Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 78
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Sci Total Environ ; 721: 137647, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-32197286

RESUMO

This review documents recent advances in terrestrial mercury cycling. Terrestrial mercury (Hg) research has matured in some areas, and is developing rapidly in others. We summarize the state of the science circa 2010 as a starting point, and then present the advances during the last decade in three areas: land use, sulfate deposition, and climate change. The advances are presented in the framework of three Hg "gateways" to the terrestrial environment: inputs from the atmosphere, uptake in food, and runoff with surface water. Among the most notable advances: These and other advances reported here are of value in evaluating the effectiveness of the Minamata Convention on reducing environmental Hg exposure to humans and wildlife.

2.
Hum Mol Genet ; 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32186706

RESUMO

Cobalamin C deficiency (cblC), the most common inborn error of intracellular cobalamin metabolism, is caused by mutations in MMACHC, a gene responsible for the processing and intracellular trafficking of vitamin B12. This recessive disorder is characterized by a failure to metabolize cobalamin into adenosyl- and methylcobalamin, which results in the biochemical perturbations of methylmalonic acidemia, hyperhomocysteinemia, and hypomethioninemia caused by impaired activity of the downstream enzymes, methylmalonyl-CoA mutase and methionine synthase. Cobalamin C deficiency can be accompanied by a wide spectrum of clinical manifestations, including progressive blindness, and in mice, manifests with very early embryonic lethality. Because zebrafish harbor a full complement of cobalamin metabolic enzymes, we used genome editing to study loss of mmachc function and to develop the first viable animal model of cblC deficiency. Mmachc mutants survived the embryonic period but perished in early juvenile life. The mutants displayed metabolic and clinical features of cblC deficiency including methylmalonic acidemia, severe growth retardation, and lethality. Morphologic and metabolic parameters improved when the mutants were raised in water supplemented with small molecules used to treat patients, including hydroxocobalamin, methylcobalamin, methionine, and betaine. Furthermore, mmachc mutants bred to express rod and or cone fluorescent reporters, manifested a retinopathy and thin optic nerves. Expression analysis using whole eye mRNA revealed dysregulation of genes involved in phototransduction and cholesterol metabolism. Zebrafish with mmachc deficiency recapitulate the several of the phenotypic and biochemical features of the human disorder, including ocular pathology, and show a response to established treatments.

3.
Sci Total Environ ; 718: 137306, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32087589

RESUMO

Peatlands are abundant elements of boreal landscapes where inorganic mercury (IHg) can be transformed into bioaccumulating and highly toxic methylmercury (MeHg). We studied fifteen peatlands divided into three age classes (young, intermediate and old) along a geographically constrained chronosequence to determine the role of biogeochemical factors and nutrient availability in controlling the formation of MeHg. In the 10 cm soil layer just below the average annual growing season water table, concentrations of MeHg and %MeHg (of total Hg) were higher in younger, more mesotrophic peatlands than in older, more oligotrophic peatlands. In contrast, total mercury (THg) concentrations were higher in the older peatlands. Partial least squares (PLS) analysis indicates that the net MeHg production was positively correlated to trophic demands of vegetation and an increased availability of potential electron acceptors and donors for Hg methylating microorganisms. An important question for further studies will be to elucidate why there is less THg in the younger peatlands compared to the older peatlands, even though the age of the superficial peat itself is similar for all sites. We hypothesize that ecosystem features which enhance microbial processes involved in Hg methylation also promote Hg reduction that makes previously deposited Hg more available for evasion back to the atmosphere.

