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Virtual reality (VR) is an emerging technology that has demonstrated incredible value within medical education. However, medical institutions adopting VR as a learning tool need to ensure that the immersive technology product they pick possesses standard usability criteria. The current literature is limited in defining what specific criteria institutions should look for, or how to select between various VR products. Since there have been little to no algorithms available to the medical education community to aid in this process, a reproducible matrix has been developed to evaluate multiple VR platforms at once which can help identify the best option for medical education programs. The matrix is a 10-point scoring system that includes what the research team considered to be the 10 most important factors when selecting a VR product for medical education. The scores of any two or more VR products can be quantitatively compared. Therefore, the matrix is to be used as a methodological framework to help objectively select the highest-rated immersive technology platform. The research team involved in the development of the matrix consisted of an associate dean for simulation and technology, a director of simulation and technology, and eight medical students.
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Identifying genetic modifiers of familial amyotrophic lateral sclerosis (ALS) may reveal targets for therapeutic modulation with potential application to sporadic ALS. GGGGCC (G4C2) repeat expansions in the C9orf72 gene underlie the most common form of familial ALS, and generate toxic arginine-containing dipeptide repeats (DPRs), which interfere with membraneless organelles, such as the nucleolus. Here we considered senataxin (SETX), the genetic cause of ALS4, as a modifier of C9orf72 ALS, because SETX is a nuclear helicase that may regulate RNA-protein interactions involved in ALS dysfunction. After documenting that decreased SETX expression enhances arginine-containing DPR toxicity and C9orf72 repeat expansion toxicity in HEK293 cells and primary neurons, we generated SETX fly lines and evaluated the effect of SETX in flies expressing either (G4C2)58 repeats or glycine-arginine-50 [GR(50)] DPRs. We observed dramatic suppression of disease phenotypes in (G4C2)58 and GR(50) Drosophila models, and detected a striking relocalization of GR(50) out of the nucleolus in flies co-expressing SETX. Next-generation GR(1000) fly models, that show age-related motor deficits in climbing and movement assays, were similarly rescued with SETX co-expression. We noted that the physical interaction between SETX and arginine-containing DPRs is partially RNA-dependent. Finally, we directly assessed the nucleolus in cells expressing GR-DPRs, confirmed reduced mobility of proteins trafficking to the nucleolus upon GR-DPR expression, and found that SETX dosage modulated nucleolus liquidity in GR-DPR-expressing cells and motor neurons. These findings reveal a hitherto unknown connection between SETX function and cellular processes contributing to neuron demise in the most common form of familial ALS.
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Esclerose Lateral Amiotrófica , Demência Frontotemporal , Humanos , Animais , Esclerose Lateral Amiotrófica/metabolismo , Dipeptídeos/genética , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Arginina/genética , Arginina/metabolismo , Células HEK293 , Neurônios Motores/metabolismo , Drosophila/metabolismo , RNA/metabolismo , Demência Frontotemporal/genética , Expansão das Repetições de DNA/genética , DNA Helicases/genética , RNA Helicases/genética , Enzimas Multifuncionais/genéticaRESUMO
Repeat expansion diseases, including fragile X syndrome, Huntington's disease, and C9orf72-related motor neuron disease and frontotemporal dementia, are a group of disorders associated with polymorphic expansions of tandem repeat nucleotide sequences. These expansions are highly repetitive and often hundreds to thousands of repeats in length, making accurate identification and determination of repeat length via PCR or sequencing challenging. Here we describe a protocol for monitoring repeat length in Drosophila models carrying 1,000 repeat C9orf72-related dipeptide repeat transgenes using Southern blotting. This protocol has been used regularly to check the length of these lines for over 100 generations with robust and repeatable results and can be implemented for monitoring any repeat expansion in Drosophila.
