bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Nonsurgical Chin Augmentation in Full Face Rejuvenation: A Review and Our Experience
Authors: Vanaman Wilson Monique J. , Jones Isabela T. , Butterwick Kimberly , Fabi Sabrina G.
Published: January 2018

BACKGROUND

The chin is a critical component to the perception of facial attractiveness. Dermal fillers offer a nonsurgical, temporary method of correcting mild to moderate chin retrusion and resorption. Thus far, discussion of this procedure has been largely limited to the plastic surgery and otolaryngology literature.

OBJECTIVE

To review pertinent aspects of anatomy, patient evaluation, injection technique, concomitant therapies, and complications in chin augmentation using injectable fillers.

METHODS

A brief review of the literature surrounding chin augmentation using injectable fillers, as well as the authors' experience in this area, is provided.

RESULTS

Chin augmentation using injectable fillers can be performed effectively and safely with adequate background knowledge of the regional anatomy and appropriate patient selection. The authors discuss both injection techniques in the published literature and their own approach. Potential complications and concomitant therapies are also reviewed.

CONCLUSION

As chin augmentation is increasingly recognized as an essential component to complete facial aesthetic rejuvenation, dermatologic surgeons should be familiar with how to safely and effectively perform augmentation with injectable fillers to achieve an optimal cosmetic outcome.
A Pilot Examination of the Methods Used to Counteract Insider Threat Security Risks Associated with the Use of Radioactive Materials in the Research and Clinical Setting
Authors: Tsenov B.G. , Emery R.J. , Whitehead L.W. , Gonzalez J. Reingle , Gemeinhardt G.L.
Published: January 2018

While many organizations maintain multiple layers of security control methodologies to prevent outsiders from gaining unauthorized access, persons such as employees or contractors who have been granted legitimate access can represent an “insider threat” risk. Interestingly, some of the most notable radiological events involving the purposeful contamination or exposure of individuals appear to have been perpetrated by insiders. In the academic and medical settings, radiation safety professionals focus their security efforts on (1) ensuring controls are in place to prevent unauthorized access or removal of sources, and (2) increasing security controls for the unescorted accessing of large sources of radioactivity (known as “quantities of concern”). But these controls may not completely address the threat insiders represent when radioactive materials below these quantities are present. The goal of this research project was to characterize the methodologies currently employed to counteract the insider security threat for the misuse or purposeful divergence of radioactive materials used in the academic and medical settings. A web-based survey was used to assess how practicing radiation safety professionals in academic and medical settings anticipate, evaluate, and control insider threat security risks within their institutions. While all respondents indicated that radioactive sources are being used in amounts below quantities of concern, only 6 % consider insider threat security issues as part of the protocol review for the use of general radioactive materials. The results of this survey identify several opportunities for improvement for institutions to address security gaps.
A Distinct Malignant Epithelioid Neoplasm With GLI1 Gene Rearrangements, Frequent S100 Protein Expression, and Metastatic Potential
Authors: Antonescu Cristina R. , Agaram Narasimhan P. , Sung Yun-Shao , Zhang Lei , Swanson David , Dickson Brendan C.
Published: January 2018

ACTB-GLI1 fusions have been reported as the pathognomonic genetic abnormality defining an unusual subset of actin-positive, perivascular myoid tumors, known as “pericytoma with the t(7;12) translocation.” In addition, GLI1 oncogenic activation through a related MALAT1-GLI1 gene fusion has been recently reported in 2 unrelated gastric tumors, namely plexiform fibromyxoma and gastroblastoma. Triggered by unexpected targeted RNA-sequencing results detecting GLI1-related fusions in a group of malignant neoplasms with round to epithelioid morphology, and frequently strong S100 protein immunoreactivity, we investigated their clinicopathologic features in relation to other known pathologic entities sharing similar genetics. On the basis of a combined approach of targeted RNA sequencing and fluorescence in situ hybridization screening, we identified 6 cases with GLI1 gene fusions, including 4 fused to ACTB, 1 with MALAT1 and 1 with PTCH1 gene. Patients had a mean age of 36 years at diagnosis (range, 16 to 79 y) and slight female predilection all except 1 tumor originated in the soft tissue. Microscopically, the tumors had a monomorphic epithelioid phenotype arranged in a distinctive nested or cord-like architecture, separated by thin septae and delicate capillary network. All except 2 cases were strongly positive for S100 protein, whereas being negative for SOX10, SMA, and EMA. Only 1 tumor showed focal cytokeratin positivity in rare cells. Although the tumors showed some resemblance to pericytic/glomus tumors or myoepithelial tumors, the immunoprofile was not supportive of either lineage. Moreover, in contrast to the benign course of so-called pericytoma with t(7;12), 3 patients in this series developed metastatic disease to either lymph nodes or lung. In fact the only patient with lung metastases showed a novel PTCH1-GLI1 gene fusion. It remains to be determined whether these tumors represent a clinically and immunohistologically distinct subset of pericytoma, or an altogether novel soft tissue sarcoma. Our findings open new opportunities for targeted therapy, as tumors with GLI1 oncogenic activation, and subsequent PTCH1 overexpression, might be sensitive to sonic hedgehog pathway inhibitors.
American Urogynecologic Society Prolapse Consensus Conference Summary Report
Authors: Siddiqui Nazema Y. , Gregory W. Thomas , Handa Victoria L. , DeLancey John O.L. , Richter Holly E. , Moalli Pamela , Barber Matthew D. , Pulliam Samantha , Visco Anthony G. , Alperin Marianna , Medina Carlos , Fraser Matthew O. , Bradley Catherine S.
Published: January 2018