4.
Thyroid ; 30(2): 314-328, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31952464

RESUMO

Background: Patients with mutations of the thyroid hormone receptor alpha (THRA) gene show resistance to thyroid hormone alpha (RTHα). No amendable mouse models are currently available to elucidate deleterious effects of TRα1 mutants during early development. Zebrafish with transient suppressed expression by morpholino knockdown and ectopic expression of TRα1 mutants in the embryos have been reported. However, zebrafish with germline transmittable mutations have not been reported. The stable expression of thra mutants from embryos to adulthood facilitated the study of molecular actions of TRα1 mutants during development. Methods: In contrast to human and mice, the thra gene is duplicated in zebrafish, thraa, and thrab. Using CRISPR/Cas9-mediated targeted mutagenesis, we created dominant negative mutations in the two duplicated thra genes. We comprehensively analyzed the molecular and phenotypic characteristics of mutant fish during development. Results: Adult and juvenile homozygous thrab 1-bp ins (m/m) mutants exhibited severe growth retardation, but adult homozygous thraa 8-bp ins (m/m) mutants had very mild growth impairment. Expression of the growth hormone (gh1) and insulin-like growth factor 1 was markedly suppressed in homozygous thrab 1-bp ins (m/m) mutants. Decreased messenger RNA and protein levels of triiodothyronine-regulated keratin genes and inhibited keratinocyte proliferation resulted in hypoplasia of the epidermis in adult and juvenile homozygous thrab 1-bp ins (m/m) mutants, but not homozygous thraa 8-bp ins (m/m) mutants. RNA-seq analysis showed that homozygous thrab 1-bp ins (m/m) mutation had global impact on the functions of the adult pituitary. However, no morphological defects nor any changes in the expression of gh1 and keratin genes were observed in the embryos and early larvae. Thus, mutations of either the thraa or thrab gene did not affect initiation of embryogenesis. But the mutation of the thrab gene, but not the thraa gene, is detrimental in postlarval growth and skin development. Conclusions: The thra duplicated genes are essential to control temporal coordination in postlarval growth and development in a tissue-specific manner. We uncovered novel functions of the duplicated thra genes in zebrafish in development. These mutant zebrafish could be used as a model for further analysis of TRα1 mutant actions and for rapid screening of therapeutics for RTHα.

5.
J Hazard Mater ; 387: 121967, 2020 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-31901845

RESUMO

Peatlands are globally important ecosystems where inorganic mercury is converted to bioaccumulating and highly toxic methylmercury, resulting in high risks of methylmercury exposure in adjacent aquatic ecosystems. Although biological mercury methylation has been known for decades, there is still a lack of knowledge about the organisms involved in mercury methylation and the drivers controlling their methylating capacity. In order to investigate the metabolisms responsible for mercury methylation and methylmercury degradation as well as the controls of both processes, we studied a chronosequence of boreal peatlands covering fundamentally different biogeochemical conditions. Potential mercury methylation rates decreased with peatland age, being up to 53 times higher in the youngest peatland compared to the oldest. Methylation in young mires was driven by sulfate reduction, while methanogenic and syntrophic metabolisms became more important in older systems. Demethylation rates were also highest in young wetlands, with a gradual shift from biotic to abiotic methylmercury degradation along the chronosequence. Our findings reveal how metabolic shifts drive mercury methylation and its ratio to demethylation as peatlands age.

6.
Environ Pollut ; 257: 113543, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31753634

RESUMO

Aquaculture can affect the polyunsaturated fatty acids (PUFA) and mercury (Hg) in fish by altering their diet. Here, planktivorous (silver carp and bighead carp), omnivorous and carnivorous fish with different dietary strategies were selected from two reservoirs, one with on-going aquaculture (WJD) and another without aquaculture (HF) in Southwest China. We compared the total mercury (THg), methylmercury (MeHg) contents and PUFA profiles of fish and their potential diets in these two reservoirs. THg and MeHg contents in omnivorous and carnivorous fish were lower from the WJD Reservoir, which is related to the lower THg and MeHg contents in the artificial fish food. THg and MeHg contents in silver carp from the WJD Reservoir were lower than those from the HF Reservoir, while they were similar in bighead carps from the two reservoirs. The Hg variation in planktivorous fish were inconsistent with that in plankton. THg contents in phyto- and zooplankton from the HF Reservoir were higher than those from the WJD Reservoir, yet their MeHg contents were similar. Artificial fish food which contained higher total PUFA eicosapentaenoic (EPA; 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3), significantly increased the total PUFA and EPA + DHA contents in carnivorous fish, but had less effect on that in omnivorous fish from the WJD Reservoir. Eutrophication caused by aquaculture reduced total PUFA and EPA + DHA contents of plankton in WJD, yet did not reduce those in planktivorous fish. The impacts of aquaculture on Hg and PUFA accumulated in fish were varied among different fish species, and the mechanism needs further exploration.

