Pex19 is involved in importing dually targeted tail‐anchored proteins to both mitochondria and peroxisomes

Tail‐anchored (TA) proteins are embedded into their corresponding membrane via a single transmembrane segment at their C‐terminus whereas the majority of the protein is facing the cytosol. So far, cellular factors that mediate the integration of such proteins into the mitochondrial outer membrane were not found. Using budding yeast as a model system, we identified the cytosolic Hsp70 chaperone Ssa1 and the peroxisome import factor Pex19 as import mediators for a subset of mitochondrial TA proteins. Accordingly, deletion of PEX19 results in: (1) growth defect under respiration conditions, (2) alteration in mitochondrial morphology, (3) reduced steady‐state levels of the mitochondrial TA proteins Fis1 and Gem1, and (4) hampered in organello import of the TA proteins Fis1 and Gem1. Furthermore, recombinant Pex19 can bind directly the TA proteins Fis1 and Gem1. Collectively, this work identified the first factors that are involved in the biogenesis of mitochondrial TA proteins and uncovered an unexpected function of Pex19.      

Induction of a Citrus gene highly homologous to plant and yeast thi genes involved in thiamine biosynthesis during natural and ethylene-induced fruit maturation

Maturing citrus fruit undergo pigment changes which can be enhanced by exogenous ethylene. In order to identify genes induced by ethylene in citrus fruit peel, we cloned the gene c-thi1. mRNA corresponding to c-thi1 increased gradually in the peel during natural fruit maturation and in response to ethylene. GA₃ pretreatment reduced the inductive effect of ethylene. Levels of c-thi1 increased also in juice sacs but the effect of ethylene was much less prominent. c-thi1 is homologous to yeast and plant genes encoding for an enzyme belonging to the pathway of thiamine biosynthesis. The data suggest that thiamine is involved in citrus fruit maturation.     

“See One,Sim One,Do One”- A National Pre-Internship Boot-Camp to Ensure a Safer "Student to Doctor" Transition

Introduction

The transition for being a medical student to a full functioning intern is accompanied by considerable stress and sense of unpreparedness. Simulation based workshops were previously reported to be effective in improving the readiness of interns and residents to their daily needed skills but only few programs were implemented on a large scale.

Methods

A nationally endorsed and mandated pre-internship simulation based workshop is reported. We hypothesized that this intervention will have a meaningful and sustained impact on trainees'' perception of their readiness to internship with regard to patient safety and quality of care skills. Main outcome measure was the workshop’s contribution to professional training in general and to critical skills and error prevention in particular, as perceived by participants.

Results

Between 2004 and 2011, 85 workshops were conducted for a total of 4,172 trainees. Eight-hundred and six of the 2,700 participants approached by e-mail, returned feedback evaluation forms, which were analyzed. Eighty five percent of trainees perceived the workshop as an essential component of their professional training, and 87% agreed it should be mandatory. These ratings peaked during internship and were generally sustained 3 years following the workshop. Contribution to emergency care skills was especially highly ranked (83%).

Conclusion

Implementation of a mandatory, simulation-based, pre-internship workshop on a national scale made a significant perceived impact on interns and residents. The sustained impact should encourage adopting this approach to facilitate the student to doctor transition.     

Frequencies of protan and deutan alleles in some Israeli communities and a note on the selection-relaxation hypothesis

Anomaloscopic diagnoses of red-green vision defects are reported and compared to the Ishihara tests for six Israeli populations. The highest frequencies of defects, about 10%, were found in an Arab sample and among Ashkenazi Jews; the lowest — about 4% — among Yemenite Jews. Heterogeneity was also found regarding the relative frequencies of the different alleles; these differences are due primarily to alleles causing milder defects (particularly deuteranomaly) while frequencies of anopias are rather similar. It seems that the same phenomenon prevails for other population differences as well. These findings are discussed in relation to the hypothesis that present-day high rates of colorblindness in some populations may be explained by the relaxation of selection pressure against colorblindness.     

Functional Switching and Stability of Regulatory T Cells

It is widely accepted that the primary immune system contains a subpopulation of cells, known as regulatory T cells whose function is to regulate the immune response. There is conflicting biological evidence regarding the ability of regulatory cells to lose their regulatory capabilities and turn into immune promoting cells. In this paper, we develop mathematical models to investigate the effects of regulatory T cell switching on the immune response. Depending on environmental conditions, regulatory T cells may transition, becoming effector T cells that are immunostimulatory rather than immunoregulatory. We consider this mechanism both in the context of a simple, ordinary differential equation (ODE) model and in the context of a more biologically detailed, delay differential equation (DDE) model of the primary immune response. It is shown that models that incorporate such a mechanism express the usual characteristics of an immune response (expansion, contraction, and memory phases), while being more robust with respect to T cell precursor frequencies. We characterize the affects of regulatory T cell switching on the peak magnitude of the immune response and identify a biologically testable range for the switching parameter. We conclude that regulatory T cell switching may play a key role in controlling immune contraction.     

Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites

mirSVR is a new machine learning method for ranking microRNA target sites by a down-regulation score. The algorithm trains a regression model on sequence and contextual features extracted from miRanda-predicted target sites. In a large-scale evaluation, miRanda-mirSVR is competitive with other target prediction methods in identifying target genes and predicting the extent of their downregulation at the mRNA or protein levels. Importantly, the method identifies a significant number of experimentally determined non-canonical and non-conserved sites.     

Genetic elucidation of human hyperosmia to isovaleric acid

The genetic basis of odorant-specific variations in human olfactory thresholds, and in particular of enhanced odorant sensitivity (hyperosmia), remains largely unknown. Olfactory receptor (OR) segregating pseudogenes, displaying both functional and nonfunctional alleles in humans, are excellent candidates to underlie these differences in olfactory sensitivity. To explore this hypothesis, we examined the association between olfactory detection threshold phenotypes of four odorants and segregating pseudogene genotypes of 43 ORs genome-wide. A strong association signal was observed between the single nucleotide polymorphism variants in OR11H7P and sensitivity to the odorant isovaleric acid. This association was largely due to the low frequency of homozygous pseudogenized genotype in individuals with specific hyperosmia to this odorant, implying a possible functional role of OR11H7P in isovaleric acid detection. This predicted receptor–ligand functional relationship was further verified using the Xenopus oocyte expression system, whereby the intact allele of OR11H7P exhibited a response to isovaleric acid. Notably, we also uncovered another mechanism affecting general olfactory acuity that manifested as a significant inter-odorant threshold concordance, resulting in an overrepresentation of individuals who were hyperosmic to several odorants. An involvement of polymorphisms in other downstream transduction genes is one possible explanation for this observation. Thus, human hyperosmia to isovaleric acid is a complex trait, contributed to by both receptor and other mechanisms in the olfactory signaling pathway.     

Anxiolytic effects of a novel herbal treatment in mice models of anxiety

AimsAnxiety and stress disorders are currently among the ten most important public health concerns, and in recent years, have reached epidemic proportions. The current success rate of treatments for anxiety disorders is not high, reaching 50% at most. These treatments are also associated with a wide variety of side effects. The aim of the present study was to investigate the anxiolytic properties of a novel herbal treatment produced in our laboratory compared to a conventional treatment for anxiety disorders, namely SSRIs.Main methodsAnxiety-like behavior was evaluated in adult mice exposed to stress during childhood following 1, 2 and 3 weeks of treatment with the novel herbal treatment or escitalopram, using the novel open field and the elevated plus maze paradigms. The behavioral evaluation in these mice was followed by a biochemical assessment of their brain hippocampal BDNF levels and blood corticosterone levels.Key findingsThe study showed that (1) the novel herbal treatment reduced anxiety-like behaviors in both behavioral tests. Interestingly, this reduction was observed only following a 3-week treatment; (2) following the novel treatment, corticosterone levels in the plasma of treated mice were reduced and this reduction was similar to the one observed following escitalopram treatment; and (3) BDNF levels in the hippocampus of mice treated both with the novel herbal treatment and escitalopram were increased.SignificanceThese behavioral and biological findings indicate that our novel herbal compound has the potential of being highly efficacious in treating anxiety disorders.     

Is There an Optimal Level of Open-Endedness in Prebiotic Evolution?

In this paper we explore the question of whether there is an optimal set up for a putative prebiotic system leading to open-ended evolution (OEE) of the events unfolding within this system. We do so by proposing two key innovations. First, we introduce a new index that measures OEE as a function of the likelihood of events unfolding within a universe given its initial conditions. Next, we apply this index to a variant of the graded autocatalysis replication domain (GARD) model, Segre et al. (P Natl Acad Sci USA 97(8):4112-4117, 2000; Markovitch and Lancet Artif Life 18(3), 2012), and use it to study - under a unified and concise prebiotic evolutionary framework - both a variety of initial conditions of the universe and the OEE of species that evolve from them.