Objectives

The 2016 American Urogynecologic Society Prolapse Consensus Conference brought together thought leaders in the field of pelvic organ prolapse (POP). The goal was to identify critical areas of need for future research. This article summarizes the findings.

Methods

Prior to the conference, 5 major focus areas were identified. Focus areas were explored over the 2-day conference. Clinicians, clinical and basic science researchers, and representatives from government agencies, industry, patient advocacy groups, and the public convened to identify the major gaps in knowledge in each of these focus areas.

Results

The 5 major topics were as follows: (1) mechanistic research on pelvic supportive structures and how these are altered with pregnancy, delivery, and aging; (2) novel prostheses or implants that address pathophysiology and provide mechanical support; (3) large-scale community-based research; (4) clinical trials to optimize outcomes after POP surgery; and (5) evidence-based quality measures for POP outcomes. Key recommendations were made for each topic.

Conclusions

Critical gaps in our knowledge were identified. These limit scientific discovery across all 5 topic areas. Further scientific progress would be advanced by (1) developing a standardized group of POP outcomes and quality measures for large trials and community-based research, (2) creating specimen biorepositories that are integrated with robust clinical data, and (3) developing collaborative teams with expertise from a variety of disciplines, convened to tackle our most challenging and complex scientific questions.
Modeling sound attenuation in heterogeneous environments for improved bioacoustic sampling of wildlife populations
Authors: Royle J. Andrew
Published: January 2018

Acoustic sampling methods are becoming increasingly important in biological monitoring. Sound attenuation is one of the most important dynamics affecting the utility of bioacoustic data as it directly affects the probability of detection of individuals from bioacoustic arrays and especially the localization of acoustic signals necessary in telemetry studies. Therefore, models of sound attenuation are necessary to make efficient use of bioacoustic data in ecological monitoring and assessment applications. Models of attenuation in widespread use are based on Euclidean distance between source and sensor, which is justified under spherical attenuation of sound waves in homogeneous environments. In some applications there are efforts to evaluate the detection range of sensors in response to local environmental characteristics at the sensor or at sentinel source locations with known environmental characteristics. However, attenuation is a function of the total environment between source and sensor, not just their locations. In this paper I develop a model of signal attenuation based on a non-Euclidean cost-weighted distance metric which contains resistance parameters that relate to environmental heterogeneity in the vicinity of an array. Importantly, these parameters can be estimated by maximum likelihood using experimental data from an array of fixed sources, thus allowing investigators who use bioacoustic methods to devise explicit models of sound attenuationin situ. In addition, drawing on analogy with classes of models known as spatial capture-recapture, I show that parameters of the non-Euclidean model of attenuation can be estimated when source locations areunknown. Thus, the models can be applied to real field studies which require localization of signals in heterogeneous environments.
Cytokinin activity ofN6-benzyladenine derivatives assayed by interaction with the receptorsin planta, in vitro, andin silico
Authors: Savelieva Ekaterina M. , Oslovsky Vladimir E. , Karlov Dmitry S. , Kurochkin Nikolay N. , Getman Irina A. , Lomin Sergey N. , Sidorov Georgy V. , Mikhailov Sergey N. , Osolodkin Dmitry I. , Romanov Georgy A.
Published: January 2018

Biological effects of hormones in both plants and animals are based on high-affrnity interaction with cognate receptors resulting in their activation. The signal of cytokinins, classical plant hormones, is perceived inArabidopsisby three homologous membrane receptors: AHK2, AHK3, and CRE1/AHK4. To study the cytokinin–receptor interaction, we used 25 derivatives of potent cytokininN6-benzyladenine (BA) with substituents in the purine heterocycle and/or in the side chain. The study was focused primarily on individual cytokinin receptors fromArabidopsis. The mainin plantaassay system was based onArabidopsisdouble mutants retaining only one isoform of cytokinin receptors and harboring cytokinin-sensitive reporter gene. Classical cytokinin biotest withAmaranthusseedlings was used as an additional biotest. In parallel, the binding of ligands to individual cytokinin receptors was assessed in thein vitrotest system. Quantitative comparison of results of different assays confirmed the partial similarity of ligand-binding properties of receptor isoforms. Substituents at positions 8 and 9 of adenine moiety, elongated linker up to 4 methylene units, replacement ofN6by sulfur or oxygen, resulted in suppression of cytokinin activity of the derivative towards all receptors. Introduction of a halogen into position 2 of adenine moiety, on the contrary, often increased the ligand activity, especially toward AHK3. Features both common and distinctive of cytokinin receptors inArabidopsisandAmaranthuswere revealed, highlighting species specificity of the cytokinin perception apparatus. Correlations between extent of compound binding to a receptorin vitroand its ability to activate the same receptorin plantawere evaluated for each AHK protein. Interaction patterns between individual receptors and ligands were rationalized by structure analysis and molecular docking in sensory modules of AHK receptors. The best correlation between docking scores and specific binding was observed for AHK3. In addition, receptor-specific ligands have been discovered with unique properties to predominantly activate or block distinct cytokinin receptors. These ligands are promising for practical application and as molecular tools in the study of the cytokinin perception by plant cells.

