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1.
Cell ; 184(18): 4734-4752.e20, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34450029

RESUMO

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.


Assuntos
Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Proteínas Morfogenéticas Ósseas/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Compartimento Celular , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Estudos de Coortes , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA/genética , Células Endoteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade , Inflamação/patologia , Monócitos/patologia , Células Mieloides/patologia , Neutrófilos/patologia , Células Estromais/metabolismo , Linfócitos T/metabolismo , Transcrição Gênica
2.
Cell ; 178(3): 714-730.e22, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31348891

RESUMO

Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4+ enterocytes, microfold-like cells, and IL13RA2+IL11+ inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and co-regulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.


Assuntos
Colite Ulcerativa/patologia , Colo/metabolismo , Adulto , Idoso , Anticorpos Monoclonais/uso terapêutico , Bestrofinas/metabolismo , Antígenos CD8/metabolismo , Estudos de Casos e Controles , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Colo/patologia , Enterócitos/citologia , Enterócitos/metabolismo , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Interleucina-17/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Linfócitos T/citologia , Linfócitos T/metabolismo , Trombospondinas/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
3.
Cell ; 175(5): 1307-1320.e22, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30392957

RESUMO

In the small intestine, a niche of accessory cell types supports the generation of mature epithelial cell types from intestinal stem cells (ISCs). It is unclear, however, if and how immune cells in the niche affect ISC fate or the balance between self-renewal and differentiation. Here, we use single-cell RNA sequencing (scRNA-seq) to identify MHC class II (MHCII) machinery enrichment in two subsets of Lgr5+ ISCs. We show that MHCII+ Lgr5+ ISCs are non-conventional antigen-presenting cells in co-cultures with CD4+ T helper (Th) cells. Stimulation of intestinal organoids with key Th cytokines affects Lgr5+ ISC renewal and differentiation in opposing ways: pro-inflammatory signals promote differentiation, while regulatory cells and cytokines reduce it. In vivo genetic perturbation of Th cells or MHCII expression on Lgr5+ ISCs impacts epithelial cell differentiation and IEC fate during infection. These interactions between Th cells and Lgr5+ ISCs, thus, orchestrate tissue-wide responses to external signals.


Assuntos
Diferenciação Celular , Autorrenovação Celular , Interleucina-10/metabolismo , Células-Tronco/citologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Autorrenovação Celular/efeitos dos fármacos , Citocinas/farmacologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Antígenos de Histocompatibilidade Classe II/metabolismo , Sistema Imunitário/metabolismo , Intestinos/citologia , Intestinos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Organoides/citologia , Organoides/efeitos dos fármacos , Organoides/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Salmonella enterica/patogenicidade , Células-Tronco/metabolismo , Linfócitos T Auxiliares-Indutores/citologia
4.
Immunity ; 51(4): 696-708.e9, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618654

RESUMO

Signaling abnormalities in immune responses in the small intestine can trigger chronic type 2 inflammation involving interaction of multiple immune cell types. To systematically characterize this response, we analyzed 58,067 immune cells from the mouse small intestine by single-cell RNA sequencing (scRNA-seq) at steady state and after induction of a type 2 inflammatory reaction to ovalbumin (OVA). Computational analysis revealed broad shifts in both cell-type composition and cell programs in response to the inflammation, especially in group 2 innate lymphoid cells (ILC2s). Inflammation induced the expression of exon 5 of Calca, which encodes the alpha-calcitonin gene-related peptide (α-CGRP), in intestinal KLRG1+ ILC2s. α-CGRP antagonized KLRG1+ ILC2s proliferation but promoted IL-5 expression. Genetic perturbation of α-CGRP increased the proportion of intestinal KLRG1+ ILC2s. Our work highlights a model where α-CGRP-mediated neuronal signaling is critical for suppressing ILC2 expansion and maintaining homeostasis of the type 2 immune machinery.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Inflamação/imunologia , Intestinos/imunologia , Linfócitos/imunologia , Neuropeptídeos/metabolismo , Animais , Peptídeo Relacionado com Gene de Calcitonina/genética , Células Cultivadas , Biologia Computacional , Imunidade Inata , Interleucina-5/genética , Interleucina-5/metabolismo , Lectinas Tipo C/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Neuropeptídeos/genética , Receptores Imunológicos/metabolismo , Análise de Sequência de RNA , Transdução de Sinais , Análise de Célula Única , Células Th2/imunologia , Transcriptoma , Regulação para Cima
5.
Am J Hum Genet ; 109(11): 1960-1973, 2022 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-36332611