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Alzheimer's disease (AD) is one of the biggest human health threats due to increases in aging of the global population. Unfortunately, drugs for treating AD have been largely ineffective. Interestingly, downregulation of macroautophagy (autophagy) plays an essential role in AD pathogenesis. Therefore, targeting autophagy has drawn considerable attention as a therapeutic approach for the treatment of AD. However, developing new therapeutics is time-consuming and requires huge investments. One of the strategies currently under consideration for many diseases is "drug repositioning" or "drug repurposing". In this comprehensive review, we have provided an overview of the impact of autophagy on AD pathophysiology, reviewed the therapeutics that upregulate autophagy and are currently used in the treatment of other diseases, including cancers, and evaluated their repurposing as a possible treatment option for AD. In addition, we discussed the potential of applying nano-drug delivery to neurodegenerative diseases, such as AD, to overcome the challenge of crossing the blood brain barrier and specifically target molecules/pathways of interest with minimal side effects.
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Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Autofagia , Barreira Hematoencefálica/patologia , Reposicionamento de Medicamentos , HumanosRESUMO
Alpha-tocopherol (vitamin E) is an essential nutrient that functions as a major lipid-soluble antioxidant in humans. The alpha-tocopherol transfer protein (TTP) binds α-tocopherol with high affinity and selectivity and regulates whole-body distribution of the vitamin. Heritable mutations in the TTPA gene result in familial vitamin E deficiency, elevated indices of oxidative stress, and progressive neurodegeneration that manifest primarily in spinocerebellar ataxia. Although the essential role of vitamin E in neurological health has been recognized for over 50 years, the mechanisms by which this essential nutrient is transported in the central nervous system are poorly understood. Here we found that, in the murine cerebellum, TTP is selectively expressed in glial fibrillary acidic protein-positive astrocytes, where it facilitates efflux of vitamin E to neighboring neurons. We also show that induction of oxidative stress enhances the transcription of the TtpA gene in cultured cerebellar astrocytes. Furthermore, secretion of vitamin E from astrocytes is mediated by an ABC-type transporter, and uptake of the vitamin into neurons involves the low-density lipoprotein receptor-related protein 1. Taken together, our data indicate that TTP-expressing astrocytes control the delivery of vitamin E from astrocytes to neurons, and that this process is homeostatically responsive to oxidative stress. These are the first observations that address the detailed molecular mechanisms of vitamin E transport in the central nervous system, and these results have important implications for understanding the molecular underpinnings of oxidative stress-related neurodegenerative diseases.
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Astrócitos , Proteínas de Transporte , Cerebelo , Neurônios , Vitamina E , alfa-Tocoferol , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Proteínas de Transporte/metabolismo , Cerebelo/citologia , Cerebelo/metabolismo , Humanos , Camundongos , Neurônios/citologia , Neurônios/metabolismo , Ativador de Plasminogênio Tecidual/metabolismo , Tocoferóis , Vitamina E/metabolismo , Vitaminas , alfa-Tocoferol/metabolismoRESUMO
An intronic hexanucleotide (GGGGCC) expansion in the C9orf72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In the decade following its discovery, much progress has been made in enhancing our understanding of how it precipitates disease. Both loss of function caused by reduced C9orf72 transcript levels, and gain of function mechanisms, triggered by the production of repetitive sense and antisense RNA and dipeptide repeat proteins, are thought to contribute to the toxicity. Drosophila models, with their unrivaled genetic tractability and short lifespan, have played a key role in developing our understanding of C9orf72-related FTD/ALS. There is no C9orf72 homolog in fly, and although this precludes investigations into loss of function toxicity, it is useful for elucidating mechanisms underpinning gain of function toxicity. To date there are a range of Drosophila C9orf72 models, encompassing different aspects of gain of function toxicity. In addition to pure repeat transgenes, which produce both repeat RNA and dipeptide repeat proteins (DPRs), RNA only models and DPR models have been generated to unpick the individual contributions of RNA and each dipeptide repeat protein to C9orf72 toxicity. In this review, we discuss how Drosophila models have shaped our understanding of C9orf72 gain of function toxicity, and address opportunities to utilize these models for further research.
