bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantification of translation uncovers the functions of the alternative transcriptome
Authors: Calviello Lorenzo , Hirsekorn Antje , Ohler Uwe
Published: April 2019

At the center of the gene expression cascade, translation is fundamental in defining the fate of much of the transcribed genome. RNA sequencing enables the quantification of complex transcript mixtures, often detecting several splice isoforms of unknown functions for one gene. We have developed ORFquant, a new approach to annotate and quantify translation at the single open reading frame (ORF) level, using information from Ribo-seq data. Relying on a novel approach for transcript filtering, we quantify translation on thousands of ORFs, showing the power of Ribo-seq in revealing alternative ORFs on multiple isoforms per gene. While we find that one ORF represents the dominant translation product for most genes, we also detect genes with translated ORFs on multiple transcript isoforms, including targets of RNA surveillance mechanisms. Assessing the translation output across human cell lines reveals the extent of gene-specific differences in protein production, which are supported by steady-state protein abundance estimates. Computational analysis of Ribo-seq data with ORFquant (available at https://github.com/lcalviell/ORFquant) provides a window into the heterogeneous functions of complex transcriptomes.
Translational control of Bcl-2 promotes apoptosis of gastric carcinoma cells
Authors: Tao Shuangfen , Gu Jianchun , Wang Qing , Zheng Leizhen
Published: April 2019

Aberrantly expressed microRNAs (miRNAs) are essential for the tumorigenesis of gastric carcinoma (GC). Nevertheless, an effect of miR-383 on GC cells apoptosis has not been acknowledged previously. Here, we investigated the miR-383 level and anti-apoptotic protein Bcl-2 level in specimens of GC. Bioinformatics analyses was performed, and assay of luciferase-reporter was used for analyzing the relationship between Bcl-2 and miR-383. We analyzed survival of GC cells upon Fluorouracil treatment in an assay of CCK, and measured apoptosis of cells using flow cytometric FITC Annexin V apoptosis detection assay. The level of miR-383 was found extremely lower while the level of Bcl-2 levels was found extremely higher in GC specimens, in comparison with tissue from the adjacent non-tumor region. Additionally, the miR-383 level and Bcl-2 level inversely correlated in specimens of GC. In comparison with miR-383-high subjects, MiR-383-low subjects showed overall lower survival. Bioinformatics analyses revealed that miR-383 targeted the 3’-UTR of Bcl-2 mRNA to restrain its translation, demonstrated in a luciferase reporter assay. MiR-383 overexpression inhibited the Bcl-2-mediated survival of cell against apoptosis induced by Fluorouracil, while miR-383 depletion enhanced the cell survival. Together, these data indicate that suppression of miR-383 in GC improves the Bcl-2-mediated cell survival of GC against the chemotherapy-induced cell death. MiR-383 re-expression in cells of GC might augment apoptosis of GC cells during chemotherapy.
Genomics, Molecular and Evolutionary Perspective of NAC Transcription Factors
Authors: Mohanta Tapan Kumar , Yadav Dhananjay , Khan Adil , Hashem Abeer , Tabassum Baby , Khan Abdul Latif , Abda_Allah Eslayed Fathi , Al-Harrasi Ahmed
Published: April 2019

NAC (NAM, ATAF1,2, and CUC2) transcription factors are one of the largest transcription factor families found in plants and are involved in diverse developmental and signalling events. Despite the availability of comprehensive genomic information from diverse plant species, the basic genomic, biochemical, and evolutionary details of NAC TFs have not been established. Therefore, NAC TFs family proteins from 160 plant species were analyzed in the current study. The analysis, among other things, identified the first algal NAC TF in the Charophyte, Klebsormidium flaccidum. Furthermore, our analysis revealed that NAC TFs are membrane bound and contain monopartite, bipartite, and multipartite nuclear localization signals. NAC TFs were also found to encode a novel chimeric protein domain and are part of a complex interactome network. Synonymous codon usage is absent in NAC TFs and it appears that they have evolved from orthologous ancestors and undergone significant duplication events to give rise to paralogous NAC TFs.
The Anticipation of Events in Time
Authors: Grabenhorst Matthias , Michalareas Georgios , Maloney Laurence T. , Poeppel David
Published: April 2019

Humans use sensory input to anticipate events. The brain’s capacity to predict cues in time is commonly assumed to be modulated by two uncertainty parameters, the hazard rate (HR) of event probability and the uncertainty in time estimation, which increases with elapsed time. We investigate both assumptions by manipulating event probability density functions (PDF) in three sensory modalities. First we show, contrary to expectation, that perceptual systems use the reciprocal PDF – and not the HR – to model event probability density. Next we demonstrate that temporal uncertainty does not necessarily grow with elapsed time but also diminishes, depending on the event PDF. Finally we show that reaction time (RT) distributions comprise modality-specific and modality-independent components, the latter likely reflecting similarity in processing of probability density across sensory modalities. The results are consistent across vision, audition, and somatosensation, indicating that probability density is more fundamental than hazard rate in terms of the neural operations determining event anticipation and temporal uncertainty. Previous research identified neuronal activitity related to event probability in multiple levels of the cortical hierarchy such as early and higher sensory (V1, V4), association (LIP), motor and other areas. This work proposed that the elementary neuronal computation in estimation of probability across time is the HR. In contrast, our results suggest that the neurobiological implementation of probability estimation is based on a different, much simpler and more stable computation than HR: the reciprocal PDF of events in time.
In Silico Genetics Revealing Novel Mutations inCEBPAGene Associated with Acute Myeloid Leukemia
Authors: Mustafa Mujahed I. , Mohammed Zainab O. , Murshed Naseem S. , Elfadol Nafisa M. , Abdelmoneim Abdelrahman H. , Hassan Mohamed A.
Published: April 2019

Background

Myelodysplastic syndrome/Acute myeloid leukemia (MDS/AML) is a highly heterogeneous malignant disease; affects children and adults of all ages. AML is one of the main causes of death in children with cancer. However, It is the most common acute leukemia in adults, with a frequency of over 20 000 cases per year in the United States of America alone.

