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1.
Cell ; 180(2): 323-339.e19, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31928845

RESUMO

Teneurins are ancient metazoan cell adhesion receptors that control brain development and neuronal wiring in higher animals. The extracellular C terminus binds the adhesion GPCR Latrophilin, forming a trans-cellular complex with synaptogenic functions. However, Teneurins, Latrophilins, and FLRT proteins are also expressed during murine cortical cell migration at earlier developmental stages. Here, we present crystal structures of Teneurin-Latrophilin complexes that reveal how the lectin and olfactomedin domains of Latrophilin bind across a spiraling beta-barrel domain of Teneurin, the YD shell. We couple structure-based protein engineering to biophysical analysis, cell migration assays, and in utero electroporation experiments to probe the importance of the interaction in cortical neuron migration. We show that binding of Latrophilins to Teneurins and FLRTs directs the migration of neurons using a contact repulsion-dependent mechanism. The effect is observed with cell bodies and small neurites rather than their processes. The results exemplify how a structure-encoded synaptogenic protein complex is also used for repulsive cell guidance.

2.
Proc Natl Acad Sci U S A ; 116(11): 4804-4809, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30808803

RESUMO

Correlative light and electron cryo-microscopy (cryo-CLEM) combines information from the specific labeling of fluorescence cryo-microscopy (cryo-FM) with the high resolution in environmental context of electron cryo-microscopy (cryo-EM). Exploiting super-resolution methods for cryo-FM is advantageous, as it enables the identification of rare events within the environmental background of cryo-EM at a sensitivity and resolution beyond that of conventional methods. However, due to the need for relatively high laser intensities, current super-resolution cryo-CLEM methods require cryo-protectants or support films which can severely reduce image quality in cryo-EM and are not compatible with many samples, such as mammalian cells. Here, we introduce cryogenic super-resolution optical fluctuation imaging (cryo-SOFI), a low-dose super-resolution imaging scheme based on the SOFI principle. As cryo-SOFI does not require special sample preparation, it is fully compatible with conventional cryo-EM specimens, and importantly, it does not affect the quality of cryo-EM imaging. By applying cryo-SOFI to a variety of biological application examples, we demonstrate resolutions up to ∼135 nm, an improvement of up to three times compared with conventional cryo-FM, while maintaining the specimen in a vitrified state for subsequent cryo-EM. Cryo-SOFI presents a general solution to the problem of specimen devitrification in super-resolution cryo-CLEM. It does not require a complex optical setup and can easily be implemented in any existing cryo-FM system.


Assuntos
Microscopia Crioeletrônica/métodos , Animais , Linhagem Celular , Retículo Endoplasmático/ultraestrutura , Humanos , Microscopia de Fluorescência , Mitocôndrias/ultraestrutura
3.
Front Psychiatry ; 9: 9, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29445345

RESUMO

Background: Social interactive functions such as facial emotion recognition and smell identification have been shown to differ between women and men. However, little is known about how these differences are mirrored in patients with schizophrenia and how these abilities interact with each other and with other clinical variables in patients vs. healthy controls. Methods: Standardized instruments were used to assess facial emotion recognition [Facially Expressed Emotion Labelling (FEEL)] and smell identification [University of Pennsylvania Smell Identification Test (UPSIT)] in 51 patients with schizophrenia spectrum disorders and 79 healthy controls; furthermore, working memory functions and clinical variables were assessed. Results: In both the univariate and the multivariate results, illness showed a significant influence on UPSIT and FEEL. The inclusion of age and working memory in the MANOVA resulted in a differential effect with sex and working memory as remaining significant factors. Duration of illness was correlated with both emotion recognition and smell identification in men only, whereas immediate general psychopathology and negative symptoms were associated with emotion recognition only in women. Conclusion: Being affected by schizophrenia spectrum disorder impacts one's ability to correctly recognize facial affects and identify odors. Converging evidence suggests a link between the investigated basic and social cognitive abilities in patients with schizophrenia spectrum disorders with a strong contribution of working memory and differential effects of modulators in women vs. men.

