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Within the eukaryotic cell, the actin cytoskeleton is a crucial structural framework that maintains cellular form, regulates cell movement and division, and facilitates the internal transportation of proteins and organelles. External cues induce alterations in the actin cytoskeleton primarily through the activation of Rho GTPases, which then bind to a diverse array of effector proteins to promote the local assembly or disassembly of actin. We have harnessed the extensively studied functions of RhoA in the dynamics of the actin cytoskeleton to craft a practical series for Stage 2 Biology students. This series not only imparts essential tissue culture laboratory skills but also reinforces them through repetition. These activities are presented in a scenario designed for students to explore the function of a hypothetical RhoA family member. Students produce slides from transfected cells, undertake fluorescence microscopy, process the images using ImageJ, and compile their findings in a comprehensive scientific report. The composition of the report requires independent acquisition of new knowledge and synoptic learning. According to student feedback, this early experience greatly aids in solidifying and honing the skills required to report on more extensive and intricate research projects, such as capstone projects.
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In 2002, heterozygous suppressor of fused variants (SUFU+/-) in the germline were described to have a tumor suppressor role in the development of pediatric medulloblastoma (MB). Other neoplasms associated with pathologic germline SUFU+/- variants have also been described among patients with basal cell nevus syndrome (BCNS; BCNS is also known as Gorlin syndrome, nevoid basal cell carcinoma [BCC] syndrome or Gorlin-Goltz syndrome; OMIM 109400), an autosomal-dominant cancer predisposition syndrome. The phenotype of patients with germline SUFU+/- variants is very poorly characterized due to a paucity of large studies with long-term follow-up. As such, there is a clinical need to better characterize the spectrum of neoplasms among patients with germline SUFU+/- variants so that clinicians can provide accurate counseling and optimize tumor surveillance strategies. The objective of this study is to perform a scoping review to map the evidence on the rate of medulloblastoma and to describe the spectrum of other neoplasms among patients with germline SUFU+/- variants. A review of all published literature in PubMed (MEDLINE), EMBASE, Cochrane, and Web of Science were searched from the beginning of each respective database until October 9, 2021. Studies of pediatric and adult patients with a confirmed germline SUFU+/- variant who were evaluated for the presence of any neoplasm (benign or malignant) were included. There were 176 patients (N = 30 studies) identified with a confirmed germline SUFU+/- variant who met inclusion criteria. Data were extracted from two cohort studies, two case-control studies, 18 case series, and eight case reports. The median age at diagnosis of a germline SUFU+/- variant was 4.5 years where 44.4% identified as female and 13.4% of variants were de novo. There were 34 different neoplasms (benign and malignant) documented among patients with confirmed germline SUFU+/- variants, and the most common were medulloblastoma (N = 59 patients), BCC (N = 21 patients), and meningioma (N = 19 patients). The median age at medulloblastoma diagnosis was 1.42 years (range 0.083-3; interquartile range 1.2). When data were available for these three most frequent neoplasms (N = 95 patients), 31 patients (32.6%) had neither MB, BCC nor meningioma; 51 patients (53.7%) had one of medulloblastoma or BCC or meningioma; eight patients (8.4%) had two of medulloblastoma or BCC or meningioma, and five patients (5.3%) had medulloblastoma and BCC and meningioma. This is the first study to synthesize the data on the frequency and spectrum of neoplasms specifically among patients with a confirmed germline SUFU+/- variant. This scoping review is a necessary step forward in optimizing evidence-based tumor surveillance strategies for medulloblastoma and estimating the risk of other neoplasms that could impact patient outcomes.
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Mutação em Linhagem Germinativa , Heterozigoto , Meduloblastoma , Proteínas Repressoras , Humanos , Meduloblastoma/genética , Meduloblastoma/patologia , Mutação em Linhagem Germinativa/genética , Predisposição Genética para Doença , Síndrome do Nevo Basocelular/genética , Síndrome do Nevo Basocelular/patologia , Masculino , Feminino , CriançaRESUMO
BACKGROUND: The occurrence of hyperostotic bilateral spheno-orbital meningiomas (BSOMs) is very rare. Patients present with bilateral symptoms and require bilateral treatment. This series describes 6 patients presenting to 2 UK neurosurgical units and includes a literature review. To the best of the authors' knowledge, this is the largest series documented. OBSERVATIONS: This is a retrospective review of patients with BSOMs presenting between 2006 and 2023. Six females, whose mean age was 43 (range: 36-64) years, presented with features of visual disturbance. Bilateral sphen-oorbital meningiomas were identified. All patients underwent bilateral staged resections. The patients had an initial improvement in their symptoms. Extensive genetic testing was performed in 4 patients, with no variants in the NF2, LZTR1, SMARCB1, SMARCE1, and SMARCA4 genes or other variants detected. The mean follow-up was 100.3 (range: 64-186) months. Sixty-seven percent of patients had good long-term visual acuity. The progression rate was 75% and was particularly aggressive in 1 patient. Four patients required radiation therapy, and 2 needed further surgery. LESSONS: Hyperostotic BSOMs are extensive, challenging tumors causing significant disability. They can recur, with significant patient impact. Multidisciplinary management and indefinite long-term follow-up are essential. The biology of these tumors remains unclear. As molecular testing expands, the understanding of BSOM oncogenesis and potential therapeutic targets is likely to improve.