Methods

The SNPs were retrieved from the dbSNP database. this SNPs were submitted into various functional analysis tools that done by SIFT, PolyPhen-2, PROVEAN, SNAP2, SNPs&GO, PhD-SNP and PANTHER, while structural analysis were done by I-mutant3 and MUPro. The most damaging SNPs were selected for further analysis by Mutation3D, Project hope, ConSurf and BioEdit softwares.

Results

A total of five novel nsSNPs out of 248 missense mutations were predicted to be responsible for the structural and functional variations of CEBPA protein.

Conclusion

In this study the impact of functional SNPs in the CEBPA gene was investigated through different computational methods, which determined that (R339W, R288P, N292S N292T and D63N) are novel SNPs have a potential functional effect and can thus be used as diagnostic markers and may facilitate in genetic studies with a special consideration of the large heterogeneity of AML among the different populations.
Microbial species coexistence depends on the host environment
Authors: Deines Peter , Hammerschmidt Katrin , Bosch Thomas CG
Published: April 2019

Organisms and their resident microbial communities form a complex and mostly stable ecosystem. It is known that the specific composition and abundance of certain bacterial species affect host health and fitness, but the processes that lead to these microbial patterns are unknown. We investigate this by deconstructing the simple microbiome of the freshwater polyp Hydra. We contrast the performance of its two main bacterial associates, Curvibacter and Duganella, on germ free hosts with two in vitro environments over time. We show that interactions within the microbiome but also the host environment lead to the observed species frequencies and abundances. More specifically, we find that both microbial species can only stably coexist in the host environment, whereas Duganella outcompetes Curvibacter in both in vitro environments irrespective of initial starting frequencies. While Duganella seems to benefit through secretions of Curvibacter, its competitive effect on Curvibacter depends upon direct contact. The competition might potentially be mitigated through the spatial structure of the two microbial species on the host, which would explain why both species stably coexist on the host. Interestingly, the fractions of both species on the host do not match the fractions reported previously nor the overall microbiome carrying capacity as reported in this study. Both observations indicate that the rare microbial community members might be relevant for achieving the native community composition and carrying capacity. Our study highlights that for dissecting microbial interactions the specific environmental conditions need to be replicated, a goal difficult to achieve with in vitro systems.

Importance

This work studies microbial interactions within the microbiome of the simple cnidarian, Hydra, and investigates whether microbial species coexistence and community stability depends on the host environment. We find that the outcome of the interaction between the two most dominant bacterial species in Hydra’s microbiome differs depending on the environment and only results in a stable coexistence in the host context. The interactive ecology between the host, the two most dominant microbes, but also the less abundant members of the microbiome, are critically important for achieving the native community composition. This indicates that the metaorganism environment needs to be taken into account when studying microbial interactions.
Large-scale functional integration, rather than functional dissociation along dorsal and ventral streams, underlies visual perception and action
Authors: Ray Dipanjan , Hajare Nilambari , Roy Dipanjan , Banerjee Arpan
Published: April 2019

Visual dual stream theory posits that two distinct neural pathways of specific functional significance originate from primary visual areas and reach the inferior temporal (ventral) and posterior parietal areas (dorsal). However, there are several unresolved questions concerning the fundamental aspects of this theory. For example, is the functional dissociation between ventral and dorsal stream driven by features in input stimuli or is it driven by categorical differences between visuo-perceptual and visuo-motor functions? Is the dual stream rigid or flexible? What is the nature of the interactions between two streams? We addressed these questions using fMRI recordings on healthy human volunteers and employing stimuli and tasks that can tease out the divergence between visuo-perceptual and visuo-motor models of dual stream theory. fMRI scans were repeated after seven practice sessions that were conducted in a non-MRI environment to investigate the effects of neuroplasticity. Brain activation analysis supports an input-based functional dissociation and existence of context-dependent neuroplasticity in dual stream areas. Intriguingly, premotor cortex activation was observed in the position perception task and distributed deactivated regions were observed in all perception tasks thus, warranting a network level analysis. Dynamic causal modelling (DCM) analysis incorporating activated and deactivated brain areas during perception tasks indicates that the brain dynamics during visual perception and actions could be interpreted within the framework of predictive coding. Effectively, the network level findings point towards the existence of more intricate context-driven functional networks selective of “what” and “where” information rather than segregated streams of processing along ventral and dorsal brain regions.
Maturation of the human B-cell receptor repertoire with age
Authors: Ghraichy Marie , Galson Jacob D. , Kovaltsuk Aleksandr , Niederhäusern Valentin von , Schmid Jana Pachlopnik , Recher Mike , Jauch Annaïse J , Miho Enkelejda , Kelly Dominic F. , Deane Charlotte M. , Trück Johannes
Published: April 2019

