The Prohibitin-Binding Compound Fluorizoline Activates the Integrated Stress Response through the eIF2α Kinase HRI.

Fluorizoline is a synthetic molecule that induces apoptosis, by selectively targeting prohibitins (PHBs), through induction of the BH3-only protein NOXA. This induction is transcriptionally regulated by the integrated stress response (ISR)-related transcription factors ATF3 and ATF4. Here, we evaluate the role of the four eIF2α kinases, to decipher which is responsible for the mechanism of ISR activation triggered by fluorizoline in HeLa and HAP1 cells. First, we demonstrated the involvement of the eIF2α kinases using ISR inhibitor (ISRIB) and by simultaneous downregulation of all four eIF2α kinases, as both approaches were able to increase cell resistance to fluorizoline-induced apoptosis. Furthermore, we confirmed that fluorizoline treatment results in endoplasmic reticulum (ER) stress, as evidenced by PERK activation. Despite PERK activation, this kinase was not directly involved in the ISR activation by fluorizoline. In this regard, we found that the eIF2α kinases are capable of compensating for each other's loss of function. Importantly, we demonstrated that the mitochondrial-stress-related eIF2α kinase HRI mediates ISR activation after fluorizoline treatment.

Charting the Chemical Reaction Space around a Multicomponent Combination: Controlled Access to a Diverse Set of Biologically Relevant Scaffolds.

Charting the chemical reaction space around the combination of carbonyls, amines, and isocyanoacetates allows the description of new multicomponent processes leading to a variety of unsaturated imidazolone scaffolds. The resulting compounds display the chromophore of the green fluorescent protein and the core of the natural product coelenterazine. Despite the competitive nature of the pathways involved, general protocols provide selective access to the desired chemotypes. Moreover, we describe unprecedented reactivity at the C-2 position of the imidazolone core to directly afford C, S, and N-derivatives featuring natural products (e.g. leucettamines), potent kinase inhibitors, and fluorescent probes with suitable optical and biological profiles.

A Survey of Self-Supervised and Few-Shot Object Detection.

Labeling data is often expensive and time-consuming, especially for tasks such as object detection and instance segmentation, which require dense labeling of the image. While few-shot object detection is about training a model on novel (unseen) object classes with little data, it still requires prior training on many labeled examples of base (seen) classes. On the other hand, self-supervised methods aim at learning representations from unlabeled data which transfer well to downstream tasks such as object detection. Combining few-shot and self-supervised object detection is a promising research direction. In this survey, we review and characterize the most recent approaches on few-shot and self-supervised object detection. Then, we give our main takeaways and discuss future research directions. Project page: https://gabrielhuang.github.io/fsod-survey/.

Charting the Chemical Reaction Space around a Multicomponent Combination: Controlled Access to a Diverse Set of Biologically Relevant Scaffolds.

Charting the chemical reaction space around the combination of carbonyls, amines, and isocyanoacetates allows the description of new multicomponent processes leading to a variety of unsaturated imidazolone scaffolds. The resulting compounds display the chromophore of the green fluorescent protein and the core of the natural product coelenterazine. Despite the competitive nature of the pathways involved, general protocols provide selective access to the desired chemotypes. Moreover, we describe unprecedented reactivity at the C-2 position of the imidazolone core to directly afford C, S, and N-derivatives featuring natural products (e.g. leucettamines), potent kinase inhibitors, and fluorescent probes with suitable optical and biological profiles.

Heterocycle-Based Multicomponent Reactions in Drug Discovery: From Hit Finding to Rational Design.

In the context of the structural complexity necessary for a molecule to selectively display a therapeutical action and the requirements for suitable pharmacokinetics, a robust synthetic approach is essential. Typically, thousands of relatively similar compounds should be prepared along the drug discovery process. In this respect, heterocycle-based multicomponent reactions offer advantages over traditional stepwise sequences in terms of synthetic economy, as well as the fast access to chemsets to study the structure activity relationships, the fine tuning of properties, and the preparation of larger amounts for preclinical phases. In this account, we briefly summarize the scientific methodology backing the research line followed by the group. We comment on the main results, clustered according to the targets and, finally, in the conclusion section, we offer a general appraisal of the situation and some perspectives regarding future directions in academic and private research.

Deep Pain: Exploiting Long Short-Term Memory Networks for Facial Expression Classification.