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Fragment-based hit identification (FBHI) allows proportionately greater coverage of chemical space using fewer molecules than traditional high-throughput screening approaches. However, effectively exploiting this advantage is highly dependent on the library design. Solubility, stability, chemical complexity, chemical/shape diversity, and synthetic tractability for fragment elaboration are all critical aspects, and molecule design remains a time-consuming task for computational and medicinal chemists. Artificial neural networks have attracted considerable attention in automated de novo design applications and could also prove useful for fragment library design. Chemical autoencoders are neural networks consisting of encoder and decoder parts, which respectively compress and decompress molecular representations. The decoder is applied to samples drawn from the space of compressed representations to generate novel molecules that can be scored for properties of interest. Here, we report an autoencoder model using a recurrent neural network architecture, which was trained using 486,565 fragments curated from commercial sources, to simultaneously reconstruct both SMILES and chemical fingerprints. To explore its utility in fragment design, we applied transfer learning to the fingerprint decoder layers to train a classifier using 66 frequent hitter fragments identified from our screening campaigns. Using a particle swarm optimization sampling approach, we compare the performance of this "dual" model to an architecture encoding SMILES only. The dual model produced valid SMILES with improved features, considering a range of properties including aromatic ring counts, heavy atom count, synthetic accessibility, and a new fragment complexity score we term Feature Complexity (FeCo). Additionally, we demonstrate that generative performance is further enhanced by use of a simple syntax-correction procedure during training, in which invalid and undesirable SMILES are spiked into the training set. Finally, we used the syntax-corrected model to generate a library of novel candidate privileged fragments.
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Aprendizado de Máquina , Redes Neurais de ComputaçãoRESUMO
BACKGROUND: The roles of pharmacy technicians in clinical practice are being explored. Medication prior authorizations (PAs) from insurers can lead to delays in pharmacotherapy. OBJECTIVE: To assess the efficiency of our clinical pharmacy technicians in processing PAs for medications. PRACTICE DESCRIPTION: Outpatient clinics in a comprehensive health care provider group. PRACTICE INNOVATION: PA requests are routed to technicians for initial data collection. Clinical pharmacists can review their work before submission. EVALUATION METHODS: Clinical pharmacy staff in 4 clinics recorded information about PA requests from January 21, 2020, to April 21, 2020. In 3 of the clinics, PA requests were primarily processed by clinical pharmacy technicians. In another clinic, requests were processed by a clinical pharmacist. Information collected included the date the request was received, outcomes (e.g., approval, therapy change, or nonapproval), and the date of final outcome. Descriptive statistics were prepared, including number of requests that were approved, number of business days between request and decision, and final outcome. RESULTS: Overall, 720 PA requests were received. Of these, 88.6% were approved with first response, and 673 (93.5%) were eventually approved. Median time to first response was 0 business days, regardless of clinic. In 75% of cases, first response was within 1 business day. PA characteristics varied across clinics; however, PA approval percentages were comparable (91.2%-94.3%). CONCLUSION: In an assessment of clinical pharmacy technicians' efficiency in responding to pharmacy plan PA requests, more than 90% were approved, often within one business day. Our results must be interpreted in light of local factors and a virus pandemic during the study. However, results of requests handled by technicians were similar to results when the requests were handled by a clinical pharmacist. Clinical pharmacy technicians can be efficient and cost-effective in this role.