B cells play a central role in adaptive immune processes, mainly through the production of antibodies. The maturation of the B-cell system with age is poorly studied. We extensively investigated age-related alterations of naïve and antigen-experienced B-cell receptor (BCR) repertoires. The most significant changes were observed in the first 10 years of life, and were characterized by altered immunoglobulin gene usage and an increased frequency of mutated antibodies structurally diverging from their germline precursors. Older age was associated with an increased usage of downstream constant region genes and fewer antibodies with self-reactive properties. As mutations accumulated with age, the frequency of germline-encoded self-reactive antibodies decreased, indicating a possible beneficial role of self-reactive B-cells in the developing immune system. Our results suggest a continuous process of change through childhood across a broad range of parameters characterizing BCR repertoires and stress the importance of using well-selected, age-appropriate controls in BCR studies.
Foundress Number, But Not Queen Size or Boldness, Predicts Colony Life-History in Wild Paper Wasps
Authors: Wright Colin M. , Fisher David N. , Nerone Wayne V. , Lichtenstein James L.L. , Tibbetts Elizabeth A. , Pruitt Jonathan N.
Published: April 2019

Colonies of social insects exhibit a spectacular variety of life histories. Here we documented the degree of variation in colony life-history traits, mostly related to productivity, in two species of wild paper wasps. We then tested for associations between colony life-history traits to look for trade-offs or positively associated syndromes, and examined whether individual differences in the behavioral tendencies of foundresses (Polistes metricus) or the number of cofoundresses (P. fuscatus) influenced colony life-history. The majority of our measures of colony life-history were positively related, indicating no obvious resource allocation trade-offs. Instead, the positive association of traits into a productivity syndrome appears to be driven by differences in queen or microhabitat quality. Syndrome structure differed only marginally between species. Queen boldness and body size were not associated with colony life-history inP. metricus. Colonies initiated by multipleP. fuscatusfoundresses were generally more productive, and this advantage was approximately proportional to the number of cofoundresses. These findings demonstrate that colony life-history traits can be associated together much like individual life-history traits, and the associations seen here convey that differences in overall productivity drive between-colony differences in life-history.
Imperfect strategy transmission can reverse the role of population viscosity on the evolution of altruism
Authors: Débarre F.
Published: April 2019

Population viscosity,i.e., low emigration out of the natal deme, leads to high within-deme relatedness, which is beneficial to the evolution of altruistic behavior when social interactions take place among deme-mates. However, a detrimental side-effect of low emigration is the increase in competition among related individuals. The evolution of altruism depends on the balance between these opposite effects. This balance is already known to be affected by details of the life cycle; we show here that it further depends on the fidelity of strategy transmission from parents to their offspring. We consider different life cycles and identify thresholds of parent-offspring strategy transmission inaccuracy, above which higher emigration can increase the frequency of altruists maintained in the population. Predictions were first obtained analytically assuming weak selection and equal deme sizes, then confirmed with stochastic simulations relaxing these assumptions. Contrary to what happens with perfect strategy transmission from parent to off-spring, our results show that higher emigration can be favorable to the evolution of altruism.
Extensive impact of low-frequency variants on the phenotypic landscape at population-scale
Authors: Fournier T. , Saada O. Abou , Hou J. , Peter J. , Caudal E. , Schacherer J.
Published: April 2019

Genome-wide association studies (GWAS) allows to dissect the genetic basis of complex traits at the population level1. However, despite the extensive number of trait-associated loci found, they often fail to explain a large part of the observed phenotypic variance2–4. One potential source of this discrepancy could be the preponderance of undetected low-frequency genetic variants in natural populations5,6. To increase the allele frequency of those variants and assess their phenotypic effects at the population level, we generated a diallel panel consisting of 3,025 hybrids, derived from pairwise crosses between a subset of natural isolates from a completely sequenced 1,011 Saccharomyces cerevisiae population. We examined each hybrid across a large number of growth traits, resulting in a total of 148,225 cross/trait combinations. Parental versus hybrid regression analysis showed that while most phenotypic variance is explained by additivity, a significant proportion (29%) is governed by non-additive effects. This is confirmed by the fact that a majority of complete dominance is observed in 25% of the traits. By performing GWAS on the diallel panel, we detected 1,723 significantly associated genetic variants, with 16.3% of them being low-frequency variants in the initial population. These variants, which would not be detected using classical GWAS, explain 21% of the phenotypic variance on average. Altogether, our results demonstrate that low-frequency variants should be accounted for as they contribute to a large part of the phenotypic variation observed in a population.
Accelerated trans-sulfuration metabolically defines a discrete subclass of ALS patients
Authors: Chen Qiuying , Sandhu Davinder , Konrad Csaba , Roychoudhury Dipa , Schwartz Benjamin I. , Cheng Roger R. , Bredvik Kirsten , Kawamata Hibiki , Calder Elizabeth L. , Studer Lorenz , Fischer Steven. M. , Manfredi Giovanni , Gross Steven. S.
Published: April 2019

