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1.
Biosci Rep ; 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35006257

RESUMO

Breast cancer is the most common cancer and the leading cause of cancer-related death in women. The estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are important biomarkers in the prognosis of breast cancer, and their expression is used to categorize breast cancer into subtypes. We aimed to analyze the concordance between ER, PR, and HER2 expression levels and breast cancer subtyping results obtained by immunohistochemistry (IHC, for protein) and reverse transcriptase-polymerase chain reaction (RT-PCR, for mRNA) and to assess the recurrence-free survival (RFS) of the different subtypes as determined by the two methods. We compared biomarker expression by IHC and RT-PCR in 397 operable breast cancer patients and categorized all patients into luminal, HER2, and triple-negative (TN) subtypes. The concordance of biomarker expression between the two methods was 81.6% (kappa = 0.4075) for ER, 87.2% (kappa = 0.5647) for PR, and 79.1% (kappa = 0.2767) for HER2. The kappa statistic was 0.3624 for the resulting luminal, HER2, and TN subtypes. The probability of a 5-year RFS was 0.78 for the luminal subtype versus 0.77 for HER2 and 0.51 for TN, when determined by IHC (p = 0.007); and 0.80, 0.71, and 0.61, respectively, when determined by the RT-PCR method (p = 0.008). Based on the current evidence, subtyping by RT-PCR performs similarly to conventional IHC with regard to the 5-year prognosis. The PCR method may thus provide a complementary means of subtyping when IHC results are ambiguous.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34976307

RESUMO

Most marine mollusks have a pelagic larval phase, and they need to undergo metamorphosis to develop into adults. Metamorphosis is affected by many factors, including abiotic factors such as temperature, salinity and illumination as well as biological factors such as food and microorganisms. In our previous study, we found that the metamorphosis of Rapana venosa requires induction by juvenile oysters, which are the food source of R. venosa. However, the regulatory mechanism of this induction is largely unknown. In the present study, we evaluated the impacts of induction by juvenile oysters on competent larvae of R. venosa. Competent larvae were experimentally divided into two pools, and scallop shells without juvenile oysters and scallop shells with juvenile oysters were added for 2 h and 12 h to monitor alterations in critical gene expression, symbiotic microbiota and metabolomic responses. The carboxypeptidase gene was increased while the cellulase gene was decreased, which may mean that the food habit transition was induced by juvenile oysters. Meanwhile, critical genes in the neuroendocrine system were also significantly altered in juvenile oysters. Furthermore, dramatic changes in the symbiotic microbiota and metabolism profiles were observed, with many of them associated with the digestive system and neuroendocrine system. In conclusion, juveniles as food resources may induce metamorphosis in R. venosa by regulating the neuroendocrine system and promoting the development of the digestive system and changes in digestive enzymes. This study may provide evidence that induction by juvenile oysters can promote food habit transition and metamorphosis in R. venosa by regulating the metabolome and microbiome and further altering the digestive and neuroendocrine systems of R. venosa, which expands our understanding of the regulatory mechanism of metamorphosis in R. venosa. However, further studies are needed to explore the specific substance inducing metamorphosis released by juvenile oysters.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34662694

RESUMO

BACKGROUND: Accumulating evidence suggest that behavioral sensitization is involved in the process of drug addiction. Zebrafish are sensitive to a variety of addictive drugs and are thus suitable for the study of behavioral sensitization. However, in contrast to mature rodent models of behavioral sensitization, how this phenomenon manifests in aquatic organisms, especially zebrafish, is largely unknown. In this study, we developed a morphine-induced behavioral sensitization adult zebrafish model and performed a preliminary investigation of the underlying mechanisms. METHODS: Behavioral sensitization was established in zebrafish by observing their behavior after treatment and challenge with morphine. The effect of morphine was evaluated by a behavioral locomotor test. Different doses of morphine and withdrawal times were used to evaluate the establishment of the behavioral sensitization model. RESULTS: Hyperlocomotion was induced after administration of morphine in adult zebrafish. After withdrawing the drug for a period, challenge with low-dose morphine evoked behavioral sensitization in zebrafish acutely pre-treated with morphine. Low-dose morphine failed to induce behavioral sensitization in zebrafish if the withdrawal time was less than 5 days or more than 7 days. Morphine induced behavioral sensitization in zebrafish may involve dopaminergic, glutamatergic and opioid systems. CONCLUSION: A single low-dose of morphine could induce behavioral sensitization in zebrafish acutely pre-treated with morphine, and this phenomenon was highly correlated with drug dose and withdrawal time. These findings suggest that zebrafish is a suitable model for the study of behavioral sensitization.

