Associazioni non profit e linked open data: un esperimento

Le Associazioni Non Profit giocano un ruolo sempre più rilevante nella vita dei cittadini e rappresentano un'importante realtà produttiva del nostro paese; molto spesso però risulta difficile trovare informazioni relative ad eventi, attività o sull'esistenza stessa di queste associazioni. Per venire in contro alle esigenze dei cittadini molte Regioni e Province mettono a disposizione degli elenchi in cui sono raccolte le informazioni relative alle varie organizzazioni che operano sul territorio. Questi elenchi però, presentano spesso grossi problemi, sia per quanto riguarda la correttezza dei dati, sia per i formati utilizzati per la pubblicazione. Questi fattori hanno portato all'idea e alla necessità di realizzare un sistema per raccogliere, sistematizzare e rendere fruibili le informazioni sulle Associazioni Non Profit presenti sul territorio, in modo che questi dati possano essere utilizzati liberamente da chiunque per scopi diversi. Il presente lavoro si pone quindi due obiettivi principali: il primo consiste nell'implementazione di un tool in grado di recuperare le informazioni sulle Associazioni Non Profit sfruttando i loro Siti Web; questo avviene per mezzo dell'utilizzo di tecniche di Web Crawling e Web Scraping. Il secondo obiettivo consiste nel pubblicare le informazioni raccolte, secondo dei modelli che ne permettano un uso libero e non vincolato; per la pubblicazione e la strutturazione dei dati è stato utilizzato un modello basato sui principi dei linked open data.

Comprehensive analysis of lymph node stroma-expressed Ig superfamily members reveals redundant and nonredundant roles for ICAM-1, ICAM-2, and VCAM-1 in lymphocyte homing

Although it is well established that stromal intercellular adhesion molecule-1 (ICAM-1), ICAM-2, and vascular cell adhesion molecule-1 (VCAM-1) mediate lymphocyte recruitment into peripheral lymph nodes (PLNs), their precise contributions to the individual steps of the lymphocyte homing cascade are not known. Here, we provide in vivo evidence for a selective function for ICAM-1 > ICAM-2 > VCAM-1 in lymphocyte arrest within noninflamed PLN microvessels. Blocking all 3 CAMs completely inhibited lymphocyte adhesion within PLN high endothelial venules (HEVs). Post-arrest extravasation of T cells was a 3-step process, with optional ICAM-1-dependent intraluminal crawling followed by rapid ICAM-1- or ICAM-2-independent diapedesis and perivascular trapping. Parenchymal motility of lymphocytes was modestly reduced in the absence of ICAM-1, while ICAM-2 and alpha4-integrin ligands were not required for B-cell motility within follicles. Our findings highlight nonredundant functions for stromal Ig family CAMs in shear-resistant lymphocyte adhesion in steady-state HEVs, a unique role for ICAM-1 in intraluminal lymphocyte crawling but redundant roles for ICAM-1 and ICAM-2 in lymphocyte diapedesis and interstitial motility.

Comparison of immortalized bEnd5 and primary mouse brain microvascular endothelial cells as in vitro blood-brain barrier models for the study of T cell extravasation

Important insights into the molecular mechanism of T cell extravasation across the blood-brain barrier (BBB) have already been obtained using immortalized mouse brain endothelioma cell lines (bEnd). However, compared with bEnd, primary brain endothelial cells have been shown to establish better barrier characteristics, including complex tight junctions and low permeability. In this study, we asked whether bEnd5 and primary mouse brain microvascular endothelial cells (pMBMECs) were equally suited as in vitro models with which to study the cellular and molecular mechanisms of T cell extravasation across the BBB. We found that both in vitro BBB models equally supported both T cell adhesion under static and physiologic flow conditions, and T cell crawling on the endothelial surface against the direction of flow. In contrast, distances of T cell crawling on pMBMECs were strikingly longer than on bEnd5, whereas diapedesis of T cells across pMBMECs was dramatically reduced compared with bEnd5. Thus, both in vitro BBB models are suited to study T cell adhesion. However, because pMBMECs better reflect endothelial BBB specialization in vivo, we propose that more reliable information about the cellular and molecular mechanisms of T cell diapedesis across the BBB can be attained using pMBMECs.