RESUMO

Sharing genomic variant interpretations across laboratories promotes consistency in variant assertions. A landscape analysis of Australian clinical genetic-testing laboratories in 2017 identified that, despite the national-accreditation-body recommendations encouraging laboratories to submit genotypic data to clinical databases, fewer than 300 variants had been shared to the ClinVar public database. Consultations with Australian laboratories identified resource constraints limiting routine application of manual processes, consent issues, and differences in interpretation systems as barriers to sharing. This information was used to define key needs and solutions required to enable national sharing of variant interpretations. The Shariant platform, using both the GRCh37 and GRCh38 genome builds, was developed to enable ongoing sharing of variant interpretations and associated evidence between Australian clinical genetic-testing laboratories. Where possible, two-way automated sharing was implemented so that disruption to laboratory workflows would be minimized. Terms of use were developed through consultation and currently restrict access to Australian clinical genetic-testing laboratories. Shariant was designed to store and compare structured evidence, to promote and record resolution of inter-laboratory classification discrepancies, and to streamline the submission of variant assertions to ClinVar. As of December 2021, more than 14,000 largely prospectively curated variant records from 11 participating laboratories have been shared. Discrepant classifications have been identified for 11% (28/260) of variants submitted by more than one laboratory. We have demonstrated that co-design with clinical laboratories is vital to developing and implementing a national variant-interpretation sharing effort. This approach has improved inter-laboratory concordance and enabled opportunities to standardize interpretation practices.


Assuntos
Bases de Dados Genéticas , Laboratórios , Humanos , Variação Genética , Austrália , Testes Genéticos
6.
BMC Infect Dis ; 22(1): 558, 2022 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-35718768

RESUMO

BACKGROUND: A global pandemic has been declared for coronavirus disease 2019 (COVID-19), which has serious impacts on human health and healthcare systems in the affected areas, including Vietnam. None of the previous studies have a framework to provide summary statistics of the virus variants and assess the severity associated with virus proteins and host cells in COVID-19 patients in Vietnam. METHOD: In this paper, we comprehensively investigated SARS-CoV-2 variants and immune responses in COVID-19 patients. We provided summary statistics of target sequences of SARS-CoV-2 in Vietnam and other countries for data scientists to use in downstream analysis for therapeutic targets. For host cells, we proposed a predictive model of the severity of COVID-19 based on public datasets of hospitalization status in Vietnam, incorporating a polygenic risk score. This score uses immunogenic SNP biomarkers as indicators of COVID-19 severity. RESULT: We identified that the Delta variant of SARS-CoV-2 is most prevalent in southern areas of Vietnam and it is different from other areas in the world using various data sources. Our predictive models of COVID-19 severity had high accuracy (Random Forest AUC = 0.81, Elastic Net AUC = 0.7, and SVM AUC = 0.69) and showed that the use of polygenic risk scores increased the models' predictive capabilities. CONCLUSION: We provided a comprehensive analysis for COVID-19 severity in Vietnam. This investigation is not only helpful for COVID-19 treatment in therapeutic target studies, but also could influence further research on the disease progression and personalized clinical outcomes.


