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1.
Gene Expr Patterns ; 43: 119229, 2021 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-34968768

RESUMO

BACKGROUND: IFNLR1 has been recently identified to be related to autosomal dominant nonsyndromic sensorineural hearing loss (ADNSHL). It is reported to be expressed in the inner ear of mice and the lateral line of zebrafish. However, it remains unclear how defects in this gene lead to hearing loss. OBJECTIVES: To elucidate the global gene expression changes in zebrafish when the expression of ifnlr1 is downregulated. METHODS: Transcriptome analysis was performed on ifnlr1 morpholino knockdown zebrafish and the control zebrafish using RNA-seq technology. RESULTS: The results show that 262 differentially expressed genes (DEGs) were up-regulated while 146 DEGs were down-regulated in the E4I4-Mo zebrafish larvae compared to the control-Mo. Six pathways were significantly enriched, including steroid biosynthesis pathway, adipocytokine signaling pathway, cytokine-cytokine receptor interaction pathway, p53 signaling pathway, AGE-RAGE signaling pathway in diabetic complications, and terpenoid backbone biosynthesis pathway. Among them, three pathways (steroid biosynthesis pathway, cytokine-cytokine receptor interaction pathway and p53 signaling pathway) are immune-associated. CONCLUSIONS: The transcriptome analysis results contribute to the groundwork for future research on the pathogenesis of IFNLR1-associated hearing loss.

2.
EBioMedicine ; 74: 103714, 2021 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-34818622

RESUMO

BACKGROUND: Molecular features underlining the multistage progression of gastric lesions and development of early gastric cancer (GC) are poorly understood, restricting the ability to GC prevention and management. METHODS: We portrayed proteomic landscape and explored proteomic signatures associated with progression of gastric lesions and risk of early GC. Tissue proteomic profiling was conducted for a total of 324 subjects. A case-control study was performed in the discovery stage (n=169) based on populations from Linqu, a known high-risk area for GC in China. We then conducted two-stage validation, including a cohort study from Linqu (n = 56), with prospective follow-up for progression of gastric lesions (280-473 days), and an independent case-control study from Beijing (n = 99). FINDINGS: There was a clear distinction in proteomic features for precancerous gastric lesions and GC. We derived four molecular subtypes of gastric lesions and identified subtype-S4 with the highest progression risk. We found 104 positively-associated and 113 inversely-associated proteins for early GC, with APOA1BP, PGC, HPX and DDT associated with the risk of gastric lesion progression. Integrating these proteomic signatures, the ability to predict progression of gastric lesions was significantly strengthened (areas-under-the-curve=0.88 (95%CI: 0.78-0.99) vs. 0.56 (0.36-0.76), Delong's P = 0.002). Immunohistochemistry assays and examination at mRNA level validated the findings for four proteins. INTERPRETATION: We defined proteomic signatures for progression of gastric lesions and risk of early GC, which may have translational significance for identifying particularly high-risk population and detecting GC at an early stage, improving potential for targeted GC prevention. FUNDING: The funders are listed in the Acknowledgement.

3.
Exp Cell Res ; 409(1): 112892, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34688609

RESUMO

Carnitine palmitoyltransferase 2 (CPT2) has been demonstrated to act as a tumor promotor or suppressor in different types of cancers. However, little is known about the effect of CPT2 on colorectal cancer (CRC). In the present study, we analyzed CPT2 expression in CRC tissues and cells. CPT2 was overexpressed in CRC cell lines (SW480 and RKO), and its effects and molecular mechanism on the proliferation, glycolysis, stemness, and oxaliplatin sensitivity were investigated. The xenograft experiment was used to confirm the influence of CPT2 on CRC tumorigenesis in vivo. We found that CPT2 expression was significantly downregulated in CRC patients, and its lower expression was associated with the poor prognosis, large tumor size, advanced TNM stage, and poor histological grade differentiation of patients. Upregulation of CPT2 significantly inhibited the proliferation, glycolytic metabolism, cancer stem cell properties, and oxaliplatin resistance in CRC cells. Also, the increase of CPT2 inhibited tumorigenesis, stemness and glycolysis, while enhanced oxaliplatin sensitivity in mouse models. Mechanistically, CPT2 functioned via suppressing the activation of Wnt/ß-catenin pathway through repressing ROS production. In conclusion, our results demonstrated that CPT2 was decreased in CRC, and CPT2 downregulation could trigger stemness and oxaliplatin resistance in CRC via activating the ROS/Wnt/ß-catenin-induced glycolytic metabolism. This study indicates that CPT2 is a potential therapeutic target for CRC.

