Circadian and feeding rhythms differentially affect rhythmic mRNA transcription and translation in mouse liver.

Diurnal oscillations of gene expression are a hallmark of rhythmic physiology across most living organisms. Such oscillations are controlled by the interplay between the circadian clock and feeding rhythms. Although rhythmic mRNA accumulation has been extensively studied, comparatively less is known about their transcription and translation. Here, we quantified simultaneously temporal transcription, accumulation, and translation of mouse liver mRNAs under physiological light-dark conditions and ad libitum or night-restricted feeding in WT and brain and muscle Arnt-like 1 (Bmal1)-deficient animals. We found that rhythmic transcription predominantly drives rhythmic mRNA accumulation and translation for a majority of genes. Comparison of wild-type and Bmal1 KO mice shows that circadian clock and feeding rhythms have broad impact on rhythmic gene expression, Bmal1 deletion affecting surprisingly both transcriptional and posttranscriptional levels. Translation efficiency is differentially regulated during the diurnal cycle for genes with 5'-Terminal Oligo Pyrimidine tract (5'-TOP) sequences and for genes involved in mitochondrial activity, many harboring a Translation Initiator of Short 5'-UTR (TISU) motif. The increased translation efficiency of 5'-TOP and TISU genes is mainly driven by feeding rhythms but Bmal1 deletion also affects amplitude and phase of translation, including TISU genes. Together this study emphasizes the complex interconnections between circadian and feeding rhythms at several steps ultimately determining rhythmic gene expression and translation.

Swiss family physicians' perceptions and attitudes towards knowledge translation practices.

BACKGROUND: Several studies have been performed to understand the way family physicians apply knowledge from medical research in practice. However, very little is known concerning family physicians in Switzerland. In an environment in which information constantly accumulates, it is crucial to identify the major sources of scientific information that are used by family physicians to keep their medical knowledge up to date and barriers to use these sources. Our main objective was to examine medical knowledge translation (KT) practices of Swiss family physicians. METHODS: The population consisted of French- and German-speaking private practice physicians specialised in family medicine. We conducted four interviews and three focus groups (n = 25). The interview guides of the semi-structured interviews and focus groups focused on (a) ways and means used by physicians to keep updated with information relevant to clinical practice; (b) how they consider their role in translating knowledge into practice; (c) potential barriers to KT; (d) solutions proposed by physicians for effective KT. RESULTS: Family physicians find themselves rather ambivalent about the translation of knowledge based on scientific literature, but generally express much interest in KT. They often feel overwhelmed by "information floods" and perceive clinical practice guidelines and other supports to be of limited usefulness for their practice. They often combine various formal and informal information sources to keep their knowledge up to date. Swiss family physicians report considering themselves as artisans, caring for patients with complex needs. CONCLUSION: Improved performance of KT initiatives in family medicine should be tailored to actual needs and based on high quality evidence-based sources.

A mild form of SLC29A3 disorder: a frameshift deletion leads to the paradoxical translation of an otherwise noncoding mRNA splice variant

We investigated two siblings with granulomatous histiocytosis prominent in the nasal area, mimicking rhinoscleroma and Rosai-Dorfman syndrome. Genome-wide linkage analysis and whole-exome sequencing identified a homozygous frameshift deletion in SLC29A3, which encodes human equilibrative nucleoside transporter-3 (hENT3). Germline mutations in SLC29A3 have been reported in rare patients with a wide range of overlapping clinical features and inherited disorders including H syndrome, pigmented hypertrichosis with insulin-dependent diabetes, and Faisalabad histiocytosis. With the exception of insulin-dependent diabetes and mild finger and toe contractures in one sibling, the two patients with nasal granulomatous histiocytosis studied here displayed none of the many SLC29A3-associated phenotypes. This mild clinical phenotype probably results from a remarkable genetic mechanism. The SLC29A3 frameshift deletion prevents the expression of the normally coding transcripts. It instead leads to the translation, expression, and function of an otherwise noncoding, out-of-frame mRNA splice variant lacking exon 3 that is eliminated by nonsense-mediated mRNA decay (NMD) in healthy individuals. The mutated isoform differs from the wild-type hENT3 by the modification of 20 residues in exon 2 and the removal of another 28 amino acids in exon 3, which include the second transmembrane domain. As a result, this new isoform displays some functional activity. This mechanism probably accounts for the narrow and mild clinical phenotype of the patients. This study highlights the"rescue" role played by a normally noncoding mRNA splice variant of SLC29A3, uncovering a new mechanism by which frameshift mutations can be hypomorphic.

Risk factors of postictal generalized EEG suppression in generalized convulsive seizures.

OBJECTIVE: To identify the clinical determinants of occurrence of postictal generalized EEG suppression (PGES) after generalized convulsive seizures (GCS). METHODS: We reviewed the video-EEG recordings of 417 patients included in the REPO2MSE study, a multicenter prospective cohort study of patients with drug-resistant focal epilepsy. According to ictal semiology, we classified GCS into 3 types: tonic-clonic GCS with bilateral and symmetric tonic arm extension (type 1), clonic GCS without tonic arm extension or flexion (type 2), and GCS with unilateral or asymmetric tonic arm extension or flexion (type 3). Association between PGES and person-specific or seizure-specific variables was analyzed after correction for individual effects and the varying number of seizures. RESULTS: A total of 99 GCS in 69 patients were included. Occurrence of PGES was independently associated with GCS type (p < 0.001) and lack of early administration of oxygen (p < 0.001). Odds ratio (OR) for GCS type 1 in comparison with GCS type 2 was 66.0 (95% confidence interval [CI 5.4-801.6]). In GCS type 1, risk of PGES was significantly increased when the seizure occurred during sleep (OR 5.0, 95% CI 1.2-20.9) and when oxygen was not administered early (OR 13.4, 95% CI 3.2-55.9). CONCLUSION: The risk of PGES dramatically varied as a function of GCS semiologic characteristics. Whatever the type of GCS, occurrence of PGES was prevented by early administration of oxygen.