Assuntos
Tratamento Farmacológico da COVID-19 , COVID-19 , Infecções por Coronavirus , Pneumonia Viral , Betacoronavirus , COVID-19/epidemiologia , Estudo de Associação Genômica Ampla , Humanos , SARS-CoV-2/genética , Vietnã/epidemiologia
7.
Environ Res ; 214(Pt 4): 114130, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35998691

RESUMO

The present work focused on the synthesis of novel ZnLaxFe2-xO4 catalysts (x = 0, 0.01, 0.03, 0.05) and their utilization for the photocatalytic degradation of Rhodamine B dye. Structurally, the band gap energy of the catalysts tended to decrease (1.94-1.70 eV) with increasing the amount of La3+ dopant. ZnLa0.05Fe1.95O4 had an average particle size (40 nm), high surface area (41.07 m2 g-1) and large pore volume (0.186 cm3 g-1). Moreover, the effect of doping ratio, reaction time, H2O2 concentration, catalyst loading on the treatment performance of La3+ substituted ZnFe2O4 nanocomposites was investigated. ZnLa0.05Fe1.95O4/H2O2 system exhibited the highest degradation efficiency of 99.5% and nonlinear pseudo first-order kinetic reaction rate (14.8 × 10-3 min-1) in the presence of visible light irradiation. The key role of reactive oxygen species involving •O2- and •OH radicals was well explained through the scavenger study. A plausible mechanism of the degradation of Rhodamine B dye was also proposed. Due to two advantageous points including high recyclability (up to 4 cycles) and stability, La3+ substituted ZnFe2O4 nanocomposites can be an effective and competitive catalyst for the visible light-driven photodegradation of toxic dyes in the real wastewaters.

8.
J Paediatr Child Health ; 58(2): 281-287, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34387892

RESUMO

AIM: Familial hypercholesterolaemia (FH) is a common and treatable cause of premature coronary artery disease. However, the majority of individuals with FH remain undiagnosed. This study investigated the feasibility, acceptability and cost-effectiveness of screening children aged 1-2 years for FH at the time of an immunisation. METHODS: Children 1-2 years of age were offered screening for FH with a point-of-care total cholesterol (TC) test by capillary-collected blood sample at the time of an immunisation. An additional blood sample was taken to allow genetic testing if the TC level was above the 95th percentile (>5.3 mmol/L). Parents of children diagnosed with FH were offered testing. Following detection of the affected parent, cascade testing of their first-degree blood relatives was performed. RESULTS: We screened 448 children with 32 (7.1%) having a TC ≥ 5.3 mmol/L. The FH diagnosis was confirmed in three children (1:150 screened). Reverse cascade testing of other family members identified a further five individuals with FH; hence, eight new cases of FH were diagnosed from screening 448 children (1:56 screened). Ninety-six percent of parents would screen future children for FH. The approach was cost-effective, at $3979 per quality-adjusted life year gained. CONCLUSION: In Western Australia, universal screening of children aged 1-2 years for FH, undertaken at the time of an immunisation, was a feasible and effective approach to detect children, parents and other blood relatives with FH. The approach was acceptable to parents and is potentially a highly cost-effective detection strategy for families at risk of FH.


Assuntos
Hiperlipoproteinemia Tipo II , Austrália , Pré-Escolar , Testes Genéticos , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Lactente , Programas de Rastreamento , Pais , Projetos Piloto
9.
Clin Chem Lab Med ; 58(11): 1941-1949, 2020 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-32598297

RESUMO

Objectives High-sensitivity (hs) cardiac troponin (cTn) assays can quantitate small fluctuations in cTn concentration. Determining biological variation allows calculation of reference change values (RCV), to define significant changes. We assessed the short- and long-term biological variation of cardiac troponin I (cTnI) in healthy individuals and patients with renal failure requiring haemodialysis or cardiomyopathy. Methods Plasma samples were collected hourly for 4 h and weekly for seven further weeks from 20 healthy individuals, 9 renal failure patients and 20 cardiomyopathy patients. Pre- and post-haemodialysis samples were collected weekly for 7 weeks. Samples were analysed using a hs-cTnI assay (Abbott Alinity ci-series). Within-subject biological variation (CVI), analytical variation (CVA) and between-subject biological variation (CVG) was used to calculate RCVs and index of individuality (II). Results For healthy individuals, CVI, CVA, CVG, RCV and II values were 8.8, 14.0, 43.1, 45.8% and 0.38 respectively for short-term, and 41.4, 14.0, 25.8, 121.0% and 1.69 for long-term. For renal failure patients, these were 2.6, 5.8, 50.5, 17.6% and 0.30 respectively for short-term, and 19.1, 5.8, 11.2, 55.2% and 1.78 for long-term. For cardiomyopathy patients, these were 4.2, 10.0, 65.9, 30.0% and 0.16 respectively for short-term, and 17.5, 10.0, 63.1, 55.8% and 0.32 for long-term. Mean cTnI concentration was lower post-haemodialysis (15.2 vs. 17.8 ng/L, p < 0.0001), with a 16.9% mean relative change. Conclusions The biological variation of cTnI is similar between end-stage renal failure and cardiomyopathy patients, but proportionately greater in well-selected healthy individuals with very low baseline cTnI concentrations.