4.
Curr Biol ; 27(19): R1054-R1055, 2017 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-29017036

RESUMO

Centrioles are small barrel-shaped structures that form centrosomes and cilia [1]. Centrioles assemble around a central cartwheel comprising the Sas-6 and Ana2/STIL proteins. The amino termini of nine Sas-6 dimers form a central hub of ∼12 nm radius from which nine dimer spokes radiate, placing the Sas-6 carboxyl termini at the outer edge of the ∼60 nm radius cartwheel [2]. Several centriole proteins are distributed in a toroid around the cartwheel, and super-resolution light microscopy studies have measured the average radii of these ∼100-200 nm radius toroids with a 'precision' - or standard deviation (s.d. or 1σ) - of ±âˆ¼10-40 nm. The organization of Ana2/STIL within the cartwheel, however, has not been resolvable. Here, we develop methods to calculate the average toroidal radius of centriolar proteins in the ∼20-60 nm range with a s.d. of just ±âˆ¼4-5 nm, revealing that the amino and carboxyl termini of Ana2 are located in the outer cartwheel region.


Assuntos
Centríolos/ultraestrutura , Proteínas de Drosophila/ultraestrutura , Drosophila melanogaster/ultraestrutura , Imagem Individual de Molécula/métodos , Animais , Drosophila melanogaster/crescimento & desenvolvimento , Larva/ultraestrutura
5.
Methods Mol Biol ; 1663: 163-177, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28924667

RESUMO

Correlative super-resolution light and electron microscopy (super-resolution CLEM) is a powerful and emerging tool in biological research. The practical realization of these two very different microscopy techniques with their individual requirements remains a challenging task. There is a broad range of approaches to choose from, each with their own advantages and limitations. Here, we present a detailed protocol for in-resin super-resolution CLEM of high-pressure frozen and freeze substituted cultured cells. The protocol makes use of a strategy to preserve the fluorescence and photo-switching capabilities of standard fluorescent proteins, such as GFP and YFP, to enable single-molecule localization microscopy (SMLM) in-resin sections followed by transmission electron microscopy (TEM) imaging. This results in a fivefold improvement in resolution in the fluorescence image and a more precise correlation of the distribution of fluorescently labeled molecules with EM ultrastructure compared with conventional CLEM.


Assuntos
Proteínas Luminescentes/metabolismo , Microscopia Eletrônica/métodos , Microscopia de Fluorescência/métodos , Células Cultivadas , Células HEK293 , Células HeLa , Humanos , Processamento de Imagem Assistida por Computador , Imagem Individual de Molécula/métodos
6.
Methods Cell Biol ; 140: 49-67, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28528641

RESUMO

There are many different correlative light and electron microscopy (CLEM) techniques available. The use of super-resolution microscopy in CLEM is an emerging application and while offering the obvious advantages of improved resolution in the fluorescence image, and therefore more precise correlation to electron microscopy (EM) ultrastructure, it also presents new challenges. Choice of fluorophore, method of fixation, and timing of the fluorescence imaging are critical to the success of super-resolution CLEM and the relative importance, and technical difficulty, of each of these factors depends on the type of super-resolution microscopy being employed. This chapter details the method we developed for in-resin super-resolution CLEM using single molecule localization microscopy (SMLM) with standard fluorescent proteins (e.g., GFP and mVenus). The key to this approach is being able to preserve not only the fluorescence, but also, and more importantly, the photoswitching ability of the fluorescent proteins throughout the EM sample preparation procedure. Cells are cryofixed using high pressure freezing for optimal structural preservation and then freeze substituted in tannic acid, which preserves the photoswitching ability of the fluorescent proteins and is essential for high-quality SMLM imaging. Resin sections are then imaged using SMLM, achieving a structural resolution of 40-50nm and a localization precision of ∼17nm, followed by transmission electron microscopy. This produces high quality correlative images without the use of specialized fluorescent proteins or antibodies.