7.
Sci Total Environ ; 711: 134616, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31812420

RESUMO

Excessive phosphorus (P) inputs from agriculture are well established as a contributor to freshwater eutrophication. Decreasing these inputs is an important step in improving the ecological state of impaired waters. Particulate P (PP) is a significant contributor to diffuse P inputs in agricultural catchments. Identifying the main correlates for PP losses is an important step in reducing these inputs. However, there are few studies of long term temporal and spatial dynamics of PP in agricultural streams. Here, we investigate the relative importance of hydrology, catchment characteristics and geochemistry on PP concentrations and fluxes in agricultural headwaters. We evaluate long-term monitoring data from eleven small (<35 km2) Swedish catchments with at least seven years of measured flow and flow proportional water quality sampling. Using parametric and non-parametric regression together with principal components analysis (PCA), we identify in-stream and catchment variables relevant for predicting PP concentrations, e.g., suspended solids concentrations (SS), soil texture and average catchment soil P content, measured as ammonium lactate/acetic acid extractable P (P-AL). We show that PP is primarily correlated to SS concentrations, which in turn are correlated to average clay content and land use. However, the SS:PP relationships differ between catchments. No correlation between PP concentrations in the stream and soil P content was found. An increasing clay content decreases the slope of the relationship between SS and PP, i.e., in catchments with higher clay content, less PP is transported per unit SS. The PP/SS ratio increased significantly (p < 0.05) over time in four catchments, despite limited changes in SS or PP concentrations. Our study highlights the importance of long time series since the enrichment of P on SS in the streams is only detected when using long term monitoring data.

8.
Dis Model Mech ; 12(12)2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31727854

RESUMO

Mutations in the gene AK2 are responsible for reticular dysgenesis (RD), a rare and severe form of primary immunodeficiency in children. RD patients have a severely shortened life expectancy and without treatment die, generally from sepsis soon after birth. The only available therapeutic option for RD is hematopoietic stem cell transplantation (HSCT). To gain insight into the pathophysiology of RD, we previously created zebrafish models for Ak2 deficiencies. One of the clinical features of RD is hearing loss, but its pathophysiology and causes have not been determined. In adult mammals, sensory hair cells of the inner ear do not regenerate; however, their regeneration has been observed in several non-mammalian vertebrates, including zebrafish. Therefore, we used our RD zebrafish models to determine whether Ak2 deficiency affects sensory organ development and/or hair cell regeneration. Our studies indicated that Ak2 is required for the correct development, survival and regeneration of sensory hair cells. Interestingly, Ak2 deficiency induces the expression of several oxidative stress markers and it triggers an increased level of cell death in the hair cells. Finally, we show that glutathione treatment can partially rescue hair cell development in the sensory organs in our RD models, pointing to the potential use of antioxidants as a therapeutic treatment supplementing HSCT to prevent or ameliorate sensorineural hearing deficits in RD patients.

9.
Hum Mol Genet ; 28(24): 4173-4185, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31691804

RESUMO

DHX15, a DEAH box containing RNA helicase, is a splicing factor required for the last step of splicing. Recent studies identified a recurrent mutational hotspot, R222G, in DHX15 in ∼ 6% of acute myeloid leukemia (AML) patients that carry the fusion protein RUNX1-RUNX1T1 produced by t (8;21) (q22;q22). Studies using yeast mutants showed that substitution of G for the residue equivalent to R222 leads to loss of its helicase function, suggesting that it is a loss-of-function mutation. To elucidate the role of DHX15 during development, we established the first vertebrate knockout model with CRISPR/Cas9 in zebrafish. Our data showed that dhx15 expression is enriched in the brain, eyes, pectoral fin primordia, liver and intestinal bulb during embryonic development. Dhx15 deficiency leads to pleiotropic morphological phenotypes in homozygous mutant embryos starting at 3 days post fertilization (dpf) that result in lethality by 7 dpf, revealing an essential role during embryonic development. RNA-seq analysis suggested important roles of Dhx15 in chromatin and nucleosome assembly and regulation of the Mdm2-p53 pathway. Interestingly, exons corresponding to the alternate transcriptional start sites for tp53 and mdm2 were preferentially expressed in the mutant embryos, leading to significant upregulation of their alternate isoforms, Δ113p53 (orthologous to Δ133p53 isoform in human) and mdm2-P2 (isoform using distal promoter P2), respectively. We speculate that these alterations in the Mdm2-p53 pathway contribute to the development of AML in patients with t(8;21) and somatically mutated DHX15.