Assuntos
Variação Biológica Individual , Cardiomiopatias/sangue , Falência Renal Crônica/sangue , Troponina I/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Renal , Fatores de Tempo , Adulto Jovem
10.
Obes Pillars ; 9: 100099, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38304225

RESUMO

Background: A fixed-dose combination of phentermine and extended-release topiramate (PHEN/TPM - approved for weight management) has demonstrated in-clinic reduction of blood pressure (BP). Ambulatory BP monitoring (ABPM) may be a better predictor of cardiovascular disease risk than in-clinic BP. Methods: This randomized, multicenter, double-blind study enrolled 565 adults with overweight/obesity. Inclusion criteria included participants willing to wear ABPM device for 24 h. Exclusion criteria included screening blood pressure >140/90 mmHg and antihypertensive medications not stable for 3 months prior to randomization. Participants received placebo (n = 184), phentermine 30 mg; (n = 191), or PHEN 15 mg/TPM 92 mg; (n = 190). 24-hour ABPM was performed at baseline and at week 8. The primary endpoint was mean 24-h systolic BP (SBP) as measured by ABPM, in the per protocol population. Results: Participants were mostly female (73.5 â€‹%) and White (81.6 â€‹%), with a mean age of 53.4 years; 32.4 â€‹% had no hypertension diagnosis or treatment, 62.5 â€‹% had hypertension using 0 to 2 antihypertensive medications, and 5.1 â€‹% had hypertension using ≥ 3 antihypertensive medications. Baseline mean SBP/diastolic BP (DBP) was 123.9/77.6 â€‹mmHg. At week 8, mean SBP change was -0.1 â€‹mmHg (placebo), +1.4 â€‹mmHg (phentermine 30 â€‹mg), and -3.3 â€‹mmHg (PHEN/TPM). Between-group difference for PHEN/TPM versus placebo was -3.2 â€‹mmHg (95 â€‹% CI: -5.48, -0.93 â€‹mmHg; p â€‹= â€‹0.0059). The between-group difference for PHEN/TPM versus phentermine 30 â€‹mg was -4.7 â€‹mmHg (95 â€‹% CI: -6.96, -2.45 â€‹mmHg; p â€‹< â€‹0.0001). Common (>2 â€‹% in any treatment group) adverse events (i.e., dry mouth, constipation, nausea, dizziness, paresthesia, dysgeusia, headache, COVID-19, urinary tract infection, insomnia, and anxiety) were mostly mild or moderate. Conclusions: In this randomized, multicenter, double-blind ABPM study, PHEN/ TPM reduced SBP compared to either placebo or phentermine 30 mg (Funding: Vivus LLC; ClinicalTrials.gov: NCT05215418).

11.
Cell Rep ; 43(6): 114253, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38781074

RESUMO

Diabetic kidney disease (DKD), the most common cause of kidney failure, is a frequent complication of diabetes and obesity, and yet to date, treatments to halt its progression are lacking. We analyze kidney single-cell transcriptomic profiles from DKD patients and two DKD mouse models at multiple time points along disease progression-high-fat diet (HFD)-fed mice aged to 90-100 weeks and BTBR ob/ob mice (a genetic model)-and report an expanding population of macrophages with high expression of triggering receptor expressed on myeloid cells 2 (TREM2) in HFD-fed mice. TREM2high macrophages are enriched in obese and diabetic patients, in contrast to hypertensive patients or healthy controls in an independent validation cohort. Trem2 knockout mice on an HFD have worsening kidney filter damage and increased tubular epithelial cell injury, all signs of worsening DKD. Together, our studies suggest that strategies to enhance kidney TREM2high macrophages may provide therapeutic benefits for DKD.


