Evolutionary adaptation of the essential tRNA methyltransferase TrmD to the signaling molecule 3,5-cAMP in bacteria.

The nucleotide signaling molecule 3',5'-cyclic adenosine monophosphate (3',5'-cAMP) plays important physiological roles, ranging from carbon catabolite repression in bacteria to mediating the action of hormones in higher eukaryotes, including human. However, it remains unclear whether 3',5'-cAMP is universally present in the Firmicutes group of bacteria. We hypothesized that searching for proteins that bind 3',5'-cAMP might provide new insight into this question. Accordingly, we performed a genome-wide screen, and identified the essential Staphylococcus aureus tRNA m1G37 methyltransferase enzyme TrmD, which is conserved in all three domains of life, as a tight 3',5'-cAMP binding protein. TrmD enzymes are known to use S-adenosyl-L-methionine (AdoMet) as substrate; we shown that 3',5'-cAMP binds competitively with AdoMet to the S. aureus TrmD protein, indicating an overlapping binding site. However, the physiological relevance of this discovery remained unclear, as we were unable to identify a functional adenylate cyclase in S. aureus and only detected 2',3'-cAMP but not 3',5'-cAMP in cellular extracts. Interestingly, TrmD proteins from Escherichia coli and Mycobacterium tuberculosis, organisms known to synthesize 3',5'-cAMP, did not bind this signaling nucleotide. Comparative bioinformatics, mutagenesis and biochemical analyses revealed that the highly conserved Tyr86 residue in E. coli TrmD is essential to discriminate between 3',5'-cAMP and the native substrate AdoMet. Combined with a phylogenetic analysis, these results suggest that amino acids in the substrate binding pocket of TrmD underwent an adaptive evolution to accommodate the emergence of adenylate cyclases and thus the signaling molecule 3',5'-cAMP. Altogether this further indicates that S. aureus does not produce 3',5'-cAMP, which would otherwise competitively inhibit an essential enzyme

Harnessing Demographic Differences in Organizations: What Moderates the Effects of Workplace Diversity?

To account for the double-edged nature of demographic workplace diversity (i.e. relational demography, work group diversity, and organizational diversity) effects on social integration, performance and well-being related variables, research has moved away from simple main effect approaches and started examining variables that moderate these effects. While there is no shortage of primary studies of the conditions under which diversity leads to positive or negative outcomes, it remains unclear which contingency factors make it work. Using the Categorization-Elaboration Model (van Knippenberg, DeDreu, & Homan 2004) as our theoretical lens we review variables moderating the effects of workplace diversity on social integration, performance and well-being outcomes, focusing on factors that organizations and managers have control over (i.e. strategy, unit design, HR, leadership, climate/culture, and individual differences). We point out avenues for future research and conclude with practical implications

A timely computer-aided detection system for acute ischemic and hemorrhagic stroke on CT in an emergency environment

Standalone Presentations: no. LL-IN1105BACKGROUND: When a patient is accepted in the emergency room suspected of stroke, time is of the most importance. The infarct brain area suffers irreparable damage as soon as three hours after the onset of stroke symptoms. Non-contrast CT scan is the standard first line of investigation used to identify hemorrhagic stroke cases. However, CT brain images do not show hyperacute ischemia and small hemorrhage clearly and thus may be missed by emergency physicians. We reported a timely computer-aided detection (CAD) system for small hemorrhages on CT that has been successfully developed as an aid to ER physicians to help improve detection for Acute Intracranial Hemorrhage (AIH). This CAD system has been enhanced for diagnosis of acute ischemic stroke in addition to hemorrhagic stroke, which becomes a more complete and clinically useful tool for assisting emergency physicians and radiologists. In the detection algorithm, brain matter is first segmented, realigned, and left-right brain symmetry is evaluated. As in the AIH system, the system confirms hemorrhagic stroke by detecting blood presence with anatomical and medical knowledge-based criteria. For detecting ischemia, signs such as regional hypodensity, blurring of grey and white matter differentiation, effacement of cerebral sulci, and hyperdensity in middle cerebral artery, are evaluated …published_or_final_versio

Expressiveness of Temporal Query Languages: On the Modelling of Intervals, Interval Relationships and States

Storing and retrieving time-related information are important, or even critical, tasks on many areas of Computer Science (CS) and in particular for Artificial Intelligence (AI). The expressive power of temporal databases/query languages has been studied from different perspectives, but the kind of temporal information they are able to store and retrieve is not always conveniently addressed. Here we assess a number of temporal query languages with respect to the modelling of time intervals, interval relationships and states, which can be thought of as the building blocks to represent and reason about a large and important class of historic information. To survey the facilities and issues which are particular to certain temporal query languages not only gives an idea about how useful they can be in particular contexts, but also gives an interesting insight in how these issues are, in many cases, ultimately inherent to the database paradigm. While in the area of AI declarative languages are usually the preferred choice, other areas of CS heavily rely on the extended relational paradigm. This paper, then, will be concerned with the representation of historic information in two well known temporal query languages: it Templog in the context of temporal deductive databases, and it TSQL2 in the context of temporal relational databases. We hope the results highlighted here will increase cross-fertilisation between different communities. This article can be related to recent publications drawing the attention towards the different approaches followed by the Databases and AI communities when using time-related concepts

Increased insolation threshold for runaway greenhouse processes on Earth like planets