Graphical abstract

Individual cytokinin receptors fromArabidopsiswere assayedin planta,in vitroandin silicowith 25 different 6-benzyladenine derivatives, new receptor-specific cytokinins were revealed.
Listeria monocytogenesInlP interacts with afadin and facilitates basement membrane crossing
Authors: Faralla Cristina , Bastounis Effie E. , Ortega Fabian E. , Light Samuel H. , Rizzuto Gabrielle , Nocadello Salvatorre , Anderson Wayne F. , Robbins Jennifer R. , Theriot Julie A. , Bakardjiev Anna I.
Published: January 2018

During pregnancy, the placenta protects the fetus against the maternal immune response, as well as bacterial and viral pathogens. Bacterial pathogens that have evolved specific mechanisms of breaching this barrier, such asListeria monocytogenes, present a unique opportunity for learning how the placenta carries out its protective function. We previously identified theL. monocytogenesprotein Internalin P (InlP) as a secreted virulence factor critical for placental infection (1). Here, we show that InlP, but not the highly similarL. monocytogenesinternalin Lmo2027, binds to human afadin (encoded byAF-6), a protein associated with cell-cell junctions. A crystal structure of InlP reveals several unique features, including an extended leucine-rich repeat (LRR) domain with a distinctive Ca2+-binding site. Despite afadin’s involvement in the formation of cell-cell junctions, MDCK epithelial cells expressing InlP displayed a decrease in the magnitude of the traction stresses they could exert on deformable substrates, similar to the decrease in traction exhibited byAF-6knock-out MDCK cells.L. monocytogenes ΔinlPmutants were deficient in their ability to form actin-rich protrusions from the basal face of polarized epithelial monolayers, a necessary step in the crossing of such monolayers (transcytosis). A similar phenotype was observed for bacteria expressing an internal in-frame deletion ininlP(inlPDLRR5) that specifically disrupts its interaction with afadin. However, afadin deletion in the host cells did not rescue the transcytosis defect. We conclude that secreted InlP targets cytosolic afadin to specifically promoteL. monocytogenestranscytosis across the basal face of epithelial monolayers, which may contribute to the crossing of the basement membrane during placental infection.
Modeling Functional Genetic Alteration in Cancer Reveals New Candidate Driver Genes
Authors: Brandes Nadav , Linial Nathan , Linial Michal
Published: January 2018

Compiling the catalogue of genes actively involved in tumorigenesis (known as cancer drivers) is an ongoing endeavor, with profound implications to the understanding of tumorigenesis and treatment of the disease. An abundance of computational methods have been developed to screening the genome for candidate driver genes based on genomic data of somatic mutations in tumors. Most methods rely on detecting genes displaying excessive mutation rates compared to some background model. This approach is susceptible to false discoveries, due to its sensitivity to the assumptions of the background model, such as the need to account for hyper-mutated samples, cancer types and genomic loci. We present a fundamentally different approach. Instead of focusing on the number of mutations, we examine their content, and their expected effects on the functions of genes. We use a machine-learning model to predict functional effect scores of somatic mutations. For each gene, we compare the distribution of observed effect scores with the distribution expected at random, and report genes showing significant bias. By applying our framework on the ~20k protein-coding human genes, we detected 593 genes showing significant bias towards harmful mutations in the context of cancer. In contrast, we found only 6 significant genes biased in the opposite direction. The list of 593 genes, constructed without any prior knowledge of their role in cancer, shows an overwhelming overlap with known cancer driver genes, but also highlights many overlooked genes. These overlooked genes are promising candidates for novel cancer drivers. Our model is generic and is not restricted to the context of cancer. Applying the same framework to data of human-population genetic variation reveals the opposite trend. Unlike cancer, which is dominated by a bias towards harmful mutations, long-term evolution in healthy individuals results a bias towards less harmful mutations. The underlying assumptions of our framework are minimal, making it ideal for analyzing genetic data in search of genes subjected to positive or negative selection. It is fully open sourced and available for installation and use. Our framework presents a substantial development towards the application of state-of-the-art machine-learning algorithms in genetic studies.
Protein-coding variation and introgression of regulatory alleles drive plumage pattern diversity in the rock pigeon
Authors: Vickrey Anna I. , Bruders Rebecca , Kronenberg Zev , Mackey Emma , Bohlender Ryan J. , Maclary Emily T. , Osborne E.J. , Johnson Kevin P. , Huff Chad D. , Yandell Mark , Shapiro Michael D.
Published: January 2018