In vivo analysis of uropod function during physiological T cell trafficking

Migrating lymphocytes acquire a polarized phenotype with a leading and a trailing edge, or uropod. Although in vitro experiments in cell lines or activated primary cell cultures have established that Rho-p160 coiled-coil kinase (ROCK)-myosin II-mediated uropod contractility is required for integrin de-adhesion on two-dimensional surfaces and nuclear propulsion through narrow pores in three-dimensional matrices, less is known about the role of these two events during the recirculation of primary, nonactivated lymphocytes. Using pharmacological antagonists of ROCK and myosin II, we report that inhibition of uropod contractility blocked integrin-independent mouse T cell migration through narrow, but not large, pores in vitro. T cell crawling on chemokine-coated endothelial cells under shear was severely impaired by ROCK inhibition, whereas transendothelial migration was only reduced through endothelial cells with high, but not low, barrier properties. Using three-dimensional thick-tissue imaging and dynamic two-photon microscopy of T cell motility in lymphoid tissue, we demonstrated a significant role for uropod contractility in intraluminal crawling and transendothelial migration through lymph node, but not bone marrow, endothelial cells. Finally, we demonstrated that ICAM-1, but not anatomical constraints or integrin-independent interactions, reduced parenchymal motility of inhibitor-treated T cells within the dense lymphoid microenvironment, thus assigning context-dependent roles for uropod contraction during lymphocyte recirculation.

Differential requirement for ROCK in dendritic cell migration within lymphatic capillaries in steady-state and inflammation

Dendritic cell (DC) migration via lymphatic vessels to draining lymph nodes (dLNs) is crucial for the initiation of adaptive immunity. We imaged this process by intravital microscopy (IVM) in the ear skin of transgenic mice bearing red-fluorescent vasculature and yellow-fluorescent DCs. DCs within lymphatic capillaries were rarely transported by flow, but actively migrated within lymphatics and were significantly faster than in the interstitium. Pharmacologic blockade of the Rho-associated protein kinase (ROCK), which mediates nuclear contraction and de-adhesion from integrin ligands, significantly reduced DC migration from skin to dLNs in steady-state. IVM revealed that ROCK blockade strongly reduced the velocity of interstitial DC migration, but only marginally affected intralymphatic DC migration. By contrast, during tissue inflammation, ROCK blockade profoundly decreased both interstitial and intralymphatic DC migration. Inhibition of intralymphatic migration was paralleled by a strong up-regulation of ICAM-1 in lymphatic endothelium, suggesting that during inflammation ROCK mediates de-adhesion of DC-expressed integrins from lymphatic-expressed ICAM-1. Flow chamber assays confirmed an involvement of lymphatic-expressed ICAM-1 and DC-expressed ROCK in DC crawling on lymphatic endothelium. Overall, our findings further define the role of ROCK in DC migration to dLNs and reveal a differential requirement for ROCK in intralymphatic DC crawling during steady-state and inflammation.

Going against the tide--how encephalitogenic T cells breach the blood-brain barrier

During multiple sclerosis or its animal model, experimental autoimmune encephalomyelitis, circulating immune cells enter the central nervous system (CNS) causing neuroinflammation. Extravasation from the blood circulation across the vessel wall occurs through a multistep process regulated by adhesion and signal transducing molecules on the immune cells and on the endothelium. Since the CNS is shielded by the highly specialized blood-brain barrier (BBB), immune cell extravasation into the CNS requires breaching this particularly tight endothelial border. Consequently, travelling into the CNS demands unique adaptations which account for the extreme tightness of the BBB. Modern imaging tools have shown that after arresting on BBB endothelium, in vivo or in vitro encephalitogenic effector/memory T cells crawl for long distances, possibly exceeding 150 µm along the surface of the BBB endothelium before rapidly crossing the BBB. Interestingly, in addition to the distance of crawling, the preferred direction of crawling against the flow is unique for T cell crawling on the luminal surface of CNS microvessels. In this review, we will summarize the cellular and molecular mechanisms involved in the unique T cell behavior that is obviously required for finding a site permissive for diapedesis across the unique vascular bed of the BBB.

Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells

Activated T cells use very late antigen-4/α4β1 integrin for capture, rolling on, and firm adhesion to endothelial cells, and use leukocyte function-associated antigen-1/αLβ2 integrin for subsequent crawling and extravasation. Inhibition of α4β1 is sufficient to prevent extravasation of activated T cells and is successfully used to combat autoimmune diseases, such as multiple sclerosis. Here we show that effector T cells lacking the integrin activator Kindlin-3 extravasate and induce experimental autoimmune encephalomyelitis in mice immunized with autoantigen. In sharp contrast, adoptively transferred autoreactive T cells from Kindlin-3-deficient mice fail to extravasate into the naïve CNS. Mechanistically, autoreactive Kindlin-3-null T cells extravasate when the CNS is inflamed and the brain microvasculature expresses high levels of integrin ligands. Flow chamber assays under physiological shear conditions confirmed that Kindlin-3-null effector T cells adhere to high concentrations of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, albeit less efficiently than WT T cells. Although these arrested T cells polarize and start crawling, only few remain firmly adherent over time. Our data demonstrate that the requirement of Kindlin-3 for effector T cells to induce α4β1 and αLβ2 integrin ligand binding and stabilization of integrin-ligand bonds is critical when integrin ligand levels are low, but of less importance when integrin ligand levels are high.

Cell surface levels of endothelial ICAM-1 influence the transcellular or paracellular T-cell diapedesis across the blood-brain barrier

The extravasation of CD4(+) effector/memory T cells (TEM cells) across the blood-brain barrier (BBB) is a crucial step in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis (MS). Endothelial ICAM-1 and ICAM-2 are essential for CD4(+) TEM cell crawling on the BBB prior to diapedesis. Here, we investigated the influence of cell surface levels of endothelial ICAM-1 in determining the cellular route of CD4(+) TEM -cell diapedesis across cytokine treated primary mouse BBB endothelial cells under physiological flow. Inflammatory conditions, inducing high levels of endothelial ICAM-1, promoted rapid initiation of transcellular diapedesis of CD4(+) T cells across the BBB, while intermediate levels of endothelial ICAM-1 favored paracellular CD4(+) T-cell diapedesis. Importantly, the route of T-cell diapedesis across the BBB was independent of loss of BBB barrier properties. Unexpectedly, a low number of CD4(+) TEM cells was found to cross the inflamed BBB in the absence of endothelial ICAM-1 and ICAM-2 via an obviously alternatively regulated transcellular pathway. In vivo, this translated to the development of ameliorated EAE in ICAM-1(null) //ICAM-2(-/-) C57BL/6J mice. Taken together, our study demonstrates that cell surface levels of endothelial ICAM-1 rather than the inflammatory stimulus or BBB integrity influence the pathway of T-cell diapedesis across the BBB.

Multi-Environment Model Estimation for Motility Analysis of Caernorhabditis elegans

The nematode Caenorhabditis elegans is a well-known model organism used to investigate fundamental questions in biology. Motility assays of this small roundworm are designed to study the relationships between genes and behavior. Commonly, motility analysis is used to classify nematode movements and characterize them quantitatively. Over the past years, C. elegans' motility has been studied across a wide range of environments, including crawling on substrates, swimming in fluids, and locomoting through microfluidic substrates. However, each environment often requires customized image processing tools relying on heuristic parameter tuning. In the present study, we propose a novel Multi-Environment Model Estimation (MEME) framework for automated image segmentation that is versatile across various environments. The MEME platform is constructed around the concept of Mixture of Gaussian (MOG) models, where statistical models for both the background environment and the nematode appearance are explicitly learned and used to accurately segment a target nematode. Our method is designed to simplify the burden often imposed on users; here, only a single image which includes a nematode in its environment must be provided for model learning. In addition, our platform enables the extraction of nematode ‘skeletons’ for straightforward motility quantification. We test our algorithm on various locomotive environments and compare performances with an intensity-based thresholding method. Overall, MEME outperforms the threshold-based approach for the overwhelming majority of cases examined. Ultimately, MEME provides researchers with an attractive platform for C. elegans' segmentation and ‘skeletonizing’ across a wide range of motility assays.