4.
PLoS Pathog ; 17(10): e1009987, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34669717

RESUMO

Salmonella enterica represents over 2500 serovars associated with a wide-ranging spectrum of disease; from self-limiting gastroenteritis to invasive infections caused by non-typhoidal serovars (NTS) and typhoidal serovars, respectively. Host factors strongly influence infection outcome as malnourished or immunocompromised individuals can develop invasive infections from NTS, however, comparative analyses of serovar-specific host responses have been constrained by reliance on limited model systems. Here we used human intestinal organoids (HIOs), a three-dimensional "gut-like" in vitro system derived from human embryonic stem cells, to elucidate similarities and differences in host responses to NTS and typhoidal serovars. HIOs discriminated between the two most prevalent NTS, Salmonella enterica serovar Typhimurium (STM) and Salmonella enterica serovar Enteritidis (SE), and typhoidal serovar Salmonella enterica serovar Typhi (ST) in epithelial cell invasion, replication and transcriptional responses. Pro-inflammatory signaling and cytokine output was reduced in ST-infected HIOs compared to NTS infections, consistent with early stages of NTS and typhoidal diseases. While we predicted that ST would induce a distinct transcriptional profile from the NTS strains, more nuanced expression profiles emerged. Notably, pathways involved in cell cycle, metabolism and mitochondrial functions were downregulated in STM-infected HIOs and upregulated in SE-infected HIOs. These results correlated with suppression of cellular proliferation and induction of host cell death in STM-infected HIOs and in contrast, elevated levels of reactive oxygen species production in SE-infected HIOs. Collectively, these results suggest that the HIO model is well suited to reveal host transcriptional programming specific to infection by individual Salmonella serovars, and that individual NTS may provoke unique host epithelial responses during intestinal stages of infection.


Assuntos
Perfilação da Expressão Gênica , Intestinos/microbiologia , Intestinos/fisiopatologia , Infecções por Salmonella/microbiologia , Infecções por Salmonella/fisiopatologia , Humanos , Organoides , Salmonella enterica , Sorogrupo , Transcriptoma
5.
Front Neurosci ; 15: 716476, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34557066

RESUMO

Objective: To explore quantitative measurements of the visual attention and neuroelectrophysiological relevance of memory deficits in temporal lobe epilepsy (TLE) by eye tracking and electroencephalography (EEG). Methods: Thirty-four TLE patients and twenty-eight healthy controls were invited to complete neurobehavioral assessments, cognitive oculomotor tasks, and 24-h video EEG (VEEG) recordings using an automated computer-based memory assessment platform with an eye tracker. Visit counts, visit time, and time of first fixation on areas of interest (AOIs) were recorded and analyzed in combination with interictal epileptic discharge (IED) characteristics from the bilateral temporal lobes. Results: The TLE patients had significantly worse Wechsler Digit Span scores [F(1, 58) = 7.49, p = 0.008]. In the Short-Term Memory Game with eye tracking, TLE patients took a longer time to find the memorized items [F(1, 57) = 17.30, p < 0.001]. They had longer first fixation [F(1, 57) = 4.06, p = 0.049] and more visit counts [F(1, 57) = 7.58, p = 0.008] on the target during the recall. Furthermore, the performance of the patients in the Digit Span task was negatively correlated with the total number of IEDs [r(28) = -0.463, p = 0.013] and the number of spikes per sleep cycle [r(28) = -0.420, p = 0.026]. Conclusion: Eye tracking appears to be a quantitative, objective measure of memory evaluation, demonstrating memory retrieval deficits but preserved visual attention in TLE patients. Nocturnal temporal lobe IEDs are closely associated with memory performance, which might be the electrophysiological mechanism for memory impairment in TLE.