Birds and other vertebrates display stunning variation in pigmentation patterning, yet the genes controlling this diversity remain largely unknown. Rock pigeons (Columba livia) are fundamentally one of four color pattern phenotypes, in decreasing order of melanism: T-check, checker, bar (ancestral), or barless. Using whole-genome scans, we identifiedNDPas a candidate gene for this variation. Allele-specific expression differences inNDPindicatecis-regulatory differences between ancestral and melanistic alleles. Sequence comparisons suggest that derived alleles originated in the speckled pigeon (Columba guinea), providing a striking example of introgression of alleles that are favored by breeders and are potentially advantageous in the wild. In contrast, barless rock pigeons have an increased incidence of vision defects and, like two human families with hereditary blindness, carry start-codon mutations inNDP. In summary, we find unexpected links between color pattern, introgression, and vision defects associated with regulatory and coding variation at a single locus.
The Homeostatic Logic of Reward
Authors: Morville Tobias , Friston Karl , Burdakov Denis , Siebner Hartwig R. , Hulme Oliver J.
Published: January 2018

Energy homeostasis depends on behavior to predictively regulate metabolic states within narrow bounds. Here we review three theories of homeostatic control and ask how they provide insight into the circuitry underlying energy homeostasis. We offer two contributions. First, we detail how control theory and reinforcement learning are applied to homeostatic control. We show how these schemes rest on implausible assumptions; either via circular definitions, unprincipled drive functions, or by ignoring environmental volatility. We argue active inference can elude these shortcomings while retaining important features of each model. Second, we review the neural basis of energetic control. We focus on a subset of arcuate subpopulations that project directly to, and are thus in a privileged position to opponently modulate, dopaminergic cells as a function of energetic predictions over a spectrum of time horizons. We discuss how this can be interpreted under these theories, and how this can resolve paradoxes that have arisen. We propose this circuit constitutes a homeostatic-reward interface that underwrites the conjoint optimisation of physiological and behavioural homeostasis.
Crumble: reference free lossy compression of sequence quality values
Authors: Bonfield James K , McCarthy Shane A , Durbin Richard
Published: January 2018

Motivation

The bulk of space taken up by NGS sequencing CRAM files consists of per-base quality values. Most of these are unnecessary for variant calling, offering an opportunity for space saving.

Results

On the CHM1+CHM13 test set, a 17 fold reduction in quality storage can be achieved while maintaining variant calling accuracy.

Availability

Crumble is OpenSource and can be obtained from https://github.com/jkbonfield/crumble.

Contact

jkb@sanger.ac.uk

Supplementary information

Supplementary data are available.
An empirical, 21st century evaluation of phrenology
Authors: Jones O. Parker , Alfaro-Almagro F. , Jbabdi S.
Published: January 2018

Phrenology was a nineteenth century endeavour to link personality traits with scalp morphology, which has been both influential and fiercely criticised, not least because of the assumption that scalp morphology can be informative of underlying brain function. Here we test the idea empirically rather than dismissing it out of hand. Whereas nineteenth century phrenologists had access to coarse measurement tools (digital technology referring then to fingers), we were able to re-examine phrenology using 21stcentury methods and thousands of subjects drawn from the largest neuroimaging study to date. High-quality structural MRI was used to quantify local scalp curvature. The resulting curvature statistics were compared against lifestyle measures acquired from the same cohort of subjects, being careful to match a subset of lifestyle measures to phrenological ideas of brain organisation, in an effort to evoke the character of Victorian times. The results represent the most rigorous evaluation of phrenological claims to date.
Conditioning nausea in a laboratory setting: A pilot study
Authors: Van Hedger Kathryne , Cavallo Joel S. , Ruiz Nicholas A. , de Wit Harriet
Published: January 2018

Cancer patients can experience nausea as they approach the place where they have received chemotherapy treatment. This nausea is likely the result of Pavlovian conditioning, where the previously neutral environment acquires conditioned properties, in this case conditioned nausea, because its association with feeling ill. To investigate this phenomenon under controlled conditions, we studied the acquisition of conditioned nausea using a distinct environment paired with an emetic drug in healthy young adults. We measured two indices of conditioning: i) conditioned place aversion, and ii) conditioned drug-like (nausea) responses. Healthy volunteers (N=32) first rated their preference for two testing rooms, and then underwent four conditioning sessions in which they received either syrup of ipecac (5 ml) or placebo. A Paired Group (PG; N=17) always received ipecac in their initially preferred room and placebo in the other, while an Unpaired Group (UG; N=15) received ipecac and placebo in both rooms. Conditioned responses were assessed with i) time spent in each room, ii) room liking and preference, and iii) feelings of nausea in each room. There was no evidence of conditioned place aversion as measured by either time spent or ratings of room liking. However, the PG did report a small increase in nausea in the ipecac-paired room. Although the conditioned responses in this study were not robust, this procedure is a first step towards studying conditioned aversive drug responses in humans, which will enable development of future studies to prevent or treat anticipatory nausea.
GSK3 Controls Migration of the Neural Crest Lineage
Authors: Malagon Sandra G. Gonzalez , Muñoz Anna M. Lopez , Doro Daniel , Bolger Triòna G. , Poon Evon , Tucker Elizabeth R. , Al-Lami Hadeel Adel , Krause Matthias , Phiel Christopher , Chesler Louis , Liu Karen J.
Published: January 2018