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This review is about the ethical use of sensors to monitor occupational exposure to hazards. It considers whether the same or different, ethical measures apply to using sensors, compared to conventional hazard monitoring surveys. To undertake the review, subject experts developed a research question, identified suitable search terms, and set the scope of these searches. Candidate research papers dating from 2000 to mid-2022 that met inclusion criteria were identified and reviewed by each author. Ethical concerns were identified by the authors of studies in which sensors were used to monitor employee health and well-being, but most of the studies that used them to monitor employee exposure to hazards focused on the technical aspects of their deployment. These ethical concerns included questions about employee rights and privacy, the anonymity of the data collected with sensors, and how the security of this data is managed. The review considers ethical standards and codes of practice for occupational hygiene work and the ethical risks when sensors are used to gather data. Sensors may provide insight into occupational exposure to hazards, but their use is not always adequately explained to employees by those managing this monitoring work. The ethical concerns identified were relevant to many areas of industrial hygiene work, but more studies are required that consider the ethical use of sensors in workplaces. Studies that monitored employee health, well-being, and productivity, identified ethical risks in using sensors to monitor these endpoints. An ethical framework and checklist for hygienists are proposed including a set of questions that consider the risks of using sensors to monitor occupational hazards. Industrial hygiene professional bodies provide ethical codes of practice for their members but may also need to consider the implications of using sensors in workplaces. Ethical standards support the collection of industrial hygiene exposure data whilst maintaining the privacy rights of employees.
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Exposição Ocupacional , Saúde Ocupacional , Humanos , Local de Trabalho , OcupaçõesRESUMO
The ZAK gene encodes two functionally distinct kinases, ZAKα and ZAKß. Homozygous loss of function mutations affecting both isoforms causes a congenital muscle disease. ZAKß is the only isoform expressed in skeletal muscle and is activated by muscle contraction and cellular compression. The ZAKß substrates in skeletal muscle or the mechanism whereby ZAKß senses mechanical stress remains to be determined. To gain insights into the pathogenic mechanism, we exploited ZAK-deficient cell lines, zebrafish, mice and a human biopsy. ZAK-deficient mice and zebrafish show a mild phenotype. In mice, comparative histopathology data from regeneration, overloading, ageing and sex conditions indicate that while age and activity are drivers of the pathology, ZAKß appears to have a marginal role in myoblast fusion in vitro or muscle regeneration in vivo. The presence of SYNPO2, BAG3 and Filamin C (FLNC) in a phosphoproteomics assay and extended analyses suggested a role for ZAKß in the turnover of FLNC. Immunofluorescence analysis of muscle sections from mice and a human biopsy showed evidence of FLNC and BAG3 accumulations as well as other myofibrillar myopathy markers. Moreover, endogenous overloading of skeletal muscle exacerbated the presence of fibres with FLNC accumulations in mice, indicating that ZAKß signalling is necessary for an adaptive turnover of FLNC that allows for the normal physiological response to sustained mechanical stress. We suggest that accumulation of mislocalized FLNC and BAG3 in highly immunoreactive fibres contributes to the pathogenic mechanism of ZAK deficiency.