Analyzing the temporal regulation of translation efficiency in mouse liver.

Mammalian physiology and behavior follow daily rhythms that are orchestrated by endogenous timekeepers known as circadian clocks. Rhythms in transcription are considered the main mechanism to engender rhythmic gene expression, but important roles for posttranscriptional mechanisms have recently emerged as well (reviewed in Lim and Allada (2013) [1]). We have recently reported on the use of ribosome profiling (RPF-seq), a method based on the high-throughput sequencing of ribosome protected mRNA fragments, to explore the temporal regulation of translation efficiency (Janich et al., 2015 [2]). Through the comparison of around-the-clock RPF-seq and matching RNA-seq data we were able to identify 150 genes, involved in ribosome biogenesis, iron metabolism and other pathways, whose rhythmicity is generated entirely at the level of protein synthesis. The temporal transcriptome and translatome data sets from this study have been deposited in NCBI's Gene Expression Omnibus under the accession number GSE67305. Here we provide additional information on the experimental setup and on important optimization steps pertaining to the ribosome profiling technique in mouse liver and to data analysis.

Generalized three-sided assignment markets: consistency and the core

A class of three-sided markets (and games) is considered, where value is generated by pairs or triplets of agents belonging to different sectors, as well as by individuals. For these markets we analyze the situation that arises when some agents leave the market with some payoff To this end, we introduce the derived market (and game) and relate it to the Davis and Maschler (1965) reduced game. Consistency with respect to the derived market, together with singleness best and individual anti-monotonicity axiomatically characterize the core for these generalized three-sided assignment markets. These markets may have an empty core, but we define a balanced subclass, where the worth of each triplet is defined as the addition of the worths of the pairs it contains. Keywords: Multi-sided assignment market, Consistency, Core, Nucleolus. JEL Classification: C71, C78

Parallel characterizations of a generalized shapley value and a generalized banzhaf value for cooperative games with level structure of cooperation

We present parallel characterizations of two different values in the framework of restricted cooperation games. The restrictions are introduced as a finite sequence of partitions defined on the player set, each of them being coarser than the previous one, hence forming a structure of different levels of a priori unions. On the one hand, we consider a value first introduced in Ref. [18], which extends the Shapley value to games with different levels of a priori unions. On the other hand, we introduce another solution for the same type of games, which extends the Banzhaf value in the same manner. We characterize these two values using logically comparable properties.

A Gendered Voice in Translation: Translating Like a Feminist

This paper addresses some of the challenges inherent in finding and showing a gendered voice in translation. The starting point is my own experience as a feminist translator of both feminist and non-feminist texts. Textual practices like translating necessarily interact with current theoretical debates. In turn, theoretical writing on feminism enriches and informs one’s translating activity. This interplay between theoretical models and textual practices was particularly made evident to me as I rendered Essentially speaking, by Diana Fuss, into Catalan. In this article I intend to transcend anecdotes of translating individual texts and consider how translating equals rewriting oneself; it involves rethinking writing practices. I will specifically address the rethinking of (1) one’s identity when translating ‘like’ a feminist, (2) performativity in gender and in translation, and (3) agency and (In)visibility.

Rule-based machine translation between Bulgarian and Macedonian

This paper describes the development of a two-way shallow-transfer rule-based machine translation system between Bulgarian and Macedonian. It gives an account of the resources and the methods used for constructing the system, including the development of monolingual and bilingual dictionaries, syntactic transfer rules and constraint grammars. An evaluation of thesystem's performance was carried out and compared to another commercially available MT system for the two languages. Some future work was suggested.

Random walk radiosity with generalized absorption probabilities

The author studies random walk estimators for radiosity with generalized absorption probabilities. That is, a path will either die or survive on a patch according to an arbitrary probability. The estimators studied so far, the infinite path length estimator and finite path length one, can be considered as particular cases. Practical applications of the random walks with generalized probabilities are given. A necessary and sufficient condition for the existence of the variance is given, together with heuristics to be used in practical cases. The optimal probabilities are also found for the case when one is interested in the whole scene, and are equal to the reflectivities

On the structure of cooperative and competitive solutions for a generalized assignment game

We study cooperative and competitive solutions for a many- to-many generalization of Shapley and Shubik (1972)'s assignment game. We consider the Core, three other notions of group stability and two al- ternative definitions of competitive equilibrium. We show that (i) each group stable set is closely related with the Core of certain games defined using a proper notion of blocking and (ii) each group stable set contains the set of payoff vectors associated to the two definitions of competitive equilibrium. We also show that all six solutions maintain a strictly nested structure. Moreover, each solution can be identified with a set of ma- trices of (discriminated) prices which indicate how gains from trade are distributed among buyers and sellers. In all cases such matrices arise as solutions of a system of linear inequalities. Hence, all six solutions have the same properties from a structural and computational point of view.