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1.
Food Chem ; 356: 129697, 2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33838606

RESUMO

The purpose of this umbrella review was to evaluate the quality of evidence, validity and biases of the associations between red and processed meat consumption and multiple cancer outcomes according to existing systematic reviews and meta-analyses. The umbrella review identified 72 meta-analyses with 20 unique outcomes for red meat and 19 unique outcomes for processed meat. Red meat consumption was associated with increased risk of overall cancer mortality, non-Hodgkin lymphoma (NHL), bladder, breast, colorectal, endometrial, esophageal, gastric, lung and nasopharyngeal cancer. Processed meat consumption might increase the risk of overall cancer mortality, NHL, bladder, breast, colorectal, esophageal, gastric, nasopharyngeal, oral cavity and oropharynx and prostate cancer. Dose-response analyses revealed that 100 g/d increment of red meat and 50 g/d increment of processed meat consumption were associated with 11%-51% and 8%-72% higher risk of multiple cancer outcomes, respectively, and seemed to be not correlated with any benefit.

2.
Sci Immunol ; 6(57)2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33653907

RESUMO

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8+ T cells that correlated with the use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct from one another and implicate CD8+ T cells in the clinical presentation and trajectory of MIS-C.


Assuntos
/imunologia , Ativação Linfocitária , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Envelhecimento/imunologia , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Leucopenia/imunologia , Masculino , Adulto Jovem
4.
Nat Immunol ; 22(3): 370-380, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33574619

RESUMO

During chronic infection and cancer, a self-renewing CD8+ T cell subset maintains long-term immunity and is critical to the effectiveness of immunotherapy. These stem-like CD8+ T cells diverge from other CD8+ subsets early after chronic viral infection. However, pathways guarding stem-like CD8+ T cells against terminal exhaustion remain unclear. Here, we show that the gene encoding transcriptional repressor BACH2 is transcriptionally and epigenetically active in stem-like CD8+ T cells but not terminally exhausted cells early after infection. BACH2 overexpression enforced stem-like cell fate, whereas BACH2 deficiency impaired stem-like CD8+ T cell differentiation. Single-cell transcriptomic and epigenomic approaches revealed that BACH2 established the transcriptional and epigenetic programs of stem-like CD8+ T cells. In addition, BACH2 suppressed the molecular program driving terminal exhaustion through transcriptional repression and epigenetic silencing. Thus, our study reveals a new pathway that enforces commitment to stem-like CD8+ lineage and prevents an alternative terminally exhausted cell fate.

5.
Nat Commun ; 12(1): 1094, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33597547

RESUMO

Seahorses have a circum-global distribution in tropical to temperate coastal waters. Yet, seahorses show many adaptations for a sedentary, cryptic lifestyle: they require specific habitats, such as seagrass, kelp or coral reefs, lack pelvic and caudal fins, and give birth to directly developed offspring without pronounced pelagic larval stage, rendering long-range dispersal by conventional means inefficient. Here we investigate seahorses' worldwide dispersal and biogeographic patterns based on a de novo genome assembly of Hippocampus erectus as well as 358 re-sequenced genomes from 21 species. Seahorses evolved in the late Oligocene and subsequent circum-global colonization routes are identified and linked to changing dynamics in ocean currents and paleo-temporal seaway openings. Furthermore, the genetic basis of the recurring "bony spines" adaptive phenotype is linked to independent substitutions in a key developmental gene. Analyses thus suggest that rafting via ocean currents compensates for poor dispersal and rapid adaptation facilitates colonizing new habitats.