Migration of the neural crest lineage is critical to its physiological function. Mechanisms controlling neural crest migration are comparatively unknown, due to difficulties accessing this cell populationin vivo. Here, we uncover novel requirements of glycogen synthase kinase 3 (GSK3) in regulating the neural crest. We demonstrate that GSK3 is tyrosine phosphorylated (pY) in neural crest cells and that this activation depends on anaplastic lymphoma kinase (ALK), a protein associated with neuroblastoma. Consistent with this, neuroblastoma cells with pathologically increased ALK activity express high levels of pY-GSK3 and migration of these cells can be inhibited by GSK3 or ALK blockade. In normal neural crest cells, loss of GSK3 leads to increased pFAK and misregulation of Rac1 and lamellipodin, key regulators of cell migration. Genetic reduction of GSK-3 results in failure of migration. All together, this work identifies a role for GSK3 in cell migration during neural crest development and cancer.
Methionine metabolism influences the genomic architecture of H3K4me3 with the link to gene expression encoded in peak width
Authors: Dai Ziwei , Mentch Samantha J. , Gao Xia , Nichenametla Sailendra N. , Locasale Jason W.
Published: January 2018

Nutrition and metabolism are known to influence chromatin biology and epigenetics by modifying the levels of post-translational modifications on histones, yet how changes in nutrient availability influence specific aspects of genomic architecture and connect to gene expression is unknown. To investigate this question we considered, as a model, the metabolically-driven dynamics of H3K4me3, a histone methylation mark that is known to encode information about active transcription, cell identity, and tumor suppression. We analyzed the genome-wide changes in H3K4me3 and gene expression in response to alterations in methionine availability under conditions that are known to affect the global levels of histone methylation in both normal rodent physiology and in human cancer cells. Surprisingly, we found that the location of H3K4me3 peaks at specific genomic loci was largely preserved under conditions of methionine restriction. However, upon examining different geometrical features of peak shape, it was found that the response of H3K4me3 peak width encoded almost all aspects of H3K4me3 biology including changes in expression levels, and the presence of cell identity and cancer associated genes. These findings reveal simple yet new and profound principles for how nutrient availability modulates specific aspects of chromatin dynamics to mediate key biological features.
SLO potassium channels antagonize premature decision making in C. elegans
Authors: Aoki Ichiro , Tateyama Michihiro , Shimomura Takushi , lhara Kunio , Kubo Yoshihiro , Nakano Shunji , Mori Ikue
Published: January 2018

Animals have to modify their behavior at the right timing to respond to changes in environments. Yet, the molecular and neural mechanisms regulating the timing of behavioral transition remain largely unknown. Performing forward genetics on a plasticity of thermotaxis behavior in C. elegans, we demonstrated that SLO potassium channels together with a cyclic nucleotide-gated channel CNG-3 determine the timing of the transition of temperature preference after shift of cultivation temperature. We further revealed that SLO and CNG-3 channels regulate the alteration in responsiveness of thermosensory neurons. Our results suggest that the regulation of sensory adaptation is a major determinant of the latency for animals to make decisions in changing behavior.

Highlights

Slo-1 and SLO-2 K+ channels decelerated transition of temperature preference in thermotaxis behavior after upshift of cultivation temperature

SLO K+ channels slowed down the adaptation of AFD thermosensory neuron to new cultivation temperature

A cyclic nucleotide-gated channel CNG-3 functioned together with SLO-2

Thermotaxis serves as could be a model system for early onset epilepsies
Coexistence theory and the frequency-dependence of priority effects
Authors: Ke Po-Ju , Letten Andrew D.
Published: January 2018

Priority effects encompass a broad suite of ecological phenomena. Several studies have suggested reframing priority effects around the stabilizing and equalizing concepts of coexistence theory. We show that the only compatible priority effects are those characterized by positive frequency dependence.
Synaptic transmission may provide an evolutionary benefit to HIV through modulation of latency
Authors: Vargas-Garcia Cesar , Zurakowski Ryan , Singh Abhyudai
Published: January 2018