10.
Cell Syst ; 9(2): 187-206.e16, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31445892

RESUMO

Tumor cells encounter a myriad of physical cues upon arrest and extravasation in capillary beds. Here, we examined the role of physical factors in non-random organ colonization using a zebrafish xenograft model. We observed a two-step process by which mammalian mammary tumor cells showed non-random organ colonization. Initial homing was driven by vessel architecture, where greater numbers of cells became arrested in the topographically disordered blood vessels of the caudal vascular plexus (CVP) than in the linear vessels in the brain. Following arrest, bone-marrow- and brain-tropic clones exhibited organ-specific patterns of extravasation. Extravasation was mediated by ß1 integrin, where knockdown of ß1 integrin reduced extravasation in the CVP but did not affect extravasation of a brain-tropic clone in the brain. In contrast, silencing myosin 1B redirected early colonization from the brain to the CVP. Our results suggest that organ selectivity is driven by both vessel topography and cell-type-dependent extravasation.

11.
Sci Total Environ ; 669: 821-832, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30897439

RESUMO

Dietary uptake is a key step in conveying both toxic mercury (Hg; particularly as highly bioavailable methylmercury, MeHg) and essential dietary biochemicals, such as polyunsaturated fatty acids (PUFA), across trophic levels within aquatic food webs. Using stable isotopes and fatty acids we evaluated the role of food sources in size-fractioned plankton and littoral macroinvertebrates for the bioaccumulation of total Hg and MeHg in six oligotrophic and one mesotrophic Swedish lakes with differing concentrations of dissolved organic carbon (DOC). We found that the consumption of both algal and terrestrial diets (assessed by PUFA and long-chain saturated fatty acids, respectively) predicted >66% of the Hg concentration variability in meso- (100-500 µm) and macrozooplankton (>500 µm) in oligotrophic lakes. In the mesotrophic lake, total Hg bioaccumulation in higher trophic level biota, carnivorous macroinvertebrates was also significantly related to terrestrial diet sources (R2 = 0.65, p < 0.01). However, lake pH and DOC correlated to total Hg bioaccumulation and bioconcentration across all lakes, suggesting the consumption of different diet sources is mediated by the influence of lake characteristics. This field study reveals that using dietary biomarkers (stable isotopes and fatty acids) together with the physico-chemical lake parameters pH and nutrients together improve our ability to predict Hg bioaccumulation in aquatic food webs. Fatty acids used as dietary biomarkers provide correlative evidence of specific diet source retention in consumers and their effect on Hg bioaccumulation, while pH and nutrients are the underlying physico-chemical lake parameters controlling differences in Hg bioaccumulation between lakes.


Assuntos
Monitoramento Ambiental , Invertebrados/metabolismo , Mercúrio/metabolismo , Poluentes Químicos da Água/metabolismo , Zooplâncton/metabolismo , Animais , Carbono , Exposição Dietética/análise , Exposição Dietética/estatística & dados numéricos , Cadeia Alimentar , Lagos , Compostos de Metilmercúrio/metabolismo
12.
Sci Rep ; 9(1): 1759, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30741975

RESUMO

The inflammatory response, modulated both by tissue resident macrophages and recruited monocytes from peripheral blood, plays a critical role in human diseases such as cancer and neurodegenerative disorders. Here, we sought a model to interrogate human immune behavior in vivo. We determined that primary human monocytes and macrophages survive in zebrafish for up to two weeks. Flow cytometry revealed that human monocytes cultured at the physiological temperature of the zebrafish survive and differentiate comparable to cohorts cultured at human physiological temperature. Moreover, key genes that encode for proteins that play a role in tissue remodeling were also expressed. Human cells migrated within multiple tissues at speeds comparable to zebrafish macrophages. Analysis of gene expression of in vivo educated human macrophages confirmed expression of activated macrophage phenotypes. Here, human cells adopted phenotypes relevant to cancer progression, suggesting that we can define the real time immune modulation of human tumor cells during the establishment of a metastatic lesion in zebrafish.

13.
Sci Rep ; 9(1): 518, 2019 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-30679728

RESUMO

The formation of the potent neurotoxic methylmercury (MeHg) is a microbially mediated process that has raised much concern because MeHg poses threats to wildlife and human health. Since boreal forest soils can be a source of MeHg in aquatic networks, it is crucial to understand the biogeochemical processes involved in the formation of this pollutant. High-throughput sequencing of 16S rRNA and the mercury methyltransferase, hgcA, combined with geochemical characterisation of soils, were used to determine the microbial populations contributing to MeHg formation in forest soils across Sweden. The hgcA sequences obtained were distributed among diverse clades, including Proteobacteria, Firmicutes, and Methanomicrobia, with Deltaproteobacteria, particularly Geobacteraceae, dominating the libraries across all soils examined. Our results also suggest that MeHg formation is also linked to the composition of non-mercury methylating bacterial communities, likely providing growth substrate (e.g. acetate) for the hgcA-carrying microorganisms responsible for the actual methylation process. While previous research focused on mercury methylating microbial communities of wetlands, this study provides some first insights into the diversity of mercury methylating microorganisms in boreal forest soils.