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Farmácias , Serviço de Farmácia Hospitalar , Humanos , Farmacêuticos , Técnicos em Farmácia , Autorização PréviaRESUMO
Frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are two neurodegenerative diseases with clinical, genetic and pathological overlap. As such, they are commonly regarded as a single spectrum disorder, with pure FTD and pure ALS representing distinct ends of a continuum. Dysfunctional endo-lysosomal and autophagic trafficking, leading to impaired proteostasis is common across the FTD-ALS spectrum. These pathways are, in part, mediated by CHMP2B, a protein that coordinates membrane scission events as a core component of the ESCRT machinery. Here we review how ALS and FTD disease causing mutations in CHMP2B have greatly contributed to our understanding of how endosomal-lysosomal and autophagic dysfunction contribute to neurodegeneration, and how in vitro and in vivo models have helped elucidate novel candidates for potential therapeutic intervention with implications across the FTD-ALS spectrum.
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Esclerose Lateral Amiotrófica/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Demência Frontotemporal/genética , Animais , Humanos , MutaçãoRESUMO
A large intronic hexanucleotide repeat expansion (GGGGCC) within the C9orf72 (C9orf72-SMCR8 Complex Subunit) locus is the most prevalent genetic cause of both Frontotemporal Dementia (FTD) and Motor Neuron Disease (MND). In patients this expansion is typically hundreds to thousands of repeat units in length. Repeat associated non-AUG translation of the expansion leads to the formation of toxic, pathological Dipeptide-Repeat Proteins (DPRs). To date there remains a lack of in vivo models expressing C9orf72 related DPRs with a repeat length of more than a few hundred repeats. As such our understanding of how physiologically relevant repeat length DPRs effect the nervous system in an ageing in vivo system remains limited. In this study we generated Drosophila models expressing DPRs over 1000 repeat units in length, a known pathological length in humans. Using these models, we demonstrate each DPR exhibits a unique, age-dependent, phenotypic and pathological profile. Furthermore, we show co-expression of specific DPR combinations leads to distinct, age-dependent, phenotypes not observed through expression of single DPRs. We propose these models represent a unique, in vivo, tool for dissecting the molecular mechanisms implicated in disease pathology, opening up new avenues in the study of both MND and FTD.
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Expansão das Repetições de DNA/genética , Dipeptídeos/genética , Modelos Animais de Doenças , Demência Frontotemporal , Doença dos Neurônios Motores , Animais , Proteína C9orf72/genética , Drosophila , FenótipoRESUMO
Mutations in CHMP2B, encoding a protein in the endosomal sorting complexes required for transport (ESCRT) machinery, causes frontotemporal dementia linked to chromosome 3 (FTD3). FTD, the second most common form of pre-senile dementia, can also be caused by genetic mutations in other genes, including TANK-binding kinase 1 (TBK1). How FTD-causing disease genes interact is largely unknown. We found that partial loss function of Ik2, the fly homologue of TBK1 also known as I-kappaB kinase ε (IKKε), enhanced the toxicity of mutant CHMP2B in the fly eye and that Ik2 overexpression suppressed the effect of mutant CHMP2B in neurons. Partial loss of function of Spn-F, a downstream phosphorylation target of Ik2, greatly enhanced the mutant CHMP2B phenotype. An interactome analysis to understand cellular processes regulated by Spn-F identified a network of interacting proteins including Spn-F, Ik2, dynein light chain, and Hook, an adaptor protein in early endosome transport. Partial loss of function of dynein light chain or Hook also enhanced mutant CHMP2B toxicity. These findings identify several evolutionarily conserved genes, including ik2/TBK1, cut up (encoding dynein light chain) and hook, as genetic modifiers of FTD3-associated mutant CHMP2B toxicity and implicate early endosome transport as a potential contributing pathway in FTD.
