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1.
Nature ; 615(7953): 705-711, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36922598

RESUMO

Artificial sweeteners are used as calorie-free sugar substitutes in many food products and their consumption has increased substantially over the past years1. Although generally regarded as safe, some concerns have been raised about the long-term safety of the consumption of certain sweeteners2-5. In this study, we show that the intake of high doses of sucralose in mice results in immunomodulatory effects by limiting T cell proliferation and T cell differentiation. Mechanistically, sucralose affects the membrane order of T cells, accompanied by a reduced efficiency of T cell receptor signalling and intracellular calcium mobilization. Mice given sucralose show decreased CD8+ T cell antigen-specific responses in subcutaneous cancer models and bacterial infection models, and reduced T cell function in models of T cell-mediated autoimmunity. Overall, these findings suggest that a high intake of sucralose can dampen T cell-mediated responses, an effect that could be used in therapy to mitigate T cell-dependent autoimmune disorders.


Assuntos
Sacarose , Edulcorantes , Linfócitos T , Animais , Camundongos , Sacarose/análogos & derivados , Edulcorantes/administração & dosagem , Edulcorantes/efeitos adversos , Edulcorantes/farmacologia , Edulcorantes/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/patologia , Inocuidade dos Alimentos , Sinalização do Cálcio/efeitos dos fármacos , Receptores de Antígenos de Linfócitos T/efeitos dos fármacos , Receptores de Antígenos de Linfócitos T/imunologia , Infecções Bacterianas/imunologia , Neoplasias/imunologia , Autoimunidade/efeitos dos fármacos , Autoimunidade/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia
2.
Angew Chem Int Ed Engl ; 63(21): e202401987, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38526053

RESUMO

The in-depth understanding of the composition-property-performance relationship of solid electrolyte interphase (SEI) is the basis of developing a reliable SEI to stablize the Zn anode-electrolyte interface, but it remains unclear in rechargeable aqueous zinc ion batteries. Herein, a well-designed electrolyte based on 2 M Zn(CF3SO3)2-0.2 M acrylamide-0.2 M ZnSO4 is proposed. A robust polymer (polyacrylamide)-inorganic (Zn4SO4(OH)6.xH2O) hybrid SEI is in situ constructed on Zn anodes through controllable polymerization of acrylamide and coprecipitation of SO4 2- with Zn2+ and OH-. For the first time, the underlying SEI composition-property-performance relationship is systematically investigated and correlated. The results showed that the polymer-inorganic hybrid SEI, which integrates the high modulus of the inorganic component with the high toughness of the polymer ingredient, can realize high reversibility and long-term interfacial stability, even under ultrahigh areal current density and capacity (30 mA cm-2~30 mAh cm-2). The resultant Zn||NH4V4O10 cell also exhibits excellent cycling stability. This work will provide a guidance for the rational design of SEI layers in rechargeable aqueous zinc ion batteries.

3.
Anal Chem ; 95(49): 18287-18294, 2023 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-38044628

RESUMO

Bacterial biofilms are structured communities consisting of cells enmeshed in a self-generated extracellular matrix usually attached to a surface. They contain diverse classes of molecules including polysaccharides, lipids, proteins, nucleic acids, and diverse small organic molecules (primary and secondary metabolites) which are organized to optimize survival and facilitate dispersal to new colonization sites. In situ characterization of the chemical composition and structure of bacterial biofilms is necessary to fully understand their development on surfaces relevant to biofouling in health, industry, and the environment. Biofilm development has been extensively studied using confocal microscopy using targeted fluorescent labels providing important insights into the architecture of biofilms. Recently, cryopreparation has been used to undertake targeted in situ chemical characterization using Orbitrap secondary ion mass spectrometry (OrbiSIMS), providing a label-free method for imaging biofilms in their native state. Although the high mass resolution of OrbiSIMS enables more confident peak assignments, it is still very challenging to assign most of the peaks in the spectra due to complexity of SIMS spectra and lack of automatic peak assignment methods. Here, we analyze the same OrbiSIMS depth profile data generated from the frozen-hydrated biofilm, but employ a new untargeted chemical filtering process utilizing mass spectral databases to assign secondary ions to decipher the large number of fragments present in the SIMS spectra. To move towards comprehensive analysis of different chemistries in the sample, we apply a molecular formula prediction approach which putatively assigns 81% of peaks in the 3D OrbiSIMS depth profile analysis. This enables us to catalog over 1000 lipids and their fragments, 3500 protein fragments, 71 quorum sensing-related molecules (2-alkyl-4-quinolones and N-acylhomoserine lactones), 150 polysaccharide fragments, and glycolipids simultaneously from one data set and map these separated molecular classes spatially through a Pseudomonas aeruginosa biofilm. Assignment of different chemistries in this sample facilitates identification of differences between biofilms grown on biofilm-promoting and biofilm-resistant polymers.