Assuntos
Adaptação Fisiológica/genética , Distribuição Animal , Evolução Molecular , Smegmamorpha/genética , Animais , Sequência de Bases , DNA/genética , Ecossistema , Geografia , Filogenia , Smegmamorpha/classificação , Smegmamorpha/fisiologia , Especificidade da Espécie
6.
Cell ; 184(5): 1262-1280.e22, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33636129

RESUMO

Improving effector activity of antigen-specific T cells is a major goal in cancer immunotherapy. Despite the identification of several effector T cell (TEFF)-driving transcription factors (TFs), the transcriptional coordination of TEFF biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a key mechanism restraining TEFF biology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced TEFF responses without compromising memory or exhaustion precursors. Fli1 restrained TEFF lineage differentiation by binding to cis-regulatory elements of effector-associated genes. Loss of Fli1 increased chromatin accessibility at ETS:RUNX motifs, allowing more efficient Runx3-driven TEFF biology. CD8+ T cells lacking Fli1 provided substantially better protection against multiple infections and tumors. These data indicate that Fli1 safeguards the developing CD8+ T cell transcriptional landscape from excessive ETS:RUNX-driven TEFF cell differentiation. Moreover, genetic deletion of Fli1 improves TEFF differentiation and protective immunity in infections and cancer.

7.
Sci Immunol ; 6(55)2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33452106

RESUMO

The developmental origins of memory T cells remain incompletely understood. During the expansion phase of acute viral infection, we identified a distinct subset of virus-specific CD8+ T cells that possessed distinct characteristics including expression of CD62L, T cell factor 1 (TCF-1), and Eomesodermin; relative quiescence; expression of activation markers; and features of limited effector differentiation. These cells were a quantitatively minor subpopulation of the TCF-1+ pool and exhibited self-renewal, heightened DNA damage surveillance activity, and preferential long-term recall capacity. Despite features of memory and somewhat restrained proliferation during the expansion phase, this subset displayed evidence of stronger TCR signaling than other responding CD8+ T cells, coupled with elevated expression of multiple inhibitory receptors including programmed cell death 1 (PD-1), lymphocyte activating gene 3 (LAG-3), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), CD5, and CD160. Genetic ablation of PD-1 and LAG-3 compromised the formation of this CD62Lhi TCF-1+ subset and subsequent CD8+ T cell memory. Although central memory phenotype CD8+ T cells were formed in the absence of these cells, subsequent memory CD8+ T cell recall responses were compromised. Together, these results identify an important link between genome integrity maintenance and CD8+ T cell memory. Moreover, the data indicate a role for inhibitory receptors in preserving key memory CD8+ T cell precursors during initial activation and differentiation. Identification of this rare subpopulation within the memory CD8+ T cell precursor pool may help reconcile models of the developmental origin of long-term CD8+ T cell memory.

8.
Protein Expr Purif ; 178: 105767, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32987121

RESUMO

Nicotine contamination in tobacco waste effluent (TWE) from tobacco industry is a serious threat to public health and environment. Microbial degradation is an impending approach to remove nicotine and transform it into some other high value chemicals. Pseudomonas sp. JY-Q exhibits high efficiency of degradation, which can degrade 5 g/L of nicotine within 24 h. In strain JY-Q, we found the co-occurrence of two homologous key enzymes NicA2 and Nox, which catalyze nicotine to N-methylmyosmine, and then to pseudooxylnicotine via simultaneous hydrolysis. In this study, recombinant NicA2 and Nox were expressed in E. coli BL21(DE3) and purified. In vitro, the activity of recombinant NicA2 and Nox was accelerated by adding co-factor NAD+, suggesting that they worked as dehydrogenases. The optimal reaction conditions, substrate affinity, catabolism efficiency, pH-stability and thermal-stability were determined. Nox showed lower efficiency, but at a higher stability level than NicA2. Nox exhibited wider pH range and higher temperature as optimal conditions for the enzymatic reaction. In addition, The Nox showed higher thermo-stability and acid-stability than that of NicA2. The study on enzymatic reaction kinetics showed that Nox had a lower Km and higher substrate affinity than NicA2. These results suggest that Nox plays more significant role than NicA2 in nicotine degradation in TWE, which usually is processed at low pH (4-5) and high temperature (above 40 °C). Genetic engineering is required to enhance the affinity and suitability of NicA2 for an increased additive effect on homologous NicA2 and Nox in strain JY-Q.