14.
Sci Total Environ ; 646: 357-367, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30055496

RESUMO

Methylmercury (MeHg) transfer from water into the base of the food web (bioconcentration) and subsequent biomagnification in the aquatic food web leads to most of the MeHg in fish. But how important is bioconcentration compared to biomagnification in predicting MeHg in fish? To answer this question we reviewed articles in which MeHg concentrations in water, plankton (seston and/or zooplankton), as well as fish (planktivorous and small omnivorous fish) were reported. This yielded 32 journal articles with data from 59 aquatic ecosystems at 22 sites around the world. Although there are many case studies of particular aquatic habitats and specific geographic areas that have examined MeHg bioconcentration and biomagnification, we performed a meta-analysis of such studies. Aqueous MeHg was not a significant predictor of MeHg in fish, but MeHg in seston i.e., the base of the aquatic food web, predicted 63% of the variability in fish MeHg. The MeHg bioconcentration factors (i.e., transfer of MeHg from water to seston; BCFw-s) varied from 3 to 7 orders of magnitude across sites and correlated significantly with MeHg in fish. The MeHg biomagnification factors from zooplankton to fish varied much less (logBMFz-f, 0.75 ±â€¯0.31), and did not significantly correlate with fish MeHg, suggesting that zooplanktivory is not as important as bioconcentration in the biomagnification of fish MeHg across the range of ecosystems represented in our meta-analysis. Partial least square (PLS) and linear regression analyses identified several environmental factors associated with increased BCF, including low dissolved organic carbon, low pH, and oligotrophy. Our study reveals the widespread importance of MeHg bioconcentration into the base of the aquatic food web for MeHg at higher trophic levels in aquatic food webs, as well as the major influences on the variability in this bioconcentration.


Assuntos
Monitoramento Ambiental , Cadeia Alimentar , Compostos de Metilmercúrio/metabolismo , Poluentes Químicos da Água/metabolismo , Animais , Peixes/metabolismo , Mercúrio , Zooplâncton/metabolismo
15.
PLoS Genet ; 14(12): e1007821, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30540754

RESUMO

Fanconi Anemia (FA) is a genomic instability syndrome resulting in aplastic anemia, developmental abnormalities, and predisposition to hematological and other solid organ malignancies. Mutations in genes that encode proteins of the FA pathway fail to orchestrate the repair of DNA damage caused by DNA interstrand crosslinks. Zebrafish harbor homologs for nearly all known FA genes. We used multiplexed CRISPR/Cas9-mediated mutagenesis to generate loss-of-function mutants for 17 FA genes: fanca, fancb, fancc, fancd1/brca2, fancd2, fance, fancf, fancg, fanci, fancj/brip1, fancl, fancm, fancn/palb2, fanco/rad51c, fancp/slx4, fancq/ercc4, fanct/ube2t, and two genes encoding FA-associated proteins: faap100 and faap24. We selected two indel mutations predicted to cause premature truncations for all but two of the genes, and a total of 36 mutant lines were generated for 19 genes. Generating two independent mutant lines for each gene was important to validate their phenotypic consequences. RT-PCR from homozygous mutant fish confirmed the presence of transcripts with indels in all genes. Interestingly, 4 of the indel mutations led to aberrant splicing, which may produce a different protein than predicted from the genomic sequence. Analysis of RNA is thus critical in proper evaluation of the consequences of the mutations introduced in zebrafish genome. We used fluorescent reporter assay, and western blots to confirm loss-of-function for several mutants. Additionally, we developed a DEB treatment assay by evaluating morphological changes in embryos and confirmed that homozygous mutants from all the FA genes that could be tested (11/17), displayed hypersensitivity and thus were indeed null alleles. Our multiplexing strategy helped us to evaluate 11 multiple gene knockout combinations without additional breeding. Homozygous zebrafish for all 19 single and 11 multi-gene knockouts were adult viable, indicating FA genes in zebrafish are generally not essential for early development. None of the mutant fish displayed gross developmental abnormalities except for fancp-/- fish, which were significantly smaller in length than their wildtype clutch mates. Complete female-to-male sex reversal was observed in knockouts for 12/17 FA genes, while partial sex reversal was seen for the other five gene knockouts. All adult females were fertile, and among the adult males, all were fertile except for the fancd1 mutants and one of the fancj mutants. We report here generation and characterization of zebrafish knockout mutants for 17 FA disease-causing genes, providing an integral resource for understanding the pathophysiology associated with the disrupted FA pathway.