6.
Teach Learn Med ; : 1-9, 2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34565245

RESUMO

PHENOMENON: Dementia is a huge burden to the economic and health care system in China. As the next generation of health care providers, undergraduate health professional students play a pivotal role in caring for dementia patients during their clinical placements and in independent practice. Nevertheless, they may not be adequately prepared to care for patients with dementia by their undergraduate programs. Measuring the knowledge and attitudes of health professional students could be an important step in providing evidence regarding the need to enhance dementia care training in the curriculum. Approach: Responses from 325 Chinese health professional (nursing, medical, and public health) students were included in the analyses. After providing informed consent, students answered questionnaires including a demographic data questionnaire, the Alzheimer's Disease Knowledge Scale (ADKS) and the Dementia Attitudes Scale (DAS). Univariate analyses were performed to test the association between outcomes and potential explanatory variables. Multiple linear regression analysis was used to determine the predictive factors for knowledge and attitudes toward dementia. Findings: Chinese health professional students had a mean ADKS score of 18.92 (SD = 3.20). Better knowledge was associated with advanced education, having family members with medical knowledge, having heard of dementia, and having interest in learning about dementia. Students had a mean DAS score of 89.10 (SD = 8.93), and their attitudes were significantly associated with majoring in public health and having heard of dementia. Students' knowledge was positively, but weakly related with attitudes (r = 0.122, P = 0.028). Insights: Chinese undergraduate health professional students demonstrate insufficient knowledge and less positive attitudes toward dementia than their counterparts in developed countries. Enhanced dementia care-specific curriculum and training are urgently needed in China to meet the growing demand for dementia care services.

7.
Chem Rec ; 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34473401

RESUMO

The construction of a structurally rigid architecture with chiral complexity, necessary to enhance the interaction with binding sites of drug targets, has been adapted as an intriguing approach in drug development. In the past few years, we have been interested in the synthesis of biologically significant and bridged alkaloids via novel synthetic methods and strategies based on recognition of the privileged pattern. Therefore, nitroso-ene and aza-Wacker cyclizations were elevated for the first time to construct bridged alkaloids, such as hosieine A, kopsone, melinonine-E and strychnoxanthine. Mechanistic investigations, including computational calculations for nitroso-ene reaction and deuterated experiments for aza-Wacker reaction, enable us to gain more insights into the chemical reactivity and selectivity of specific functional groups in developing viable synthetic methods.

9.
Sensors (Basel) ; 21(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34450832

RESUMO

Complementary metal-oxide-semiconductor (CMOS) image sensors can cause noise in images collected or transmitted in unfavorable environments, especially low-illumination scenarios. Numerous approaches have been developed to solve the problem of image noise removal. However, producing natural and high-quality denoised images remains a crucial challenge. To meet this challenge, we introduce a novel approach for image denoising with the following three main contributions. First, we devise a deep image prior-based module that can produce a noise-reduced image as well as a contrast-enhanced denoised one from a noisy input image. Second, the produced images are passed through a proposed image fusion (IF) module based on Laplacian pyramid decomposition to combine them and prevent noise amplification and color shift. Finally, we introduce a progressive refinement (PR) module, which adopts the summed-area tables to take advantage of spatially correlated information for edge and image quality enhancement. Qualitative and quantitative evaluations demonstrate the efficiency, superiority, and robustness of our proposed method.