4.
Materials (Basel) ; 14(23)2021 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-34885534

RESUMO

Coating on the surface is one of the main ways to improve the corrosion resistance and wear resistance of materials. In this work, the corrosion, erosion, and wear resistance of WC-10Co4Cr coating and 27CrMoV substrate were compared by simulating the actual working conditions of the drill pipe. The simulation results show that the most serious corrosion occurred at the pipe body and the dominating erosion arose at the pipe joint closing to the inlet of the flow field. WC-10Co4Cr coating has excellent protection to 27CrMoV substrate, resulting in a 400 mV increase in corrosion potential, a two-orders-of-magnitude decrease in the corrosion current, and four times the improvement of the impedance value. The erosion resistance of the WC-10Co4Cr coating increased to more than 30% higher than that of the 27CrMoV substrate. The friction coefficient of the WC-10Co4Cr coating was much lower than that of the 27CrMoV substrate, and the wear resistance of the coating was higher than that of the substrate.

5.
Aging (Albany NY) ; 13(23): 25213-25240, 2021 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-34897031

RESUMO

Glioma is a primary intracranial tumor with high morbidity and mortality. We acquired miR-338-5p, which suppresses the development of glioma, from the GEO and CGGA databases. In addition, we predicted that hsa_circ_0072389, hsa_circ_0072386, hsa_circ_0008621, hsa_circ_0072387, and hsa_circ_0072391 could relieve the silencing of IKBIP by miR-338-5p. By analyzing genes related to IKBIP expression, possible pathways affecting glioma were identified. This study provides new ideas for investigating multiple circRNAs in ceRNAs.

6.
Front Vet Sci ; 8: 784898, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34966812

RESUMO

The fruits of Ailanthus altissima Swingle (AS) possess a variety of pharmacological activities. Its antioxidant activity and the potential mode of action have not yet been investigated. In in vitro studies, AS revealed the strong reducing power and DPPH scavenging effect, but hydroxyl radical scavenging activity and ferrous ions-chelating ability were not strong. Meanwhile, the oxidative stress RAW264.7 cell injury model was established, the low and medium-doses of AS showed significant protective effects on the viability of H2O2-treated cells by CCK-8 method. Besides, three doses of AS all increased the activities of SOD, CAT, and GSH-Px and decreased the MDA level compared with the H2O2 group, suggesting it significantly relieved oxidative stress of cells. The active ingredients and related targets of AS were collected by HERB and Swiss Target Prediction database, the common targets of drugs and diseases database were conducted by GeneCards database platform and the Venny platform. We screened the core targets of AS like threonine kinase1 (AKT1), mitogen-activated protein kinase 1 (MAPK1), sirtuin-1 (SIRT1), mechanistic target of rapamycin kinase (MTOR) by STRING database, and the key pathways involved PI3K-AKT and FoxO signaling pathway by KEGG pathway enrichment analysis. Besides, qRT-PCR revealed AS preconditioning significantly up-regulated the expression level of AKT1, SIRT1, MAPK1, and MTOR in model cells, and the effect was related to the regulation of FoxO and PI3K/AKT signaling pathway. In summary, AS showed significant antioxidant activity and its potential mechanism was regulating FoxO and PI3K/AKT signaling pathway.