The physiological roles of ICAM-1 and ICAM-2 in neutrophil migration into tissues

PURPOSE OF REVIEW Neutrophil extravasation from the blood into tissues is initiated by tethering and rolling of neutrophils on endothelial cells, followed by neutrophil integrin activation and shear resistant arrest, crawling, diapedesis and breaching the endothelial basement membrane harbouring pericytes. Endothelial intercellular cell adhesion molecule (ICAM)-1 and ICAM-2, in conjunction with ICAM-1 on pericytes, critically contribute to each step. In addition, epithelial ICAM-1 is involved in neutrophil migration to peri-epithelial sites. The most recent findings on the role of ICAM-1 and ICAM-2 for neutrophil migration into tissues will be reviewed here. RECENT FINDINGS Signalling via endothelial ICAM-1 and ICAM-2 contributes to stiffness of the endothelial cells at sites of chronic inflammation and junctional maturation, respectively. Endothelial ICAM-2 contributes to neutrophil crawling and initiation of paracellular diapedesis, which then proceeds independent of ICAM-2. Substantial transcellular neutrophil diapedesis across the blood-brain barrier is strictly dependent on endothelial ICAM-1 and ICAM-2. Endothelial ICAM-1 or ICAM-2 is involved in neutrophil-mediated plasma leakage. ICAM-1 on pericytes assists the final step of neutrophil extravasation. Epithelial ICAM-1 rather indirectly promotes neutrophil migration to peri-epithelial sites. SUMMARY ICAM-1 and ICAM-2 are involved in each step of neutrophil extravasation, and have redundant but also distinct functions. Analysis of the role of endothelial ICAM-1 requires simultaneous consideration of ICAM-2.

Seawater carbonate chemistry and Littorina obtusata biological processes during experiments, 2009

Our understanding of the effects of ocean acidification on whole organism function is growing, but most current information is for adult stages of development. Here, we show the effects of reduced pH seawater (pH 7.6) on aspects of the development, physiology and behaviour of encapsulated embryos of the marine intertidal gastropod Littorina obtusata. We found reduced viability and increased development times under reduced pH conditions, and the embryos had significantly altered behaviours and physiologies. In acidified seawater, embryos spent more time stationary, had slower rotation rates, spent less time crawling, but increased their movement periodicity compared with those maintained under control conditions. Larval and adult heart rates were significantly lower in acidified seawater, and hatchling snails had an altered shell morphology (lateral length and spiral shell length) compared to control snails. Our findings show that ocean acidification may have multiple, subtle effects during the early development of marine animals that may have implications for their survival beyond those predicted using later life stages.