Assuntos
Anemia de Fanconi/genética , Peixe-Zebra/genética , Animais , Sistemas CRISPR-Cas , Dano ao DNA , Anemia de Fanconi/fisiopatologia , Feminino , Fertilidade/genética , Fertilidade/fisiologia , Mutação da Fase de Leitura , Técnicas de Inativação de Genes , Humanos , Masculino , Fenótipo , Processamento de RNA/genética , Processos de Determinação Sexual/genética , Processos de Determinação Sexual/fisiologia , Desenvolvimento Sexual/genética , Desenvolvimento Sexual/fisiologia , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/fisiologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/fisiologia
16.
IEEE Trans Biomed Circuits Syst ; 12(5): 1046-1055, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30010595

RESUMO

Direct sensing in liquids using CMOS-integrated optical and electrical sensors is attractive for lab-on-chip applications, where close physical proximity between sample and sensor can obviate optical lenses, enhance electrical sensitivity, and decrease noise due to parasitics. However, controlled delivery of fluid samples to the chip surface presents an ongoing challenge for lab-on-CMOS development, where traditional wire-bond packaging prevents integration of planar microfluidics. In this paper, we present a method for scalable heterogeneous integration of microfluidic channels and silicon-integrated circuit substrates using a commercial fan-out wafer-level packaging approach. The planar surface supports multiple approaches for fluidic integration; we present both a stacked laser-cut fluidic assembly and the fabrication of monolithic SU-8 microchannels over the IC surface. As a proof-of-principle, both electrical and fluidic routing are provided to a custom 0.18-m CMOS optical sensor IC, and optical transmission and fluorescence measurement experiments are demonstrated.


Assuntos
Técnicas Biossensoriais/métodos , Transistores Eletrônicos , Técnicas Biossensoriais/instrumentação , Corantes/química , Dispositivos Lab-On-A-Chip , Microfluídica/métodos , Pontos Quânticos/química
17.
Sci Total Environ ; 622-623: 1353-1362, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29890601

RESUMO

A number of studies have evaluated the effects of forest harvest on mercury (Hg) concentrations and exports in surface waters, but few studies have tested the effect from forest harvest on the change in fish Hg concentrations over the course of several years after harvest. To address this question, mercury (Hg) concentrations in perch (Perca fluviatilis) muscle tissue from five lakes were analyzed for two years before (2010-2011) and three years after (2013-2015) forest harvest conducted in 2012. Fish Hg concentrations in the clear-cut catchments (n=1373 fish specimens) were related to temporal changes of fish Hg in reference lakes (n=1099 fish specimen) from 19 lakes in the Swedish National Environmental Monitoring Programme. Small (length<100mm) and large perch (length≥100mm) were analyzed separately, due to changing feeding habitats of fish over growing size. There was considerable year-to-year and lake-to-lake variation in fish Hg concentrations (-14%-121%) after forest harvest in the clearcut lakes, according to our first statistical model that count for fish Hg changes. While the effect ascribed to forest harvest varied between years, after three years (in 2015), a significant increase of 26% (p<0.0001) in Hg concentrations of large fish was identified in our second statistical model that pooled all 5 clearcut lakes. The large fish Hg concentrations in the 19 reference lakes also varied, and in 2015 had decreased by 7% (p=0.03) relative to the concentrations in 2010-2011. The majority of the annual changes in fish Hg concentrations in the clearcut lakes after harvest were in the lower range of earlier predictions for high-latitude lakes extrapolated primarily from the effects of forest harvest operations on Hg concentrations in water. Since the risk of forest harvest impacts on Hg extends to fish and not just surface water concentrations, there is even more reason to consider Hg effects in forestry planning, alongside other ecosystem effects.