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Proteínas de Drosophila/genética , Endossomos/fisiologia , Demência Frontotemporal/genética , Proteínas de Transporte Vesicular/genética , Animais , Modelos Animais de Doenças , Drosophila , Dineínas/genética , Quinase I-kappa B/genética , Proteínas Associadas aos Microtúbulos/genéticaRESUMO
Frontotemporal dementia (FTD) is one of the most prevalent forms of early-onset dementia. It represents part of the FTD-Amyotrophic Lateral Sclerosis (ALS) spectrum, a continuum of genetically and pathologically overlapping disorders. FTD-causing mutations in CHMP2B, a gene encoding a core component of the heteromeric ESCRT-III Complex, lead to perturbed endosomal-lysosomal and autophagic trafficking with impaired proteostasis. While CHMP2B mutations are rare, dysfunctional endosomal-lysosomal signalling is common across the FTD-ALS spectrum. Using our established Drosophila and mammalian models of CHMP2BIntron5 induced FTD we demonstrate that the FDA-approved compound Ursodeoxycholic Acid (UDCA) conveys neuroprotection, downstream of endosomal-lysosomal dysfunction in both Drosophila and primary mammalian neurons. UDCA exhibited a dose dependent rescue of neuronal structure and function in Drosophila pan-neuronally expressing CHMP2BIntron5. Rescue of CHMP2BIntron5 dependent dendritic collapse and apoptosis with UDCA in rat primary neurons was also observed. UDCA failed to ameliorate aberrant accumulation of endosomal and autophagic organelles or ubiquitinated neuronal inclusions in both models. We demonstrate the neuroprotective activity of UDCA downstream of endosomal-lysosomal and autophagic dysfunction, delineating the molecular mode of action of UDCA and highlighting its potential as a therapeutic for the treatment of FTD-ALS spectrum disorders.
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Apoptose/efeitos dos fármacos , Proteínas de Drosophila/genética , Demência Frontotemporal/genética , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Sinapses/efeitos dos fármacos , Ácido Ursodesoxicólico/farmacologia , Proteínas de Transporte Vesicular/genética , Animais , Sobrevivência Celular/efeitos dos fármacos , Dendritos/efeitos dos fármacos , Dendritos/patologia , Modelos Animais de Doenças , Drosophila , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Endossomos/efeitos dos fármacos , Endossomos/metabolismo , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/patologia , Cultura Primária de Células , Ratos , Sinapses/patologia , Proteínas Ubiquitinadas/efeitos dos fármacos , Proteínas Ubiquitinadas/metabolismoRESUMO
The relationship between microscopic and macroscopic properties in fat-continuous dispersions is multifaceted compared to bulk oils, which limits the ability to extrapolate results from bulk systems towards complex formulations. The impact of confectioner's sugar on the crystallization and rheology of palm oil (PO) and mid-fraction blend (PMF) was investigated in this study. Adding sugar significantly increased storage modulus (G') and firmness (F) of the oils while exhibiting increased sensitivity towards processing conditions. Multiple regression analysis was used to create predictive models that correct for the effects caused by confectioner's sugar, such as altered fat crystal morphology and increased network rigidity, through the binary variable ζ. With limited studies on the use of PO in confectionery applications, these models may be used by industry as tools for production that do not rely on anecdote and overcome any shortcomings associated with the extrapolation from bulk systems.
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Doces , Óleo de Palmeira/química , Sacarose/química , Cristalização , Armazenamento de Alimentos , Modelos Teóricos , Pós/química , Análise de Regressão , Reologia , TemperaturaRESUMO
Reactive oxygen species (ROS) have been extensively studied as damaging agents associated with ageing and neurodegenerative conditions. Their role in the nervous system under non-pathological conditions has remained poorly understood. Working with the Drosophila larval locomotor network, we show that in neurons ROS act as obligate signals required for neuronal activity-dependent structural plasticity, of both pre- and postsynaptic terminals. ROS signaling is also necessary for maintaining evoked synaptic transmission at the neuromuscular junction, and for activity-regulated homeostatic adjustment of motor network output, as measured by larval crawling behavior. We identified the highly conserved Parkinson's disease-linked protein DJ-1ß as a redox sensor in neurons where it regulates structural plasticity, in part via modulation of the PTEN-PI3Kinase pathway. This study provides a new conceptual framework of neuronal ROS as second messengers required for neuronal plasticity and for network tuning, whose dysregulation in the ageing brain and under neurodegenerative conditions may contribute to synaptic dysfunction.