Amyotrophic lateral sclerosis (ALS) is a disease characterized by progressive paralysis and death. Most ALS cases are sporadic (sALS) and patient heterogeneity poses a formidable challenge for the development of viable biomarkers and effective therapies. Applying untargeted metabolite profiling on 77 sALS patient-derived primary dermal fibroblast lines and 45 sex/age matched controls, we found that ∼25% of cell lines (termed sALS-1) are characterized by upregulated trans-sulfuration, where methionine-derived homocysteine is channeled into cysteine and glutathione synthesis. sALS-1 fibroblasts exhibit a growth defect when grown under oxidative conditions, that can be fully-rescued by N-acetylcysteine. [U-13C]-glucose tracing shows that activation of the trans-sulfuration pathway is associated with accelerated glucose flux into the TCA cycle. Based on four metabolites, we developed a support vector machine model capable of distinguishing sALS-1 with 97.5% accuracy. Importantly, plasma metabolite profiling identifies a systemic perturbation of cysteine metabolism as a hallmark of sALS-1. These results indicate that sALS patients can be stratified into distinct metabotypes, differently sensitive to metabolic stress, and provides new insights into metabolic biomarkers for personalized sALS therapy.
Bottom trawl catch comparison in the Mediterranean Sea: Flexible Turtle Excluder Device (TED)vstraditional gear
Authors: Vasapollo Claudio , Virgili Massimo , Petetta Andrea , Bargione Giada , Sala Antonello , Lucchetti Alessandro
Published: April 2019

The Mediterranean Sea is a hotspot of biodiversity, but the high fishing pressure results in high bycatch rates of protected (sea turtles and cetaceans) and top predator species (sharks). The reduction of bycatch is challenging for fishery scientists, as conservation of these species has become a priority. Among the animals threatened by fishing activities, the loggerhead (Caretta caretta) represents a charismatic species considered as “vulnerable” at the global scale by IUCN.

In the Mediterranean Sea, trawl nets show the highest probabilities of bycatch of protected species, with high rates of mortality. A new flexible Turtle Excluder Device (TED) has been tested for the first time on a commercial scale in the Mediterranean Sea to assess its effectiveness in reducing bycatch. The results did not show any significant (α = 0.05) loss in terms of commercial weight, but a significant reduction of debris in the codend of the nets mounting the TED respect to traditional nets. The catch comparison of the main commercial species showed similar rates without any significant loss of sizes, with the only exception of anglerfishes (Lophiusspp.) that showed a loss of the largest individuals by TED. In terms of bycatch, the traditional nets captured mostly rays and sharks, while no turtles were captured, at all. In this regard, the authors were informed by other vessels operating in the same areas at the time of the trials about some accidental catches of loggerhead turtles. Our results demonstrated that the flexible TED represents a practical and effective solution to reduce the bycatch of endangered species in coastal Mediterranean demersal multispecies fisheries, as demonstrated experimentally also in other areas of the world. The measures involving technical modifications of fishing gears require significant investments but are technically feasible and could guarantee the success of the conservation.
TLR4-dependent signaling drives extracellular catabolism of low-density lipoprotein aggregates
Authors: Singh Rajesh K. , Haka Abigail S. , Asmal Arky , Barbosa-Lorenzi Valéria C. , Grosheva Inna , Chin Harvey F. , Xiong Yuquan , Hla Timothy , Maxfield Frederick R.
Published: April 2019

Objective

Aggregation and modification of low-density lipoproteins (LDL) promotes their retention and accumulation in the arteries. This is a critical initiating factor during atherosclerosis. Macrophage catabolism of aggregated LDL (agLDL) occurs using a specialized extracellular, hydrolytic compartment, the lysosomal synapse (LS). Compartment formation by local actin polymerization and delivery of lysosomal contents by exocytosis promotes acidification of the compartment and degradation of agLDL. Internalization of metabolites such as cholesterol promotes foam cell formation, a process that drives atherogenesis. Further, there is accumulating evidence for the involvement of TLR4 and its adaptor protein MyD88 in atherosclerosis. Here, we investigated the role of TLR4 in catabolism of agLDL using the LS and foam cell formation.

Approach and Results

Using bone marrow-derived macrophages (BMMs) from knockout mice, we find that TLR4 and MyD88 regulate compartment formation, lysosome exocytosis, acidification of the compartment and foam cell formation. Using siRNA, pharmacological inhibition and knockout BMMs, we implicate SYK, PI3 kinase and Akt in agLDL catabolism using the LS. Using bone marrow transplantation of LDL receptor knockout mice with TLR4KO bone marrow, we show that deficiency of TLR4 protects macrophages from lipid accumulation during atherosclerosis. Finally, we demonstrate that macrophagesin vivoform an extracellular compartment and exocytose lysosome contents similar to that observedin vitrofor degradation of agLDL.

Conclusions

We present a mechanism in which interaction of macrophages with agLDL initiates a TLR4 signaling pathway, resulting in formation of the LS, catabolism of agLDL and lipid accumulationin vitroandin vivo.
Identification of new viruses specific to the honey bee mite Varroa destructor
Authors: Herrero Salvador , Coll Sandra , González-Martínez Rosa M. , Parenti Stefano , Millán-Leiva Anabel , González-Cabrera Joel
Published: April 2019