Assuntos
Luz , Proteínas Luminescentes/metabolismo , Microscopia Eletrônica/métodos , Células HEK293 , Humanos , Processamento de Imagem Assistida por Computador , Polimerização , Resinas Sintéticas
7.
Neuron ; 91(3): 548-60, 2016 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-27397516

RESUMO

Class A plexins (PlxnAs) act as semaphorin receptors and control diverse aspects of nervous system development and plasticity, ranging from axon guidance and neuron migration to synaptic organization. PlxnA signaling requires cytoplasmic domain dimerization, but extracellular regulation and activation mechanisms remain unclear. Here we present crystal structures of PlxnA (PlxnA1, PlxnA2, and PlxnA4) full ectodomains. Domains 1-9 form a ring-like conformation from which the C-terminal domain 10 points away. All our PlxnA ectodomain structures show autoinhibitory, intermolecular "head-to-stalk" (domain 1 to domain 4-5) interactions, which are confirmed by biophysical assays, live cell fluorescence microscopy, and cell-based and neuronal growth cone collapse assays. This work reveals a 2-fold role of the PlxnA ectodomains: imposing a pre-signaling autoinhibitory separation for the cytoplasmic domains via intermolecular head-to-stalk interactions and supporting dimerization-based PlxnA activation upon ligand binding. More generally, our data identify a novel molecular mechanism for preventing premature activation of axon guidance receptors.


Assuntos
Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Multimerização Proteica , Receptores de Superfície Celular/química , Receptores de Superfície Celular/metabolismo , Animais , Camundongos , Modelos Moleculares , Proteínas do Tecido Nervoso/ultraestrutura , Receptores de Superfície Celular/ultraestrutura , Relação Estrutura-Atividade
8.
Sci Rep ; 6: 27290, 2016 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-27264341

RESUMO

Many biological questions require fluorescence microscopy with a resolution beyond the diffraction limit of light. Super-resolution methods such as Structured Illumination Microscopy (SIM), STimulated Emission Depletion (STED) microscopy and Single Molecule Localisation Microscopy (SMLM) enable an increase in image resolution beyond the classical diffraction-limit. Here, we compare the individual strengths and weaknesses of each technique by imaging a variety of different subcellular structures in fixed cells. We chose examples ranging from well separated vesicles to densely packed three dimensional filaments. We used quantitative and correlative analyses to assess the performance of SIM, STED and SMLM with the aim of establishing a rough guideline regarding the suitability for typical applications and to highlight pitfalls associated with the different techniques.


Assuntos
Macrófagos/citologia , Microtúbulos/ultraestrutura , Imagem Óptica/métodos , Animais , Células COS , Humanos , Microscopia de Fluorescência , Imagem Individual de Molécula
9.
Biol Cell ; 108(9): 245-58, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27225383

RESUMO

Correlative light and electron microscopy (CLEM) has become a powerful tool in life sciences. Particularly cryo-CLEM, the combination of fluorescence cryo-microscopy (cryo-FM) permitting for non-invasive specific multi-colour labelling, with electron cryo-microscopy (cryo-EM) providing the undisturbed structural context at a resolution down to the Ångstrom range, has enabled a broad range of new biological applications. Imaging rare structures or events in crowded environments, such as inside a cell, requires specific fluorescence-based information for guiding cryo-EM data acquisition and/or to verify the identity of the structure of interest. Furthermore, cryo-CLEM can provide information about the arrangement of specific proteins in the wider structural context of their native nano-environment. However, a major obstacle of cryo-CLEM currently hindering many biological applications is the large resolution gap between cryo-FM (typically in the range of ∼400 nm) and cryo-EM (single nanometre to the Ångstrom range). Very recently, first proof of concept experiments demonstrated the feasibility of super-resolution cryo-FM imaging and the correlation with cryo-EM. This opened the door towards super-resolution cryo-CLEM, and thus towards direct correlation of structural details from both imaging modalities.


Assuntos
Microscopia Crioeletrônica/métodos , Microscopia de Fluorescência/métodos , Animais , Microscopia Crioeletrônica/instrumentação , Fluorescência , Humanos , Microscopia de Fluorescência/instrumentação , Modelos Moleculares , Imagem Óptica/instrumentação , Imagem Óptica/métodos
12.
Sci Rep ; 5: 15915, 2015 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-26525406

RESUMO

Three-dimensional structured illumination microscopy (3D-SIM) is a versatile and accessible method for super-resolution fluorescence imaging, but generating high-quality data is challenging, particularly for non-specialist users. We present SIMcheck, a suite of ImageJ plugins enabling users to identify and avoid common problems with 3D-SIM data, and assess resolution and data quality through objective control parameters. Additionally, SIMcheck provides advanced calibration tools and utilities for common image processing tasks. This open-source software is applicable to all commercial and custom platforms, and will promote routine application of super-resolution SIM imaging in cell biology.