Assuntos
Biofilmes , Pseudomonas aeruginosa , Pseudomonas aeruginosa/química , Percepção de Quorum , Espectrometria de Massa de Íon Secundário/métodos , Glicolipídeos
4.
Anal Chem ; 95(40): 15078-15085, 2023 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-37715701

RESUMO

Quantitative analysis of binary mixtures of tris(2-phenylpyridinato)iridium(III) (Ir(ppy)3) and tris(8-hydroxyquinolinato)aluminum (Alq3) by using an artificial neural network (ANN) system to mass spectra was attempted based on the results of a VAMAS (Versailles Project on Advanced Materials and Standards) interlaboratory study (TW2 A31) to evaluate matrix-effect correction and to investigate interface determination. Monolayers of binary mixtures having different Ir(ppy)3 ratios (0, 0.25, 0.50, 0.75, and 1.00), and the multilayers containing these mixtures and pure samples were measured using time-of-flight secondary ion mass spectrometry (ToF-SIMS) with different primary ion beams, OrbiSIMS (SIMS with both Orbitrap and ToF mass spectrometers), laser desorption ionization (LDI), desorption/ionization induced by neutral clusters (DINeC), and X-ray photoelectron spectroscopy (XPS). The mass spectra were analyzed using a simple ANN with one hidden layer. The Ir(ppy)3 ratios of the unknown samples and the interfaces of the multilayers were predicted using the simple ANN system, even though the mass spectra of binary mixtures exhibited matrix effects. The Ir(ppy)3 ratios at the interfaces indicated by the simple ANN were consistent with the XPS results and the ToF-SIMS depth profiles. The simple ANN system not only provided quantitative information on unknown samples, but also indicated important mass peaks related to each molecule in the samples without a priori information. The important mass peaks indicated by the simple ANN depended on the ionization process. The simple ANN results of the spectra sets obtained by a softer ionization method, such as LDI and DINeC, suggested large ions such as trimers. From the first step of the investigation to build an ANN model for evaluating mixture samples influenced by matrix effects, it was indicated that the simple ANN method is useful for obtaining candidate mass peaks for identification and for assuming mixture conditions that are helpful for further analysis.

5.
BMC Psychiatry ; 23(1): 89, 2023 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-36747152

RESUMO

BACKGROUND: There is strong evidence for the co-occurrence of mental health conditions and alcohol problems, yet physical health outcomes among this group are not well characterised. This study aimed to identify clusters of physical health conditions and their associations with mental health and problematic alcohol use in England's general population. METHODS: Cross-sectional analysis of the 2014 Adult Psychiatric Morbidity Survey (N = 7546) was conducted. The survey used standardised measures of problematic alcohol use and mental health conditions, including the Alcohol Use Disorders Identification Test (AUDIT) and the Clinical Interview Schedule-Revised. Participants self-reported any lifetime physical health conditions. Latent class analysis considered 12 common physical illnesses to identify clusters of multimorbidity. Multinomial logistic regression (adjusting for age, gender, ethnicity, education, and occupational grade) was used to explore associations between mental health, hazardous drinking (AUDIT 8 +), and co-occurring physical illnesses. RESULTS: Five clusters were identified with statistically distinct and clinically meaningful disease patterns: 'Physically Healthy' (76.62%), 'Emerging Multimorbidity' (3.12%), 'Hypertension & Arthritis' (14.28%), 'Digestive & Bowel Problems'' (3.17%), and 'Complex Multimorbidity' (2.8%). Having a mental health problem was associated with increased odds of 'Digestive & Bowel Problems' (adjusted multinomial odds ratio (AMOR) = 1.58; 95% CI [1.15-2.17]) and 'Complex Multimorbidity' (AMOR = 2.02; 95% CI [1.49-2.74]). Individuals with co-occurring mental health conditions and problematic alcohol use also had higher odds of 'Digestive & Bowel Problems' (AMOR = 2.64; 95% CI [1.68-4.15]) and 'Complex Multimorbidity' (AMOR = 2.62; 95% CI [1.61-4.23]). CONCLUSIONS: Individuals with a mental health condition concurrent with problematic alcohol use experience a greater burden of physical illnesses, highlighting the need for timely treatment which is likely to include better integration of alcohol and mental health services.