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Miopatias Congênitas Estruturais , Peixe-Zebra , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Filaminas/genética , Filaminas/metabolismo , Músculo Esquelético/metabolismo , Mutação , Miopatias Congênitas Estruturais/metabolismo , Isoformas de Proteínas/genética , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genéticaRESUMO
BACKGROUND: Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. METHODS: We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. RESULTS: In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). CONCLUSIONS: Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudo de Associação Genômica Ampla , Judeus/genética , Israel/epidemiologia , Predisposição Genética para Doença , Fatores de Risco , Herança Multifatorial/genética , Fatores de TranscriçãoRESUMO
The yeast (Saccharomyces cerevisiae) plasma membrane (PM) is organised into specific subdomains that regulate surface membrane proteins. Surface transporters actively uptake nutrients in particular regions of the PM where they are also susceptible to substrate-induced endocytosis. However, transporters also diffuse into distinct subdomains termed eisosomes, where they are protected from endocytosis. Although most nutrient transporter populations are downregulated in the vacuole following glucose starvation, a small pool is retained in eisosomes to provide efficient recovery from starvation. We find the core eisosome subunit Pil1, a Bin, Amphiphysin and Rvs (BAR) domain protein required for eisosome biogenesis, is phosphorylated primarily by the kinase Pkh2. In response to acute glucose starvation, Pil1 is rapidly dephosphorylated. Enzyme localisation and activity screens suggest that the phosphatase Glc7 is the primary enzyme responsible for Pil1 dephosphorylation. Defects in Pil1 phosphorylation, achieved by depletion of GLC7 or expression of phospho-ablative or phospho-mimetic mutants, correlate with reduced retention of transporters in eisosomes and inefficient starvation recovery. We propose that precise post-translational control of Pil1 modulates nutrient transporter retention within eisosomes, depending on extracellular nutrient levels, to maximise recovery following starvation.
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Proteínas de Saccharomyces cerevisiae , Proteínas de Saccharomyces cerevisiae/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Membrana Celular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Processamento de Proteína Pós-Traducional , Glucose/metabolismoRESUMO
Intracellular Ca2+ signaling and Na+ homeostasis are inextricably linked via ion channels and co-transporters, with alterations in the concentration of one ion having profound effects on the other. Evidence indicates that intracellular Na+ concentration ([Na+ ]i ) is elevated in breast tumors, and that aberrant Ca2+ signaling regulates numerous key cancer hallmark processes. The present study therefore aimed to determine the effects of Na+ depletion on intracellular Ca2+ handling in metastatic breast cancer cell lines. The relationship between Na+ and Ca2+ was probed using fura-2 and SBFI fluorescence imaging and replacement of extracellular Na+ with equimolar N-methyl-D-glucamine (0Na+ /NMDG) or choline chloride (0Na+ /ChoCl). In triple-negative MDA-MB-231 and MDA-MB-468 cells and Her2+ SKBR3 cells, but not ER+ MCF-7 cells, 0Na+ /NMDG and 0Na+ /ChoCl resulted in a slow, sustained depletion in [Na+ ]i that was accompanied by a rapid and sustained increase in intracellular Ca2+ concentration ([Ca2+ ]i ). Application of La3+ in nominal Ca2+ -free conditions had no effect on this response, ruling out reverse-mode NCX activity and Ca2+ entry channels. Moreover, the Na+ -linked [Ca2+ ]i increase was independent of membrane potential hyperpolarization (NS-1619), but was inhibited by pharmacological blockade of IP3 receptors (2-APB), phospholipase C (PLC, U73122) or following depletion of endoplasmic reticulum Ca2+ stores (cyclopiazonic acid). Thus, Na+ is linked to PLC/IP3 -mediated activation of endoplasmic reticulum Ca2+ release in metastatic breast cancer cells and this may have an important role in breast tumors where [Na+ ]i is perturbed.
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Neoplasias da Mama , Sinalização do Cálcio , Humanos , Feminino , Sinalização do Cálcio/fisiologia , Sódio/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Canais Iônicos/metabolismo , Cálcio/metabolismoRESUMO
Garlic (Allium sativum L.) has long been grown for its culinary and health-promoting qualities. The seasonal nature of garlic cropping requires that bulbs be stored for many months after harvest to ensure a year-round supply. During this time, quality is known to deteriorate, and efforts have been made to improve the longevity of stored bulbs. Cold temperatures within the stores prolong shelf life, but fine temperature control is needed to avoid freezing damage or cold induced stress. Here, quality traits (alliinase activity, firmness, and water content) are measured in response to a 96 h - 5 °C cold stress, to simulate the effect of non-isothermic temperature control in a - 1.5 °C warehouse. Volatile organic compounds (VOCs) are measured by thermal desorption gas chromatography time of flight mass spectrometry to identify markers of non-isothermic storage in garlic. 129 compounds were putatively identified and four (L-lactic acid, 2,6-dimethylhetpadecane, 4-methyldodecane, and methylcyclopentane) showed high predictive accuracy for cold stress. VOCs were also sampled directly from a cold storage facility and the whole profile discriminated between sampling time points. Five VOCS were highly predictive for storage time in the warehouse but were different to VOCs previously shown to discriminate between storage times in a laboratory setting. This indicates the need for realistic warehouse experiments to test quality markers.