7.
Curr Psychol ; : 1-14, 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34776718

RESUMO

As a response to the COVID-19 pandemic, our societies went into a lockdown model and many organizations required or permitted their employees to work from home. As a result, employees need to deal with the COVID-19 pandemic while they work from home, providing an opportunity to examine how COVID-19 prevention experiences influence those who are working from home. Based on the interpersonal self-regulation perspective, we propose that employees who perceive having more disagreements with their partners over COVID-19 prevention measures are more likely to experience a reduction in their identification with the partner which is subsequently associated with their negative work outcomes through emotional exhaustion. Results from a two-wave survey study with a sample of 282 employees who worked from home during the COVID-19 pandemic supported our predictions: perceived self-partner disagreements over COVID-19 prevention measures related to a reduction in identification with the partner, which was subsequently associated with exhausted regulatory resources and undermined work outcomes. Furthermore, these negative effects were particularly salient for individuals who were not married. Theoretical and practical implications for family-to-work interference and working from home in times of crisis are discussed.

8.
J Clin Invest ; 131(21)2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34720095

RESUMO

To explore how the immune system controls clearance of SARS-CoV-2, we used a single-cell, mass cytometry-based proteomics platform to profile the immune systems of 21 patients who had recovered from SARS-CoV-2 infection without need for admission to an intensive care unit or for mechanical ventilation. We focused on receptors involved in interactions between immune cells and virus-infected cells. We found that the diversity of receptor repertoires on natural killer (NK) cells was negatively correlated with the viral clearance rate. In addition, NK subsets expressing the receptor DNAM1 were increased in patients who more rapidly recovered from infection. Ex vivo functional studies revealed that NK subpopulations with high DNAM1 expression had cytolytic activities in response to target cell stimulation. We also found that SARS-CoV-2 infection induced the expression of CD155 and nectin-4, ligands of DNAM1 and its paired coinhibitory receptor TIGIT, which counterbalanced the cytolytic activities of NK cells. Collectively, our results link the cytolytic immune responses of NK cells to the clearance of SARS-CoV-2 and show that the DNAM1 pathway modulates host-pathogen interactions during SARS-CoV-2 infection.


Assuntos
COVID-19/imunologia , COVID-19/virologia , Células Matadoras Naturais/imunologia , Receptores de Células Matadoras Naturais/imunologia , SARS-CoV-2/imunologia , Adolescente , Adulto , Idoso , Animais , Antígenos de Diferenciação de Linfócitos T/imunologia , Moléculas de Adesão Celular/imunologia , Estudos de Coortes , Citotoxicidade Imunológica , Feminino , Xenoenxertos , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunofenotipagem , Técnicas In Vitro , Ligantes , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Subfamília D de Receptores Semelhantes a Lectina de Células NK/imunologia , Pandemias , Receptores Imunológicos/imunologia , Receptores Virais/imunologia , Carga Viral , Adulto Jovem
9.
Front Immunol ; 12: 739837, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34721406

RESUMO

We have developed a new binary epitope-presenting CVP platform based on bamboo mosaic virus (BaMV) by using the sortase A (SrtA)-mediated ligation technology. The reconstructed BaMV genome harbors two modifications: 1) a coat protein (CP) with N-terminal extension of the tobacco etch virus (TEV) protease recognition site plus 4 extra glycine (G) residues as the SrtA acceptor; and 2) a TEV protease coding region replacing that of the triple-gene-block proteins. Inoculation of such construct, pKB5G, on Nicotiana benthamiana resulted in the efficient production of filamentous CVPs ready for SrtA-mediated ligation with desired proteins. The second part of the binary platform includes an expression vector for the bacterial production of donor proteins. We demonstrated the applicability of the platform by using the recombinant envelope protein domain III (rEDIII) of Japanese encephalitis virus (JEV) as the antigen. Up to 40% of the BaMV CP subunits in each CVP were loaded with rEDIII proteins in 1 min. The rEDIII-presenting BaMV CVPs (BJLPET5G) could be purified using affinity chromatography. Immunization assays confirmed that BJLPET5G could induce the production of neutralizing antibodies against JEV infections. The binary platform could be adapted as a useful alternative for the development and mass production of vaccine candidates.