9.
Cell ; 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33306960

RESUMO

Lymphocyte migration is essential for adaptive immune surveillance. However, our current understanding of this process is rudimentary, because most human studies have been restricted to immunological analyses of blood and various tissues. To address this knowledge gap, we used an integrated approach to characterize tissue-emigrant lineages in thoracic duct lymph (TDL). The most prevalent immune cells in human and non-human primate efferent lymph were T cells. Cytolytic CD8+ T cell subsets with effector-like epigenetic and transcriptional signatures were clonotypically skewed and selectively confined to the intravascular circulation, whereas non-cytolytic CD8+ T cell subsets with stem-like epigenetic and transcriptional signatures predominated in tissues and TDL. Moreover, these anatomically distinct gene expression profiles were recapitulated within individual clonotypes, suggesting parallel differentiation programs independent of the expressed antigen receptor. Our collective dataset provides an atlas of the migratory immune system and defines the nature of tissue-emigrant CD8+ T cells that recirculate via TDL.

10.
J Invest Dermatol ; 2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33333123

RESUMO

Psoriasis is a common inflammatory skin disease characterized by aberrant inflammation and epidermal hyperplasia. Molecular mechanisms that regulate psoriasis-like skin inflammation remain to be fully understood. Here, we show that the expression of Ovol1 (encoding ovo-like 1 transcription factor) is upregulated in psoriatic skin, and its deletion results in aggravated psoriasis-like skin symptoms following stimulation with imiquimod. Using bulk and single-cell RNA sequencing, we identify molecular changes in the epidermal, fibroblast, and immune cells of Ovol1-deficient skin that reflect an altered course of epidermal differentiation and enhanced inflammatory responses. Furthermore, we provide evidence for excessive full-length IL-1α signaling in the microenvironment of imiquimod-treated Ovol1-deficient skin that functionally contributes to immune cell infiltration and epidermal hyperplasia. Collectively, our study uncovers a protective role for OVOL1 in curtailing psoriasis-like inflammation and the associated skin pathology.

11.
Artigo em Inglês | MEDLINE | ID: mdl-33187996

RESUMO

Nicotine is a toxic environmental pollutant that widely exists in tobacco wastes. As a natural nicotine-degrading strain, Pseudomonas sp. JY-Q still has difficulties to degrade high-concentrations of nicotine. In this study, we investigated the effect of two homologous transcriptional regulators and endogenous ectopic strong promoters on the efficiency of nicotine degradation. Comparative genomics analysis showed that two homologous transcriptional regulators NicR2A and NicR2Bs can repress nicotine-degrading genes expression. When both of nicR2A and nicR2Bs were deleted, the resulting mutant QΔnicR2AΔnicR2B1ΔnicR2B2 exhibit 17% higher nicotine degradation efficiency than wide type JY-Q. The RNA-seq analysis showed that the transcription level (FPKM value) of six genes was particularly higher than the other genes in JY-Q. Based on the genetic organization of these genes, three putative promoters, PRS28250 , PRS09985 and PRS24685 , were identified. Their promoter activities were evaluated by comparing their expression levels using RT-qPCR. We found that the transcription levels of RS28250, RS09985 and RS24685 were 16.8-, 2.6-, and 1.6-times higher than that of hspB2, encoding 6-hydroxy-3-succinylpyridine hydroxylase involved in nicotine degradation. Thus, two strong endogenous promoters PRS28250 and PRS09985 were selected to replace the original promoters of Nic2 gene clusters. The effect of endogenous ectopic promoter was also related to the replaced position of target gene clusters. When the promoter PRS28250 replaced the promoter of hspB2, the resultant mutant, QΔABs-ΔPhspB2 ::PRS28250, exhibited 69% higher nicotine degrading efficiency than the JY-Q. This research suggests a feasible strategy to enhance strain ability by removal of repressing regulatory proteins and replacing target promoter with strong endogenous ectopic promoters.IMPORTANCE This study evaluated the differential effects of homologous NicR2A/NicR2Bs and endogenous ectopic strong promoters on nicotine metabolism in Pseudomonas sp. JY-Q. Based on our differential analysis, a feasible strategy is presented to modify wild type strain JY-Q by removing repressing regulatory proteins, NicR2A/NicR2Bs, and replacing the target promoter with strong endogenous ectopic promoters. The resulting mutants exhibited high tolerance and degradation of nicotine. These findings should be beneficial for improving pollutant-degrading capacity of naturally strains through genomic modification.