Assuntos
Nefropatias Diabéticas , Dieta Hiperlipídica , Rim , Macrófagos , Glicoproteínas de Membrana , Camundongos Knockout , Obesidade , Receptores Imunológicos , Animais , Receptores Imunológicos/metabolismo , Receptores Imunológicos/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Macrófagos/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Obesidade/complicações , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Camundongos , Rim/patologia , Rim/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Feminino
12.
RSC Adv ; 13(16): 10650-10656, 2023 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-37056968

RESUMO

Rare earth metal doping spinel ferrites offer excellent electronic, magnetic, and photocatalytic properties, but they have not been well explored for environmental mitigation. Herein, we report the facile fabrication of novel CoNd x Fe2-x O4 (x = 0-0.05) photocatalysts based on Nd3+ incorporated into CoFe2O4 for the degradation of Rhodamine B under visible light irradiation. The Nd3+ dopant considerably increased the specific surface area (35 m2 g-1) and enhanced the degradation performance (94.7%) of CoNd x Fe2-x O4 catalysts. Nd3+-doped CoFe2O4 played a role in the formation of radicals, including ˙OH, h+, and ˙O2 -. With high recyclability and performance, CoNd0.05Fe1.95O4 nanoparticles can be efficient and reusable photocatalysts for degrading organic dyes, including Rhodamine B from wastewaters.

13.
Vaccines (Basel) ; 11(11)2023 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-38006019

RESUMO

African swine fever virus (ASFV) is circulating in many swine-producing countries, causing significant economic losses. It is observed that pigs experimentally vaccinated with a live-attenuated virus (LAV) but not a killed virus (KV) vaccine develop solid homologous protective immunity. The objective of this study was to comparatively analyze antibody profiles between pigs vaccinated with an LAV vaccine and those vaccinated with a KV vaccine to identify potential markers of vaccine-induced protection. Thirty ASFV seronegative pigs were divided into three groups: Group 1 received a single dose of an experimental LAV, Group 2 received two doses of an experimental KV vaccine, and Group 3 was kept as a non-vaccinated (NV) control. At 42 days post-vaccination, all pigs were challenged with the parental virulent ASFV strain and monitored for 21 days. All pigs vaccinated with the LAV vaccine survived the challenge. In contrast, eight pigs from the KV group and seven pigs from the NV group died within 14 days post-challenge. Serum samples collected on 41 days post-vaccination were analyzed for their reactivity against a panel of 29 viral structural proteins. The sera of pigs from the LAV group exhibited a strong antibody reactivity against various viral structural proteins, while the sera of pigs in the KV group only displayed weak antibody reactivity against the inner envelope (p32, p54, p12). There was a negative correlation between the intensity of antibody reactivity against five ASFV antigens, namely p12, p14, p15, p32, and pD205R, and the viral DNA titers in the blood of animals after the challenge infection. Thus, antibody reactivities against these five antigens warrant further evaluation as potential indicators of vaccine-induced protection.

14.
Artigo em Inglês | MEDLINE | ID: mdl-38097835

RESUMO

Methylene blue (MB) is hazardous in natural water because this dye causes serious diseases that endangers public health and ecosystems. Photocatalytic degradation is a prominent technique for achieving the effective elimination of dye pollutants from wastewater and contribute vitally to ecology and environmental safety. Herein, Cu2+-substituted ZnFe2O4 nanomaterials (CuxZn1-xFe2O4; x = 0, 0.1, 0.2, 0.3, 0.4, 0.6) were synthesized, characterized, and applied for the photocatalytic degradation of MB dye beneath visible light with the assistance of hydrogen peroxide (H2O2). The feature of the photo-catalysts was determined by XRD, EDX, FTIR, DRS, BET, SEM, and TEM techniques. Incorporation of Cu2+ ions changed the crystalline phase, particle size, morphology, and surface area. The photocatalysis condition was optimized with the following major factors, the amout of doping Cu2+ ions, H2O2 concentration, adsorbent dosage, and MB concentration. As a result, the photocatalytic MB degradation efficiency by Cu0.6Zn0.4Fe2O4 catalyst was 99.83% within 90 min under LED light (λ ≥ 420 nm), which was around 4 folds higher than that of pure ZnFe2O4. The photo-Fenton kinetics were in accordance with the pseudo-first-order kinetic model (R2 = 0.981), giving the highes rate constant of 0.034 min-1. It can be, therefore, concluded that Cu2+ substitution considerably boosted the photocatalytic activity of CuxZn1-xFe2O4 ZnFe2O4, suggesting a bright prospect of Cu0.6Zn0.4Fe2O4 as a photo-catalyst in the dyes wastewater treatment.