Transmission of HIV is known to occur by two mechanisms in vivo: the free virus pathway, where viral particles bud off an infected cell before attaching to an uninfected cell, and the cell-cell pathway, where infected cells form virological synapses through close contact with an uninfected cell. It has also been shown that HIV replication includes a positive feedback loop controlled by the viral protein Tat, which may act as a stochastic switch in determining whether an infected cell enters latency. In this paper, we introduce a simple mathematical model of HIV replication containing both the free virus and cell-cell pathways. Using this model, we demonstrate that the high multiplicity of infection in cell-cell transmission results in a suppression of latent infection, and that this modulation of latency through balancing the two transmission mechanisms can provide an evolutionary benefit to the virus. This benefit increases with decreasing overall viral fitness, which may provide a within-host evolutionary pressure toward more cell-cell transmission in late-stage HIV infection.
Building online genomics applications using BioPyramid
Authors: Stephenson Liam , Wakeham Yoshua , Seidenman Nick , Choi Jarny
Published: January 2018

BioPyramid is a python package, which can serve as a scaffold for building an online genomics application. BioPyramid contains a number of components designed to reduce the time and effort in building such an application from scratch, including gene annotation, dataset models and visualisation tools. The user can rapidly deploy a data portal with the example dataset included, and start customising components as required. BioPyramid is implemented in python and javascript and freely available at http://github.com/jarny/biopyramid.
Characterization of mannitol metabolism genes inSaccharinaexplains its key role in mannitol biosynthesis and evolutionary significance in Laminariales
Authors: Chi Shan , Liu Tao , Liu Cui , Jin Yuemei , Yin Hongxin , Xu Xin , Li Yue
Published: January 2018

As a unique photosynthetic product in brown algae, mannitol exhibits high synthesis and accumulation inSaccharina japonica. Mannitol acts as a carbon-storage compound and is an osmoprotectant, imparting increased tolerance to osmotic stress. However, the underlying biochemical and molecular mechanisms in macroalgae have not been studied. Analysis of genomic and transcriptomic data has shown that mannitol metabolism inS. japonicais a circular pathway composed of four steps. In this study, oneS. japonicamannitol-1-phosphate dehydrogenase (M1PDH2) and two mannitol-1-phosphatase (M1Pase) proteins were recombinantly expressed to analysis enzyme biochemical properties. RNA sequencing and droplet digital polymerase chain reaction were used to analyze the gene expression patterns of mannitol metabolism in different generations, tissues, sexes, and abiotic stresses. Our findings revealed insights into the mannitol synthesis pathways in brown algae. All genes were constitutively expressed in all samples, allowing maintenance of basic mannitol anabolism and dynamic maintenance of the “saccharide pool”in vivoas the main storage and antistress mechanism. Enzyme assays confirmed that the recombinant proteins produced mannitol, with the specific activity of SjaM1Pase1 being 1.8–4831 times that of other algal enzymes. Combined with the transcriptional analysis, SjaM1Pase1 was shown to be the dominant gene of mannitol metabolism. Mannitol metabolism genes in multicellular filamentous (gametophyte) and large parenchyma thallus (sporophyte) generations had different expression levels and responded differently under environmental stresses (hyposaline and hyperthermia) in gametophytes and sporophytes. The considerable variation in enzyme characteristics and expression of mannitol synthesis genes suggest their important ecophysiological significance in the evolution of complex systems (filamentous and thallus) and environmental adaptation of Laminariales.
Coordinated activity of sleep and arousal neurons for stabilizing sleep/wake states in Drosophila
Authors: Ni Jinfei D. , Ogunmowo Tyler H. , Hackbart Hannah , Elsheikh Ahmed , Gurav Adishthi S. , Verdegaal Andrew A. , Montell Craig
Published: January 2018

The output arm of the sleep homeostat in Drosophila is a group of neurons with projections to the dorsal fan-shaped body (dFSB) of the central complex in the brain. However, neurons that regulate the sleep homeostat remain poorly understood. Using neurogenetic approaches combined with ex vivo Ca2+ imaging, we identify two groups of sleep-regulatory neurons that modulate the activity of the sleep homeostat in an opposing fashion. The sleep-promoting neurons activate the sleep homeostat with glutamate, whereas the arousal-promoting neurons down-regulate the sleep homeostat’s output with dopamine. Co-activating these two inputs leads to frequent shifts between sleep and wake states. We also show that dFSB sleep homeostat neurons release the neurotransmitter GABA that inhibits octopaminergic arousal neurons. Taken together, we suggest coordinated neuronal activity of sleep- and arousal-promoting neurons is essential for stabilizing sleep/wake states.