Pain is an unpleasant feeling that has been shown to be an important factor for the recovery of patients. Since this is costly in human resources and difficult to do objectively, there is the need for automatic systems to measure it. In this paper, contrary to current state-of-the-art techniques in pain assessment, which are based on facial features only, we suggest that the performance can be enhanced by feeding the raw frames to deep learning models, outperforming the latest state-of-the-art results while also directly facing the problem of imbalanced data. As a baseline, our approach first uses convolutional neural networks (CNNs) to learn facial features from VGG_Faces, which are then linked to a long short-term memory to exploit the temporal relation between video frames. We further compare the performances of using the so popular schema based on the canonically normalized appearance versus taking into account the whole image. As a result, we outperform current state-of-the-art area under the curve performance in the UNBC-McMaster Shoulder Pain Expression Archive Database. In addition, to evaluate the generalization properties of our proposed methodology on facial motion recognition, we also report competitive results in the Cohn Kanade+ facial expression database.

Weakly supervised underwater fish segmentation using affinity LCFCN.

Estimating fish body measurements like length, width, and mass has received considerable research due to its potential in boosting productivity in marine and aquaculture applications. Some methods are based on manual collection of these measurements using tools like a ruler which is time consuming and labour intensive. Others rely on fully-supervised segmentation models to automatically acquire these measurements but require collecting per-pixel labels which are also time consuming. It can take up to 2 minutes per fish to acquire accurate segmentation labels. To address this problem, we propose a segmentation model that can efficiently train on images labeled with point-level supervision, where each fish is annotated with a single click. This labeling scheme takes an average of only 1 second per fish. Our model uses a fully convolutional neural network with one branch that outputs per-pixel scores and another that outputs an affinity matrix. These two outputs are aggregated using a random walk to get the final, refined per-pixel output. The whole model is trained end-to-end using the localization-based counting fully convolutional neural network (LCFCN) loss and thus we call our method Affinity-LCFCN (A-LCFCN). We conduct experiments on the DeepFish dataset, which contains several fish habitats from north-eastern Australia. The results show that A-LCFCN outperforms a fully-supervised segmentation model when the annotation budget is fixed. They also show that A-LCFCN achieves better segmentation results than LCFCN and a standard baseline.

Preoperative nutritional status assessment predicts postoperative outcomes in patients with surgically resected non-small cell lung cancer.

BACKGROUND: As nutritional status plays an important role in outcomes after surgery, this study evaluated the association between preoperative nutritional status (NS) and postoperative outcomes after major resection for lung cancer. METHODS: We identified 219 patients with a diagnosis of cancer who underwent pulmonary resection from 2010 to 2012. Preoperative NS was assessed by anthropometric and biological parameters, body mass index (BMI), and the Nutritional Risk Index (NRI). We stratified this population into 4 BMI groups: underweight, normal weight, overweight and obese and 4 NRI groups: well-nourished; mildly malnourished; moderately malnourished and severely malnourished. The outcomes measured were postoperative complications; 30-day postoperative mortality; hospital length of stay (LOS), overall survival (OS) and disease-free survival (DFS). We performed both unadjusted analysis and adjusted multivariable analysis, controlling for statistically significant variables. RESULTS: Mean BMI and NRI were, respectively, 26.5 ± 4.3 and 112.4 ± 3.3. There were no significant differences between BMI categories and resection type, pathological stage, or overall postoperative complications. By contrast, significant differences (p < 0.05) in postoperative complications were observed among the NRI groups. LOS was longer in underweight and/or malnourished patients. In terms of OS, we found no significant differences according to NRI and BMI; however, patients with underweight had significantly shorter DFS compared with patients with overweight and obesity (log-rank p-value = 0.001). CONCLUSION: NS as measured by the NRI is an independent predictor of the risk of postsurgical complications, regardless of clinicopathologic characteristics. NRI might therefore be an useful tool for identifying early-stage lung cancer patients at risk for postoperative complications.

Toxins Secreted by Bacillus Isolated from Lung Adenocarcinomas Favor the Penetration of Toxic Substances.

The aim was to explore the eventual role of bacteria in the induction of lung cancer by smoking habits. Viable bacteria closely related to the genus Bacillus were detected at high frequencies in lung-cancer biopsies. Similar, if not identical, microbes were isolated from cigarettes and in smog. Bacteria present in cigarettes could be transferred to a physiological solution via a "smoker" device that mimicked their potential transfer during smoking those bacteria produce exotoxins able to open transmembrane pores. These channels can be used as a way to penetrate cells of benzopyrenes and other toxic substances present in tobacco products. We hypothesize that Bacillaceae present in tobacco play a key role in the development of lung cancer.