Assuntos
Alcoolismo , Saúde Mental , Adulto , Humanos , Estudos Transversais , Alcoolismo/epidemiologia , Análise por Conglomerados
6.
Lancet ; 397(10286): 1770-1780, 2021 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-33714360

RESUMO

This Review, in addressing the unacceptably high mortality of patients with liver disease admitted to acute hospitals, reinforces the need for integrated clinical services. The masterplan described is based on regional, geographically sited liver centres, each linked to four to six surrounding district general hospitals-a pattern of care similar to that successfully introduced for stroke services. The plan includes the establishment of a lead and deputy lead clinician in each acute hospital, preferably a hepatologist or gastroenterologist with a special interest in liver disease, who will have prime responsibility for organising the care of admitted patients with liver disease on a 24/7 basis. Essential for the plan is greater access to intensive care units and high-dependency units, in line with the reconfiguration of emergency care due to the COVID-19 pandemic. This Review strongly recommends full implementation of alcohol care teams in hospitals and improved working links with acute medical services. We also endorse recommendations from paediatric liver services to improve overall survival figures by diagnosing biliary atresia earlier based on stool colour charts and better caring for patients with impaired cognitive ability and developmental mental health problems. Pilot studies of earlier diagnosis have shown encouraging progress, with 5-6% of previously undiagnosed cases of severe fibrosis or cirrhosis identified through use of a portable FibroScan in primary care. Similar approaches to the detection of early asymptomatic disease are described in accounts from the devolved nations, and the potential of digital technology in improving the value of clinical consultation and screening programmes in primary care is highlighted. The striking contribution of comorbidities, particularly obesity and diabetes (with excess alcohol consumption known to be a major factor in obesity), to mortality in COVID-19 reinforces the need for fiscal and other long delayed regulatory measures to reduce the prevalence of obesity. These measures include the food sugar levy and the introduction of the minimum unit price policy to reduce alcohol consumption. Improving public health, this Review emphasises, will not only mitigate the severity of further waves of COVID-19, but is crucial to reducing the unacceptable burden from liver disease in the UK.


Assuntos
Hospitalização , Hepatopatias/prevenção & controle , Diagnóstico Precoce , Humanos , Hepatopatias/diagnóstico , Reino Unido
7.
Anal Chem ; 94(28): 10035-10044, 2022 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-35786855

RESUMO

In this study, we examine the suitability of desorption electro-flow focusing ionization (DEFFI) for mass spectrometry imaging (MSI) of biological tissue. We also compare the performance of desorption electrospray ionization (DESI) with and without the flow focusing setup. The main potential advantages of applying the flow focusing mechanism in DESI is its rotationally symmetric electrospray jet, higher intensity, more controllable parameters, and better portability due to the robustness of the sprayer. The parameters for DEFFI have therefore been thoroughly optimized, primarily for spatial resolution but also for intensity. Once the parameters have been optimized, DEFFI produces similar images to the existing DESI. MS images for mouse brain samples, acquired at a nominal pixel size of 50 µm, are comparable for both DESI setups, albeit the new sprayer design yields better sensitivity. Furthermore, the two methods are compared with regard to spectral intensity as well as the area of the desorbed crater on rhodamine-coated slides. Overall, the implementation of a flow focusing mechanism in DESI is shown to be highly suitable for imaging biological tissue and has potential to overcome some of the shortcomings experienced with the current geometrical design of DESI.


