.


Assuntos
Asma , Músculo Liso , Doença Pulmonar Obstrutiva Crônica , Receptores Acoplados a Proteínas G , Ativação Transcricional , Animais , Asma/genética , Asma/metabolismo , Asma/fisiopatologia , Broncodilatadores/farmacologia , Cálcio/metabolismo , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Ratos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais
15.
Front Plant Sci ; 13: 796694, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35498667

RESUMO

Mung bean is characterized by having a good edible and medicinal value, while its flowers and pods have low production. Being a tertiary amine, DCPTA [2-(3,4-dichlorophenoxy) triethylamine] substantially regulates the growth and development of crops, maintaining production. Yet it is still limited in terms of the regulation of DCPTA on growth and development, including the yield and sugar metabolism of mung bean. In this study, DCPTA was sprayed at the beginning of mung flowering through a two-season cultivation, to assess its effects on the yield, leaf area per plant, plant height, seed setting rate, photosynthesis, chlorophyll content, and endogenous protective enzymes. Experimental results illustrated that relative to the control (CK), the DCPTA application significantly (p < 0.05) improved the yield of Bailv 11 mung bean, which rose to 6.9% in 2020 and 7.8% in 2021, respectively. This effect positively corresponded to a significant (p<0.05) increase in the number of pods and grains per plant and pod setting rate, but a non-significant difference in 1,000-grain weight. DCPA application also increased the area and fresh weight of leaf, mung height, and its organ dry weight (i.e., leaf, branch, and stem). During plant growth over DCPTA application, the increased activities of SOD, POD, and CAT improved the net photosynthetic rate, stomatal conductance, and transpiration. In addition, transcriptome sequencing further demonstrated that DCPTA treatment significantly (p < 0.05) up-regulated the sucrose synthase, invertase, and fructose kinase in all organs (i.e., leaves, pod skins, and grains) of the plant. In particular, this effect was much greater in the sucrose synthesis (i.e., sucrose content) in leaves. Our study, therefore, concludes that DCPTA application promotes the yield of mung bean via likely enhancing its photosynthetic capacity and sucrose synthase, fructokinase, and beta-fructofuranosidase expression regulation.

16.
J Clin Invest ; 132(14)2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35617029

RESUMO

Intractable functional constipation (IFC) is the most severe form of constipation, but its etiology has long been unknown. We hypothesized that IFC is caused by refractory infection by a pathogenic bacterium. Here, we isolated from patients with IFC a Shigella species - peristaltic contraction-inhibiting bacterium (PIB) - that significantly inhibited peristaltic contraction of the colon by production of docosapentenoic acid (DPA). PIB colonized mice for at least 6 months. Oral administration of PIB was sufficient to induce constipation, which was reversed by PIB-specific phages. A mutated PIB with reduced DPA was incapable of inhibiting colonic function and inducing constipation, suggesting that DPA produced by PIB was the key mediator of the genesis of constipation. PIBs were detected in stools of 56% (38 of 68) of the IFC patients, but not in those of non-IFC or healthy individuals (0 of 180). DPA levels in stools were elevated in 44.12% (30 of 68) of the IFC patients but none of the healthy volunteers (0 of 97). Our results suggest that Shigella sp. PIB may be the critical causative pathogen for IFC, and detection of fecal PIB plus DPA may be a reliable method for IFC diagnosis and classification.


Assuntos
Motilidade Gastrointestinal , Shigella , Animais , Colo , Constipação Intestinal/diagnóstico , Constipação Intestinal/genética , Fezes , Humanos , Camundongos , Shigella/genética
17.
Biochem Pharmacol ; 199: 115025, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35367196

RESUMO

Clinically, 5-fluorouracil (5-Fu) is a first-line drug for the treatment of patients with colorectal cancer (CRC). However, chemoresistance to 5-Fu-based chemotherapy is a leading obstacle in achieving effective treatment for CRC, especially microsatellite stable (MSS) CRC. Since the cytotoxicity of 5-Fu is negatively correlated with oxytocin receptor (OXTR) expression in MSS CRC cell lines, our current study aimed to investigate the synergistic antitumor activity of 5-Fu combined with atosiban, an antagonist of OXTR. Our results suggested that atosiban remarkably potentiated the inhibitory effect of 5-Fu on the growth of MSS-type CRC cells in vitro and in vivo. Moreover, 5-Fu induced GATA3 in MSS CRC cells and tumors, which were eradicated by atosiban. Further investigation showed that atosiban strengthened the antitumor activity of 5-Fu through eradiation of 5-Fu-induced GATA3 in MSS-type CRC cells. Taken together, our findings suggest that atosiban potentiates the antitumor effect of 5-Fu by abolishing 5-Fu-induced GATA3, which provides a novel therapeutic strategy for MSS-type CRC via the combination of atosiban and 5-Fu.