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The studyMarcinkute R, Woodward ER, Gandhi A, et al. Uptake and efficacy of bilateral risk reducing surgery in unaffected female BRCA1 and BRCA2 carriers. J Med Genet 2021;0:1-8.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/earlier-decisions-breast-ovarian-surgery-reduce-risk-cancer/.
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Genes BRCA2 , Neoplasias Ovarianas , Feminino , Genes BRCA1 , Heterozigoto , Humanos , Mutação , Neoplasias Ovarianas/genéticaRESUMO
This study explores the natural history of vestibular, trigeminal and lower cranial nerve schwannomas (VS, TS, LCNS) in patients with Neurofibromatosis type 2 (NF2), to understand how pathogenic variants (PVs) of the NF2 gene affect tumour burden and growth rate, via a retrospective analysis of a UK NF2 centre database and imaging. VS, TS and LCNS location and size were measured in accordance with a standardised protocol. PVs were categorised in accordance with the UK NF2 Genetic Severity Score (GSS). 153 patients (age 5-82) had 458 schwannomas, of which 362 were previously untreated comprising: 204 VS, 93 TS, and 65 LCNS (IX, X, XI). 322 schwannomas had sequential imaging allowing growth rate analysis with a mean follow-up of 45 months. VS were universally present, and bilateral in 146/153 cases. 65% of tumours grew >2 mm during the study period at mean rate 2.0 mm/year. Significant association was found between increasing GSS and growth rate. TS occurred in 66/153 patients (bilateral in 27/153); 31% of tumours showed growth (mean 1.8 mm/yr). Significant increase in tumour prevalence was noted with increasing GSS. LCNS were found in 47/153 patients (bilateral in 19/153); 27% of tumours showed growth (mean 1.9 mm/yr). The trend for increased prevalence with increasing GSS did not reach significance. VS growth rate was significantly influenced by GSS and they were much more likely to grow than TS and LCNS. TS prevalence also correlated with increasing GSS.
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Neurilemoma , Neurofibromatose 2 , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Humanos , Pessoa de Meia-Idade , Neurilemoma/epidemiologia , Neurilemoma/genética , Neurilemoma/patologia , Neurofibromatose 2/epidemiologia , Neurofibromatose 2/genética , Neurofibromatose 2/patologia , Prevalência , Estudos Retrospectivos , Adulto JovemRESUMO
Wales' education system is part-way through an extensive journey of reform. This contextual paper explores the evolution of that journey, from the establishment of the Welsh Parliament in 1999 to late 2020, as Wales readies itself for the launch of a radical, new national curriculum. Drawing from a range of international literature and experience, it provides an overview of key policy developments and insight into the rationale for decisions taken by the Welsh Government to effect change. To do this, it separates reform into three core phases, each with its own characteristics borne out of landmark events that helped shape contemporary political and public discourse. In particular, the paper examines the impact of Wales' shifting approach to policy development on the teaching workforce and considers implications for those at the site of practice. Ahead of forthcoming parliamentary elections, the paper resolves that a new, long-term approach to policy reform and teacher development is needed if Wales is to realise its ambitious vision for education.
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BACKGROUND: Dionysia tapetodes, a small cushion-forming mountainous evergreen in the Primulaceae, possesses a vast surface-covering of long silky fibres forming the characteristic "woolly" farina. This contrasts with some related Primula which instead form a fine powder. Farina is formed by specialized cellular factories, a type of glandular trichome, but the precise composition of the fibres and how it exits the cell is poorly understood. Here, using a combination of cell biology (electron and light microscopy) and analytical chemical techniques, we present the principal chemical components of the wool and its mechanism of exit from the glandular trichome. RESULTS: We show the woolly farina consists of micron-diameter fibres formed from a mixture of flavone and substituted flavone derivatives. This contrasts with the powdery farina, consisting almost entirely of flavone. The woolly farina in D. tapetodes is extruded through specific sites at the surface of the trichome's glandular head cell, characterised by a small complete gap in the plasma membrane, cell wall and cuticle and forming a tight seal between the fibre and hole. The data is consistent with formation and thread elongation occurring from within the cell. CONCLUSIONS: Our results suggest the composition of the D. tapetodes farina dictates its formation as wool rather than powder, consistent with a model of thread integrity relying on intermolecular H-bonding. Glandular trichomes produce multiple wool fibres by concentrating and maintaining their extrusion at specific sites at the cell cortex of the head cell. As the wool is extensive across the plant, there may be associated selection pressures attributed to living at high altitudes.