Assuntos
Processamento de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Iluminação/métodos , Microscopia de Fluorescência/métodos , Algoritmos , Calibragem , Reprodutibilidade dos Testes
13.
PLoS One ; 10(6): e0128555, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26042422

RESUMO

It has been well established that the architecture of chromatin in cell nuclei is not random but functionally correlated. Chromatin damage caused by ionizing radiation raises complex repair machineries. This is accompanied by local chromatin rearrangements and structural changes which may for instance improve the accessibility of damaged sites for repair protein complexes. Using stably transfected HeLa cells expressing either green fluorescent protein (GFP) labelled histone H2B or yellow fluorescent protein (YFP) labelled histone H2A, we investigated the positioning of individual histone proteins in cell nuclei by means of high resolution localization microscopy (Spectral Position Determination Microscopy = SPDM). The cells were exposed to ionizing radiation of different doses and aliquots were fixed after different repair times for SPDM imaging. In addition to the repair dependent histone protein pattern, the positioning of antibodies specific for heterochromatin and euchromatin was separately recorded by SPDM. The present paper aims to provide a quantitative description of structural changes of chromatin after irradiation and during repair. It introduces a novel approach to analyse SPDM images by means of statistical physics and graph theory. The method is based on the calculation of the radial distribution functions as well as edge length distributions for graphs defined by a triangulation of the marker positions. The obtained results show that through the cell nucleus the different chromatin re-arrangements as detected by the fluorescent nucleosomal pattern average themselves. In contrast heterochromatic regions alone indicate a relaxation after radiation exposure and re-condensation during repair whereas euchromatin seemed to be unaffected or behave contrarily. SPDM in combination with the analysis techniques applied allows the systematic elucidation of chromatin re-arrangements after irradiation and during repair, if selected sub-regions of nuclei are investigated.


Assuntos
Cromatina/química , Cromatina/efeitos da radiação , Raios gama , Microscopia de Fluorescência/métodos , Conformação de Ácido Nucleico , Estatística como Assunto , Análise por Conglomerados , Eucromatina , Genoma Humano , Células HeLa , Heterocromatina , Humanos , Probabilidade
14.
Sci Rep ; 5: 9583, 2015 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-25823571

RESUMO

We introduce a method for correlative in-resin super-resolution fluorescence and electron microscopy (EM) of biological structures in mammalian culture cells. Cryo-fixed resin embedded samples offer superior structural preservation, performing in-resin super-resolution, however, remains a challenge. We identified key aspects of the sample preparation procedure of high pressure freezing, freeze substitution and resin embedding that are critical for preserving fluorescence and photo-switching of standard fluorescent proteins, such as mGFP, mVenus and mRuby2. This enabled us to combine single molecule localization microscopy with transmission electron microscopy imaging of standard fluorescent proteins in cryo-fixed resin embedded cells. We achieved a structural resolution of 40-50 nm (~17 nm average single molecule localization accuracy) in the fluorescence images without the use of chemical fixation or special fluorophores. Using this approach enabled the correlation of fluorescently labeled structures to the ultrastructure in the same cell at the nanometer level and superior structural preservation.


Assuntos
Proteínas Luminescentes/química , Proteínas Luminescentes/metabolismo , Microscopia Eletrônica/métodos , Linhagem Celular , Histonas , Humanos , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo
15.
Nano Lett ; 14(7): 4171-5, 2014 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-24884378

RESUMO

We introduce a super-resolution technique for fluorescence cryo-microscopy based on photoswitching of standard genetically encoded fluorescent marker proteins in intact mammalian cells at low temperature (81 K). Given the limit imposed by the lack of cryo-immersion objectives, current applications of fluorescence cryo-microscopy to biological specimens achieve resolutions between 400-500 nm only. We demonstrate that the single molecule characteristics of reversible photobleaching of mEGFP and mVenus at liquid nitrogen temperature are suitable for the basic concept of single molecule localization microscopy. This enabled us to perform super-resolution imaging of vitrified biological samples and to visualize structures in unperturbed fast frozen cells for the first time with a structural resolution of ∼125 nm (average single molecule localization accuracy ∼40 nm), corresponding to a 3-5 fold resolution improvement.