10.
J Sci Food Agric ; 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34741310

RESUMO

BACKGROUND: Garlic (Allium sativum L.), whose bioactive components are mainly organosulfur compounds (OSCs), is a herbaceous perennial widely consumed as a green vegetable and a condiment. Yet, the metabolic enzymes involved in the biosynthesis of OSCs are not identified in garlic. RESULTS: Here, a full-length transcriptome of purple garlic was generated via PacBio and Illumina sequencing, to characterize the garlic transcriptome and identify key proteins mediating the biosynthesis of OSCs. Overall, 22.56 Gb of clean data were generated, resulting in 454 698 circular consensus sequence (CCS) reads, of which 83.4% (379 206) were identified as being full-length non-chimeric reads - their further transcript clustering facilitated identification of 36 571 high-quality consensus reads. Once corrected, their genome-wide mapping revealed that 6140 reads were novel isoforms of known genes, and 2186 reads were novel isoforms from novel genes. We detected 1677 alternative splicing events, finding 2902 genes possessing either two or more poly(A) sites. Given the importance of serine O-acetyltransferase (SERAT) in cysteine biosynthesis, we investigated the five SERAT homologs in garlic. Phylogenetic analysis revealed a three-tier classification of SERAT proteins, each featuring a serine acetyltransferase domain (N-terminal) and one or two hexapeptide transferase motifs. Template-based modeling showed that garlic SERATs shared a common homo-trimeric structure with homologs from bacteria and other plants. The residues responsible for substrate recognition and catalysis were highly conserved, implying a similar reaction mechanism. In profiling the five SERAT genes' transcript levels, their expression pattern varied significantly among different tissues. CONCLUSION: This study's findings deepen our knowledge of SERAT proteins, and provide timely genetic resources that could advance future exploration into garlic's genetic improvement and breeding. © 2021 Society of Chemical Industry.

11.
Clin Neurol Neurosurg ; 211: 107023, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34800814

RESUMO

Alexander disease (AxD) is a rare, autosomal dominant genetic disorder with an incidence of approximately 1 in 27,00.000. It is caused by a missense mutation in the GFAP gene encoding the glial fibrillary acidic protein. Fragile X-associated tremor/ataxia syndrome (FXTAS) is an X-linked dominant genetic disease, usually caused by a pre-mutation: an unmethylated expansion in the range of 50-200 CGG repeats in the fragile X mental retardation 1 (FMR1) gene. The clinical manifestations of these two diseases are complex and have some similarities. Both type II AxD and FXTAS may have ataxia as the first symptom. Here, we describe a case of type II AxD with ataxia as the first symptom accompanying a hemizygous mutation in the FMR1 gene (NM_001185081, exon13, c 0.1256C>T, p.T419M, g 0.147026507C>T). A sporadic genetic mutation led us to misdiagnose the patient with FXTAS initially. Whole-genome sequencing confirmed a heterozygous mutation in the GFAP gene (NM_002055.5, exon4, c 0.1158C>A, p.N386K, g 0.6310C>A). This report indicates that when the patient's clinical manifestation is ataxia, and imaging results suggest that the midbrain, medulla oblongata, and other subcerebellar structures are atrophied, AxD should be considered. Whole-genome sequencing is thus feasible to avoid missed diagnoses and misdiagnoses.

12.
Health Qual Life Outcomes ; 19(1): 258, 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34794439

RESUMO

OBJECTIVE: Resilience instruments specific to family caregivers (FCs) in cancer are limited. This study was designed to validate the 10-item Resilience Scale Specific to Cancer (RS-SC-10) in FCs using multidimensional item response theory (MIRT) analysis. METHODS: 382 FCs were enrolled from Be Resilient to Cancer Program (BRCP) and administered with RS-SC-10 and 36-item Short Form Health Survey (SF-36). MIRT was performed to evaluate item parameters while Generalized Additive Model (GAM) and Latent Profile Analysis (LPA) were performed to test the non-linear relationship between resilience (RS-SC-10) and Quality of Life (QoL, SF-36). RESULTS: RS-SC-10 retained 10 items with high multidimensional discrimination, monotonous thresholds and its original two-factor structure (Generic and Shift-Persist). Four latent resilience subgroups were identified and a non-linear dose-response pattern between resilience and QoL was confirmed (per-SD increase OR = 1.62, 95% CI 1.16-2.13, p = 0.0019). CONCLUSION: RS-SC-10 is a brief and suitable resilience instrument for FCs in cancer. The resilience screening of patients and FCs can be performed simultaneously in clinical practice.