Large-scale colony losses among managed Western honey bees have become a serious threat to the beekeeping industry in the last decade. There are multiple factors contributing to these losses but the impact of Varroa destructor parasitism is by far the most important, along with the contribution of some pathogenic viruses vectored by the mite. So far, more than 20 viruses have been identified infecting the honey bee, most of them RNA viruses. They may be maintained either as covert infections or causing severe symptomatic infections, compromising the viability of the colony. In silico analysis of available transcriptomic data obtained from mites collected in the USA and Europe as well as additional investigation with new samples collected locally allowed the description of three novel RNA viruses. Our results showed that these viruses were widespread among samples and that they were present in the mites and in the bees but with differences in the relative abundance and prevalence. However, we have obtained strong evidence showing that these three viruses were able to replicate in the mite, but not in the bee, suggesting that they are selectively infecting the mite. To our knowledge, this is the first demonstration of Varroa-specific viruses, which open the door to future applications that might help controlling the mite through biological control approaches.
Monocarboxylate Transport inDrosophilaLarval Brain during Low and High Neuronal Activity
Authors: Gonzalez-Gutierrez Andres , Ibacache Andrés , Esparza Andrés , Barros L. Felipe , Sierralta Jimena
Published: April 2019

The transport of lactate and pyruvate between glial cells and neurons plays an important role in the nervous system metabolic coupling. However, the mechanisms and characteristics that underlie the transport of monocarboxylates (MC-T)in vivoare poorly described. Here we useDrosophilaexpressing genetically-encoded FRET sensors to provide anex vivocharacterization of the MC-T in motor neurons and glial cells from the ventral nerve cord. We show that lactate/pyruvate transport on glial cells is coupled to protons and is more efficient than in neurons. Glial cells maintain higher levels of intracellular lactate generating a positive gradient towards neurons. Moreover, our results show that under increased activity lactate and pyruvate rise on motor neurons and suggest that this depends on the transfer of lactate from glial cells mediated in part by the previously described MC transporter Chaski, giving support to thein vivoglia to neurons lactate shuttling during activity.
A programmable DNA-origami platform for studying protein-mediated lipid transfer between bilayers
Authors: Bian Xin , Zhang Zhao , De Camilli Pietro , Lin Chenxiang
Published: April 2019

Non-vesicular lipid transport between bilayers at membrane contact sites plays important physiological roles. Mechanistic insight into the action of lipid transport proteins localized at these sites (bridge/tunnel versus shuttle models) requires a determination of the distance between bilayers at which this transport can occur. Here, we developed DNA-origami nanostructures to organize size-defined liposomes at precise distances and used them to study lipid transfer by the SMP domain of E-Syt1. Pairs of DNA ring-templated donor and acceptor liposomes were docked through DNA pillars, which determined their distance. The SMP domain was anchored to donor liposomes via an unstructured linker and lipid transfer was assessed via a FRET-based assay. We show that lipid transfer can occur over distances that exceed the length of SMP dimer, compatible with a shuttle model. The DNA nanostructures developed here can be adapted to study other processes occurring where two membranes are closely apposed to each other.
The more the merrier? Multivariate approaches to genome-wide association analysis
Authors: Vroom César-Reyer , de Leeuw Christiaan , Posthuma Danielle , Dolan Conor V. , van der Sluis Sophie
Published: April 2019

The vast majority of genome-wide association (GWA) studies analyze a single trait while large-scale multivariate data sets are available. As complex traits are highly polygenic, and pleiotropy seems ubiquitous, it is essential to determine when multivariate association tests (MATs) outperform univariate approaches in terms of power. We discuss the statistical background of 19 MATs and give an overview of their statistical properties. We address the Type I error rates of these MATs and demonstrate which factors can cause bias. Finally, we examine, compare, and discuss the power of these MATs, varying the number of traits, the correlational pattern between the traits, the number of affected traits, and the sign of the genetic effects. Our results demonstrate under which circumstances specific MATs perform most optimal. Through sharing of flexible simulation scripts, we facilitate a standard framework for comparing Type I error rate and power of new MATs to that of existing ones.
Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions at different rates across generations
Authors: Meshnik Lana , Bar-Yaacov Dan , Kasztan Dana , Neiger Tali , Cohen Tal , Kishner Mor , Valenci Itay , Dadon Sara , Klein Christopher J. , Vance Jeffery M. , Nevo Yoram , Zuchner Stephan , Mishmar Dan , Ben-Zvi Anat
Published: April 2019

Deleterious and intact mitochondrial DNA (mtDNA) mutations frequently co-exist (heteroplasmy). Such mutations likely survive and are inherited due to complementation via the intra-cellular mitochondrial network. Hence, we hypothesized that compromised mitochondrial fusion would hamper such complementation, thereby affecting heteroplasmy inheritance. To test this hypothesis, we assessed heteroplasmy levels in three Caenorhabditis elegans strains carrying different heteroplasmic mtDNA deletions (ΔmtDNA) in the background of mutant mitofusin. Firstly, these animals displayed severe embryonic lethality and developmental delay. Strikingly, these phenotypes were relieved during subsequent generations in association with complete ΔmtDNA removal. Moreover, the rates of deletion loss negatively correlated with the size of mtDNA deletions, suggesting that mitochondrial fusion is essential and sensitive to the nature of the heteroplasmic mtDNA mutations. While introducing the ΔmtDNA into a fzo-1;pdr-1 (PARKIN ortholog) double mutant, we observed skew in the mendelian distribution of progeny, in contrast to normal distribution in the ΔmtDNA;fzo-1 mutant, and severely reduced brood size. Notably, the ΔmtDNA was lost across generations in association with improved phenotypes. This underlines the importance of cross-talk between mitochondrial fusion and mitophagy in modulating the inheritance of mtDNA heteroplasmy. Finally, while investigating heteroplasmy patterns in three Charcot-Marie-Tooth disease type 2A pedigrees, which carry a mutated mitofusin 2, we found a single potentially deleterious heteroplasmic mutation, whose levels were selectively reduced in the patient versus healthy maternal relatives. Taken together our findings show that when mitochondrial fusion is compromised, deleterious heteroplasmic mutations cannot evade natural selection, while inherited from generation to generation.
Enhanced visuomotor learning and generalization in expert surgeons
Authors: Hewitson Christopher L. , Kaplan David M.
Published: April 2019