Assuntos
Algoritmos , Aumento da Imagem , Razão Sinal-Ruído
10.
Biochem Biophys Res Commun ; 571: 14-19, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34298337

RESUMO

Restoration of hair follicle (HF) regenerative capacity is the cornerstone in tissue engineering for the loss of regenerative capacity during in vitro expansion of skin-derived precursors (SKPs). Microenvironmental cues facilitated tissue or organ regeneration offers a potential strategy to overcome this difficulty. In our previous work, plantar dermis matrix homogenate (PD) has been proved to induce sweat glands regeneration both in vivo and in vitro. Here, we found PD also restore regenerative capacity of culture impaired HF spheroids (IHFS). Further, followed by our previous iTRAQ results, the CTHRC1 was identified as a potential regulator in PD facilitated restorative effects in HF regeneration. Knockout of Cthrc1 impaired HF regenerative capacity in spheroids, decreased the diameter of HF in 28 postnatal days mice and shortened invagination of HF bud in 18 days of gestation mice. In IHFS and Cthrc1-/- spheroids, PD partially restored HF regenerative capacity while Cthrc1-/- PD (PDKO) has less or no effect. Taken together, PD is an effective microenvironmental cues for HF regenerative capacity restoration and CTHRC1 played an important role in HF regeneration.


Assuntos
Derme/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Folículo Piloso/metabolismo , Animais , Proteínas da Matriz Extracelular/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
11.
Inflamm Bowel Dis ; 2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34302470

RESUMO

BACKGROUND: Intestinal fibrosis and subsequent intestinal obstruction are common complications of Crohn's disease (CD). Current therapeutics combat inflammation, but no pharmacological therapy exists for fibrostenotic disease. Pathological persistence of activated intestinal myofibroblasts is a key driver of fibrosis in CD. In other organ systems, BH-3 mimetic drugs that affect Bcl-2 apoptotic pathways induce apoptosis in activated myofibroblasts and reduce fibrogenic gene expression, thereby reducing fibrosis. METHODS: We evaluated the proapoptotic and antifibrotic efficacy of several classes of BH-3 mimetics in 2 in vitro fibrogenesis models. The candidate molecule, ABT-263, was advanced to a 3-dimensional human intestinal organoid (HIO) model. Finally, the therapeutic efficacy of ABT-263 was evaluated in the mouse Salmonella typhimurium intestinal fibrosis model. RESULTS: The BH-3 mimetics induced apoptosis, repressed fibrotic protein expression, and reduced fibrogenic gene expression in normal human intestinal myofibroblasts. The BH-3 mimetics that target Bcl-2 and Bcl-xl demonstrated the greatest efficacy in vitro. The ABT-199 and ABT-263 induced apoptosis and ameliorated fibrogenesis in the in vitro myofibroblast models. In the HIO model, ABT-263 inhibited fibrogenesis and induced apoptosis. In the mouse S. typhimurium model, dose-dependent reduction in macroscopic pathology, histological inflammation, inflammatory and fibrotic gene expression, and extracellular matrix protein expression indicated ABT-263 may reduce intestinal fibrosis. CONCLUSIONS: In vitro, the antifibrotic efficacy of BH-3 mimetics identifies the Bcl-2 pathway as a druggable target and BH-3 mimetics as putative therapeutics. Reduction of inflammation and fibrosis in the mouse intestinal fibrosis model by ABT-263 indicates BH-3 mimetics as potential, novel antifibrotic therapeutics for Crohn's disease.