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Flavonas/análise , Primulaceae/ultraestrutura , Tricomas/ultraestrutura , Microscopia , Microscopia Eletrônica , Primulaceae/químicaRESUMO
Point-of-care monitoring of chemical biomarkers in real-time holds great potential in rapid disease diagnostics and precision medicine. However, monitoring is still rare in practice, as the measurement of biomarkers often requires time consuming and labour intensive assay procedures such as enzyme linked immunosorbent assay (ELISA), which pose a challenge to an autonomous point-of-care device. This paper describes a prototype device capable of performing ELISA autonomously and repeatedly in a high frequency using droplet microfluidics. Driven by a specially designed peristaltic pump, the device can collect liquid samples from a reservoir, produce trains of droplets, complete magnetic bead based ELISA protocols and provide readouts with colourimetric measurement. Here, cortisol was chosen as a target analyte as its concentration in the human body varies on a circadian rhythm which may be perturbed by disease. The prototype device draws in and analyses 350 nL of the sample containing free bioactive cortisol every 10 seconds, with a sample-to-signal time of 10 minutes, and measures favourably in the analytical range of 3.175-100 ng ml-1, with reliably lower variability compared with the well plate based assay. As most ELISA type assays share similar procedures, we envisage that this approach could form a platform technology for measurement or even continuous monitoring of biomarkers in biological fluids at the point-of-care.
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Dispositivos Lab-On-A-Chip , Microfluídica , Ensaio de Imunoadsorção Enzimática , Humanos , Hidrocortisona , Sistemas Automatizados de Assistência Junto ao LeitoRESUMO
This case describes the strong utility of optical coherence tomography in multidisciplinary management of a complex case of type 2 neurofibromatosis.
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The coming years are expected to bring rapid changes in the nanotechnology regulatory landscape, with the establishment of a new framework for nano-risk governance, in silico approaches for characterisation and risk assessment of nanomaterials, and novel procedures for the early identification and management of nanomaterial risks. In this context, Safe(r)-by-Design (SbD) emerges as a powerful preventive approach to support the development of safe and sustainable (SSbD) nanotechnology-based products and processes throughout the life cycle. This paper summarises the work undertaken to develop a blueprint for the deployment and operation of a permanent European Centre of collaborating laboratories and research organisations supporting safe innovation in nanotechnologies. The proposed entity, referred to as "the Centre", will establish a 'one-stop shop' for nanosafety-related services and a central contact point for addressing stakeholder questions about nanosafety. Its operation will rely on significant business, legal and market knowledge, as well as other tools developed and acquired through the EU-funded EC4SafeNano project and subsequent ongoing activities. The proposed blueprint adopts a demand-driven service update scheme to allow the necessary vigilance and flexibility to identify opportunities and adjust its activities and services in the rapidly evolving regulatory and nano risk governance landscape. The proposed Centre will play a major role as a conduit to transfer scientific knowledge between the research and commercial laboratories or consultants able to provide high quality nanosafety services, and the end-users of such services (e.g., industry, SMEs, consultancy firms, and regulatory authorities). The Centre will harmonise service provision, and bring novel risk assessment and management approaches, e.g. in silico methodologies, closer to practice, notably through SbD/SSbD, and decisively support safe and sustainable innovation of industrial production in the nanotechnology industry according to the European Chemicals Strategy for Sustainability.