Although human motor learning has been intensively studied for many decades, it remains unknown whether group differences are present in expert cohorts that must routinely cope with and learn new visuomotor mappings such as minimally invasive surgeons. Here we show that expert surgeons exhibit greater adaptation and generalization compared to naive controls in a standard visuomotor adaptation task. These findings run counter to a widespread background assumption in the field of motor learning that visuomotor adaptation performance should be largely uniform across the adult human population. Our findings also indicate that differences in basic visuomotor learning capacities, either innate or acquired, might be an important source of difficulty in learning and performing minimally invasive surgery. This information holds potential to guide surgical candidate selection or optimize training programs to address individual needs.
Slow‐release vaginal insert of misoprostol versus orally administrated solution of misoprostol for the induction of labour in primiparous term pregnant women: a randomised controlled trial
Authors: Wallström T , Strandberg M , Gemzell‐Danielsson K , Pilo C , Jarnbert‐Pettersson H , Friman‐Mathiasson M , Wiberg‐Itzel E
Published: April 2019

Objective

To compare the World Health Organization (WHO) recommended orally administrated dosage of misoprostol (25 μg) with a vaginal slow‐release (7 μg/hour) insert of misoprostol regarding time from induction to delivery and safety of the method.

Design

Open label, Randomised controlled trial (RCT).

Setting

Delivery ward at a secondary referral hospital in Stockholm, Sweden, from 1 October 2016 to 21 February 2018.

Population

One hundred and ninety‐six primiparous women with singletons in cephalic presentation at ≥37 weeks of gestation and with a Bishop score of ≤4.

Methods

Women were randomised to an oral solution of misoprostol (Cytotec® n = 99) or vaginal slow‐release misoprostol (Misodel® [MVI] n = 97).

Main outcome measures

Primary outcome: time from induction to vaginal delivery. Secondary outcomes: mode of delivery; proportion of vaginal deliveries within 24 hours (VD24); neonates with an Apgar score of <7 at 5 minutes; pH < 7.10; postpartum haemorrhage (PPH) of >1000 ml; hyperstimulation; and women's delivery experience (VAS).

Results

There was no difference in the time to vaginal delivery (median 21.1 hours in the MVI group and 23.2 hours in the oral group; Kaplan–Mayer log rank P = 0.31). There was no difference regarding the proportion of VD24 (50.5 versus 55.7%, P = 0.16). Hyperstimulation with non‐reassuring cardiotocography (CTG) was more common in the MVI group (14.4 versus 3.0%, P < 0.01). Terbutaline (Bricanyl®) was used more often for hyperstimulation in the MVI group (22.7 versus 4.0%, P < 0.01). There was no difference in the numbers of children admitted to the neonatal intensive care unit (NICU).

Conclusions

Vaginal delivery after induction of labour (IOL) with slow‐release misoprostol did not result in a shorter time from induction to vaginal delivery, compared with oral misoprostol solution, but was associated with a higher risk for hyperstimulation and fetal distress. There were no differences in mode of delivery or neonatal outcome.

Tweetable abstract

IOL with MVI was similar to oral solution of misoprostol but hyperstimulation and fetal distress were more common.
Role of autonomic dysfunction in the regulation of myocardial blood flow in systemic sclerosis evaluated by cardiac magnetic resonance
Authors: Gigante Antonietta , Galea Nicola , Borrazzo Cristian , Tubani Luigi , Liberatori Marta , Ciolina Federica , Fiorelli Andrea , Romaniello Antonella , Barbano Biagio , Romaggioli Laura , Francone Marco , Catalano Carlo , Carbone Iacopo , Rosato Edoardo
Published: April 2019

Aim

Autonomic dysfunction (AD) is an early feature of systemic sclerosis (SSc). A regular endothelial function is a prerequisite for normal response of the myocardial blood flow (MBF) to cold pressure test (CPT). The aim of the study was to evaluate the relation between MBF and AD at rest and after CPT in asymptomatic SSc patients.

Methods

Twenty SSc patients and 10 age‐, sex‐ and body mass index‐matched healthy controls underwent cardiac magnetic resonance at rest and after CPT. All subjects underwent 24 hours ambulatory 3‐channel electrocardiogram Holter to evaluate AD by heart rate variability.

Results

We did not observe any significant difference in MBF (mL/g/min) at rest and after CPT between SSc patients and healthy controls. Delta of MBF (difference between MBF after CPT and rest MBF) was lower (P = 0.039) in SSc patients than healthy controls (0.28 [0.04‐0.40] vs 0.33 [0.24‐0.54]). The low frequency/high frequency (LF/HF) was higher (P = 0.002) in SSc patients than healthy controls (3 [1.7‐6] vs 1.8 [1.1‐2.8]). The high frequencies (HF), modulated mainly by paraympathetic system, was lower (P = 0.003) in SSc patients than healthy controls (30 [16‐42] vs 36.5 [24‐44]). Sympathetic hyperactivity, due to reduction of parasympathetic activity (HF), is present in SSc patients. A negative correlation was observed between Delta of MBF and LF/HF (r = −0.572, P = 0.0031).