Assuntos
Corantes Fluorescentes/análise , Proteínas Luminescentes/análise , Microscopia de Fluorescência/instrumentação , Animais , Células COS , Temperatura Baixa , Desenho de Equipamento , Congelamento , Vitrificação
16.
Curr Opin Chem Biol ; 20: 86-91, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24951858

RESUMO

Studying biological structures with fine details does not only require a microscope with high resolution, but also a sample preparation process that preserves the structures in a near-native state. Live-cell imaging is restricted mostly to the field of light microscopy. For studies requiring much higher resolution, fast freezing techniques (vitrification) are successfully used to immobilize the sample in a near-native state for imaging with electron and X-ray cryo-microscopy. Fluorescence cryo-microscopy combines imaging of vitrified samples with the advantages of fluorescence labeling of biological structures. Technical considerations as well as the behavior of fluorophores at low temperatures have to be taken into account for developing or adapting super-resolution methods under cryo conditions to exploit the full potential of this technique.


Assuntos
Microscopia de Fluorescência/instrumentação , Microscopia de Fluorescência/métodos , Corantes Fluorescentes/química , Humanos , Temperatura
17.
Histochem Cell Biol ; 142(1): 61-7, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24504601

RESUMO

Novel approaches of localization microscopy have opened new insights into the molecular nano-cosmos of cells. We applied a special embodiment called spectral position determination microscopy (SPDM) that has the advantage to run with standard fluorescent dyes or proteins under standard preparation conditions. Pointillist images with a resolution in the order of 10 nm can be obtained by SPDM. Therefore, vector pEYFP-m164, encoding the murine cytomegalovirus glycoprotein gp36.5/m164 fused to enhanced yellow fluorescent protein, was transiently transfected into COS-7 cells. This protein shows exceptional intracellular trafficking dynamics, moving within the endoplasmic reticulum (ER) and outer nuclear membrane. The molecular positions of gp36.5/m164 were visualized and determined by SPDM imaging. From the position point patterns of the protein molecules, their arrangements were quantified by next neighbour distance analyses. Three different structural arrangements were discriminated: (a) a linear distribution along the membrane, (b) a highly structured distribution in the ER, and (c) a homogenous distribution in the cellular cytoplasm. The results indicate that the analysis of next neighbour distances on the nano-scale allows the identification and discrimination of different structural arrangements of molecules within their natural cellular environment.


Assuntos
Glicoproteínas/análise , Muromegalovirus/química , Proteínas do Envelope Viral/análise , Animais , Proteínas de Bactérias/química , Células COS , Células Cultivadas , Glicoproteínas/genética , Proteínas Luminescentes/química , Camundongos , Microscopia de Fluorescência , Proteínas do Envelope Viral/genética
18.
Ultramicroscopy ; 143: 41-51, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24262358

RESUMO

Correlative light and electron microscopy (CLEM) is an emerging technique which combines functional information provided by fluorescence microscopy (FM) with the high-resolution structural information of electron microscopy (EM). So far, correlative cryo microscopy of frozen-hydrated samples has not reached better than micrometre range accuracy. Here, a method is presented that enables the correlation between fluorescently tagged proteins and electron cryo tomography (cryoET) data with nanometre range precision. Specifically, thin areas of vitrified whole cells are examined by correlative fluorescence cryo microscopy (cryoFM) and cryoET. Novel aspects of the presented cryoCLEM workflow not only include the implementation of two independent electron dense fluorescent markers to improve the precision of the alignment, but also the ability of obtaining an estimate of the correlation accuracy for each individual object of interest. The correlative workflow from plunge-freezing to cryoET is detailed step-by-step for the example of locating fluorescence-labelled adenovirus particles trafficking inside a cell.