Because the solar luminosity increases over geological timescales, Earth climate is expected to warm, increasing water evaporation which, in turn, enhances the atmospheric greenhouse effect. Above a certain critical insolation, this destabilizing greenhouse feedback can "runaway" until all the oceans are evaporated. Through increases in stratospheric humidity, warming may also cause oceans to escape to space before the runaway greenhouse occurs. The critical insolation thresholds for these processes, however, remain uncertain because they have so far been evaluated with unidimensional models that cannot account for the dynamical and cloud feedback effects that are key stabilizing features of Earth's climate. Here we use a 3D global climate model to show that the threshold for the runaway greenhouse is about 375 W/m$^2$, significantly higher than previously thought. Our model is specifically developed to quantify the climate response of Earth-like planets to increased insolation in hot and extremely moist atmospheres. In contrast with previous studies, we find that clouds have a destabilizing feedback on the long term warming. However, subsident, unsaturated regions created by the Hadley circulation have a stabilizing effect that is strong enough to defer the runaway greenhouse limit to higher insolation than inferred from 1D models. Furthermore, because of wavelength-dependent radiative effects, the stratosphere remains cold and dry enough to hamper atmospheric water escape, even at large fluxes. This has strong implications for Venus early water history and extends the size of the habitable zone around other stars.Comment: Published in Nature. Online publication date: December 12, 2013. Accepted version before journal editing and with Supplementary Informatio

Oral vinorelbine and cisplatin with concomitant radiotherapy in stage III non-small cell lung cancer (NSCLC): A feasibility study

Background: Concurrent chemoradiotherapy has improved survival in inoperable stage III non-small cell lung cancer (NSCLC). This phase I trial was performed in order to establish a dose recommendation for oral vinorelbine in combination with cisplatin and simultaneous radiotherapy. Patients and Methods: Previously untreated patients with stage IIIB NSCLC received concurrent chemoradiotherapy with 66 Gy and 2 cycles of cisplatin and oral vinorelbine which was administered at 3 different levels (40, 50 and 60 mg/m(2)). This was to be followed by 2 cycles of cisplatin/vinorelbine oral consolidation chemotherapy. The study goal was to determine the maximal recommended dose of oral vinorelbine during concurrent treatment. Results: 11 stage IIIB patients were entered into the study. The median radiotherapy dose was 66 Gy. Grade 3-4 toxicity included neutropenia, esophagitis, gastritis and febrile neutropenia. The dose-limiting toxicity for concurrent chemoradiotherapy was esophagitis. 9 patients received consolidation chemotherapy, with neutropenia and anemia/thrombocytopenia grade 3 being the only toxicities. The overall response was 73%. Conclusion: Oral vinorelbine 50 mg/m(2) (days 1, 8, 15 over 4 weeks) in combination with cisplatin 20 mg/m2 (days 1-4) is the recommended dose in combination with radiotherapy (66 Gy) and will be used for concurrent chemoradiotherapy in a forthcoming phase III trial testing the efficacy of consolidation chemotherapy in patients not progressing after chemoradiotherapy

Hacia una hoja de ruta para el escalamiento de la Agroecología en Colombia: un análisis de las políticas, programas y factores limitantes actuales

El presente estudio nuestro objetivo es comprender los retos y las oportunidades que tiene la agroecología para ser promovida desde las políticas públicas. En esta investigación, propone una hoja de ruta que logre evidenciar las problemáticas para lograr el escalamiento de la agroecología desde diversos tipos factores. Esta propuesta de hoja de ruta tiene como objetivo ser un documento de base para generar diversos caminos para hacer escalar la agroecología, desde la incidencia política a través de los diversos sectores ministeriales, así como en diversas escalas de gobierno (municipal, regional y nacional), de igual forma que pueda ser considerado por otros actores de la sociedad civil, productores y organizaciones de base

Pharmacokinetic studies in children: recommendations for practice and research.

Optimising the dosing of medicines for neonates and children remains a challenge. The importance of pharmacokinetic (PK) and pharmacodynamic (PD) research is recognised both in medicines regulation and paediatric clinical pharmacology, yet there remain barriers to undertaking high-quality PK and PD studies. While these studies are essential in understanding the dose-concentration-effect relationship and should underpin dosing recommendations, this review examines how challenges affecting the design and conduct of paediatric pharmacological studies can be overcome using targeted pharmacometric strategies. Model-based approaches confer benefits at all stages of the drug life-cycle, from identifying the first dose to be used in children, to clinical trial design, and optimising the dosing regimens of older, off-patent medications. To benefit patients, strategies to ensure that new PK, PD and trial data are incorporated into evidence-based dosing recommendations are needed. This review summarises practical strategies to address current challenges, particularly the use of model-based (pharmacometric) approaches in study design and analysis. Recommendations for practice and directions for future paediatric pharmacological research are given, based on current literature and our joint international experience. Success of PK research in children requires a robust infrastructure, with sustainable funding mechanisms at its core, supported by political and regulatory initiatives, and international collaborations. There is a unique opportunity to advance paediatric medicines research at an unprecedented pace, bringing the age of evidence-based paediatric pharmacotherapy into sight

Analytic Metaphysics versus Naturalized Metaphysics: The Relevance of Applied Ontology

The relevance of analytic metaphysics has come under criticism: Ladyman & Ross, for instance, have suggested do discontinue the field. French & McKenzie have argued in defense of analytic metaphysics that it develops tools that could turn out to be useful for philosophy of physics. In this article, we show first that this heuristic defense of metaphysics can be extended to the scientific field of applied ontology, which uses constructs from analytic metaphysics. Second, we elaborate on a parallel by French & McKenzie between mathematics and metaphysics to show that the whole field of analytic metaphysics, being useful not only for philosophy but also for science, should continue to exist as a largely autonomous field