Hierarchically-coupled hidden Markov models for learning kinetic rates from single-molecule data

We address the problem of analyzing sets of noisy time-varying signals that all report on the same process but confound straightforward analyses due to complex inter-signal heterogeneities and measurement artifacts. In particular we consider single-molecule experiments which indirectly measure the distinct steps in a biomolecular process via observations of noisy time-dependent signals such as a fluorescence intensity or bead position. Straightforward hidden Markov model (HMM) analyses attempt to characterize such processes in terms of a set of conformational states, the transitions that can occur between these states, and the associated rates at which those transitions occur; but require ad-hoc post-processing steps to combine multiple signals. Here we develop a hierarchically coupled HMM that allows experimentalists to deal with inter-signal variability in a principled and automatic way. Our approach is a generalized expectation maximization hyperparameter point estimation procedure with variational Bayes at the level of individual time series that learns an single interpretable representation of the overall data generating process.Comment: 9 pages, 5 figure

The Oncogenic Lung Cancer Fusion Kinase CD74-ROS Activates a Novel Invasiveness Pathway through E-Syt1 Phosphorylation

Patients with lung cancer often present with metastatic disease and therefore have a very poor prognosis. The recent discovery of several novel ROS receptor tyrosine kinase molecular alterations in non–small cell lung cancer (NSCLC) presents a therapeutic opportunity for the development of new targeted treatment strategies. Here, we report that the NSCLC-derived fusion CD74-ROS, which accounts for 30% of all ROS fusion kinases in NSCLC, is an active and oncogenic tyrosine kinase. We found that CD74-ROS–expressing cells were highly invasive in vitro and metastatic in vivo. Pharmacologic inhibition of CD74-ROS kinase activity reversed its transforming capacity by attenuating downstream signaling networks. Using quantitative phosphoproteomics, we uncovered a mechanism by which CD74-ROS activates a novel pathway driving cell invasion. Expression of CD74-ROS resulted in the phosphorylation of the extended synaptotagmin-like protein E-Syt1. Elimination of E-Syt1 expression drastically reduced invasiveness both in vitro and in vivo without modifying the oncogenic activity of CD74-ROS. Furthermore, expression of CD74-ROS in noninvasive NSCLC cell lines readily conferred invasive properties that paralleled the acquisition of E-Syt1 phosphorylation. Taken together, our findings indicate that E-Syt1 is a mediator of cancer cell invasion and molecularly define ROS fusion kinases as therapeutic targets in the treatment of NSCLC.National Institutes of Health (U.S.) (Grant NCI U01 CA141556

High tumor incidence and activation of the PI3K/AKT pathway in transgenic mice define AIB1 as an oncogene

AbstractThe gene encoding AIB1, an estrogen receptor coactivator, is amplified in a subset of human breast cancers. Here we show that overexpression of AIB1 in transgenic mice (AIB1-tg) leads to mammary hypertrophy, hyperplasia, abnormal postweaning involution, and the development of malignant mammary tumors. Tumors are also increased in other organs, including the pituitary and uterus. AIB1 overexpression increases mammary IGF-I mRNA and serum IGF-I protein levels. In addition, IGF-I receptor and downstream signaling molecules are activated in primary mammary epithelial cells and mammary tumor cells derived from AIB1-tg mice. Knockdown of AIB1 expression in cultured AIB1-tg mammary tumor cells leads to reduced IGF-I mRNA levels and increased apoptosis, suggesting that an autocrine IGF-I loop underlies the mechanism of AIB1-induced oncogenesis

Propuesta de traducción del videojuego Garden Story : el género y los nombres propios

Els videojocs són productes d'entreteniment gaudits per un públic cada cop més ampli i heterogeni, incloent-hi persones de diferents edats, ètnies i gèneres. A causa d'això, la necessitat d'utilitzar un llenguatge inclusiu ha guanyat molta importància tant a les versions originals com a les traduïdes, amb l'objectiu que el públic se senti representat i tingui la millor experiència de joc possible. D'altra banda, un dels temes que ha generat debat durant anys és la traducció o no-traducció dels noms propis, distingint entre postures a favor de l'acostament a la cultura meta o la conservació del caràcter exòtic de l'original. A més, a l'hora d'abordar els noms propis ficticis, s'hi afegeix la càrrega semàntica que comporten i el conflicte entre mantenir la referència original o bé adaptar-la a la cultura meta. Com que no hi ha gran quantitat d'estudis sobre aquests dos temes, aquest Treball de Fi de Màster se centra en la realització d'una proposta de traducció d'un videojoc on s'exposen possibles dificultats traductològiques i estratègies creatives que es poden adoptar de cara a la traducció inclusiva i la traducció dels noms propis ficticis.Los videojuegos constituyen productos de entretenimiento con un público cada vez más amplio y heterogéneo, incluyendo a personas de diferentes edades, etnias y géneros. Debido a ello, la necesidad de utilizar un lenguaje inclusivo ha ganado mucha importancia tanto en las versiones originales como en las traducidas, todo ello con el objetivo de que los usuarios se sientan representados y tengan la mejor experiencia de juego posible. Por otro lado, uno de los temas que ha generado debate durante años es la traducción o no traducción de los nombres propios, distinguiendo entre posturas a favor del acercamiento a la cultura meta o la conservación del carácter exótico del original. Además, a la hora de abordar los nombres propios ficticios, se suma la carga semántica que encierran y el conflicto entre mantener la referencia original o adaptarla a la cultura meta. Debido a que no abundan los estudios sobre estos dos temas, el presente trabajo se centra en la propuesta de traducción realizada del videojuego Garden Story (2021) para así exponer algunas dificultades que se pueden encontrar en relación con el género y los nombres propios y proponer algunas estrategias creativas que se pueden adoptar para abordarlas.Video games represent a form of entertainment enjoyed by an audience that is increasing in number and is becoming more diverse, including people of different ages, ethnicities, and genders. As a result, the need for an inclusive language has gained a lot of importance in both the original and translated versions to ensure that the players feel represented and have the best possible experience. On the other hand, a topic that has been the subject of debate for years is the translation or non-translation of proper nouns. This debate has resulted in two different approaches, one that focuses on adapting the nouns to bring the text closer to the target culture, and another one that gives priority to the preservation of original nouns to maintain the foreign aspect of the source language. Furthermore, fictional proper nouns usually carry a lot of meaning and they include the difficulty of choosing between maintaining the original names or adapting them to the target language. As there are not many studies centered on these two topics, this Master's thesis focuses on the translation of the video game Garden Story (2021) to show the difficulties that can be found regarding gender and proper nouns and the creative strategies that can be implemented to solve them