Semantic Service Discovery Techniques for the composable web

This PhD thesis contributes to the problem of resource and service discovery in the context of the composable web. In the current web, mashup technologies allow developers reusing services and contents to build new web applications. However, developers face a problem of information flood when searching for appropriate services or resources for their combination. To contribute to overcoming this problem, a framework is defined for the discovery of services and resources. In this framework, three levels are defined for performing discovery at content, discovery and agente levels. The content level involves the information available in web resources. The web follows the Representational Stateless Transfer (REST) architectural style, in which resources are returned as representations from servers to clients. These representations usually employ the HyperText Markup Language (HTML), which, along with Content Style Sheets (CSS), describes the markup employed to render representations in a web browser. Although the use of SemanticWeb standards such as Resource Description Framework (RDF) make this architecture suitable for automatic processes to use the information present in web resources, these standards are too often not employed, so automation must rely on processing HTML. This process, often referred as Screen Scraping in the literature, is the content discovery according to the proposed framework. At this level, discovery rules indicate how the different pieces of data in resources’ representations are mapped onto semantic entities. By processing discovery rules on web resources, semantically described contents can be obtained out of them. The service level involves the operations that can be performed on the web. The current web allows users to perform different tasks such as search, blogging, e-commerce, or social networking. To describe the possible services in RESTful architectures, a high-level feature-oriented service methodology is proposed at this level. This lightweight description framework allows defining service discovery rules to identify operations in interactions with REST resources. The discovery is thus performed by applying discovery rules to contents discovered in REST interactions, in a novel process called service probing. Also, service discovery can be performed by modelling services as contents, i.e., by retrieving Application Programming Interface (API) documentation and API listings in service registries such as ProgrammableWeb. For this, a unified model for composable components in Mashup-Driven Development (MDD) has been defined after the analysis of service repositories from the web. The agent level involves the orchestration of the discovery of services and contents. At this level, agent rules allow to specify behaviours for crawling and executing services, which results in the fulfilment of a high-level goal. Agent rules are plans that allow introspecting the discovered data and services from the web and the knowledge present in service and content discovery rules to anticipate the contents and services to be found on specific resources from the web. By the definition of plans, an agent can be configured to target specific resources. The discovery framework has been evaluated on different scenarios, each one covering different levels of the framework. Contenidos a la Carta project deals with the mashing-up of news from electronic newspapers, and the framework was used for the discovery and extraction of pieces of news from the web. Similarly, in Resulta and VulneraNET projects the discovery of ideas and security knowledge in the web is covered, respectively. The service level is covered in the OMELETTE project, where mashup components such as services and widgets are discovered from component repositories from the web. The agent level is applied to the crawling of services and news in these scenarios, highlighting how the semantic description of rules and extracted data can provide complex behaviours and orchestrations of tasks in the web. The main contributions of the thesis are the unified framework for discovery, which allows configuring agents to perform automated tasks. Also, a scraping ontology has been defined for the construction of mappings for scraping web resources. A novel first-order logic rule induction algorithm is defined for the automated construction and maintenance of these mappings out of the visual information in web resources. Additionally, a common unified model for the discovery of services is defined, which allows sharing service descriptions. Future work comprises the further extension of service probing, resource ranking, the extension of the Scraping Ontology, extensions of the agent model, and contructing a base of discovery rules. Resumen La presente tesis doctoral contribuye al problema de descubrimiento de servicios y recursos en el contexto de la web combinable. En la web actual, las tecnologías de combinación de aplicaciones permiten a los desarrolladores reutilizar servicios y contenidos para construir nuevas aplicaciones web. Pese a todo, los desarrolladores afrontan un problema de saturación de información a la hora de buscar servicios o recursos apropiados para su combinación. Para contribuir a la solución de este problema, se propone un marco de trabajo para el descubrimiento de servicios y recursos. En este marco, se definen tres capas sobre las que se realiza descubrimiento a nivel de contenido, servicio y agente. El nivel de contenido involucra a la información disponible en recursos web. La web sigue el estilo arquitectónico Representational Stateless Transfer (REST), en el que los recursos son devueltos como representaciones por parte de los servidores a los clientes. Estas representaciones normalmente emplean el lenguaje de marcado HyperText Markup Language (HTML), que, unido al estándar Content Style Sheets (CSS), describe el marcado empleado para mostrar representaciones en un navegador web. Aunque el uso de estándares de la web semántica como Resource Description Framework (RDF) hace apta esta arquitectura para su uso por procesos automatizados, estos estándares no son empleados en muchas ocasiones, por lo que cualquier automatización debe basarse en el procesado del marcado HTML. Este proceso, normalmente conocido como Screen Scraping en la literatura, es el descubrimiento de contenidos en el marco de trabajo propuesto. En este nivel, un conjunto de reglas de descubrimiento indican cómo los diferentes datos en las representaciones de recursos se corresponden con entidades semánticas. Al procesar estas reglas sobre recursos web, pueden obtenerse contenidos descritos semánticamente. El nivel de servicio involucra las operaciones que pueden ser llevadas a cabo en la web. Actualmente, los usuarios de la web pueden realizar diversas tareas como búsqueda, blogging, comercio electrónico o redes sociales. Para describir los posibles servicios en arquitecturas REST, se propone en este nivel una metodología de alto nivel para descubrimiento de servicios orientada a funcionalidades. Este marco de descubrimiento ligero permite definir reglas de descubrimiento de servicios para identificar operaciones en interacciones con recursos REST. Este descubrimiento es por tanto llevado a cabo al aplicar las reglas de descubrimiento sobre contenidos descubiertos en interacciones REST, en un nuevo procedimiento llamado sondeo de servicios. Además, el descubrimiento de servicios puede ser llevado a cabo mediante el modelado de servicios como contenidos. Es decir, mediante la recuperación de documentación de Application Programming Interfaces (APIs) y listas de APIs en registros de servicios como ProgrammableWeb. Para ello, se ha definido un modelo unificado de componentes combinables para Mashup-Driven Development (MDD) tras el análisis de repositorios de servicios de la web. El nivel de agente involucra la orquestación del descubrimiento de servicios y contenidos. En este nivel, las reglas de nivel de agente permiten especificar comportamientos para el rastreo y ejecución de servicios, lo que permite la consecución de metas de mayor nivel. Las reglas de los agentes son planes que permiten la introspección sobre los datos y servicios descubiertos, así como sobre el conocimiento presente en las reglas de descubrimiento de servicios y contenidos para anticipar contenidos y servicios por encontrar en recursos específicos de la web. Mediante la definición de planes, un agente puede ser configurado para descubrir recursos específicos. El marco de descubrimiento ha sido evaluado sobre diferentes escenarios, cada uno cubriendo distintos niveles del marco. El proyecto Contenidos a la Carta trata de la combinación de noticias de periódicos digitales, y en él el framework se ha empleado para el descubrimiento y extracción de noticias de la web. De manera análoga, en los proyectos Resulta y VulneraNET se ha llevado a cabo un descubrimiento de ideas y de conocimientos de seguridad, respectivamente. El nivel de servicio se cubre en el proyecto OMELETTE, en el que componentes combinables como servicios y widgets se descubren en repositorios de componentes de la web. El nivel de agente se aplica al rastreo de servicios y noticias en estos escenarios, mostrando cómo la descripción semántica de reglas y datos extraídos permiten proporcionar comportamientos complejos y orquestaciones de tareas en la web. Las principales contribuciones de la tesis son el marco de trabajo unificado para descubrimiento, que permite configurar agentes para realizar tareas automatizadas. Además, una ontología de extracción ha sido definida para la construcción de correspondencias y extraer información de recursos web. Asimismo, un algoritmo para la inducción de reglas de lógica de primer orden se ha definido para la construcción y el mantenimiento de estas correspondencias a partir de la información visual de recursos web. Adicionalmente, se ha definido un modelo común y unificado para el descubrimiento de servicios que permite la compartición de descripciones de servicios. Como trabajos futuros se considera la extensión del sondeo de servicios, clasificación de recursos, extensión de la ontología de extracción y la construcción de una base de reglas de descubrimiento.