Highlights

Glutamate released by AstA neurons activates dFSBAstAR1 sleep-promoting neurons

Dopamine down-regulates the activity of dFSBAstAR1 neurons

Simultaneous glutamate and dopamine input causes rapid sleep and awake swings

GABA released by dFSBAstAR1 neurons promotes sleep by inhibiting arousal neurons
Designed hybrids facilitate efficient generation of high-resolution linkage maps
Authors: Yoshitake Kazutoshi , Igarashi Yoji , Mizukoshi Misaki , Kinoshita Shigeharu , Mitsuyama Susumu , Suzuki Yutaka , Saito Kazuyoshi , Watabe Shugo , Asakawa Shuichi
Published: January 2018

In sequencing eukaryotic genomes, linkage maps are indispensable for building scaffolds with which to assemble and/or to validate chromosomes. However, current approaches to construct linkage maps are limited by marker density and cost-effectiveness, especially for wild organisms. We have now devised a new strategy based on artificially generated hybrid organisms to acquire ultra high-density genomic markers at lower cost and build highly accurate linkage maps. Using this method, linkage maps and draft sequences for two species of pufferfish were obtained simultaneously. We anticipate that the method will accelerate genomic analysis of sexually reproducing organisms.
Open source tools for temporally controlled rodent behavior suitable for electrophysiology and optogenetic manipulations
Authors: Solari Nicola , Sviatkó Katalin , Laszlovszky Tamás , Hegedüs Panna , Hangya Balázs
Published: January 2018

Understanding how the brain controls behavior requires observing and manipulating neural activity in awake behaving animals. Neuronal firing is timed at millisecond precision. Therefore, to decipher temporal coding, it is necessary to monitor and control animal behavior at the same level of temporal accuracy. However, it is technically challenging to deliver sensory stimuli and reinforcers as well as to read the behavioral responses they elicit with millisecond precision. Presently available commercial systems often excel in specific aspects of behavior control, but they do not provide a customizable environment allowing flexible experimental design while maintaining high standards for temporal control necessary for interpreting neuronal activity. Moreover, delay measurements of stimulus and reinforcement delivery are largely unavailable. We combined microcontroller-based behavior control with a sound delivery system for playing complex acoustic stimuli, fast solenoid valves for precisely timed reinforcement delivery and a custom-built sound attenuated chamber using high-end industrial insulation materials. Together this setup provides a physical environment to train head-fixed animals, enables calibrated sound stimuli and precisely timed fluid and air puff presentation as reinforcers. We provide latency measurements for stimulus and reinforcement delivery and an algorithm to perform such measurements on other behavior control systems. Combined with electrophysiology and optogenetic manipulations, the millisecond timing accuracy will help interpret temporally precise neural signals and behavioral changes. Additionally, since software and hardware provided here can be readily customized to achieve a large variety of paradigms, these solutions enable an unusually flexible design of rodent behavioral experiments.
Dynamics of ribosomes and release factors during translation termination inE. coli
Authors: Adio Sarah , Sharma Heena , Senyushkina Tamara , Karki Prajwal , Maracci Cristina , Wohlgemuth Ingo , Holtkamp Wolf , Peske Frank , Rodnina Marina V.
Published: January 2018

Release factors RF1 and RF2 promote hydrolysis of peptidyl-tRNA during translation termination. The GTPase RF3 promotes recycling of RF1 and RF2. Using single molecule FRET together with ensemble kinetics, we show that ribosome termination complexes that carry two factors, RF1–RF3 or RF2–RF3, are dynamic and fluctuate between non-rotated and rotated states, while each factor alone has its distinct signature on the ribosome dynamics and conformation. Dissociation of RF1 depends on peptide release and the presence of RF3, whereas RF2 can dissociate spontaneously. RF3 binds in the GTP-bound state and can rapidly dissociate without GTP hydrolysis from termination complex carrying RF1. GTP cleavage helps RF3 release from ribosomes stalled in the rotated state in the absence of RF1. Our data suggest how the stochastic assembly of the ribosome–RF1–RF3–GTP complex, peptide release, and ribosome fluctuations promote termination of protein synthesis and recycling of the release factors.
Theta and gamma oscillations in the rat hippocampus during attentive lever pressing
Authors: Lipponen A , Tanila H , Gurevicius K
Published: January 2018

The hippocampus is known to be pivotal for spatial memory but emerging evidence suggests its contribution to temporal memories as well. However, it is not clear how the hippocampus represents time and how it synchronizes spatial and temporal presentations into a coherent memory. We assessed the specific role of hippocampal theta and gamma oscillations and their interaction in short-term timing of motor reactions. Rats were trained to maintain lever pressing for 2.5 s and then to quickly release the lever and retrieve water reward from a nearby water port guided by a cue light. In essence, this task allows observation of hippocampal rhythms during timed anticipation when no overt movements take place. Then we implanted wire electrodes to five hippocampal layers for recording local field potentials during the task. Consistent with earlier reports, theta showed a declining trend during the lever press. We also found that fast-gamma declined in tandem with theta while slow-gamma showed an opposite trend. Theta-phase to gamma-amplitude cross-frequency coupling measured with modulation index (MI) varied significantly between the three task phases. Interestingly, also changes in MI were opposite for fast- and slow-gamma. The MI was also related to the task performance, so that during omission trials the MI for fast-gamma in CA1 was smaller than during trials with premature lever release. In addition, the MI in dentate hilus was higher during all error trials than during correctly performed trials. Collectively, these data suggest an important role of synchronization of hippocampal theta and gamma rhythms to timing of cued motor reactions.
Breast cancer brain metastases show increased levels of genomic aberration based homologous recombination deficiency scores relative to their corresponding primary tumors
Authors: Diossy M. , Reiniger L. , Sztupinszki Zs. , Krzystanek M. , Timms K. M. , Neff C. , Solimeno C. , Pruss D. , Eklund A. C. , Tóth E. , Kiss O. , Rusz O. , Cserni G. , Zombori T. , Székely B. , Csabai I. , Szallasi Z.
Published: January 2018