Conclusion

AD, characterized by sympathovagal imbalance due to a reduced parasympathetic tone with high LF/HF ratio, could be responsible for the reduced myocardial vasodilatory response after CPT.
Correlation between the protein expression levels of A‐kinase anchor protein95, p‐retinoblastoma (Ser780), cyclin D2/3, and cyclin E2 in esophageal cancer tissues
Authors: Wang Shuo , Wang Kai , Deng Zifeng , Jiang Zemin , Wang Dai , Yao Youliang , Guo Dongbei , Kong Xiangyu , Guan Zhiyu , Zhang Yongxing
Published: April 2019

Aim

This study aimed to investigate the correlation between the expression of A‐kinase anchor protein95 (AKAP95), p‐retinoblastoma (phosphorylated Rb, p‐Rb), cyclin D2, cyclin D3 and cyclin E2 in esophageal cancer tissues and clinicopathological indexes.

Method

The protein expression levels of AKAP95, p‐Rb, cyclin D2/3 and cyclin E2 in 40 esophageal cancer tissues were detected using immunohistochemistry, and the correlation between them was analyzed.

Result

The percentage of p‐Rb (Ser780)‐, cyclin D2‐, cyclin D3‐ and cyclin E2‐positive samples was 62.50%, 70.00%, 67.50% and 60.00%, respectively. Also, the positive expression did not correlate with the histological type, histological differentiation or lymph node metastasis. The expression of AKAP95 and p‐Rb (Ser780), p‐Rb (Ser780) and cyclin D2 and p‐Rb (Ser780) and cyclin D3 in esophageal cancer tissues was found to be correlated (P < 0.05).

Conclusions

The expression of AKAP95 and p‐Rb (Ser780), p‐Rb(Ser780) and cyclin D2, and p‐Rb (Ser780) and cyclin D3 in esophageal cancer tissue was correlated, suggesting that these proteins might play a synergistic role in cell‐cycle progression. Cyclin D2/D3 and p‐Rb (Ser780) were correlated whereas cyclin E2 and p‐Rb (Ser780) were not, suggesting that p‐Rb (Ser780) might be highly expressed and the Ser780 site of Rb protein might be phosphorylated in the early stage of the G1 phase. Ser780 was the site in the primary phosphorylation stage of several phosphorylation sites during stepwise phosphorylation (from primary to high phosphorylation).
The Media and the Financial Markets: A Review
Authors: Raimondo Carlo
Published: April 2019

In recent years there has been a growing body of literature about the role of the media in finance. Textual analysis techniques and greater availability of data have created the possibility of going deeper into an analysis of soft information, including newspaper articles and other media‐generated content. This paper aims to present knowledge about the media's role in finance, calling on a large variety of research from the fields of finance, accounting, management, and economics. The goal and contribution of this paper are to provide a response to these queries by referencing existing, but often unconnected, literature.
Geopolitical Risk and Trading Patterns of Foreign and Domestic Investors: Evidence from Korea
Authors: Kim Young Sik , Park Keun Jae , Kwon Oh Byung
Published: April 2019

We examine how geopolitical risk affects investors’ investment strategies in the Korean market. The information advantage hypothesis predicts that foreign investors become more reluctant to invest in the portfolios of foreign countries due to increased information asymmetry following geopolitical risk escalation while the international diversification hypothesis predicts that foreign investors will not reduce the size of their foreign portfolios because their wealth portfolios are sufficiently diversified. Using a novel measure of geopolitical risk, we find evidence consistent with the information advantage hypothesis: when North Korea risk is highly escalated, foreign investors reduce while domestic investors increase the value of their Korean portfolios, and domestic institutional investors significantly outperform foreign investors due to increased information asymmetry.
Development and validation of the Treatment Expectations in Chronic Pain Scale
Authors: Pagé M. Gabrielle , Ziemianski Daniel , Martel Marc Olivier , Shir Yoram
Published: April 2019

Objectives

To develop and examine the psychometric properties of the Treatment Expectations in Chronic Pain (TEC) scale, a brief measure of treatment expectations of chronic non‐cancer pain treatment.

Design

A cross‐sectional study design was used.

Methods

After conducting a literature review and expert discussions, a preliminary version of the TEC scale was developed. Cognitive interviews with 10 clinicians and 14 patients were conducted to examine the scale's face validity and item wording. Last, two hundred and five patients on the waitlist for a multidisciplinary pain treatment centre completed a battery of self‐report questionnaires to examine the TEC scale's reliability and construct validity. Mokken scale analysis was conducted to select the final items. Reliability (Cronbach's alpha and Guttman's lambda2) and construct validity (Pearson correlations) were assessed.

Results

The final scale was composed of nine items that each measured ideal and predicted expectations about process and outcome of treatment. Mokken scale analysis showed the presence of two subscales: ideal and predicted expectations. The TEC scale had good internal consistency (α = 0.876–0.869) and adequate discriminant validity as assessed by its low correlation with measures of depression, anxiety, and quality of life (r = −.038 to .114). The scale had however low correlation with a theoretically related measure of optimism (r = .240).