Assuntos
Diagnóstico por Imagem , Espectrometria de Massas , Espectrometria de Massas por Ionização por Electrospray , Animais , Encéfalo/diagnóstico por imagem , Camundongos , Espectrometria de Massas por Ionização por Electrospray/métodos
8.
Metabolomics ; 18(10): 77, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36181583

RESUMO

Single cell metabolomics is an emerging and rapidly developing field that complements developments in single cell analysis by genomics and proteomics. Major goals include mapping and quantifying the metabolome in sufficient detail to provide useful information about cellular function in highly heterogeneous systems such as tissue, ultimately with spatial resolution at the individual cell level. The chemical diversity and dynamic range of metabolites poses particular challenges for detection, identification and quantification. In this review we discuss both significant technical issues of measurement and interpretation, and progress toward addressing them, with recent examples from diverse biological systems. We provide a framework for further directions aimed at improving workflow and robustness so that such analyses may become commonly applied, especially in combination with metabolic imaging and single cell transcriptomics and proteomics.


Assuntos
Metaboloma , Metabolômica , Metabolômica/métodos , Proteômica , Fluxo de Trabalho
9.
Nature ; 540(7634): 574-578, 2016 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-27974806

RESUMO

The pressing global issue of food insecurity due to population growth, diminishing land and variable climate can only be addressed in agriculture by improving both maximum crop yield potential and resilience. Genetic modification is one potential solution, but has yet to achieve worldwide acceptance, particularly for crops such as wheat. Trehalose-6-phosphate (T6P), a central sugar signal in plants, regulates sucrose use and allocation, underpinning crop growth and development. Here we show that application of a chemical intervention strategy directly modulates T6P levels in planta. Plant-permeable analogues of T6P were designed and constructed based on a 'signalling-precursor' concept for permeability, ready uptake and sunlight-triggered release of T6P in planta. We show that chemical intervention in a potent sugar signal increases grain yield, whereas application to vegetative tissue improves recovery and resurrection from drought. This technology offers a means to combine increases in yield with crop stress resilience. Given the generality of the T6P pathway in plants and other small-molecule signals in biology, these studies suggest that suitable synthetic exogenous small-molecule signal precursors can be used to directly enhance plant performance and perhaps other organism function.

10.
Lancet ; 395(10219): 226-239, 2020 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-31791690

RESUMO

This final report of the Lancet Commission into liver disease in the UK stresses the continuing increase in burden of liver disease from excess alcohol consumption and obesity, with high levels of hospital admissions which are worsening in deprived areas. Only with comprehensive food and alcohol strategies based on fiscal and regulatory measures (including a minimum unit price for alcohol, the alcohol duty escalator, and an extension of the sugar levy on food content) can the disease burden be curtailed. Following introduction of minimum unit pricing in Scotland, alcohol sales fell by 3%, with the greatest effect on heavy drinkers of low-cost alcohol products. We also discuss the major contribution of obesity and alcohol to the ten most common cancers as well as measures outlined by the departing Chief Medical Officer to combat rising levels of obesity-the highest of any country in the west. Mortality of severely ill patients with liver disease in district general hospitals is unacceptably high, indicating the need to develop a masterplan for improving hospital care. We propose a plan based around specialist hospital centres that are linked to district general hospitals by operational delivery networks. This plan has received strong backing from the British Association for Study of the Liver and British Society of Gastroenterology, but is held up at NHS England. The value of so-called day-case care bundles to reduce high hospital readmission rates with greater care in the community is described, along with examples of locally derived schemes for the early detection of disease and, in particular, schemes to allow general practitioners to refer patients directly for elastography assessment. New funding arrangements for general practitioners will be required if these proposals are to be taken up more widely around the country. Understanding of the harm to health from lifestyle causes among the general population is low, with a poor knowledge of alcohol consumption and dietary guidelines. The Lancet Commission has serious doubts about whether the initiatives described in the Prevention Green Paper, with the onus placed on the individual based on the use of information technology and the latest in behavioural science, will be effective. We call for greater coordination between official and non-official bodies that have highlighted the unacceptable disease burden from liver disease in England in order to present a single, strong voice to the higher echelons of government.