Assuntos
Neoplasias Colorretais , Fluoruracila , Apoptose , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Fator de Transcrição GATA3/farmacologia , Humanos , Repetições de Microssatélites , Vasotocina/análogos & derivados
18.
Sci Adv ; 8(15): eabj8633, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35427157

RESUMO

Genetic CLN5 variants are associated with childhood neurodegeneration and Alzheimer's disease; however, the molecular function of ceroid lipofuscinosis neuronal protein 5 (Cln5) is unknown. We solved the Cln5 crystal structure and identified a region homologous to the catalytic domain of members of the N1pC/P60 superfamily of papain-like enzymes. However, we observed no protease activity for Cln5; and instead, we discovered that Cln5 and structurally related PPPDE1 and PPPDE2 have efficient cysteine palmitoyl thioesterase (S-depalmitoylation) activity using fluorescent substrates. Mutational analysis revealed that the predicted catalytic residues histidine-166 and cysteine-280 are critical for Cln5 thioesterase activity, uncovering a new cysteine-based catalytic mechanism for S-depalmitoylation enzymes. Last, we found that Cln5-deficient neuronal progenitor cells showed reduced thioesterase activity, confirming live cell function of Cln5 in setting S-depalmitoylation levels. Our results provide new insight into the function of Cln5, emphasize the importance of S-depalmitoylation in neuronal homeostasis, and disclose a new, unexpected enzymatic function for the N1pC/P60 superfamily of proteins.


Assuntos
Cisteína , Lipofuscinoses Ceroides Neuronais , Criança , Humanos , Glicoproteínas de Membrana Associadas ao Lisossomo/genética , Glicoproteínas de Membrana Associadas ao Lisossomo/metabolismo , Proteínas de Membrana/metabolismo , Lipofuscinoses Ceroides Neuronais/genética , Lipofuscinoses Ceroides Neuronais/metabolismo
19.
BMC Psychiatry ; 22(1): 278, 2022 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-35443643

RESUMO

BACKGROUND: Depression and sarcopenia are common diseases in the elderly population. However, the association between them is controversial. Based on the Chinese Longitudinal Healthy Longevity Survey (CLHLS) database, a cross-sectional study was conducted to explore the relationship of calf circumference and physical performance with depression. METHODS: From the 8th wave of CLHLS conducted in 2018, data on calf circumference, physical performance, depressive symptoms, and demographic, socioeconomic, and health-related characteristics were collected. Multiple logistic regression was conducted to explore the impact of calf circumference, physical performance and their combination on depressive symptoms. RESULTS: We enrolled a total of 12,227 participants aged 83.4 ± 11.0 years, including 5689 (46.5%) men and 6538 (53.5%) women. Patients with depression were more likely to have low calf circumference (2274 [68.2%] vs. 5406 [60.8%], p<0.001) and poor physical performance (3[0, 6] vs. 1[0, 4], p<0.001). A significant multiplicative interaction was found between calf circumference and physical performance in their effect on depression. After adjusting for confounding factors, multiple logistic regression showed that a significant inverse correlation persisted between physical performance and depressive symptoms in normal (odds ratio [OR] = 1.20, 95% confidence interval [CI]: 1.15-1.26, p<0.001) and low (OR = 1.14, 95% CI: 1.11-1.18, p<0.001) calf circumference group, while the association between calf circumference and depression disappeared. Participants with low calf circumference and poor physical performance were 2.21 times more likely to have depression than those with normal calf circumference and physical performance. All results were found to be robust in sensitivity analyses. CONCLUSIONS: Physical performance was significantly associated with depression in the elderly Chinese population. Attention should be paid to assess depressive symptoms in patients with poor physical performance.


Assuntos
Depressão , Sarcopenia , Idoso , China/epidemiologia , Estudos Transversais , Depressão/epidemiologia , Feminino , Humanos , Masculino , Desempenho Físico Funcional , Sarcopenia/diagnóstico , Sarcopenia/epidemiologia
20.
Huan Jing Ke Xue ; 43(3): 1315-1322, 2022 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-35258195

RESUMO

Composting plants are an important source of airborne fungi. At present, no research has been reported on differences in the types and abundance of escaped fungi in different working areas, which makes it very difficult to comprehensively assess the ecological health risks of the air in composting plants. In light of this situation, this study collected air samples from the composting, packaging, office, and downwind areas of the composting plants and used high-throughput sequencing technology to analyze and compare the biological diversity and community structure of airborne fungi in the four areas. The source of airborne fungi in offices and downwind areas was further traced. The results showed that the highest abundance and diversity of airborne fungi were found in the packing and composting areas of the composting plants. Ascomycota and Basidiomycota were two fungal phyla with the highest relative abundance in the four regions. Overall, the distribution of dominant fungal genera differed; Trichocomaceae and Davidiella were the dominant genera in three areas of the composting plants. Among the 136 detected fungal genera, the number of endemic airborne fungal genera in the composting and packaging area was the largest, and 52.94% of the fungal genera was shared by the four areas. At the level of fungal genera, the community structures in the air in three areas of the composting plants were similar. The statistical difference analysis results of the key genera in different areas of the composting plants showed that the number of different fungal genera between the downwind, packaging, and composting areas was the largest, and no statistically different fungal genera were detected in the air between the packaging and composting areas. The Source Tracker analysis results showed that the contribution percentage of the packaging and composting areas to the airborne fungi in the office and downwind areas was between 9.52%-15.85%. The results of this study will provide basic data for evaluating the relationship between airborne fungal exposure and human health in different areas of the composting plant, as well as its ecological impact on the surrounding air environment.


Assuntos
Microbiologia do Ar , Compostagem , Fungos/classificação , Biodiversidade , Sequenciamento de Nucleotídeos em Larga Escala
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