A genetic platform to model sarcomagenesis from primary adult mesenchymal stem cells

The regulatory factors governing adult mesenchymal stem cells (MSCs) physiology and their tumorigenic potential are still largely unknown, which substantially delays the identification of effective therapeutic approaches for the treatment of aggressive and lethal form of MSC-derived mesenchymal tumors, such as undifferentiated sarcomas. Here we have developed a novel platform to screen and quickly identify genes and pathways responsible for adult MSCs transformation, modeled undifferentiated sarcoma in vivo, and, ultimately, tested the efficacy of targeting the identified oncopathways. Importantly, by taking advantage of this new platform, we demonstrate the key role of an aberrant LRF-DLK1-SOX9 pathway in the pathogenesis of undifferentiated sarcoma with important therapeutic implications

Integrating community-based verbal autopsy into civil registration and vital statistics (CRVS): system-level considerations.

BACKGROUND: Reliable and representative cause of death (COD) statistics are essential to inform public health policy, respond to emerging health needs, and document progress towards Sustainable Development Goals. However, less than one-third of deaths worldwide are assigned a cause. Civil registration and vital statistics (CRVS) systems in low- and lower-middle-income countries are failing to provide timely, complete and accurate vital statistics, and it will still be some time before they can provide physician-certified COD for every death. Proposals: Verbal autopsy (VA) is a method to ascertain the probable COD and, although imperfect, it is the best alternative in the absence of medical certification. There is extensive experience with VA in research settings but only a few examples of its use on a large scale. Data collection using electronic questionnaires on mobile devices and computer algorithms to analyse responses and estimate probable COD have increased the potential for VA to be routinely applied in CRVS systems. However, a number of CRVS and health system integration issues should be considered in planning, piloting and implementing a system-wide intervention such as VA. These include addressing the multiplicity of stakeholders and sub-systems involved, integration with existing CRVS work processes and information flows, linking VA results to civil registration records, information technology requirements and data quality assurance. CONCLUSIONS: Integrating VA within CRVS systems is not simply a technical undertaking. It will have profound system-wide effects that should be carefully considered when planning for an effective implementation. This paper identifies and discusses the major system-level issues and emerging practices, provides a planning checklist of system-level considerations and proposes an overview for how VA can be integrated into routine CRVS systems

Social and ecological factors influencing offspring survival in wild macaques.

Premature loss of offspring decreases direct fitness of parents. In gregarious mammals, both ecological and social variables impact offspring survival and may interact with each other in this regard. Although a number of studies have investigated factors influencing offspring loss in mammals, we still know very little on how different factors interact with one another. We therefore investigated fetal and infant mortality in 3 large groups of wild crested macaques (Macaca nigra) over a period of up to 5 years by including potential social causes such as maternal dominance rank, male immigration, between group encounters, and ecological conditions such as rainfall in a multivariate survival analysis using Cox proportional hazards model. Infant but not fetal survival was most impaired after a recent takeover of the alpha-male position by an immigrant male. Furthermore, infant survival probability increased when there was an increase in number of group adult females and rainfall. Fetal survival probability also increased with an increase of these 2 factors, but more in high-ranking than low-ranking females. Fetal survival, unlike that of infants, was also improved by an increase of intergroup encounter rates. Our study thus stresses the importance of survival analyses using a multivariate approach and encompassing more than a single offspring stage to investigate the determinants of female direct fitness. We further provide evidence for fitness costs and benefits of group living, possibly deriving from high pressures of both within- and between-group competition, in a wild primate population

Stage-variations of anandamide hydrolase activity in the mouse uterus during the natural oestrus cycle

Recent studies have demonstrated that the endogenous cannabinoids are important modulators of fertility in mammals. In particular, a role of the endocannabinoid system in early stages of embryo development, oviductal transport of embryos, pregnancy maintenance and labour has been demonstrated in rodents and/or in humans. In the present paper, we report the analysis of FAAH activity and protein content in the mouse uterus as a function of the natural oestrus cycle stages. Variations of FAAH activity are discussed in relationship to changes in sex steroid levels and to the possible action of AEA on remodelling of uterine tissues