Assuntos
Alcoolismo/epidemiologia , Hepatopatias/epidemiologia , Hepatopatias/prevenção & controle , Obesidade/epidemiologia , Bebidas Alcoólicas/economia , Alcoolismo/complicações , Alcoolismo/terapia , Comércio , Redes Comunitárias/organização & administração , Comorbidade , Efeitos Psicossociais da Doença , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Legislação sobre Alimentos , Hepatopatias/diagnóstico , Hepatopatias/etiologia , Transplante de Fígado/estatística & dados numéricos , Obesidade/complicações , Pacotes de Assistência ao Paciente , Escócia , Reino Unido/epidemiologia
11.
Anal Chem ; 93(7): 3436-3444, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33571411

RESUMO

We introduce a technique for the directed transfer of molecules from an adjacent reservoir onto a sample surface inside the vacuum chamber of a ToF-SIMS instrument using gas cluster ion beam (GCIB) sputtering. An example application for in situ matrix-enhanced secondary ion mass spectrometry (ME SIMS) is provided. This protocol has attractive features since most modern SIMS instruments are equipped with a GCIB gun. No solvents are required that would delocalize analytes at the surface, and the transfer of matrix molecules can be interlaced with SIMS depth profiling and 3D imaging sputtering and analysis cycles, which is not possible with conventional ME SIMS strategies. The amount of molecular deposition can be finely tuned, which is important for such a surface sensitive technique as SIMS. To demonstrate the concept, we used 2,5-DHB as a matrix for the enhancement of three drug molecules embedded in a tissue homogenate. By automatic operation of sputter deposition and erosion (cleanup) cycles, depth profiling could be achieved with ME SIMS with good repeatability (<4% RSD). Furthermore, we explored several different matrix compounds, including α-CHCA and aqueous solutions of Brønsted acids (formic acid) and 3-nitrobenzonitrile, a volatile compound known to spontaneously produce ions. The latter two matrix compounds were applied at cryogenic measurement conditions, which extend the range of matrices applicable for ME SIMS. Enhancement ratios range from 2 to 13, depending on the analytes and matrix. The method works in principle, but enhancement ratios for the drug molecules are rather limited at this point. Further study and optimization is needed, and the technique introduced here provides a tool to perform systematic studies of matrix compounds and experimental conditions for their potential for signal enhancement in ME SIMS.

12.
Anal Chem ; 93(9): 4191-4197, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33635050

RESUMO

We report the results of a VAMAS (Versailles Project on Advanced Materials and Standards) interlaboratory study on the identification of peptide sample TOF-SIMS spectra by machine learning. More than 1000 time-of-flight secondary ion mass spectrometry (TOF-SIMS) spectra of six peptide model samples (one of them was a test sample) were collected using 27 TOF-SIMS instruments from 25 institutes of six countries, the U. S., the U. K., Germany, China, South Korea, and Japan. Because peptides have systematic and simple chemical structures, they were selected as model samples. The intensity of peaks in every TOF-SIMS spectrum was extracted using the same peak list and normalized to the total ion count. The spectra of the test peptide sample were predicted by Random Forest with 20 amino acid labels. The accuracy of the prediction for the test spectra was 0.88. Although the prediction of an unknown peptide was not perfect, it was shown that all of the amino acids in an unknown peptide can be determined by Random Forest prediction and the TOF-SIMS spectra. Moreover, the prediction of peptides, which are included in the training spectra, was almost perfect. Random Forest also suggests specific fragment ions from an amino acid residue Q, whose fragment ions detected by TOF-SIMS have not been reported, in the important features. This study indicated that the analysis using Random Forest, which enables translation of the mathematical relationships to chemical relationships, and the multi labels representing monomer chemical structures, is useful to predict the TOF-SIMS spectra of an unknown peptide.