Assuntos
Microscopia Crioeletrônica/métodos , Microscopia de Fluorescência/métodos , Linhagem Celular , Elétrons , Fluorescência , Corantes Fluorescentes/metabolismo , Células HEK293 , Humanos , Microscopia de Polarização/métodos
19.
Biochim Biophys Acta ; 1838(4): 1191-8, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24374315

RESUMO

In this report, we applied a special localization microscopy technique (Spectral Precision Distance/Spatial Position Determination Microscopy/SPDM) to quantitatively analyze the effect of influenza A virus (IAV) infection on the spatial distribution of individual HGFR (Hepatocyte Growth Factor Receptor) proteins on the membrane of human epithelial cells at the single molecule resolution level. We applied this SPDM method to Alexa 488 labeled HGFR proteins with two different ligands. The ligands were either HGF (Hepatocyte Growth Factor), or IAV. In addition, the HGFR distribution in a control group of mock-incubated cells without any ligands was investigated. The spatial distribution of 1×10(6) individual HGFR proteins localized in large regions of interest on membranes of 240 cells was quantitatively analyzed and found to be highly non-random. Between 21% and 24% of the HGFR molecules were located in 44,304 small clusters with an average diameter of 54nm. The mean density of HGFR molecule signals per individual cluster was very similar in control cells, in cells with ligand only, and in IAV infected cells, independent of the incubation time. From the density of HGFR molecule signals in the clusters and the diameter of the clusters, the number of HGFR molecule signals per cluster was estimated to be in the range between 4 and 11 (means 5-6). This suggests that the membrane bound HGFR clusters form small molecular complexes with a maximum diameter of few tens of nm, composed of a relatively low number of HGFR molecules. This article is part of a Special Issue entitled: Viral Membrane Proteins - Channels for Cellular Networking.


Assuntos
Vírus da Influenza A/patogenicidade , Microscopia de Fluorescência/métodos , Proteínas Proto-Oncogênicas c-met/análise , Membrana Celular/química , Células Cultivadas , Células Epiteliais/química , Células Epiteliais/virologia , Humanos
20.
Aust N Z J Psychiatry ; 47(12): 1176-82, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24065694

RESUMO

OBJECTIVE: Most data on duration of untreated psychosis (DUP) derives from high-income countries. An inverse relationship between DUP and income and a longer DUP in low- and middle-income (LAMI) countries has been reported. The aim of this study was to compare DUP in a high-income country with that in a LAMI country using the same methodology. METHODS: The sample consisted of in- and outpatients, aged 15-35 years for the Vienna site and 18-35 years for the Pakistani sites, with first-episode psychosis (FEP). DUP was evaluated using psychiatric interviews, medical charts and the Nottingham Onset Schedule. Differentiated reporting of duration of untreated illness (DUI) from prodrome to start of treatment, and DUP from manifest psychotic symptoms to start of treatment was ensured. Primary outcome measures, DUI and DUP, were measured at a 0.025 level of significance. RESULTS: Thirty-one FEP patients in Vienna (mean age 20.03 years, SD 4.2) and 60 FEP patients from the Pakistani sites (mean age 26.15 years, SD 5.29) participated. The mean age in Vienna was younger due to the different age range inclusion criteria. The severity of psychopathology was more pronounced in the Pakistani sample. Log DUP was significantly different between groups (i.e. longer in the Pakistani sample (p=0.001)). Log DUI showed a trend for longer duration in the Vienna sample; however, this did not reach statistical significance (p=0.036). The severity of positive psychotic symptoms was associated with length of DUI in both regions. CONCLUSION: The longer DUP in Pakistan confirms the need to provide affordable treatment for psychosis for young FEP patients in Pakistan and in other LAMI countries. The relatively long period from prodrome to treatment initiation in both regions underlines the need to further establish low-threshold early intervention strategies in order to increase detection rates and reduce factors limiting patients seeking treatment.


Assuntos
Renda , Pobreza , Transtornos Psicóticos/terapia , Adolescente , Adulto , Áustria , Cultura , Feminino , Humanos , Masculino , Paquistão , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/psicologia , Fatores Socioeconômicos , Fatores de Tempo
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