[Risk management of soybean-related asthma: monitoring and surveillance]. / Gestión del riesgo de asma por haba de soja: monitorización y vigilancia.

OBJECTIVES: Allergen emissions during soybean unloading operations in the Barcelona harbor have caused asthma epidemics. The present article aimed to describe the surveillance and control measures carried out by the public health services. METHODS: Data were extracted from control systems from 1999 to 2009, with description of the surveillance schemes for allergen emissions, environmental concentrations (with defined reference levels) and for health. RESULTS: Of 95 studies of plant emission, four were above the reference levels, and filters were found to be the most likely cause. Mean environmental concentrations were low but were above the reference levels on 13 days; these levels were related to adverse meteorological conditions and incidents in the plants. No health effects were detected in the panel of patients nor epidemic asthma days. CONCLUSIONS: The system detects incidents and has shown its usefulness in protecting public health.

[Legionellosis in a site with low risk of proliferation]. / Legionelosis en un establecimiento considerado de bajo riesgo de proliferación.

After three cases of legionellosis associated with a spa were identified, an investigation was conducted to confirm the source of infection, determine the risk factors, and establish control measures. Between November 26, 2008 and September 16, 2009, six inspections were carried out, samples were collected for Legionella pneumophila isolation, and water temperature was determined at all the sampling points of the hot water system and at the spa pools. The presence of L. pneumophila serogroup 1 with the same molecular pattern as that found in the clinical isolate was confirmed in the hot water system (with a low proliferation risk according to legislation). The crude attack rate was 0.34% (95% CI: 0.09-0.94). Samples without L. pneumophila were obtained only after structural changes were carried out. Possible factors participating in the cluster were water temperatures between 25 °C and 30 °C, stagnant water and early morning exposure.

[Indicators for the management of public health services]. / Indicadores para la gestión de los servicios de salud pública.

OBJECTIVES: To define a set of indicators for the management of the various services of an agency responsible for comprehensive public health in a defined area and population. METHODS: We analyzed the agency's activity and held discussions with those responsible for the distinct services to define indicators whose estimation is viable and which optimally describe three aspects: the services' activity, coverage, quality or effectiveness, and cost. RESULTS: Quantitative indicators were defined for all the productive public health services inventoried in the agency's services portfolio, but not all three aspects could be covered in all areas. In addition, for coordination and liaison services, the indicators were often less quantitative and less sensitive to change. Costs were estimated for the main areas of productive activity and for the 47 services or products, with indirect costs being estimated as 14% of expenditure. CONCLUSIONS: We defined a system of indicators for management control, allowing comparisons over time and with other geographical areas, and with activity indicators covering all production areas. Defining indicators reflecting coverage, quality or impact for all services is more difficult. Cost can be estimated by unit of production for some services, but less successfully for others. The yearly cost by population is always a good synthetic indicator of the cost of public health services.

Gestión del riesgo de asma por haba de soja: monitorización y vigilancia / Risk management of soybean-related asthma: monitoring and surveillance

Objetivos Las emisiones de alérgeno durante la descarga de haba de soja en el puerto de Barcelona han sido causa de asma epidémica. Este trabajo describe las acciones de vigilancia y control de los servicios de salud pública. Métodos Los datos se extraen del dispositivo de control durante el periodo de 1999 a 2009, detallando el sistema de vigilancia de emisiones y concentraciones ambientales de alérgeno (para las que se han fijado empíricamente niveles guía), y de salud. Resultados De los 95 estudios de emisión, cuatro superaron los valores de alarma, con probables causas en los filtros. Las concentraciones ambientales medias son bajas, pero superaron el nivel de alarma 13 días; se relacionan con meteorología adversa e incidencias en las instalaciones. No se detectaron efectos en los pacientes del panel de vigilancia, ni días de asma epidémica (AU)

Objectives Allergen emissions during soybean unloading operations in the Barcelona harbor have caused asthma epidemics. The present article aimed to describe the surveillance and control measures carried out by the public health services. Methods Data were extracted from control systems from 1999 to 2009, with description of the surveillance schemes for allergen emissions, environmental concentrations (with defined reference levels) and for health. Results Of 95 studies of plant emission, four were above the reference levels, and filters were found to be the most likely cause. Mean environmental concentrations were low but were above the reference levels on 13 days; these levels were related to adverse meteorological conditions and incidents in the plants. No health effects were detected in the panel of patients nor epidemic asthma days. Conclusions The system detects incidents and has shown its usefulness in protecting public health (AU)