Conclusion

The TEC scale is a reliable scale measuring pain treatment expectation. Further evaluation of its psychometric properties is needed. The scale has the potential to deepen our understanding of the role treatment expectations play in chronic non‐cancer pain treatment response.

Statement of contribution

What is already known on this subject?

Expectations play a role in pain perception and the response to pain treatment

Patients' expectations about pain and its management are associated with treatment satisfaction

The absence of a validated tool to measure treatment expectations in chronic non‐cancer pain prevents further exploration and understanding of the role of expectations in the context of multidisciplinary pain treatment

.

What does this study add?

A new, reliable 9‐item scale measuring treatment expectations among chronic non‐cancer pain patients attending specialized multidisciplinary pain clinics

.
Organic Anion Transporter Polypeptide 1B1 Polymorphism Modulates the Extent of Drug–Drug Interaction and Associated Biomarker Levels in Healthy Volunteers
Authors: Yee Sook Wah , Giacomini Marilyn M. , Shen Hong , Humphreys W. Griffith , Horng Howard , Brian William , Lai Yurong , Kroetz Deanna L. , Giacomini Kathleen M.
Published: April 2019

Understanding transporter‐mediated drug–drug interactions is an integral part of risk assessment in drug development. Recent studies support the use of hexadecanedioate (HDA), tetradecanedioate (TDA), coproporphyrin (CP)‐I, and CP‐III as clinical biomarkers for evaluating organic anion‐transporting polypeptide (OATP)1B1 (SLCO1B1) inhibition. The current study investigated the effect of OATP1B1 genotype c.521T>C (OATP1B1‐Val174Ala) on the extent of interaction between cyclosporin A (CsA) and pravastatin, and associated endogenous biomarkers of the transporter (HDA, TDA, CP‐I, and CP‐III), in 20 healthy volunteers. The results show that the levels of each clinical biomarker and pravastatin were significantly increased in plasma samples of the volunteers following administration of pravastatin plus CsA compared with pravastatin plus placebo. The overall fold change in the area under the concentration–time curve (AUC) and maximum plasma concentration (Cmax) was similar among the four biomarkers (1.8–2.5‐fold, paired t‐test P value < 0.05) in individuals who were homozygotes or heterozygotes of the major allele, c.521T. However, the fold change in AUC and Cmax for HDA and TDA was significantly abolished in the subjects who were c.521‐CC, whereas the respective fold change in AUC and Cmax for pravastatin and CP‐I and CP‐III were slightly weaker in individuals who were c.521‐CC compared with c.521‐TT/TC genotypes. In addition, this study provides the first evidence that SLCO1B1 c.521T>C genotype is significantly associated with CP‐I but not CP‐III levels. Overall, these results suggest that OATP1B1 genotype can modulate the effects of CsA on biomarker levels; the extent of modulation differs among the biomarkers.
Private equity characteristics and performance: An analysis of North American venture capital and buyout funds
Authors: Roggi Oliviero , Giannozzi Alessandro , Baglioni Tommaso , Pagliai Francesco
Published: April 2019

The paper investigates the relationship between fund performance and fund characteristics of North American private equity (PE) funds, by analyzing the interactions of fund size, fund sequence, and past fund performance on traditional fund return measures. The empirical evidence is based on both linear and polynomial regressions, on a sample of 345 venture capital (VC) and 411 buyout (BO) funds with vintage year over the period 1995–2010. We document a concave relationship between fund size and performance, persistence in PE performance, as well as a convex relationship between fund sequence and performance. We suggest both the optimal fund size and the optimal fund sequence number. Economic implications for investors and general partners are discussed as well.
Cross sex hormone treatment is linked with a reversal of cerebral patterns associated with gender dysphoria to the baseline of cisgender controls
Authors: Kilpatrick Lisa A. , Holmberg Mats , Manzouri Amirhosein , Savic Ivanka
Published: April 2019

Transgender persons experience incongruence between their gender identity and birth‐assigned sex. The resulting gender dysphoria (GD), is frequently treated with cross‐sex hormones. However, very little is known about how this treatment affects the brain of individuals with GD, nor do we know the neurobiology of GD. We recently suggested that disconnection of fronto‐parietal networks involved in own‐body self‐referential processing could be a plausible mechanism, and that the anatomical correlate could be a thickening of the mesial prefrontal and precuneus cortex, which is unrelated to sex. Here, we investigate how cross‐sex hormone treatment affects cerebral tissue in persons with GD, and how potential changes are related to self‐body perception. Longitudinal MRI measurements of cortical thickness (Cth) were carried out in 40 transgender men (TrM), 24 transgender women (TrW) and 19 controls. Cth increased in the mesial temporal and insular cortices with testosterone treatment in TrM, whereas anti‐androgen and oestrogen treatment in TrW caused widespread cortical thinning. However, after correction for treatment‐related changes in total grey and white matter volumes (increase with testosterone; decrease with anti‐androgen and oestrogen), significant Cth decreases were observed in the mesial prefrontal and parietal cortices, in both TrM and TrW (vs. controls) – regions showing greater pre‐treatment Cth than in controls. The own body – self congruence ratings increased with treatment, and correlated with a left parietal cortical thinning. These data confirm our hypothesis that GD may be associated with specific anatomical features in own‐body/self‐processing circuits that reverse to the pattern of cisgender controls after cross‐sex hormone treatment.