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Drosophila melanogaster/metabolismo , Neurônios Motores/metabolismo , Plasticidade Neuronal , Espécies Reativas de Oxigênio/metabolismo , Animais , Animais Geneticamente Modificados , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Larva/genética , Larva/metabolismo , Microscopia Eletrônica de Transmissão , Proteínas do Tecido Nervoso/metabolismo , Junção Neuromuscular/metabolismo , Junção Neuromuscular/ultraestrutura , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Terminações Pré-Sinápticas/metabolismo , Terminações Pré-Sinápticas/ultraestrutura , Proteína Desglicase DJ-1 , Transdução de Sinais , Transmissão SinápticaRESUMO
The halodecarboxylation of heteroarene carboxylic acids by treatment with N-bromosuccinimide or N-chlorosuccinimide was performed. This procedure provides a convenient route to synthetically useful mono-halogenated heteroarene intermediates such as halo-indoles, -aza-indoles, -indazoles and -aza-indazoles. The mild conditions employed and simple protocol provides an advantage over traditional halodecarboxylation procedures that require expensive and toxic metal catalysts, basic conditions, time-consuming intermediate isolation and elevated reaction temperatures.
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Sphingolipids are found in abundance at synapses and have been implicated in regulation of synapse structure, function, and degeneration. Their precise role in these processes, however, remains obscure. Serine Palmitoyl-transferase (SPT) is the first enzymatic step for synthesis of sphingolipids. Analysis of the Drosophila larval neuromuscular junction (NMJ) revealed mutations in the SPT enzyme subunit, lace/SPTLC2 resulted in deficits in synaptic structure and function. Although NMJ length is normal in lace mutants, the number of boutons per NMJ is reduced to â¼50% of the wild type number. Synaptic boutons in lace mutants are much larger but show little perturbation to the general ultrastructure. Electrophysiological analysis of lace mutant synapses revealed strong synaptic transmission coupled with predominance of depression over facilitation. The structural and functional phenotypes of lace mirrored aspects of Basigin (Bsg), a small Ig-domain adhesion molecule also known to regulate synaptic structure and function. Mutant combinations of lace and Bsg generated large synaptic boutons, while lace mutants showed abnormal accumulation of Bsg at synapses, suggesting that Bsg requires sphingolipid to regulate structure of the synapse. In support of this, we found Bsg to be enriched in lipid rafts. Our data points to a role for sphingolipids in the regulation and fine-tuning of synaptic structure and function while sphingolipid regulation of synaptic structure may be mediated via the activity of Bsg.
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Drosophila melanogaster/fisiologia , Junção Neuromuscular/anatomia & histologia , Junção Neuromuscular/fisiologia , Esfingolipídeos/fisiologia , Sinapses/fisiologia , Animais , Proteínas de Drosophila/genética , Proteínas de Drosophila/fisiologia , Fenômenos Eletrofisiológicos/fisiologia , Imuno-Histoquímica , Larva , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/fisiologia , Microdomínios da Membrana/fisiologia , Microdomínios da Membrana/ultraestrutura , Mutação/genética , Terminações Pré-Sinápticas/fisiologia , Terminações Pré-Sinápticas/ultraestrutura , Serina C-Palmitoiltransferase/genética , Serina C-Palmitoiltransferase/fisiologiaRESUMO
Frontotemporal dementia (FTD) is one of the most prevalent forms of early-onset dementia. However, the pathological mechanisms driving neuronal atrophy in FTD remain poorly understood. Here we identify a conserved role for the novel pro-apoptotic protein plenty of SH3s (POSH)/SH3 domain containing ring finger 1 in mediating neuropathology in Drosophila and mammalian models of charged multivesicular body protein 2B (CHMP2BIntron5) associated FTD. Aberrant, AKT dependent, accumulation of POSH was observed throughout the nervous system of both Drosophila and mice expressing CHMP2BIntron5. Knockdown of POSH was shown to be neuroprotective and sufficient to alleviate aberrant neuronal morphology, behavioral deficits and premature-lethality in Drosophila models, as well as dendritic collapse and cell death in CHMP2BIntron5expressing rat primary neurons. POSH knockdown also ameliorated elevated markers of Jun N-terminal kinase and apoptotic cascades in both Drosophila and mammalian models. This study provides the first characterization of POSH as a potential component of an FTD neuropathology, identifying a novel apoptotic pathway with relevance to the FTD spectrum.