Legionelosis en un establecimiento considerado de bajo riesgo de proliferación / Legionellosis in a site with low risk of proliferation

Ante tres casos de legionelosis asociados a un establecimiento balneario se inició la investigación para confirmar la fuente de infección, determinar el riesgo y controlarlo. Entre el 26 de noviembre de 2008 y el 16 de septiembre de 2009 se realizaron seis inspecciones, con toma de temperaturas y muestras de agua para el aislamiento de Legionella pneumophila en todos los puntos de la red de agua caliente sanitaria y en las piscinas climatizadas. Se confirmó la presencia de L. pneumophila del serogrupo 1 con el mismo patrón molecular que la cepa clínica en el circuito de agua caliente sanitaria (de bajo riesgo de proliferación). La tasa de ataque bruta fue del 0,34% (intervalo de confianza del 95%: 0,09–0,94). Solo se obtuvieron muestras de agua sin presencia de L. pneumophila tras realizar cambios estructurales. Las temperaturas del agua entre 25 y 30°C, el estancamiento del agua y la exposición a primera hora de la mañana serían factores participantes en la agrupación de casos (AU)

After three cases of legionellosis associated with a spa were identified, an investigation was conducted to confirm the source of infection, determine the risk factors, and establish control measures. Between November 26, 2008 and September 16, 2009, six inspections were carried out, samples were collected for Legionella pneumophila isolation, and water temperature was determined at all the sampling points of the hot water system and at the spa pools. The presence of L. pneumophila serogroup 1 with the same molecular pattern as that found in the clinical isolate was confirmed in the hot water system (with a low proliferation risk according to legislation). The crude attack rate was 0.34% (95% CI: 0.09–0.94). Samples without L. pneumophila were obtained only after structural changes were carried out. Possible factors participating in the cluster were water temperatures between 25°C and 30°C, stagnant water and early morning exposure (AU)

Indicadores para la gestión de los servicios de salud pública / Indicators for the management of public health services

Objetivos Se pretende definir indicadores apropiados para la gestión de los distintos servicios de una organización que presta servicios integrales de salud pública a una población y territorio definidos.Métodos Análisis de la actividad y discusión con los responsables de los diversos servicios para buscar indicadores de obtención viable que recojan de la mejor forma tres aspectos: su actividad, su cobertura, calidad o efectividad, y su coste.Resultados Se obtienen indicadores cuantitativos para todos los servicios productivos de salud pública relacionados en el catálogo de servicios, pero en algunas líneas de trabajo no parece factible cubrir los tres ámbitos. Además, para las actividades de coordinación y enlace los indicadores son a menudo menos cuantitativos y poco sensibles a cambios. Se ha podido cuantificar el coste para las grandes líneas de trabajo productivo y los 47 servicios o productos, y los costes indirectos se han estimado en un 14%.Conclusiones Es factible desarrollar un sistema de información de gestión para los servicios de salud pública que permita comparaciones a lo largo del tiempo o entre territorios, con indicadores de actividad para todas las líneas de trabajo productivo. Los indicadores que reflejan la cobertura, calidad o impacto de los servicios plantean las mayores dificultades. Para algunas líneas de trabajo se pueden obtener indicadores de coste por unidad de producto con sentido, y para otras es más difícil. En todos los casos, el coste por habitante y año es un buen indicador sintético del coste de los servicios de salud pública (AU)

Objectives To define a set of indicators for the management of the various services of an agency responsible for comprehensive public health in a defined area and population. Methods We analyzed the agency’s activity and held discussions with those responsible for the distinct services to define indicators whose estimation is viable and which optimally describe three aspects: the services’ activity, coverage, quality or effectiveness, and cost. Results Quantitative indicators were defined for all the productive public health services inventoried in the agency’s services portfolio, but not all three aspects could be covered in all areas. In addition, for coordination and liaison services, the indicators were often less quantitative and less sensitive to change. Costs were estimated for the main areas of productive activity and for the 47 services or products, with indirect costs being estimated as 14% of expenditure.Conclusions We defined a system of indicators for management control, allowing comparisons over time and with other geographical areas, and with activity indicators covering all production areas. Defining indicators reflecting coverage, quality or impact for all services is more difficult. Cost can be estimated by unit of production for some services, but less successfully for others. The yearly cost by population is always a good synthetic indicator of the cost of public health services (AU)