Assuntos
Neoplasias , Qualidade de Vida , Cuidadores , Humanos , Programas de Rastreamento , Psicometria , Inquéritos e Questionários
13.
Sci Total Environ ; : 151189, 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34757105

RESUMO

Marine heatwaves (MHWs) are weather-timescale extreme events in the oceans and can have devastating effects on marine bivalves and ecosystems they support, with considerable socio-economic consequences. Yet, the extent to which marine bivalves have the capacity to acclimate and adapt to MHWs remains unknown. Understanding molecular responses to MHWs is imperative to develop strategies for conservation of ecologically and economically important marine organisms. Here, using RNA-Seq, we investigate how various MHWs scenarios elicit molecular changes in threatened and vulnerable pearl oysters, Pinctada maxima (Jameson). Acute exposure of MHWs - mimicked by rapid increases of seawater temperature from 24 °C to 28 °C and 32 °C, respectively - significantly affected the expression levels of metabolic and immune-related genes, with thermal stress-responsive genes especially like HSP20, HSP70 and HSP90 being remarkably up-regulated. Following repeat exposure to MHWs, encouragingly, pearl oysters exhibited evident acclimation responses, as best exemplified by significantly lowered expression levels of key stress-responsive genes involved in metabolism and immunity in comparison to those observed during acute exposure. Findings of the present study provide a better understanding of molecular processes underpinning the acclimation and adaptation of marine bivalves to MHWs in the context of climate change.

14.
IEEE Trans Image Process ; 30: 9359-9371, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34757904

RESUMO

Domain adversarial training has become a prevailing and effective paradigm for unsupervised domain adaptation (UDA). To successfully align the multi-modal data structures across domains, the following works exploit discriminative information in the adversarial training process, e.g., using multiple class-wise discriminators and involving conditional information in the input or output of the domain discriminator. However, these methods either require non-trivial model designs or are inefficient for UDA tasks. In this work, we attempt to address this dilemma by devising simple and compact conditional domain adversarial training methods. We first revisit the simple concatenation conditioning strategy where features are concatenated with output predictions as the input of the discriminator. We find the concatenation strategy suffers from the weak conditioning strength. We further demonstrate that enlarging the norm of concatenated predictions can effectively energize the conditional domain alignment. Thus we improve concatenation conditioning by normalizing the output predictions to have the same norm of features, and term the derived method as Normalized OutpUt coNditioner (NOUN). However, conditioning on raw output predictions for domain alignment, NOUN suffers from inaccurate predictions of the target domain. To this end, we propose to condition the cross-domain feature alignment in the prototype space rather than in the output space. Combining the novel prototype-based conditioning with NOUN, we term the enhanced method as PROtotype-based Normalized OutpUt coNditioner (PRONOUN). Experiments on both object recognition and semantic segmentation show that NOUN can effectively align the multi-modal structures across domains and even outperform state-of-the-art domain adversarial training methods. Together with prototype-based conditioning, PRONOUN further improves the adaptation performance over NOUN on multiple object recognition benchmarks for UDA. Code is available at https://github.com/tim-learn/NOUN.

15.
Dalton Trans ; 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34812463

RESUMO

The development and application of metal nanoclusters (MNCs) in nucleic acid testing in the past 10 years have been summarized. Fluorescence enhancement and red shift can occur when the G-rich sequence gets close to Ag NCs or the complementary DNA strand hybridizes with Ag NCs tail strand, which can be used to identify the nucleic acid. Ag NCs with the abasic site in DNA duplex can distinguish mutant genes such as cancer suppression gene p53. Ag NCs with auxiliary DNA can be used to detect miR-21, miR-16-5p, miR-19b-3p, and miR-141. Cu NCs/Cu NPs can recognize miRNA-155, miR-21, and miR-let-7d without auxiliary DNA. Au NCs can identify H1N1 gene fragments by fluorescence quenching caused by proximity to the G-rich sequence. Besides, Au NCs can recognize miRNA-21 and let-7a. SsDNA MNCs adsorbed on the surface of GO and CNPs oxide can be used to identify HBV and HIV gene fragments. The addition of enzymes or auxiliary amplification technologies is a popular way to improve probe sensitivity. Ag NCs combined with TAIEA has the best performance and can obtain LOD as low as aM for miRNA.