12.
Pathol Res Pract ; 224: 153521, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34329839

RESUMO

BACKGROUND: Colorectal cancer (CRC) is considered as one of the commonest tumors and is the major reason of cancer-related deaths around the world. Plentiful evidences have validated that long non-coding RNAs (lncRNAs) play a significant part in various cancers, including CRC. LINC01559 is implicated in the development of various cancers. However, the detailed function of LINC01559 in CRC has not been illustrated. METHODS: LINC01559 expression was examined via RT-qPCR, and a series of functional experiments were conducted to explore the role of LINC01559 in CRC progression. Mechanism experiments were carried out to examine the underlying mechanism of LINC01559. RESULTS: LINC01559 expression was increased in CRC cells and tissues, and LINC01559 depletion restrained the biological behaviors of CRC cells. Also, LINC01559 sponged miR-1343-3p in CRC, and PARP1 was the target of miR-1343-3p. Besides, miR-1343-3p overexpression or PARP1 down-regulation affected the biological behaviors of CRC cells. In addition, up-regulation of PARP1 or adding SC79 (AKT pathway activator) could remedy the repressive effects of LINC01559 silencing on CRC cell biological behaviors. CONCLUSIONS: LINC01559 promotes CRC through sponging miR-1343-3p to modulate PARP1/PTEN/AKT pathway, which may be conducive to offering a new idea for CRC therapeutic treatment.

13.
Burns Trauma ; 9: tkab013, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34213515

RESUMO

Background: Sweat glands (SGs) and hair follicles (HFs) are two important cutaneous appendages that play crucial roles in homeostatic maintenance and thermoregulation, and their interaction is involved in wound healing. SGs can be regenerated from mesenchymal stem cell-laden 3D bioprinted scaffolds, based on our previous studies, whereas regeneration of HFs could not be achieved in the same model. Due to the lack of an in vitro model, the underlying molecular mechanism of the interaction between SGs and HFs in regeneration could not be fully understood. The purpose of the present study was to establish an in vitro model of skin constructs with SGs and HFs and explore the interaction between these two appendages in regeneration. Methods: To investigate the interaction effects between SGs and HFs during their regeneration processes, a combined model was created by seeding HF spheroids on 3D printed SG scaffolds. The interaction between SG scaffolds and HF spheroids was detected using RNA expression and immunofluorescence staining. The effects of microenvironmental cues on SG and HF regeneration were analysed by altering seed cell types and plantar dermis homogenate in the scaffold. Results: According to this model, we overcame the difficulties in simultaneously inducing SG and HF regeneration and explored the interaction effects between SG scaffolds and HF spheroids. Surprisingly, HF spheroids promoted both SG and HF differentiation in SG scaffolds, while SG scaffolds promoted SG differentiation but had little effect on HF potency in HF spheroids. Specifically, microenvironmental factors (plantar dermis homogenate) in SG scaffolds effectively promoted SG and HF genesis in HF spheroids, no matter what the seed cell type in SG scaffolds was, and the promotion effects were persistent. Conclusions: Our approach elucidated a new model for SG and HF formation in vitro and provided an applicable platform to investigate the interaction between SGs and HFs in vitro. This platform might facilitate 3D skin constructs with multiple appendages and unveil the spatiotemporal molecular program of multiple appendage regeneration.

14.
Mater Sci Eng C Mater Biol Appl ; 126: 112193, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34082990

RESUMO

Mesenchymal cells (MSCs) are an attractive option as seed cells for bioprinting. However, loss of stemness and undesired differentiation reduces their effectiveness. In this study, 12 nm bioactive nanoparticles (BNPs) which could release silicon (Si) ions were used to enhance the properties of alginate/gelatin hydrogel bioink to maintain MSC stemness. By specifically leveraging biochemical signals of BNPs, bioink with defined stiffness towards osteogenic and adipogenic potential, independent of pore structure, were designed by incorporating with different concentration of BNPs. These bioink were characterized by printability, mechanical and rheological properties as well as osteogenic and adipogenic potentials. Notably, the effect of 2% BNPs addition in alginate/gelatin hydrogel on MSC stemness maintenance was confirmed by the expression of stemness markers. At higher concentrations of BNPs (5%), printability was impacted by the gelling process. We further confirmed the enhanced stemness maintenance by sweat gland lineage commitment of bioprinted MSCs in vitro. Overall, our study proved that alginate/gelatin hydrogel bioink reinforced by BNPs in the optimal concentrations could retain MSC stemness as well as support MSC growth and prolong the desired differentiation. These findings may provide a new approach to achieve the ideal therapeutic potential of MSCs in 3D bioprinting application.