15.
bioRxiv ; 2023 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-38076853

RESUMO

The human airway contains specialized rare epithelial cells whose roles in respiratory disease are not well understood. Ionocytes express the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), while chemosensory tuft cells express asthma-associated alarmins. However, surprisingly, exceedingly few mature tuft cells have been identified in human lung cell atlases despite the ready identification of rare ionocytes and neuroendocrine cells. To identify human rare cell progenitors and define their lineage relationship to mature tuft cells, we generated a deep lung cell atlas containing 311,748 single cell RNA-Seq (scRNA-seq) profiles from discrete anatomic sites along the large and small airways and lung lobes of explanted donor lungs that could not be used for organ transplantation. Of 154,222 airway epithelial cells, we identified 687 ionocytes (0.45%) that are present in similar proportions in both large and small airways, suggesting that they may contribute to both large and small airways pathologies in CF. In stark contrast, we recovered only 3 mature tuft cells (0.002%). Instead, we identified rare bipotent progenitor cells that can give rise to both ionocytes and tuft cells, which we termed tuft-ionocyte progenitor cells (TIP cells). Remarkably, the cycling fraction of these TIP cells was comparable to that of basal stem cells. We used scRNA-seq and scATAC-seq to predict transcription factors that mark this novel rare cell progenitor population and define intermediate states during TIP cell lineage transitions en route to the differentiation of mature ionocytes and tuft cells. The default lineage of TIP cell descendants is skewed towards ionocytes, explaining the paucity of mature tuft cells in the human airway. However, Type 2 and Type 17 cytokines, associated with asthma and CF, diverted the lineage of TIP cell descendants in vitro , resulting in the differentiation of mature tuft cells at the expense of ionocytes. Consistent with this model of mature tuft cell differentiation, we identify mature tuft cells in a patient who died from an asthma flare. Overall, our findings suggest that the immune signaling pathways active in asthma and CF may skew the composition of disease-relevant rare cells and illustrate how deep atlases are required for identifying physiologically-relevant scarce cell populations.

16.
Toxics ; 10(8)2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-36006142

RESUMO

In recent years, photocatalysis has been used as an environmentally friendly method for the degradation of organic pigments in water. In this study, Ce3+/Ce4+-doped ZrO2/CuO as a mixed semiconductor oxide was successfully prepared by a one-step hydrothermal method. The Ce3+/Ce4+-doped ZrO2/CuO has shown high degradation efficiency of methylene blue (MB), and the maximum degradation percentage was observed to be 94.5% at 180 min under irradiation visible light. The photocatalytic activity increases significantly by doping Ce3+/Ce4+ in ZrO2/CuO for MB degradation. Ce3+/Ce4+ doping is shown to reduce the (e-/h+) recombination rate and improve the charge transfer, leading to enhanced photocatalytic activity of materials. The materials were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), FTIR, EDS, BET and diffuse reflectance spectroscopy (DRS).