Assuntos
Monitoramento Ambiental , Mercúrio/metabolismo , Percas/metabolismo , Poluentes Químicos da Água/metabolismo , Animais , Ecossistema , Lagos/química , Músculos/metabolismo , Suécia , Poluentes Químicos da Água/análise
18.
NPJ Regen Med ; 3: 11, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29872546

RESUMO

Regenerative medicine holds great promise for both degenerative diseases and traumatic tissue injury which represent significant challenges to the health care system. Hearing loss, which affects hundreds of millions of people worldwide, is caused primarily by a permanent loss of the mechanosensory receptors of the inner ear known as hair cells. This failure to regenerate hair cells after loss is limited to mammals, while all other non-mammalian vertebrates tested were able to completely regenerate these mechanosensory receptors after injury. To understand the mechanism of hair cell regeneration and its association with regeneration of other tissues, we performed a guided mutagenesis screen using zebrafish lateral line hair cells as a screening platform to identify genes that are essential for hair cell regeneration, and further investigated how genes essential for hair cell regeneration were involved in the regeneration of other tissues. We created genetic mutations either by retroviral insertion or CRISPR/Cas9 approaches, and developed a high-throughput screening pipeline for analyzing hair cell development and regeneration. We screened 254 gene mutations and identified 7 genes specifically affecting hair cell regeneration. These hair cell regeneration genes fell into distinct and somewhat surprising functional categories. By examining the regeneration of caudal fin and liver, we found these hair cell regeneration genes often also affected other types of tissue regeneration. Therefore, our results demonstrate guided screening is an effective approach to discover regeneration candidates, and hair cell regeneration is associated with other tissue regeneration.

19.
J Chem Phys ; 148(10): 102303, 2018 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-29544287

RESUMO

Free energy calculations are a crucial part of understanding chemical systems but are often computationally expensive for all but the simplest of systems. Various enhanced sampling techniques have been developed to improve the efficiency of these calculations in numerical simulations. However, the majority of these approaches have been applied using classical molecular dynamics. There are many situations where nuclear quantum effects impact the system of interest and a classical description fails to capture these details. In this work, path integral molecular dynamics has been used in conjunction with umbrella sampling, and it has been observed that correct results are only obtained when the umbrella sampling potential is applied to a single path integral bead post quantization. This method has been validated against a Lennard-Jones benchmark system before being applied to the more complicated water dimer system over a broad range of temperatures. Free energy profiles are obtained, and these are utilized in the calculation of the second virial coefficient as well as the change in free energy from the separated water monomers to the dimer. Comparisons to experimental and ground state calculation values from the literature are made for the second virial coefficient at higher temperature and the dissociation energy of the dimer in the ground state.

20.
Ann Rheum Dis ; 77(4): 612-619, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29358286

RESUMO

OBJECTIVES: To characterise the clinical features, immune manifestations and molecular mechanisms in a recently described autoinflammatory disease caused by mutations in TRNT1, a tRNA processing enzyme, and to explore the use of cytokine inhibitors in suppressing the inflammatory phenotype. METHODS: We studied nine patients with biallelic mutations in TRNT1 and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). Genetic studies included whole exome sequencing (WES) and candidate gene screening. Patients' primary cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM). RESULTS: We identified eight mutations in these nine patients, three of which have not been previously associated with SIFD. Three patients died in early childhood. Inflammatory cytokines, mainly interleukin (IL)-6, interferon gamma (IFN-γ) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1ß were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients' fibroblasts showed significant deficiency of mature cytosolic tRNAs. EM of bone marrow and skin biopsy samples revealed striking abnormalities across all cell types and a mix of necrotic and normal-appearing cells. By immunoprecipitation, we found evidence for dysregulation in protein clearance pathways. In 4/4 patients, treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth. CONCLUSIONS: Mutations of TRNT1 lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular diagnosis in early life will be crucial for initiating anti-TNF therapy, which might prevent some of the severe disease consequences.


Assuntos
Anemia Sideroblástica/genética , Anti-Inflamatórios/uso terapêutico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Síndromes de Imunodeficiência/genética , Mutação , Nucleotidiltransferases/genética , RNA de Transferência/genética , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Anemia Sideroblástica/sangue , Criança , Pré-Escolar , Citocinas/sangue , Citocinas/genética , Deficiências do Desenvolvimento/genética , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Humanos , Imunofenotipagem , Masculino , Linhagem , Fenótipo , Fator de Necrose Tumoral alfa/análise , Sequenciamento Completo do Exoma
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA