Translation inhibition by rocaglates is independent of eIF4E phosphorylation status

Rocaglates are natural products that inhibit protein synthesis in eukaryotes and exhibit antineoplastic activity. In vitro biochemical assays, affinity chromatography experiments coupled with mass spectrometry analysis, and in vivo genetic screens have identified eukaryotic initiation factor (eIF) 4A as a direct molecular target of rocaglates. eIF4A is the RNA helicase subunit of eIF4F, a complex that mediates cap-dependent ribosome recruitment to mRNA templates. The eIF4F complex has been implicated in tumor initiation and maintenance through elevated levels or increased phosphorylation status of its cap-binding subunit, eIF4E, thus furthering the interest toward developing rocaglates as antineoplastic agents. Recent experiments have indicated that rocaglates also interact with prohibitins 1 and 2, proteins implicated in c-Raf-MEK-ERK signaling. Because increased ERK signaling stimulates eIF4E phosphorylation status, rocaglates are also expected to inhibit eIF4E phosphorylation status, a point that has not been thoroughly investigated. It is currently unknown whether the effects on translation observed with rocaglates are solely through eIF4A inhibition or also a feature of blocking eIF4E phosphorylation. Here, we show that rocaglates inhibit translation through an eIF4E phosphorylation-independent mechanism.P50 GM067041 - NIGMS NIH HHS; R01 GM073855 - NIGMS NIH HHS; GM-067041 - NIGMS NIH HHS; MOP-106530 - Canadian Institutes of Health Researc

Synthesis of aza-rocaglates via ESIPT-mediated (3+2) photocycloaddition

Synthesis of aza-rocaglates, nitrogen-containing analogues of the rocaglate natural products, is reported. The route features ESIPT-mediated (3+2) photocycloaddition of 1-alkyl-2-aryl-3-hydroxyquinolinones with the dipolarophile methyl cinnamate. A continuous photoflow reactor was utilized for photocycloadditions. An array of compounds bearing the hexahydrocyclopenta[b]indole core structure was synthesized and evaluated in translation inhibition assays.R01 CA175744 - NCI NIH HHS; R01 GM073855 - NIGMS NIH HHS; R24 GM111625 - NIGMS NIH HHS; R35 GM118173 - NIGMS NIH HH

Error chain analysis—an effective method for tighter manufacturing process control

One of aims of manufacturing quality control is to ensure that products are made free from defects according to specifications without unnecessarily increasing time and cost of production. Over-control of a process can be as detrimental to a manufacturer as under-control. It is common in industry that operators use their personal knowhow and intuition to decide where to implement process verification, and where to tighten it when processes are not meeting specifications. This is partially because there is little scientific guidance that can assist operators in making a decision on levels of quality control of a process at varying stages. To remedy this, a new method for manufacturing quality control, namely Error Chain Analysis (ECA), is introduced and its application is illustrated in this article. ECA is capable of statistically analysing the quality of a multi-stage manufacturing process based on existing control measures, and it enables to indicate where added or tighter control may need to be effectively implemented. For testing its applicability, ECA was built into a user-friendly tool that was subsequently used to analyse data gathered from a large manufacturing company in the UK

Using Machine Learning and Natural Language Processing to Review and Classify the Medical Literature on Cancer Susceptibility Genes

PURPOSE: The medical literature relevant to germline genetics is growing exponentially. Clinicians need tools monitoring and prioritizing the literature to understand the clinical implications of the pathogenic genetic variants. We developed and evaluated two machine learning models to classify abstracts as relevant to the penetrance (risk of cancer for germline mutation carriers) or prevalence of germline genetic mutations. METHODS: We conducted literature searches in PubMed and retrieved paper titles and abstracts to create an annotated dataset for training and evaluating the two machine learning classification models. Our first model is a support vector machine (SVM) which learns a linear decision rule based on the bag-of-ngrams representation of each title and abstract. Our second model is a convolutional neural network (CNN) which learns a complex nonlinear decision rule based on the raw title and abstract. We evaluated the performance of the two models on the classification of papers as relevant to penetrance or prevalence. RESULTS: For penetrance classification, we annotated 3740 paper titles and abstracts and used 60% for training the model, 20% for tuning the model, and 20% for evaluating the model. The SVM model achieves 89.53% accuracy (percentage of papers that were correctly classified) while the CNN model achieves 88.95 % accuracy. For prevalence classification, we annotated 3753 paper titles and abstracts. The SVM model achieves 89.14% accuracy while the CNN model achieves 89.13 % accuracy. CONCLUSION: Our models achieve high accuracy in classifying abstracts as relevant to penetrance or prevalence. By facilitating literature review, this tool could help clinicians and researchers keep abreast of the burgeoning knowledge of gene-cancer associations and keep the knowledge bases for clinical decision support tools up to date

The effect of natural and extreme weathering on the mechanical properties of structural timber mortise and tenon joints

When used in the appropriate context, timber structures might have lower embodied carbon than their concrete and steel counterparts, making timber a popular material for sustainable construction practices. To continue constructing with timber we require more in-depth exploration into timber joinery which dictates the structural stability and performance of timber framed construction. In this study, the influence of cyclic humidity fluctuations and wetting and drying is tested on mortise and tenon joinery with different detailing (no additional fastening, with glue and with a dowel) for a comparative appraisal of their impact on the joint rotational stiffness. The outcomes show that exposed samples go through a reduction in rotational stiffness independently of the detailing. Peer-review under the responsibility of the organizing committee of the ICMB23

Good grief, i can speak it! Preliminary experiments in audio restaurant reviews

In this paper, we introduce a new envisioned application for speech which allows users to enter restaurant reviews orally via their mobile device, and, at a later time, update a shared and growing database of consumer-provided information about restaurants. During the intervening period, a speech recognition and NLP based system has analyzed their audio recording both to extract key descriptive phrases and to compute sentiment ratings based on the evidence provided in the audio clip. We report here on our preliminary work moving towards this goal. Our experiments demonstrate that multi-aspect sentiment ranking works surprisingly well on speech output, even in the presence of recognition errors. We also present initial experiments on integrated sentence boundary detection and key phrase extraction from recognition output

Midway towards Planetarity: (Im)mobility in The Wandering Earth (English version)

The article examines the Chinese science fiction blockbuster The Wandering Earth by looking at three levels of (im)mobility: from the planet’s surface to the subsurface, above the surface, and the planet itself. It argues that mobility and immobility in the film always go hand in hand, and that the mobility of one group/stage/level is always accompanied by the immobility of another. While the film presents cosmopolitanism across national boundaries and includes the planet itself in the migration of humankind, it does not really take a full planetary turn, but rather stops midway. This article focuses on different forms of mobility of living organisms, resources, and energy at different levels, pointing out the film’s aestheticisation of transportation and technology-fetishism and emphasising the neglected immobility of marginalised groups, other species, and even the planet itself

Cocaine Self-Administration Experience Induces Pathological Phasic Accumbens Dopamine Signals and Abnormal Incentive Behaviors in Drug-Abstinent Rats

Chronic exposure to drugs of abuse is linked to long-lasting alterations in the function of limbic system structures, including the nucleus accumbens (NAc). Although cocaine acts via dopaminergic mechanisms within the NAc, less is known about whether phasic dopamine (DA) signaling in the NAc is altered in animals with cocaine self-administration experience or if these animals learn and interact normally with stimuli in their environment. Here, separate groups of rats self-administered either intravenous cocaine or water to a receptacle (controls), followed by 30 d of enforced abstinence. Next, all rats learned an appetitive Pavlovian discrimination and voltammetric recordings of real-time DA release were taken in either the NAc core or shell of cocaine and control subjects. Cocaine experience differentially impaired DA signaling in the core and shell relative to controls. Although phasic DA signals in the shell were essentially abolished for all stimuli, in the core, DA did not distinguish between cues and was abnormally biased toward reward delivery. Further, cocaine rats were unable to learn higher-order associations and even altered simple conditioned approach behaviors, displaying enhanced preoccupation with cue-associated stimuli (sign-tracking; ST) but diminished time at the food cup awaiting reward delivery (goal-tracking). Critically, whereas control DA signaling correlated with ST behaviors, cocaine experience abolished this relationship. These findings show that cocaine has persistent, differential, and pathological effects on both DA signaling and DA-dependent behaviors and suggest that psychostimulant experience may remodel the very circuits that bias organisms toward repeated relapse