13.
Analyst ; 146(10): 3378-3390, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-33876155

RESUMO

Controlled-release formulations, in the form of micro- or nanoparticles, are increasingly attractive to the pharmaceutical industry for drug delivery. For respiratory illnesses, controlled-release microparticle formulations provide an opportunity to deliver a higher percentage of an inhaled medicament dose to the lung, thus potentially reducing the therapeutic dose, frequency of dosing, and minimising side-effects. We describe the use of a multimodal approach consisting of MALDI MS imaging, 3D depth profiling TOF-SIMS analysis, and histopathology to monitor the distribution of drug and excipients in sections taken from excised rat lungs following an inhaled administration of drug-laden microparticles. Following a single dose, the administered drug was detected in the lung via both MALDI MS and TOF-SIMS over a range of time points. Both imaging techniques enabled the characterisation of the distribution and retention of drug particles and identified differences in the capabilities of both imaging modalities. Histochemical staining of consecutive sections was used to provide biological context to the findings and will also be discussed in this presentation. We demonstrate how this multimodal approach could be used to help increase our understanding of the use of controlled release microparticles.


Assuntos
Excipientes , Pulmão , Animais , Preparações de Ação Retardada , Pulmão/diagnóstico por imagem , Imagem Multimodal , Tamanho da Partícula , Ratos
14.
Gut ; 69(4): 764-780, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31879281

RESUMO

Alcohol-related liver disease (ALD), which includes a range of disorders of different severity and is one of the most prevalent types of liver disease worldwide, has recently regained increased attention. Among other reasons, the realisation that any alcohol intake, regardless of type of beverage represents a health risk, and the new therapeutic strategies tested in recently published or undergoing clinical trials spur scientific interest in this area.In April 2019, Gut convened a round table panel of experts during the European Association for the Study of the Liver International Liver Congress in Vienna to discuss critical and up-to-date issues and clinical trial data regarding ALD, its epidemiology, diagnosis, management, pathomechanisms, possible future treatments and prevention. This paper summarises the discussion and its conclusions.


Assuntos
Hepatopatias Alcoólicas/diagnóstico , Hepatopatias Alcoólicas/epidemiologia , Humanos , Hepatopatias Alcoólicas/terapia
15.
Anal Chem ; 92(16): 10979-10988, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32627536

RESUMO

Chemical imaging techniques are increasingly being used in combination to achieve a greater understanding of a sample. This is especially true in the case of mass spectrometry imaging (MSI), where the use of different ionization sources allows detection of different classes of molecules across a range of spatial resolutions. There has been significant recent effort in the development of data fusion algorithms that attempt to combine the benefits of multiple techniques, such that the output provides additional information that would have not been present or obvious from the individual techniques alone. However, the majority of the data fusion methods currently in use rely on image registration to generate the fused data and therefore can suffer from artifacts caused by interpolation. Here, we present a method for data fusion that does not incorporate interpolation-based artifacts into the final fused data, applied to data acquired from multiple chemical imaging modalities. The method is evaluated using simulated data and a model polymer blend sample, before being applied to biological samples of mouse brain and lung.

16.
Anal Chem ; 92(13): 9008-9015, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32460495

RESUMO

Secondary ion mass spectrometry (SIMS) is gaining popularity for molecular imaging in the life sciences because it is label-free and allows imaging in two and three dimensions. The recent introduction of the OrbiSIMS has significantly improved the utility for biological imaging through combining subcellular spatial resolution with high-performance Orbitrap mass spectrometry. SIMS instruments operate in high-vacuum, and samples are typically analyzed in a freeze-dried state. Consequently, the molecular and structural information may not be well-preserved. We report a method for molecular imaging of biological materials, preserved in a native state, by using an OrbiSIMS instrument equipped with cryogenic sample handling and a high-pressure freezing protocol compatible with mass spectrometry. The performance is demonstrated by imaging a challenging sample (>90% water) of a mature Pseudomonas aeruginosa biofilm in its native state. The 3D distribution of quorum sensing signaling molecules, nucleobases, and bacterial membrane molecules is revealed with high spatial-resolution and high mass-resolution. We discover that analysis in the frozen-hydrated state yields a 10 000-fold increase in signal intensity for polar molecules such as amino acids, which has important implications for SIMS imaging of metabolites and pharmaceuticals.