Assuntos
Bioimpressão , Células-Tronco Mesenquimais , Nanopartículas , Alginatos , Animais , Células Cultivadas , Gelatina , Hidrogéis , Camundongos , Impressão Tridimensional , Engenharia Tecidual , Tecidos Suporte
15.
JAMA Netw Open ; 4(6): e2114186, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34156450

RESUMO

Importance: Metabolic deregulation plays an important role in gastric cancer (GC) development. To date, no studies have comprehensively explored the metabolomic profiles along the cascade of gastric lesions toward GC. Objective: To draw a metabolic landscape and define metabolomic signatures associated with the progression of gastric lesions and risk of early GC. Design, Setting, and Participants: A 2-stage, population-based cohort study was initiated in 2017 in Linqu County, Shandong Province, China, a high-risk area for GC. Prospective follow-up was conducted during the validation stage (June 20, 2017, to May 27, 2020). A total of 400 individuals were included based on the National Upper Gastrointestinal Cancer Early Detection Program in China. The discovery stage involved 200 individuals with different gastric lesions or GC (high-grade intraepithelial neoplasia or invasive GC). The validation stage prospectively enrolled 152 individuals with gastric lesions who were followed up for 118 to 1063 days and 48 individuals with GC. Exposures: Metabolomic profiles and metabolite signatures were examined based on untargeted plasma metabolomics assay. Main Outcomes and Measures: The risk of GC overall and early GC (high-grade intraepithelial neoplasia), and progression of gastric lesions. Results: Of the 400 participants, 124 of 200 (62.0%) in the discovery set were men; mean (SD) age was 56.8 (7.5) years. In the validation set, 136 of 200 (68.0%) were men; mean (SD) age was 57.5 (8.1) years. Distinct metabolomic profiles were noted for gastric lesions and GC. Six metabolites, including α-linolenic acid, linoleic acid, palmitic acid, arachidonic acid, sn-1 lysophosphatidylcholine (LysoPC)(18:3), and sn-2 LysoPC(20:3) were significantly inversely associated with risk of GC overall and early GC (high-grade intraepithelial neoplasia). Among these metabolites, the first 3 were significantly inversely associated with gastric lesion progression, especially for the progression of intestinal metaplasia (α-linolenic acid: OR, 0.42; 95% CI, 0.18-0.98; linoleic acid: OR, 0.43; 95% CI, 0.19-1.00; and palmitic acid: OR, 0.32; 95% CI, 0.13-0.78). Compared with models including only age, sex, Helicobacter pylori infection, and gastric histopathologic findings, integrating these metabolites significantly improved the performance for predicting the progression of gastric lesions (area under the curve [AUC], 0.86; 95% CI, 0.70-1.00 vs AUC, 0.69; 95% CI, 0.50-0.88; P = .02) and risk of early GC (AUC, 0.83; 95% CI, 0.58-1.00 vs AUC, 0.61; 95% CI, 0.31-0.91; P = .03). Conclusions and Relevance: This study defined metabolite signatures that might serve as meaningful biomarkers for assessing high-risk populations and early diagnosis of GC, possibly advancing targeted GC prevention and control.