Movement analysis in infancy may be useful for early diagnosis of autism

All of the 17 autistic children studied in the present paper showed disturbances of movement that with our methods could be detected clearly at the age of 4–6 months, and sometimes even at birth. We used the Eshkol–Wachman Movement Analysis System in combination with still-frame videodisc analysis to study videos obtained from parents of children who had been diagnosed as autistic by conventional methods, usually around 3 years old. The videos showed their behaviors when they were infants, long before they had been diagnosed as autistic. The movement disorders varied from child to child. Disturbances were revealed in the shape of the mouth and in some or all of the milestones of development, including, lying, righting, sitting, crawling, and walking. Our findings support the view that movement disturbances play an intrinsic part in the phenomenon of autism, that they are present at birth, and that they can be used to diagnose the presence of autism in the first few months of life. They indicate the need for the development of methods of therapy to be applied from the first few months of life in autism.

How well can an amoeba climb?

We report here our efforts to measure the crawling force generated by cells undergoing amoeboid locomotion. In a centrifuge microscope, acceleration was increased until amoebae of Dictyostelium discoideum were “stalled” or no longer able to “climb up.” The “apparent weight” of the amoebae at stalling rpm in myosin mutants depended on the presence of myosin II (but not myosins IA and IB) and paralleled the cortical strength of the cells. Surprisingly, however, the cell stalled not only in low-density media as expected but also in media with densities greater than the cell density where the buoyant force should push the amoeba upward. We find that the leading pseudopod is bent under centrifugal force in all stalled amoebae, suggesting that this pseudopod is very dense indeed. This finding also suggests that directional cell locomotion against resistive forces requires a turgid forward-pointing pseudopod, most likely sustained by cortical actomyosin II.

A Tropomyosin-2 Mutation Suppresses a Troponin I Myopathy in Drosophila

A suppressor mutation, D53, of the held-up2 allele of the Drosophila melanogaster Troponin I (wupA) gene is described. D53, a missense mutation, S185F, of the tropomyosin-2, Tm2, gene fully suppresses all the phenotypic effects of held-up2, including the destructive hypercontraction of the indirect flight muscles (IFMs), a lack of jumping, the progressive myopathy of the walking muscles, and reductions in larval crawling and feeding behavior. The suppressor restores normal function of the IFMs, but flight ability decreases with age and correlates with an unusual, progressive structural collapse of the myofibrillar lattice starting at the center. The S185F substitution in Tm2 is close to a troponin T binding site on tropomyosin. Models to explain suppression by D53, derived from current knowledge of the vertebrate troponin-tropomyosin complex structure and functions, are discussed. The effects of S185F are compared with those of two mutations in residues 175 and 180 of human α-tropomyosin 1 which cause familial hypertrophic cardiomyopathy (HCM).