17.
Science ; 376(6592): eabi8175, 2022 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-35482859

RESUMO

Establishing causal relationships between genetic alterations of human cancers and specific phenotypes of malignancy remains a challenge. We sequentially introduced mutations into healthy human melanocytes in up to five genes spanning six commonly disrupted melanoma pathways, forming nine genetically distinct cellular models of melanoma. We connected mutant melanocyte genotypes to malignant cell expression programs in vitro and in vivo, replicative immortality, malignancy, rapid tumor growth, pigmentation, metastasis, and histopathology. Mutations in malignant cells also affected tumor microenvironment composition and cell states. Our melanoma models shared genotype-associated expression programs with patient melanomas, and a deep learning model showed that these models partially recapitulated genotype-associated histopathological features as well. Thus, a progressive series of genome-edited human cancer models can causally connect genotypes carrying multiple mutations to phenotype.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanócitos/metabolismo , Melanoma/patologia , Mutação , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Microambiente Tumoral/genética
18.
Nat Commun ; 13(1): 4398, 2022 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-35906236

RESUMO

Fetal growth restriction (FGR) affects 5-10% of pregnancies, and can have serious consequences for both mother and child. Prevention and treatment are limited because FGR pathogenesis is poorly understood. Genetic studies implicate KIR and HLA genes in FGR, however, linkage disequilibrium, genetic influence from both parents, and challenges with investigating human pregnancies make the risk alleles and their functional effects difficult to map. Here, we demonstrate that the interaction between the maternal KIR2DL1, expressed on uterine natural killer (NK) cells, and the paternally inherited HLA-C*0501, expressed on fetal trophoblast cells, leads to FGR in a humanized mouse model. We show that the KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and modulation of uterine NK cell function. This initial effect cascades to altered transcriptional expression and intercellular communication at the maternal-fetal interface. These findings provide mechanistic insight into specific FGR risk alleles, and provide avenues of prevention and treatment.


Assuntos
Retardo do Crescimento Fetal , Trofoblastos , Animais , Comunicação Celular/genética , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/metabolismo , Feto/metabolismo , Antígenos HLA-C/genética , Antígenos HLA-C/metabolismo , Camundongos , Gravidez , Trofoblastos/metabolismo
19.
Materials (Basel) ; 14(8)2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33921759

RESUMO

In this study, nanocrystalline ZnNdxFe2-xO4 ferrites with x = 0.0, 0.01, 0.03 and 0.05 were fabricated and used as a catalyst for dye removal potential. The effect of Nd3+ ions substitution on the structural, optical and photo-Fenton activity of ZnNdxFe2-xO4 has been investigated. The addition of Nd3+ ions caused a decrease in the grain size of ferrites, the reduction of the optical bandgap energies and thus could be well exploited for the catalytic study. The photocatalytic activity of the ferrite samples was evaluated by the degradation of Rhodamine B (RhB) in the presence of H2O2 under visible light radiation. The results indicated that the ZnNdxFe2-xO4 samples exhibited higher removal efficiencies than the pure ZnFe2O4 ferrites. The highest degradation efficiency was 98.00%, attained after 210 min using the ZnNd0.03Fe1.97O4 sample. The enhanced photocatalytic activity of the ZnFe2O4 doped with Nd3+ is explained due to the efficient separation mechanism of photoinduced electron and holes. The effect of various factors (H2O2 oxidant concentration and catalyst loading) on the degradation of RhB dye was clarified.

20.
Nat Biotechnol ; 38(6): 737-746, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32341560

RESUMO

The scale and capabilities of single-cell RNA-sequencing methods have expanded rapidly in recent years, enabling major discoveries and large-scale cell mapping efforts. However, these methods have not been systematically and comprehensively benchmarked. Here, we directly compare seven methods for single-cell and/or single-nucleus profiling-selecting representative methods based on their usage and our expertise and resources to prepare libraries-including two low-throughput and five high-throughput methods. We tested the methods on three types of samples: cell lines, peripheral blood mononuclear cells and brain tissue, generating 36 libraries in six separate experiments in a single center. To directly compare the methods and avoid processing differences introduced by the existing pipelines, we developed scumi, a flexible computational pipeline that can be used with any single-cell RNA-sequencing method. We evaluated the methods for both basic performance, such as the structure and alignment of reads, sensitivity and extent of multiplets, and for their ability to recover known biological information in the samples.


Assuntos
Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Software , Animais , Encéfalo/citologia , Células Cultivadas , Humanos , Leucócitos Mononucleares/citologia , Camundongos
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