16.
Microbiol Spectr ; 9(2): e0086721, 2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34612666

RESUMO

An investigation of members of the soil keratinophilic fungi community in China resulted in the identification of one new monotypic genus, Zongqia, and 10 new species, 2 of which are affiliated with Solomyces, 1 with the new genus Zongqia, 4 with Pseudogymnoascus, and 3 with Scedosporium. These novel taxa form an independent lineage distinct from other species, based on morphological and multilocus phylogenetic analyses. Descriptions, illustrations, and notes are provided for each taxon. These new taxa of the soil keratinophilic fungi add to the increasing number of fungi known from China, and it is now evident that numerous novel taxa are waiting to be described. IMPORTANCE Keratinophilic fungi are a group that can degrade and utilize keratin-rich material. It is also because of this ability that many taxa can cause infections in animals or humans but remain poorly studied. In this study, we reported a novel genus and 10 novel species, 7 novel species belonging to the order Thelebolales and 3 to the genus Scedosporium, based on multilocus phylogenetic analyses combined with morphological characteristics. Our study significantly updates the taxonomy of Thelebolales and Scedosporium and enhances our understanding of this group of the keratin-degrading fungal community. The findings also encourage future studies on the artificially constructed keratin-degrading microbial consortia.

17.
Opt Express ; 29(18): 28178-28189, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34614955

RESUMO

Polarimetric dehazing method is very promising in enhancing the quality of images captured in the scattering media. However, it is found that the dehazing results calculated by hazy images are very sensitive to the noise, which may cause the method unstable or even invalid. To overcome this drawback and enhance the capability and stability of the polarimetric dehazing method, digital image processing algorithms or bias parameters need to be added into the method, however, they will make the algorithm complex and time consuming. In this paper, using low pass filter to suppress the noise of the hazy images, a novel polarimetric dehazing method is proposed to enhance the visibility of hazy images, especially for dense haze removal. Experimental results demonstrate that this method is totally automatic and very effective in dense haze processing. This method may have great potential usage in many applications, such as optical surveillance, underwater imaging, and bio-tissue imaging, etc.

18.
J Med Chem ; 64(19): 14793-14808, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34595917

RESUMO

One antitumor ß-elemene derivative W-105 and three novel hepatocyte-targeting prodrugs (W-1-5, W-2-9, and W-3-8) were designed and synthesized. W-105 (IC50 6.107 µM) could cause cell apoptosis through upregulating the activity of caspase-3. The hepatocyte-targeting capacities of the aimed compounds followed the W-105 (parent compound) < W-1-5 (monodentate-galactose) < W-2-9 (bidentate-galactose) < W-3-8 (tridentate-galactose) order, which is attributed to the excellent affinity of the galactose ligand to ASGPR and the galactose-cluster recognition effect. Furthermore, prodrugs W-3-8 exhibited good antitumor activity and low toxic side effects. The liquid chromatography-mass spectrometry (LC-MS) assays revealed that prodrugs (W-1-5, W-2-9, and W-3-8) could release the antitumor pharmacophore in the presence of GSH (mimic the condition of the tumor cell) and maintain the low-toxic structures in the absence of GSH (mimic the condition of the normal cell). The release mechanisms of prodrugs were also proposed. Overall, these prodrugs developed in this study had potential in the treatment of liver cancer.

19.
Cell Death Differ ; 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635817

RESUMO

Many integral membrane proteins might act as indispensable coordinators in specific functional microdomains to maintain the normal operation of known receptors, such as Notch. Gm364 is a multi-pass transmembrane protein that has been screened as a potential female fertility factor. However, there have been no reports to date about its function in female fertility. Here, we found that global knockout of Gm364 decreased the numbers of primordial follicles and growing follicles, impaired oocyte quality as indicated by increased ROS and γ-H2AX, decreased mitochondrial membrane potential, decreased oocyte maturation, and increased aneuploidy. Mechanistically, Gm364 directly binds and anchors MIB2, a ubiquitin ligase, on the membrane. Subsequently, membrane MIB2 ubiquitinates and activates DLL3. Next, the activated DLL3 binds and activates Notch2, which is subsequently cleaved within the cytoplasm to produce NICD2, the intracellular active domain of Notch2. Finally, NICD2 can directly activate AKT within the cytoplasm to regulate oocyte meiosis and quality.

20.
Lancet Respir Med ; 9(12): 1396-1406, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34655522

RESUMO

BACKGROUND: MVC-COV1901, a recombinant protein vaccine containing pre-fusion-stabilised spike protein S-2P adjuvanted with CpG 1018 and aluminium hydroxide, has been shown to be well tolerated with a good safety profile in healthy adults aged 20-49 years in a phase 1 trial, and provided a good cellular and humoral immune responses. We present the interim safety, tolerability, and immunogenicity results of a phase 2 clinical trial of the MVC-COV1901 vaccine in Taiwan. METHODS: This is a large-scale, double-blind, randomised, placebo-controlled phase 2 trial done at ten medical centres and one regional hospital in Taiwan. Individuals aged 20 years or older who were generally healthy or had stable pre-existing medical conditions were eligible for enrolment. Exclusion criteria included (but were not limited to) travel overseas within 14 days of screening, intention to travel overseas within 6 months of the screening visit, and the absence of prespecified medical conditions, including immunosuppressive illness, a history of autoimmune disease, malignancy with risk to recur, a bleeding disorder, uncontrolled HIV infection, uncontrolled hepatitis B and C virus infections, SARS-CoV-1 or SARS-CoV-2 infections, an allergy to any vaccine, or a serious medical condition that could interfere with the study. Study participants were randomly assigned (6:1) to receive two doses of either MVC-COV1901 or placebo, administered via intramuscular injection on day 1 and day 29. MVC-COV1901 contained 15 µg of S-2P protein adjuvanted with 750 µg CpG 1018 and 375 µg aluminium hydroxide in a 0·5 mL aqueous solution, and the placebo contained the same volume of saline. Randomisation was done centrally by use of an interactive web response system, stratified by age (≥20 to <65 years and ≥65 years). Participants and investigators were masked to group assignment. The primary outcomes were to evaluate the safety, tolerability, and immunogenicity of MVC-COV1901 from day 1 (the day of the first dose) to day 57 (28 days after the second dose). Safety was assessed in all participants who received at least one dose. Immunogenicity was assessed by measuring geometric mean titres (GMTs) and seroconversion rates of neutralising antibody and antigen-specific IgG in the per-protocol population. This study is registered with ClinicalTrials.gov, NCT04695652. FINDINGS: Of 4173 individuals screened between Dec 30, 2020, and April 2, 2021, 3854 were enrolled and randomly assigned: 3304 to the MVC-COV1901 group and 550 to the placebo group. A total of 3844 participants (3295 in the MVC-COV1901 group and 549 in the placebo group) were included in the safety analysis set, and 1053 participants (903 and 150) had received both doses and were included in the per-protocol immunogenicity analysis set. From the start of this phase 2 trial to the time of interim analysis, no vaccine-related serious adverse events were recorded. The most common solicited adverse events in all study participants were pain at the injection site (2346 [71·2%] of 3295 in the MVC-COV1901 group and 128 [23·3%] of 549 in the placebo group), and malaise or fatigue (1186 [36·0%] and 163 [29·7%]). Fever was rarely reported (23 [0·7%] and two [0·4%]). At 28 days after the second dose of MVC-COV1901, the wild-type SARS-CoV-2 neutralising antibody GMT was 662·3 (95% CI 628·7-697·8; 408·5 IU/mL), the GMT ratio (geometric mean fold increase in titres at day 57 vs baseline) was 163·2 (155·0-171·9), and the seroconversion rate was 99·8% (95% CI 99·2-100·0). INTERPRETATION: MVC-COV1901 has a good safety profile and elicits promising immunogenicity responses. These data support MVC-COV1901 to enter phase 3 efficacy trials. FUNDING: Medigen Vaccine Biologics and Taiwan Centres for Disease Control, Ministry of Health and Welfare.

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