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1.
Sensors (Basel) ; 24(13)2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-39001191

RESUMO

The extraction of typical features of underwater target signals and excellent recognition algorithms are the keys to achieving underwater acoustic target recognition of divers. This paper proposes a feature extraction method for diver signals: frequency-domain multi-sub-band energy (FMSE), aiming to achieve accurate recognition of diver underwater acoustic targets by passive sonar. The impact of the presence or absence of targets, different numbers of targets, different signal-to-noise ratios, and different detection distances on this method was studied based on experimental data under different conditions, such as water pools and lakes. It was found that the FMSE method has the best robustness and performance compared with two other signal feature extraction methods: mel frequency cepstral coefficient filtering and gammatone frequency cepstral coefficient filtering. Combined with the commonly used recognition algorithm of support vector machines, the FMSE method can achieve a comprehensive recognition accuracy of over 94% for frogman underwater acoustic targets. This indicates that the FMSE method is suitable for underwater acoustic recognition of diver targets.

3.
Inflamm Bowel Dis ; 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39011784

RESUMO

BACKGROUND: Thiopurine drugs are effective treatment options in inflammatory bowel disease and other conditions but discontinued in some patients due to toxicity. METHODS: We investigated thiopurine-induced toxicity in a pediatric inflammatory bowel disease cohort by utilizing exome sequencing data across a panel of 46 genes, including TPMT and NUDT15. RESULTS: The cohort included 487 patients with a median age of 13.1 years. Of the 396 patients exposed to thiopurines, myelosuppression was observed in 11%, gastroenterological intolerance in 11%, hepatotoxicity in 4.5%, pancreatitis in 1.8%, and "other" adverse effects in 2.8%. TPMT (thiopurine S-methyltransferase) enzyme activity was normal in 87.4%, intermediate 12.3%, and deficient in 0.2%; 26% of patients with intermediate activity developed toxicity to thiopurines. Routinely genotyped TPMT alleles associated with defective enzyme activity were identified in 28 (7%) patients: TPMT*3A in 4.5%, *3B in 1%, and *3C in 1.5%. Of these, only 6 (21%) patients developed toxic responses. Three rare TPMT alleles (*3D, *39, and *40) not assessed on routine genotyping were identified in 3 patients, who all developed toxic responses. The missense variant p.R139C (NUDT15*3 allele) was identified in 4 patients (azathioprine 1.6 mg/kg/d), but only 1 developed toxicity. One patient with an in-frame deletion variant p.G13del in NUDT15 developed myelosuppression at low doses. Per-gene deleteriousness score GenePy identified a significant association for toxicity in the AOX1 and DHFR genes. CONCLUSIONS: A significant association for toxicity was observed in the AOX1 and DHFR genes in individuals negative for the TPMT and NUDT15 variants. Patients harboring the NUDT15*3 allele, which is associated with myelosuppression, did not show an increased risk of toxicity.


This study reports thiopurine-induced toxicity in pediatric patients with inflammatory bowel disease. The findings are presented in the context of genetic variations, focusing on genes implicated in thiopurine drug metabolism, thereby contributing to the missing pharmacogenomic association in patients developing toxicity.

4.
Front Oncol ; 14: 1366079, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38939341

RESUMO

Objective: To investigate the feasibility of leg wound closure and reconstruction of maxillofacial soft defect by a fusiform-designed skin paddle in fibula free flap (FFF). Methods: Fifty patients who underwent FFF for reconstruction of maxillofacial soft defect were divided into two groups. The fusiform group (20 patients) was treated using a fusiform-designed skin paddle in FFF (skin paddle width less than 2 cm), and leg wound was closed using primary suturing. Reconstruction of the maxillofacial soft defect or filling of dead space was achieved by folding the fusiform skin paddle. The conventional group (30 patients) was treated using the conventional-designed skin paddle (skin paddle width no less than 2.5 cm). The leg wound was closed using mattress suturing or skin graft, while reconstruction of the maxillofacial soft defect or filling of dead space by conventional way. The average postoperative length of hospital stay, healing time of leg wound, and post-surgical complications were recorded at least 6 months after the surgery. Results: Compared with traditional method, the fusiform-designed skin paddle reduced the average healing time of the leg wound (fusiform group: 11.05 days, conventional group: 14.77 days, P < 0.05). The average length-to-width ratio in fusiform group was significantly greater than that of in conventional group (fusiform group: 5.85, conventional group: 2.93, P < 0.05), and no difference was observed on the graft size of skin paddle between two groups (fusiform group: 23.13, conventional group: 27.13, P > 0.05). The post-surgical early complications of the leg wound in the conventional group were higher than that of in the fusiform group (fusiform group: 0%, conventional group: 6.67%), while the post-surgical late complication of the donor site between the two groups showed no case. Healing disorders of maxillofacial soft reconstruction in the conventional group were higher than that of in the fusiform group (fusiform group: 5.26%, conventional group: 20.69%). Conclusions: Fusiform-designed skin paddle for closure of the leg wound and maxillofacial soft defect is a feasible alternative to the conventional- designed skin paddle. The fusiform- designed skin paddle resulted in the less postoperative length of hospital stay, shorter healing time of leg wound and less complication.

6.
Front Psychol ; 15: 1371343, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38831950

RESUMO

Introduction: Official endorsement, distinct from celebrity, expertise, and peer endorsement, introduces a new paradigm where local government officials use online platforms, particularly live streaming, to promote local products and brands. Methods: This study examines the influence of official endorsement on consumer responses using the source credibility and source attractiveness models. We developed a framework that considers official credibility and attractiveness attributes as antecedents, and consumer perceived security and enjoyment as mediators, affecting purchase intention and local brand awareness. The study also incorporates variables such as consumer region and power distance belief. Results: Data from 594 responses obtained through an online survey were analyzed using structural equation modeling. The results indicate that official credibility attributes (expertise, trustworthiness, government credibility) enhances consumer perceived security, while official attractiveness attributes (physical attractiveness, interaction friendliness, and similarity with consumers) increases consumer enjoyment. Both perceived security and enjoyment positively influence purchase intention and local brand awareness. These relationships are partially moderated by consumer region and power distance belief. Discussion: This research pioneers the study of official endorsements, expanding the endorsement literature. It also provides practical insights for marketing professionals and government officials on leveraging official endorsements to enhance the value of local products and brands..

7.
Mol Nutr Food Res ; 68(12): e2300727, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38813726

RESUMO

SCOPE: The current evidence between dietary flavonoids consumption and multiple health outcomes is inadequate and inconclusive. To summarize and evaluate the evidence for dietary flavonoids consumption and multiple health outcomes, an umbrella review of meta-analyses and systematic reviews is conducted. METHODS AND RESULTS: PubMed, Ovid-EMBASE, and the Cochrane Database of Systematic Reviews are searched up to January 2024. The study includes a total of 32 articles containing 24 unique health outcomes in this umbrella review. Meta-analyses are recalculated by using a random effects model. Separate analyses are performed based on the kind of different flavonoid subclasses. The study finds some unique associations such as flavonol and gastric cancer, isoflavone and uterine fibroids and endometrial cancer, total flavonoids consumption and lung cancer, ovarian cancer, and prostate cancer. Overall, the study confirms the negative associations between dietary flavonoids consumption and type 2 diabetes mellitus, cardiovascular diseases, breast cancer, colorectal cancer, lung cancer, and mortality, while positive associations are observed for prostate cancer and uterine fibroids. CONCLUSION: Although dietary flavonoids are significantly associated with many outcomes, firm generalizable conclusions about their beneficial or harmful effects cannot be drawn because of the low certainty of evidence for most of outcomes. More well-designed primary studies are needed.


Assuntos
Dieta , Flavonoides , Feminino , Humanos , Masculino , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/prevenção & controle , Flavonoides/farmacologia , Flavonoides/administração & dosagem , Metanálise como Assunto , Neoplasias/prevenção & controle
8.
BMJ Open ; 14(5): e076013, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38816057

RESUMO

OBJECTIVES: This study aimed to analyse the current status, trends and risk factors of disease burden from 1990 to 2019 among Chinese children. DESIGN AND PARTICIPANTS: It was a retrospective study on data from the Global Burden of Disease Study 2019 (GBD 2019). Data of disease burden and risk factors were extracted from the GBD 2019. Children were divided into two groups of <5 and 5-14 years. Data were analysed using GBD results query tool, Excel and Pareto analysis. PRIMARY OUTCOME MEASURES: Disability-Adjusted Life Years (DALYs) and deaths. RESULTS: The overall disease burden for both children <5 years and those aged 5-14 years significantly decreased from 1990 to 2019. For children aged <5 years, in 2019, the leading cause of deaths and DALYs were 'neonatal disorders', and the top risk factor was 'low birth weight'. Compared with data of 1990, the ranking of causes of deaths and DALYs in 2019 saw the most significant increase for 'HIV/AIDS and sexually transmitted infections' and 'skin and subcutaneous diseases' respectively. Conversely, the ranking of deaths/DALYs causes that dropped most significantly was 'nutritional deficiencies'. For children aged 5-14, in 2019, the leading deaths and DALYs causes were 'unintentional injuries' and 'mental disorders' respectively. The top risk factors were 'alcohol use' and 'short gestation', respectively. The ranking of deaths and DALYs causes rose most significantly were 'HIV/AIDS and sexually transmitted infections' and 'neonatal disorders', respectively. Conversely, the ranking of deaths causes that dropped most significantly were 'other infectious diseases', 'enteric infections' and 'nutritional deficiencies'. For DALYs, the causes that dropped most significantly in ranking were 'other infectious diseases'. CONCLUSIONS: The disease burden of children has significantly changed from 1990 to 2019, with notable differences between children aged <5 and 5-14 years. To optimise the allocation of health resources, it is necessary to adjust management strategies based on the latest disease burden.


Assuntos
Carga Global da Doença , Humanos , Criança , Pré-Escolar , China/epidemiologia , Estudos Retrospectivos , Adolescente , Carga Global da Doença/tendências , Fatores de Risco , Lactente , Feminino , Masculino , Recém-Nascido , Anos de Vida Ajustados por Deficiência , Efeitos Psicossociais da Doença , Causas de Morte , Anos de Vida Ajustados por Qualidade de Vida
9.
Zool Res ; 45(3): 478-491, 2024 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-38682430

RESUMO

Acetaminophen (APAP), the most frequently used mild analgesic and antipyretic drug worldwide, is implicated in causing 46% of all acute liver failures in the USA and between 40% and 70% in Europe. The predominant pharmacological intervention approved for mitigating such overdose is the antioxidant N-acetylcysteine (NAC); however, its efficacy is limited in cases of advanced liver injury or when administered at a late stage. In the current study, we discovered that treatment with a moderate intensity static magnetic field (SMF) notably reduced the mortality rate in mice subjected to high-dose APAP from 40% to 0%, proving effective at both the initial liver injury stage and the subsequent recovery stage. During the early phase of liver injury, SMF markedly reduced APAP-induced oxidative stress, free radicals, and liver damage, resulting in a reduction in multiple oxidative stress markers and an increase in the antioxidant glutathione (GSH). During the later stage of liver recovery, application of vertically downward SMF increased DNA synthesis and hepatocyte proliferation. Moreover, the combination of NAC and SMF significantly mitigated liver damage induced by high-dose APAP and increased liver recovery, even 24 h post overdose, when the effectiveness of NAC alone substantially declines. Overall, this study provides a non-invasive non-pharmaceutical tool that offers dual benefits in the injury and repair stages following APAP overdose. Of note, this tool can work as an alternative to or in combination with NAC to prevent or minimize liver damage induced by APAP, and potentially other toxic overdoses.


Assuntos
Acetaminofen , Analgésicos não Narcóticos , Doença Hepática Induzida por Substâncias e Drogas , Overdose de Drogas , Acetaminofen/toxicidade , Animais , Camundongos , Analgésicos não Narcóticos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Masculino , Campos Magnéticos , Acetilcisteína/uso terapêutico , Acetilcisteína/farmacologia
10.
Acta Biomater ; 180: 423-435, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38641183

RESUMO

Communication between tumors and lymph nodes carries substantial significance for antitumor immunotherapy. Remodeling the immune microenvironment of tumor-draining lymph nodes (TdLN) plays a key role in enhancing the anti-tumor ability of immunotherapy. In this study, we constructed a biomimetic artificial lymph node structure composed of F127 hydrogel loading effector memory T (TEM) cells and PD-1 inhibitors (aPD-1). The biomimetic lymph nodes facilitate the delivery of TEM cells and aPD-1 to the TdLN and the tumor immune microenvironment, thus realizing effective and sustained anti-tumor immunotherapy. Exploiting their unique gel-forming and degradation properties, the cold tumors were speedily transformed into hot tumors via TEM cell supplementation. Meanwhile, the efficacy of aPD-1 was markedly elevated compared with conventional drug delivery methods. Our finding suggested that the development of F127@TEM@aPD-1 holds promising potential as a future novel clinical drug delivery technique. STATEMENT OF SIGNIFICANCE: F127@TEM@aPD-1 show unique advantages in cancer treatment. When injected subcutaneously, F127@TEM@aPD-1 can continuously supplement TEM cells and aPD-1 to tumor draining lymph nodes (TdLN) and the tumor microenvironment, not only improving the efficacy of ICB therapy through slow release, but also exhibiting dual regulatory effects on the tumor and TdLN.


Assuntos
Preparações de Ação Retardada , Hidrogéis , Linfonodos , Células T de Memória , Receptor de Morte Celular Programada 1 , Animais , Hidrogéis/química , Hidrogéis/farmacologia , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Linfonodos/imunologia , Camundongos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Células T de Memória/efeitos dos fármacos , Células T de Memória/imunologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Preparações de Ação Retardada/farmacocinética , Microambiente Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Feminino , Camundongos Endogâmicos C57BL , Humanos
11.
Heliyon ; 10(8): e29368, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38655323

RESUMO

Kidney clear cell renal cell carcinoma (KIRC) is also the most lethal subtype among all kidney cancer subtypes, posing a severe threat to public health. Therefore, it is crucial to identify new, reliable biomarkers in KIRC. Therefore, it is crucial to identify novel, reliable biomarkers associated with KIRC. We analyzed RNA sequence results from TCGA and several GEO datasets. The commonly deregulated gene, ALDOB, was found in multiple data and confirmed its important prognostic value. Subsequently, we explored the specific mechanism by which ALDOB regulates anti-tumor immunity through in vivo and in vitro experiments. We found that ALDOB may play a role in regulating tumor growth by regulating CD8+ T cell infiltration. This is consistent with the results of our immune infiltration-related analysis. In addition, we have also discovered the effect of ALDOB in previous studies on other cancer types. Finally, we concluded that ALDOB may have potential reference value for immunotherapy and can also be used as an independent predictor of prognosis in KIRC.

12.
J Nanobiotechnology ; 22(1): 174, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38609922

RESUMO

Photothermal therapy is favored by cancer researchers due to its advantages such as controllable initiation, direct killing and immune promotion. However, the low enrichment efficiency of photosensitizer in tumor site and the limited effect of single use limits the further development of photothermal therapy. Herein, a photo-responsive multifunctional nanosystem was designed for cancer therapy, in which myeloid-derived suppressor cell (MDSC) membrane vesicle encapsulated decitabine-loaded black phosphorous (BP) nanosheets (BP@ Decitabine @MDSCs, named BDM). The BDM demonstrated excellent biosafety and biochemical characteristics, providing a suitable microenvironment for cancer cell killing. First, the BDM achieves the ability to be highly enriched at tumor sites by inheriting the ability of MDSCs to actively target tumor microenvironment. And then, BP nanosheets achieves hyperthermia and induces mitochondrial damage by its photothermal and photodynamic properties, which enhancing anti-tumor immunity mediated by immunogenic cell death (ICD). Meanwhile, intra-tumoral release of decitabine induced G2/M cell cycle arrest, further promoting tumor cell apoptosis. In vivo, the BMD showed significant inhibition of tumor growth with down-regulation of PCNA expression and increased expression of high mobility group B1 (HMGB1), calreticulin (CRT) and caspase 3. Flow cytometry revealed significantly decreased infiltration of MDSCs and M2-macrophages along with an increased proportion of CD4+, CD8+ T cells as well as CD103+ DCs, suggesting a potentiated anti-tumor immune response. In summary, BDM realizes photothermal therapy/photodynamic therapy synergized chemotherapy for cancer.


Assuntos
Células Supressoras Mieloides , Neoplasias , Fotoquimioterapia , Biomimética , Linfócitos T CD8-Positivos , Decitabina/farmacologia , Terapia Fototérmica , Neoplasias/tratamento farmacológico
13.
Wei Sheng Yan Jiu ; 53(2): 195-208, 2024 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-38604953

RESUMO

OBJECTIVE: To analyze the dietary patterns and dietary networks of children in China, explore regional differences in dietary habits in each region. METHODS: The subjects of the study were children aged 3-17(n=5824) in North Coast Economic Zone, Northeast, Central China, East Coast Economic Zone and Southwest Economic Zone who participated in the China Health and Nutrition Survey. The dietary pattern was obtained by factor analysis. Using mutual information, a measure to detect both linear and non-linear correlations between food groups constructed the dietary networks. RESULTS: Factor analysis resulted in five dietary patterns. Pattern 1 was related to high intakes of wheat and other cereals, pattern 2 was related to high intakes of fruits, milk, eggs and fast foods, pattern 3 was associated with high intakes of tubers, snacks, cakes, beverages and fast foods. The Northeast, Central China and North Coast Economic Zone regions had higher pattern 1 score. Pattern 2 scored higher for North Coast Economic Zone and East Coast Economic Zone regions. Pattern 3 scores in the Northeast region were higher than North Coast Economic Zone and East Coast Economic Zone regions. North Coast Economic Zone, Central China and Southwest Economic Zone regions had focused networks. The network of Northeast and East Coast Economic Zone regions were multiple. All regions were characterized by vegetables, or cereals as the hub. CONCLUSION: The dietary patterns and networks of children in the five regions of China exhibit regional differences.


Assuntos
Dieta , Padrões Dietéticos , Criança , Humanos , China , Verduras , Comportamento Alimentar
14.
Zhongguo Dang Dai Er Ke Za Zhi ; 26(3): 321-324, 2024 Mar 15.
Artigo em Chinês | MEDLINE | ID: mdl-38557387

RESUMO

The male patient, one day old, was admitted to the hospital due to hypoglycemia accompanied by apnea appearing six hours after birth. The patient had transient hypoglycemia early after birth, and acute heart failure suddenly occurred on the eighth day after birth. Laboratory tests showed significantly reduced levels of adrenocorticotropic hormone and cortisol, and pituitary magnetic resonance imaging was normal. Genetic testing results showed that the patient had probably pathogenic compound heterozygous mutations of the TBX19 gene (c.917-2A>G+c.608C>T), inherited respectively from the parents. The patient was conclusively diagnosed with congenital isolated adrenocorticotropic hormone deficiency caused by mutation of the TBX19 gene. Upon initiating hydrocortisone replacement therapy, cardiac function rapidly returned to normal. After being discharged, the patient continued with the hydrocortisone replacement therapy. By the 18-month follow-up, the patient was growing and developing well. In neonates, unexplained acute heart failure requires caution for possible endocrine hereditary metabolic diseases, and timely cortisol testing and genetic testing should be conducted.


Assuntos
Insuficiência Adrenal , Insuficiência Cardíaca , Hipoglicemia , Recém-Nascido , Humanos , Masculino , Hidrocortisona/uso terapêutico , Hipoglicemia/etiologia , Insuficiência Adrenal/congênito , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/genética , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/genética , Hormônio Adrenocorticotrópico
15.
Ecol Evol ; 14(3): e11148, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38476702

RESUMO

With over 600 valid species, the wrasses (family Labridae) are among the largest and most successful families of the marine teleosts. They feature prominently on coral reefs where they are known not only for their impressive diversity in colouration and form but also for their functional specialisation and ability to occupy a wide variety of trophic guilds. Among the wrasses, the parrotfishes (tribe Scarini) display some of the most dramatic examples of trophic specialisation. Using abrasion-resistant biomineralized teeth, parrotfishes are able to mechanically extract protein-rich micro-photoautotrophs growing in and among reef carbonate material, a dietary niche that is inaccessible to most other teleost fishes. This ability to exploit an otherwise untapped trophic resource is thought to have played a role in the diversification and evolutionary success of the parrotfishes. In order to better understand the key evolutionary innovations leading to the success of these dietary specialists, we sequenced and analysed the genome of a representative species, the spotted parrotfish (Cetoscarus ocellatus). We find significant expansion, selection and duplications within several detoxification gene families and a novel poly-glutamine expansion in the enamel protein ameloblastin, and we consider their evolutionary implications. Our genome provides a useful resource for comparative genomic studies investigating the evolutionary history of this highly specialised teleostean radiation.

16.
BMC Public Health ; 24(1): 707, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38443853

RESUMO

BACKGROUND: Ambient air pollutants have been suggested to affect pubertal development. Nevertheless, current studies indicate inconsistent effects of these pollutants, causing precocious or delayed puberty onset. This study aimed to explore the associations between long-term exposure to particulate matter with aerodynamic diameters ≤ 2.5 µm (PM2.5) along with its components and menarche timing among Chinese girls. METHOD: Self-reported age at menarche was collected among 855 girls from China Health and Nutrition Survey 2004 to 2015. The pre-menarche annual average concentrations of PM2.5 and its components were calculated on the basis of a long-term (2000-2014) high-resolution PM2.5 components dataset. Generalized linear models (GLM) and logistic regression models were used to analyze the associations of exposure to a single pollutant (PM2.5, sulfate, nitrate, ammonium, black carbon and organic matter) with age at menarche and early menarche (< 12 years), respectively. Weighted quantile sum methods were applied to examine the impacts of joint exposure on menarche timing. RESULTS: In the adjusted GLM, per 1 µg/m3 increase of annual average concentrations of nitrate and ammonium decreased age at menarche by 0.098 years and 0.127 years, respectively (all P < 0.05). Every 1 µg/m3 increase of annual average concentrations of PM2.5 (OR: 1.04, 95% CI: 1.00-1.08), sulfate (OR: 1.23, 95% CI: 1.01-1.50), nitrate (OR: 1.23, 95% CI: 1.06-1.43) and ammonium (OR: 1.32, 95% CI: 1.06-1.66) were significantly positively associated with early menarche. Higher level of joint exposure to PM2.5 and its components was associated with 11% higher odds of early menarche (P = 0.04). Additionally, the estimated weight of sulfate was the largest among the mixed pollutants. CONCLUSIONS: Long-term exposure to PM2.5 and its components could increase the risk of early menarche among Chinese girls. Moreover, sulfate might be the most critical components responsible for this relationship. Our study provides foundation for targeted prevention of PM2.5 components.


Assuntos
Compostos de Amônio , Poluentes Ambientais , Feminino , Humanos , Adolescente , Menarca , Nitratos , China , Material Particulado/efeitos adversos , Sulfatos
17.
Nature ; 626(8001): 1141-1148, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38326620

RESUMO

The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor1 (GPCR) that has a central role in regulating systemic calcium homeostasis2,3. Here we use cryo-electron microscopy and functional assays to investigate the activation of human CaSR embedded in lipid nanodiscs and its coupling to functional Gi versus Gq proteins in the presence and absence of the calcimimetic drug cinacalcet. High-resolution structures show that both Gi and Gq drive additional conformational changes in the activated CaSR dimer to stabilize a more extensive asymmetric interface of the seven-transmembrane domain (7TM) that involves key protein-lipid interactions. Selective Gi and Gq coupling by the receptor is achieved through substantial rearrangements of intracellular loop 2 and the C terminus, which contribute differentially towards the binding of the two G-protein subtypes, resulting in distinct CaSR-G-protein interfaces. The structures also reveal that natural polyamines target multiple sites on CaSR to enhance receptor activation by zipping negatively charged regions between two protomers. Furthermore, we find that the amino acid L-tryptophan, a well-known ligand of CaSR extracellular domains, occupies the 7TM bundle of the G-protein-coupled protomer at the same location as cinacalcet and other allosteric modulators. Together, these results provide a framework for G-protein activation and selectivity by CaSR, as well as its allosteric modulation by endogenous and exogenous ligands.


Assuntos
Proteínas Heterotriméricas de Ligação ao GTP , Receptores de Detecção de Cálcio , Humanos , Regulação Alostérica/efeitos dos fármacos , Cinacalcete/farmacologia , Microscopia Crioeletrônica , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Ligantes , Lipídeos , Nanoestruturas/química , Poliaminas/metabolismo , Conformação Proteica/efeitos dos fármacos , Receptores de Detecção de Cálcio/química , Receptores de Detecção de Cálcio/metabolismo , Receptores de Detecção de Cálcio/ultraestrutura , Especificidade por Substrato , Triptofano/metabolismo , Cálcio/metabolismo
18.
Nanomaterials (Basel) ; 14(4)2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38392734

RESUMO

Herein, the preparation process, morphology, structure, and magnetic properties of La1.85Sr0.15CuO4 (LSCO) cobweb-like nanofibers are reported. LSCO nanofibers with a regular grain size distribution are successfully prepared via electrospinning, followed by calcination. We conducted morphology analysis and elemental distribution using electron microscopy and energy-dispersive X-ray spectroscopy (EDS), respectively. Additionally, magnetic property testing was performed using a vibrating sample magnetometer (VSM) to confirm the superconducting properties of the samples. Interestingly, our samples exhibited a superconducting transition temperature, Tc, of 25.21 K, which showed some disparity compared to similar works. Furthermore, we observed a ferromagnetic response at low temperatures in the superconducting nanofibers. We attribute these phenomena to the effects generated by surface states of nanoscale superconducting materials.