12.
Phys Med Biol ; 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33181500

RESUMO

Mechanical properties of biological tissues are significant biomarkers for diagnosing various diseases. Assessing the viscoelastic properties of multi-layer tissues has remained challenging for a long time. Some shear wave models have been proposed to estimate thin-layer tissues' viscoelasticity recently. However, the potential applications of these models are highly restricted since few biological tissues are single-layered. Here we proposed a multi-layer model for layer-specific viscoelasticity estimation of biological tissues. Integrating the theoretical model and ultrasonic micro-elastography imaging system, the viscoelasticity of both layers was assessed. Dual-layer phantoms and ex-vivo porcine eyes were used to verify the proposed model. Results obtained from the mechanical test and shear wave rheological model using bulk phantoms were provided as validation criteria. The representative phantom had two layers with elastic moduli of 1.6 ± 0.2 kPa and 18.3 ± 1.1 kPa, and viscosity moduli of 0.56 ± 0.16 Pa∙s and 2.11 ± 0.28 Pa∙s, respectively. The estimated moduli using the proposed model were 1.3 ± 0.2 kPa and 16.20 ± 1.8 kPa, and 0.80 ± 0.31 Pa∙s and 1.87 ± 0.67 Pa∙s, more consistent with the criteria (one-tailed t-test, p<0.1). By contrast, other methods, including the group velocity method and single-layer Rayleigh-Lamb model, generate significant errors in their estimates. For the ex-vivo porcine eye, the estimated viscoelasticity was 23.2 ± 8.3 kPa and 1.0 ± 0.4 Pa∙s in the retina, and 158.0 ± 17.6 kPa and 1.2 ± 0.4 Pa∙s in the sclera. This study demonstrated the potential of the proposed method to significantly improve accuracy and expand clinical applications of shear wave elastography.

13.
Arch Virol ; 165(12): 2847-2856, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33034764

RESUMO

Here, we investigated the fecal, oral, blood, and skin virome of 10 laboratory rabbits using a viral metagenomic method. In the oral samples, we detected a novel polyomavirus (RabPyV), and phylogenetic analysis based on the large T antigen, VP1 and VP2 regions indicated that the novel strain might have undergone a recombination event. Recombination analysis based on related genomes confirmed that RabPyV is a multiple recombinant between rodent-like and avian-like polyomaviruses. In fecal samples, three partial or complete genome sequences of viruses belonging to the families Picobirnaviridae, Parvoviridae, Microviridae and Coronaviridae were characterized, and phylogenetic trees were constructed based on the predicted amino acid sequences of viral proteins. This study increases the amount of genetic information on viruses present in laboratory rabbits.


Assuntos
Metagenoma , Polyomavirus/isolamento & purificação , Coelhos/virologia , Proteínas Virais/genética , Vírus/classificação , Animais , Animais de Laboratório/virologia , Sangue/virologia , Fezes/virologia , Genoma Viral , Boca/virologia , Filogenia , Pele/virologia , Vírus/isolamento & purificação , Sequenciamento Completo do Genoma
14.
medRxiv ; 2020 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-32995826

RESUMO

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8 T cells that correlated with use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct and implicate CD8 T cells in clinical presentation and trajectory of MIS-C.