Assuntos
Biofilmes , Pseudomonas aeruginosa/fisiologia , Espectrometria de Massa de Íon Secundário/métodos , Adenina/química , Congelamento , Imageamento Tridimensional , Microscopia Confocal , Percepção de Quorum
17.
Nat Methods ; 14(12): 1175-1183, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29131162

RESUMO

We report the development of a 3D OrbiSIMS instrument for label-free biomedical imaging. It combines the high spatial resolution of secondary ion mass spectrometry (SIMS; under 200 nm for inorganic species and under 2 µm for biomolecules) with the high mass-resolving power of an Orbitrap (>240,000 at m/z 200). This allows exogenous and endogenous metabolites to be visualized in 3D with subcellular resolution. We imaged the distribution of neurotransmitters-gamma-aminobutyric acid, dopamine and serotonin-with high spectroscopic confidence in the mouse hippocampus. We also putatively annotated and mapped the subcellular localization of 29 sulfoglycosphingolipids and 45 glycerophospholipids, and we confirmed lipid identities with tandem mass spectrometry. We demonstrated single-cell metabolomic profiling using rat alveolar macrophage cells incubated with different concentrations of the drug amiodarone, and we observed that the upregulation of phospholipid species and cholesterol is correlated with the accumulation of amiodarone.


Assuntos
Dopamina/análise , Hipocampo/metabolismo , Imagem Molecular/métodos , Serotonina/análise , Frações Subcelulares/metabolismo , Ácido gama-Aminobutírico/análise , Amiodarona/metabolismo , Animais , Células Cultivadas , Desenho de Equipamento , Feminino , Glicerofosfolipídeos/análise , Imageamento Tridimensional , Macrófagos Alveolares/metabolismo , Metabolômica/instrumentação , Metabolômica/métodos , Camundongos , Imagem Molecular/instrumentação , Sensibilidade e Especificidade , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Sulfoglicoesfingolipídeos/análise , Espectrometria de Massas em Tandem
18.
Angew Chem Int Ed Engl ; 59(41): 18194-18200, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-32603009

RESUMO

OrbiSIMS is a recently developed instrument for label-free imaging of chemicals with micron spatial resolution and high mass resolution. We report a cryogenic workflow for OrbiSIMS (Cryo-OrbiSIMS) that improves chemical detection of lipids and other biomolecules in tissues. Cryo-OrbiSIMS boosts ionization yield and decreases ion-beam induced fragmentation, greatly improving the detection of biomolecules such as triacylglycerides. It also increases chemical coverage to include molecules with intermediate or high vapor pressures, such as free fatty acids and semi-volatile organic compounds (SVOCs). We find that Cryo-OrbiSIMS reveals the hitherto unknown localization patterns of SVOCs with high spatial and chemical resolution in diverse plant, animal, and human tissues. We also show that Cryo-OrbiSIMS can be combined with genetic analysis to identify enzymes regulating SVOC metabolism. Cryo-OrbiSIMS is applicable to high resolution imaging of a wide variety of non-volatile and semi-volatile molecules across many areas of biomedicine.


Assuntos
Espectrometria de Massas/métodos , Compostos Orgânicos Voláteis/análise , Temperatura Baixa , História do Século XV
19.
J Hepatol ; 70(2): 223-236, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30658724

RESUMO

Herein, we describe the evolving landscape of alcohol-related liver disease (ALD) including the current global burden of disease and cost to working-aged people in terms of death and disability, in addition to the larger spectrum of alcohol-related heath complications and its wider impact on society. We further review the most effective and cost-effective public health policies at both a population and individual level. Currently, abstinence is the only effective treatment for ALD, and yet because the majority of ALD remains undetected in the community abstinence is initiated too late to prevent premature death in the majority of cases. We therefore hope that this review will help inform clinicians of the "public health treatment options" for ALD to encourage engagement with policy makers and promote community-based hepatology as a speciality, expanding our patient cohort to allow early detection, and thereby a reduction in the enormous morbidity and mortality associated with this disease.


Assuntos
Carga Global da Doença , Hepatopatias Alcoólicas/epidemiologia , Hepatopatias Alcoólicas/mortalidade , Saúde Pública , Adulto , Abstinência de Álcool/psicologia , Consumo de Bebidas Alcoólicas/psicologia , Consumo de Bebidas Alcoólicas/tendências , Feminino , Humanos , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/psicologia , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Sistemas de Apoio Psicossocial , Fatores de Risco , Resultado do Tratamento
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