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Nanoestruturas , Nanotecnologia , Indústrias , Medição de RiscoRESUMO
A major hallmark of Alzheimer's disease is the misfolding and aggregation of the amyloid- ß peptide (Aß). While early research pointed towards large fibrillar- and plaque-like aggregates as being the most toxic species, recent evidence now implicates small soluble Aß oligomers as being orders of magnitude more harmful. Techniques capable of characterizing oligomer stoichiometry and assembly are thus critical for a deeper understanding of the earliest stages of neurodegeneration and for rationally testing next-generation oligomer inhibitors. While the fluorescence response of extrinsic fluorescent probes such as Thioflavin-T have become workhorse tools for characterizing large Aß aggregates in solution, it is widely accepted that these methods suffer from many important drawbacks, including an insensitivity to oligomeric species. Here, we integrate several biophysics techniques to gain new insight into oligomer formation at the single-molecule level. We showcase single-molecule stepwise photobleaching of fluorescent dye molecules as a powerful method to bypass many of the traditional limitations, and provide a step-by-step guide to implementing the technique in vitro. By collecting fluorescence emission from single Aß(1-42) peptides labelled at the N-terminal position with HiLyte Fluor 555 via wide-field total internal reflection fluorescence (TIRF) imaging, we demonstrate how to characterize the number of peptides per single immobile oligomer and reveal heterogeneity within sample populations. Importantly, fluorescence emerging from Aß oligomers cannot be easily investigated using diffraction-limited optical microscopy tools. To assay oligomer activity, we also demonstrate the implementation of another biophysical method involving the ratiometric imaging of Fura-2-AM loaded cells which quantifies the rate of oligomer-induced dysregulation of intracellular Ca2+ homeostasis. We anticipate that the integrated single-molecule biophysics approaches highlighted here will develop further and in principle may be extended to the investigation of other protein aggregation systems under controlled experimental conditions.
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Fotodegradação , Doença de Alzheimer , Peptídeos beta-Amiloides , Corantes Fluorescentes , Humanos , Fragmentos de Peptídeos , Agregados ProteicosRESUMO
Ajoene is a compound found in garlic extracts exhibiting a large range of biological activity. Novel ajoene analogues have been prepared in the search of compounds with superior bioactivity. Modifications include the alteration of the sulfoxide, the central alkene and the terminal allyl groups.
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Reactive oxygen species (ROS) are generated during physiological bouts of synaptic activity and as a consequence of pathological conditions in the central nervous system. How neurons respond to and distinguish between ROS in these different contexts is currently unknown. In Drosophila mutants with enhanced JNK activity, lower levels of ROS are observed and these animals are resistant to both changes in ROS and changes in synapse morphology induced by oxidative stress. In wild type flies, disrupting JNK-AP-1 signalling perturbs redox homeostasis suggesting JNK activity positively regulates neuronal antioxidant defense. We validated this hypothesis in mammalian neurons, finding that JNK activity regulates the expression of the antioxidant gene Srxn-1, in a c-Jun dependent manner. We describe a conserved 'adaptive' role for neuronal JNK in the maintenance of redox homeostasis that is relevant to several neurodegenerative diseases.
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Antioxidantes , Proteínas Quinases JNK Ativadas por Mitógeno , Animais , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases , Neurônios/metabolismo , Estresse Oxidativo , Espécies Reativas de OxigênioRESUMO
OBJECTIVES: The processing of seafood (fish and shellfish) for human consumption can lead to health consequences, including occupational asthma (OA). Several non-UK studies have reported both respiratory outcomes and airborne levels of major allergens in seafood processing. However, there is a paucity of such evidence in the UK land-based seafood processing sector, which employs some 20 000 workers. METHODS: University of Manchester's Surveillance of Work-related and Occupational Respiratory Disease (SWORD) reporting system has been interrogated over the period 1992-2017 to define the incidence rate of OA cases that can be ascribed to the UK land-based processing sector, and the seafood species implicated. Airborne allergen monitoring data undertaken at Health and Safety Executive's laboratory from 2003 to 2019 have also been collated. RESULTS: The estimated annual OA incidence rate in seafood processors was 70 [95% confidence intervals (CIs) 48.9, 91.1] per 100 000 workers compared with 2.9 (95% CIs 2.8, 3.1) in 'all other industries'. The annual calculated percentage trend in OA (1992-2017) was -8.1% (95% CIs -15.9, 0.4) in seafood processing showing a similar trend to 'all other industries' (mean -7.0%; 95% CIs -7.8, -6.1). Prawns and salmon/trout were notably implicated by SWORD as causative species related to OA. There is a general paucity of available UK airborne allergen monitoring data, particularly concerning processing salmon or trout. Available airborne monitoring for salmon parvalbumin in seven processors ranged between the limit of detection and 816 ng m-3 (n = 64). Available air monitoring levels of the major shellfish allergen (tropomyosin) during processing of crabs and prawns ranged between 1 and 101 600 ng m-3 (n = 280), highlighting that high levels of exposure can occur. CONCLUSIONS: These data show an excess incidence of OA in the UK seafood processing industry during 1992-2017, with limited airborne monitoring data for the processing of prawn, crab, and salmon suggesting that significant exposure to major seafood allergens can occur in this industry. Further investigation of current levels of respiratory ill-health and the sources of allergen exposure are warranted.