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Proteínas de Transporte/genética , Proteínas do Citoesqueleto/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Demência Frontotemporal/genética , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Proteínas de Transporte Vesicular/genética , Animais , Animais Geneticamente Modificados , Apoptose/genética , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/metabolismo , Proteínas do Citoesqueleto/antagonistas & inibidores , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Proteínas de Drosophila/antagonistas & inibidores , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Regulação da Expressão Gênica , Humanos , Íntrons , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Larva/genética , Larva/metabolismo , Longevidade/genética , Camundongos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Sistema Nervoso/metabolismo , Sistema Nervoso/patologia , Neurônios/patologia , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Transdução de Sinais , Proteínas de Transporte Vesicular/metabolismoAssuntos
Esclerose Lateral Amiotrófica , Doença de Parkinson , Humanos , Ocupações , Percepção , Estados UnidosRESUMO
New tools are required to ensure the adequate control of the neglected tropical disease human African trypanosomiasis. Annual reports of infection have recently fallen to fewer than 5000 cases per year; however, current therapies are hard to administer and have safety concerns and, hence, are far from ideal. Trypanosome alternative oxidase is an exciting target for controlling the infection; it is unique to the parasite, and inhibition of this enzyme with the natural product ascofuranone has shown to clear in vivo infections. We report the synthesis and associated structure activity relationships of inhibitors based upon this natural product with correlation to T. b. brucei growth inhibition in an attempt to generate molecules that possess improved physicochemical properties and potential for use as new treatments for human African trypanosomiasis.
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Proteínas Mitocondriais/antagonistas & inibidores , Oxirredutases/antagonistas & inibidores , Proteínas de Plantas/antagonistas & inibidores , Proteínas de Protozoários/antagonistas & inibidores , Sesquiterpenos/isolamento & purificação , Tripanossomicidas/isolamento & purificação , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma/efeitos dos fármacos , Trypanosoma/enzimologia , Concentração Inibidora 50 , Estrutura Molecular , Testes de Sensibilidade Parasitária , Sesquiterpenos/síntese química , Sesquiterpenos/química , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Trypanosoma brucei brucei/crescimento & desenvolvimentoRESUMO
There is increasing evidence for a strong genetic basis for autism, with many genetic models being developed in an attempt to replicate autistic symptoms in animals. However, current animal behaviour paradigms rarely match the social and cognitive behaviours exhibited by autistic individuals. Here, we instead assay another functional domain-sensory processing-known to be affected in autism to test a novel genetic autism model in Drosophila melanogaster. We show similar visual response alterations and a similar development trajectory in Nhe3 mutant flies (total n = 72) and in autistic human participants (total n = 154). We report a dissociation between first- and second-order electrophysiological visual responses to steady-state stimulation in adult mutant fruit flies that is strikingly similar to the response pattern in human adults with ASD as well as that of a large sample of neurotypical individuals with high numbers of autistic traits. We explain this as a genetically driven, selective signalling alteration in transient visual dynamics. In contrast to adults, autistic children show a decrease in the first-order response that is matched by the fruit fly model, suggesting that a compensatory change in processing occurs during development. Our results provide the first animal model of autism comprising a differential developmental phenotype in visual processing.