16.
Cell Rep ; 35(5): 109054, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33951433

RESUMO

The basic helix-loop-helix (bHLH) transcription factor PHYTOCHROME-INTERACTING FACTOR 7 (PIF7) is a central regulator that promotes stem growth by activating growth-related gene expression during shade-avoidance responses. Studying the co-factors of PIF7 can facilitate understanding of the mechanism of PIFs and light signal transduction. Here, we describe the identification of two bHLH transcription factors, bHLH48 and bHLH60 (bHLH48/bHLH60), as essential partners for PIF7-dependent modulation of hypocotyl elongation and function downstream of phytochrome B. These two bHLH factors display DNA binding activity and interact with PIF7. Genetic analysis indicated that bHLH48/bHLH60 and PIF7 are interdependent in promoting hypocotyl elongation. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis identified the substantially overlapping downstream targets of bHLH60 and PIF7. Biochemical analysis revealed that bHLH48/bHLH60 enhance the DNA binding ability of PIF7. These results provide evidence that bHLH48/bHLH60 act as positive partners of PIF7 for mutual benefit in the regulation of hypocotyl elongation.

17.
mBio ; 12(3)2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006652

RESUMO

The intestinal epithelium is a primary interface for engagement of the host response by foodborne pathogens, like Salmonella enterica Typhimurium. While the interaction of S Typhimurium with the mammalian host has been well studied in transformed epithelial cell lines or in the complex intestinal environment in vivo, few tractable models recapitulate key features of the intestine. Human intestinal organoids (HIOs) contain a polarized epithelium with functionally differentiated cell subtypes, including enterocytes and goblet cells and a supporting mesenchymal cell layer. HIOs contain luminal space that supports bacterial replication, are more amenable to experimental manipulation than animals and are more reflective of physiological host responses. Here, we use the HIO model to define host transcriptional responses to S Typhimurium infection, also determining host pathways dependent on Salmonella pathogenicity island-1 (SPI-1)- and -2 (SPI-2)-encoded type 3 secretion systems (T3SS). Consistent with prior findings, we find that S Typhimurium strongly stimulates proinflammatory gene expression. Infection-induced cytokine gene expression was rapid, transient, and largely independent of SPI-1 T3SS-mediated invasion, likely due to continued luminal stimulation. Notably, S Typhimurium infection led to significant downregulation of host genes associated with cell cycle and DNA repair, leading to a reduction in cellular proliferation, dependent on SPI-1 and SPI-2 T3SS. The transcriptional profile of cell cycle-associated target genes implicates multiple miRNAs as mediators of S Typhimurium-dependent cell cycle suppression. These findings from Salmonella-infected HIOs delineate common and distinct contributions of SPI-1 and SPI-2 T3SSs in inducing early host responses during enteric infection and reinforce host cell proliferation as a process targeted by Salmonella IMPORTANCE Salmonella enterica serovar Typhimurium (S Typhimurium) causes a significant health burden worldwide, yet host responses to initial stages of intestinal infection remain poorly understood. Due to differences in infection outcome between mice and humans, physiological human host responses driven by major virulence determinants of Salmonella have been more challenging to evaluate. Here, we use the three-dimensional human intestinal organoid model to define early responses to infection with wild-type S Typhimurium and mutants defective in the SPI-1 or SPI-2 type-3 secretion systems. While both secretion system mutants show defects in mouse models of oral Salmonella infection, the specific contributions of each secretion system are less well understood. We show that S Typhimurium upregulates proinflammatory pathways independently of either secretion system, while the downregulation of the host cell cycle pathways relies on both SPI-1 and SPI-2. These findings lay the groundwork for future studies investigating how SPI-1- and SPI-2-driven host responses affect infection outcome and show the potential of this model to study host-pathogen interactions with other serovars to understand how initial interactions with the intestinal epithelium may affect pathogenesis.