19.
Genet Med ; 26(4): 101073, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38245859

RESUMO

PURPOSE: The 100,000 Genomes Project diagnosed a quarter of affected participants, but 26% of diagnoses were not on the applied gene panel(s); with many being de novo variants. Assessing biallelic variants without a gene panel is more challenging. METHODS: We sought to identify missed biallelic diagnoses using GenePy, which incorporates allele frequency, zygosity, and a user-defined deleterious metric, generating an aggregate GenePy score per gene, per participant. We calculated GenePy scores for 2862 recessive disease genes in 78,216 100,000 Genomes Project participants. For each gene, we ranked participant GenePy scores and scrutinized affected participants without a diagnosis, whose scores ranked among the top 5 for each gene. In cases which participant phenotypes overlapped with the disease gene of interest, we extracted rare variants and applied phase, ClinVar, and ACMG classification. RESULTS: 3184 affected individuals without a molecular diagnosis had a top-5-ranked GenePy score and 682 of 3184 (21%) had phenotypes overlapping with a top-ranking gene. In 122 of 669 (18%) phenotype-matched cases (excluding 13 withdrawn participants), we identified a putative missed diagnosis (2.2% of all undiagnosed participants). A further 334 of 669 (50%) cases have a possible missed diagnosis but require functional validation. CONCLUSION: Applying GenePy at scale has identified 456 potential diagnoses, demonstrating the value of novel diagnostic strategies.


Assuntos
Diagnóstico Ausente , Humanos , Virulência , Frequência do Gene/genética , Fenótipo , Genes Recessivos
20.
World J Pediatr ; 20(6): 556-568, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38238638

RESUMO

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) not only significantly improves survival rates in severely ill neonates but also is associated with long-term neurodevelopmental issues. To systematically review the available literature on the neurodevelopmental outcomes of neonates and infants who have undergone ECMO treatment, with a focus on motor deficits, cognitive impairments, sensory impairments, and developmental delays. This review aims to understand the incidence, prevalence, and risk factors for these problems and to explore current nursing care and management strategies. DATA SOURCES: A comprehensive literature search was performed across PubMed, EMBASE, and Web of Science using a wide array of keywords and phrases pertaining to ECMO, neonates, infants, and various facets of neurodevelopment. The initial screening involved reviewing titles and abstracts to exclude irrelevant articles, followed by a full-text assessment of potentially relevant literature. The quality of each study was evaluated based on its research methodology and statistical analysis. Moreover, citation searches were conducted to identify potentially overlooked studies. Although the focus was primarily on neonatal ECMO, studies involving children and adults were also included due to the limited availability of neonate-specific literature. RESULTS: About 50% of neonates post-ECMO treatment exhibit varying degrees of brain injury, particularly in the frontal and temporoparietal white matter regions, often accompanied by neurological complications. Seizures occur in 18%-23% of neonates within the first 24 hours, and bleeding events occur in 27%-60% of ECMO procedures, with up to 33% potentially experiencing ischemic strokes. Although some studies suggest that ECMO may negatively impact hearing and visual development, other studies have found no significant differences; hence, the influence of ECMO remains unclear. In terms of cognitive, language, and intellectual development, ECMO treatment may be associated with potential developmental delays, including lower composite scores in cognitive and motor functions, as well as potential language and learning difficulties. These studies emphasize the importance of early detection and intervention of potential developmental issues in ECMO survivors, possibly necessitating the implementation of a multidisciplinary follow-up plan that includes regular neuromotor and psychological evaluations. Overall, further multicenter, large-sample, long-term follow-up studies are needed to determine the impact of ECMO on these developmental aspects. CONCLUSIONS: The impact of ECMO on an infant's nervous system still requires further investigation with larger sample sizes for validation. Fine-tuned management, comprehensive nursing care, appropriate patient selection, proactive monitoring, nutritional support, and early rehabilitation may potentially contribute to improving the long-term outcomes for these infants.


Assuntos
Oxigenação por Membrana Extracorpórea , Humanos , Oxigenação por Membrana Extracorpórea/efeitos adversos , Recém-Nascido , Lactente , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/epidemiologia , Feminino , Masculino , Encéfalo/crescimento & desenvolvimento , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/epidemiologia
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