16.
Sci Adv ; 6(22): eaaz7677, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32766441

RESUMO

A persistent enigma is the rarity of polyploidy in animals, compared to its prevalence in plants. Although animal polyploids are thought to experience deleterious genomic chaos during initial polyploidization and subsequent rediploidization processes, this hypothesis has not been tested. We provide an improved reference-quality de novo genome for allotetraploid goldfish whose origin dates to ~15 million years ago. Comprehensive analyses identify changes in subgenomic evolution from asymmetrical oscillation in goldfish and common carp to diverse stabilization and balanced gene expression during continuous rediploidization. The homoeologs are coexpressed in most pathways, and their expression dominance shifts temporally during embryogenesis. Homoeolog expression correlates negatively with alternation of DNA methylation. The results show that allotetraploid cyprinids have a unique strategy for balancing subgenomic stabilization and diversification. Rediploidization process in these fishes provides intriguing insights into genome evolution and function in allopolyploid vertebrates.

17.
Cancer Manag Res ; 12: 4883-4888, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606976

RESUMO

Objective: To study the effect of cryptorchidism on clinical stage (CS) of testicular seminoma (TS). Patients and Methods: In the Surveillance Epidemiology and End Results (SEER) database (2006-2016), people with TS were enrolled in our research. Multivariable logistic regression models were constructed to compare the impact of cryptorchidism on CS. Results: This research was based on the registry information of 12,991 TS patients. All patients with a median age of 36 (13-107) years were pathologically diagnosed with orchiectomy or needle biopsy specimens. Patients with CS I, II, and III TS accounted for 70.68% (n = 9182), 8.30% (n = 1078), and 5.75% (n = 747) of all patients, respectively; still there were 15.27% (n = 1984) of patients whose CS could not be identified or was not available. Among all included patients, 43.45% (n = 5644) of them had normal testis, 2.93% (n = 272) had cryptorchidism, and the primary site of 54.46% (n = 7075) of patients' testis was unavailable. According to our study, patients with cryptorchidism were more likely to suffer advanced CS [OR=1.14, 95% CI (1.01-1.28), p=0.0407]. Furthermore, this effect became more remarkable after adjusting for other factors including age, region, marital status, race, year of diagnosis and laterality [OR=1.23, 95% CI (1.13-1.32), p<0.0001]. Conclusion: According to this study, TS patients with cryptorchidism would be at a higher risk of suffering advanced cancer than patients with normal testis. It demonstrates that surgical correction for cryptorchidism should be timely, and specific management should be conducted on this kind of TS patients.

18.
Nat Rev Immunol ; 20(9): 529-536, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32728222

RESUMO

The role of T cells in the resolution or exacerbation of COVID-19, as well as their potential to provide long-term protection from reinfection with SARS-CoV-2, remains debated. Nevertheless, recent studies have highlighted various aspects of T cell responses to SARS-CoV-2 infection that are starting to enable some general concepts to emerge.

19.
Sci Rep ; 10(1): 10846, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32616740

RESUMO

In plants, the shikimate pathway generally occurs in plastids and leads to the biosynthesis of aromatic amino acids. Chorismate synthase (CS) catalyses the last step of the conversion of 5-enolpyruvylshikimate 3-phosphate (EPSP) to chorismate, but the role of CS in the metabolism of higher plants has not been reported. In this study, we found that PhCS, which is encoded by a single-copy gene in petunia (Petunia hybrida), contains N-terminal plastidic transit peptides and peroxisomal targeting signals. Green fluorescent protein (GFP) fusion protein assays revealed that PhCS was localized in chloroplasts and, unexpectedly, in peroxisomes. Petunia plants with reduced PhCS activity were generated through virus-induced gene silencing and further characterized. PhCS silencing resulted in reduced CS activity, severe growth retardation, abnormal flower and leaf development and reduced levels of folate and pigments, including chlorophylls, carotenoids and anthocyanins. A widely targeted metabolomics analysis showed that most primary and secondary metabolites were significantly changed in pTRV2-PhCS-treated corollas. Overall, the results revealed a clear connection between primary and specialized metabolism related to the shikimate pathway in petunia.

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