Assuntos
Proteínas de Bactérias/genética , Enterócitos/microbiologia , Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Proteínas de Membrana/genética , Organoides/microbiologia , Salmonella typhimurium/genética , Linhagem Celular , Regulação Bacteriana da Expressão Gênica , Humanos , Mucosa Intestinal/microbiologia , Intestinos/citologia , Intestinos/microbiologia , Salmonella typhimurium/patogenicidade , Sorogrupo , Fatores de Virulência
18.
Cell ; 184(12): 3281-3298.e22, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34019796

RESUMO

Organs are composed of diverse cell types that traverse transient states during organogenesis. To interrogate this diversity during human development, we generate a single-cell transcriptome atlas from multiple developing endodermal organs of the respiratory and gastrointestinal tract. We illuminate cell states, transcription factors, and organ-specific epithelial stem cell and mesenchyme interactions across lineages. We implement the atlas as a high-dimensional search space to benchmark human pluripotent stem cell (hPSC)-derived intestinal organoids (HIOs) under multiple culture conditions. We show that HIOs recapitulate reference cell states and use HIOs to reconstruct the molecular dynamics of intestinal epithelium and mesenchyme emergence. We show that the mesenchyme-derived niche cue NRG1 enhances intestinal stem cell maturation in vitro and that the homeobox transcription factor CDX2 is required for regionalization of intestinal epithelium and mesenchyme in humans. This work combines cell atlases and organoid technologies to understand how human organ development is orchestrated.

19.
Sci Total Environ ; 789: 147937, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34049148

RESUMO

The rapid socioeconomic development has led to severe pollution of urban soils by heavy metals. It is vital to identify and quantify the factors that affect trace-element pollution for better preventing and managing soil pollution. In this study, we collected 179 surface soil samples from Zhangzhou City in a coastal area of south China to determine the concentration of seven heavy metals (As, Cr, Cu, Hg, Ni, Pb, and Zn) and used the Nemerow Pollution Index (Pn) to estimate the level of heavy metal pollution in soils. Eighteen environmental factors, including six natural factors (e.g. soil properties, surface topography) and twelve anthropogenic factors (e.g. industry, road network, land use types and landscape pattern), were evaluated with the geodetector statistical method. The results indicate that the heavy metal contamination of soils in Zhangzhou City was highly heterogeneous. We found that the primary influencing factors for heavy metal concentrations were soil organic matter content, agriculture activities, and landscape pattern. Furthermore, the nonlinear relationship between the primary factors and their interaction factors enhanced soil contamination by the heavy metals. Among the anthropogenic factors, landscape pattern enhanced Pn the most when interacting with natural factor. In addition, the buffer zone should be considered when evaluating the effects of factors such as land use and landscape pattern, because the interactions between landscape pattern and slope aspect produce a maximum effect, accounting for 31.0% of the Pn value on the scale of 800 m. Based on this analysis, we identified the key factors of heavy metal pollution in the soils of Zhangzhou City and proposed strategic procedures for effective soil pollution prevention and treatment in the future.


Assuntos
Metais Pesados , Poluentes do Solo , China , Cidades , Monitoramento Ambiental , Metais Pesados/análise , Medição de Risco , Solo , Poluentes do Solo/análise
20.
Front Cell Dev Biol ; 9: 640388, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33842464

RESUMO

Mesenchymal stem cells (MSCs) have been widely used in the fields of tissue engineering and regenerative medicine due to their self-renewal capabilities and multipotential differentiation assurance. However, capitalizing on specific factors to precisely guide MSC behaviors is the cornerstone of biomedical applications. Fortunately, several key biophysical and biochemical cues of biomaterials that can synergistically regulate cell behavior have paved the way for the development of cell-instructive biomaterials that serve as delivery vehicles for promoting MSC application prospects. Therefore, the identification of these cues in guiding MSC behavior, including cell migration, proliferation, and differentiation, may be of particular importance for better clinical performance. This review focuses on providing a comprehensive and systematic understanding of biophysical and biochemical cues, as well as the strategic engineering of these signals in current scaffold designs, and we believe that integrating biophysical and biochemical cues in next-generation biomaterials would potentially help functionally regulate MSCs for diverse applications in regenerative medicine and cell therapy in the future.

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