Due to its mechanism of action, PARP inhibitor therapy is expected to benefit mainly tumor cases with homologous recombination deficiency (HRD). Various measures of genomic scarring based HRD scores were developed as a companion diagnostic in order to correlate it with PARP inhibitor sensitivity. We compared a variety of HRD scores in primary tumors and their corresponding brain metastases and found a significant increase in this measure in brain metastases for all measures of HRD that were tested. This discrepancy warrants further investigation to assess whether this observation is common to other metastatic sites, and potentially a significant adjustment of strategy in the application of HRD measures in clinical trials for the prioritization of patients for PARP inhibitor therapy.

Key message

We quantified homologous recombination deficiency (HRD) in paired primary breast cancer and brain metastases samples based on a previously published data set. We showed that HRD significantly increases in the brain metastases relative to its paired primary tumor. An independent validation was also performed on another set of primary breast cancer and brain metastasis pairs using the “my choice” HRD score in collaboration with Myriad Genetics.

These confirmatory results suggest that brain metastases of breast cancer tend to have significantly higher HRD scores, which would prioritize those patients for PARP inhibitor therapy with those agents that cross the blood brain barrier such as veliparib and niraparib.
A simple model for low variability in neural spike trains
Authors: Ferrari Ulisse , Deny Stéphane , Marre Olivier , Mora Thierry
Published: January 2018

Neural noise sets a limit to information transmission in sensory systems. In several areas, the spiking response (to a repeated stimulus) has shown a higher degree of regularity than predicted by a Poisson process. However, a simple model to explain this low variability is still lacking. Here we introduce a new model, with a correction to Poisson statistics, which can accurately predict the regularity of neural spike trains in response to a repeated stimulus. The model has only two parameters, but can reproduce the observed variability in retinal recordings in various conditions. We show analytically why this approximation can work. In a model of the spike emitting process where a refractory period is assumed, we derive that our simple correction can well approximate the spike train statistics over a broad range of firing rates. Our model can be easily plugged to stimulus processing models, like Linear-nonlinear model or its generalizations, to replace the Poisson spike train hypothesis that is commonly assumed. It estimates the amount of information transmitted much more accurately than Poisson models in retinal recordings. Thanks to its simplicity this model has the potential to explain low variability in other areas.
Cross-modal and non-monotonic representations of statistical regularity are encoded in local neural response patterns
Authors: Nastase Samuel A. , Davis Ben , Hasson Uri
Published: January 2018

Current neurobiological models assign a central role to predictive processes calibrated to environmental statistics. Neuroimaging studies examining the encoding of stimulus uncertainty have relied almost exclusively on manipulations in which stimuli were presented in a single sensory modality, and further assumed that neural responses vary monotonically with uncertainty. This has left a gap in theoretical development with respect to two core issues: i) are there cross-modal brain systems that encode input uncertainty in way that generalizes across sensory modalities, and ii) are there brain systems that track input uncertainty in a non-monotonic fashion? We used multivariate pattern analysis to address these two issues using auditory, visual and audiovisual inputs. We found signatures of cross-modal encoding in frontoparietal, orbitofrontal, and association cortices using a searchlight cross-classification analysis where classifiers trained to discriminate levels of uncertainty in one modality were tested in another modality. Additionally, we found widespread systems encoding uncertainty non-monotonically using classifiers trained to discriminate intermediate levels of uncertainty from both the highest and lowest uncertainty levels. These findings comprise the first comprehensive report of cross-modal and non-monotonic neural sensitivity to statistical regularities in the environment, and suggest that conventional paradigms testing for monotonic responses to uncertainty in a single sensory modality may have limited generalizability.
Modelling Signalling Networks from Perturbation Data
Authors: Dorel Mathurin , Klinger Bertram , Sieber Anja , Prahallad Anirudh , Gross Torsten , Bosdriesz Evert , Wessels Lodewyk , Blüthgen Nils
Published: January 2018

Motivation

Intracellular signalling is realized by complex signalling networks which are almost impossible to understand without network models, especially if feedbacks are involved. Modular Response Analysis (MRA) is a convenient modelling method to study signalling networks in various contexts.

Results

We developed a derivative of MRA that is suited to model signalling networks from incomplete perturbation schemes and multi-perturbation data. We applied the method to study the effect of SHP2, a protein that has been implicated in resistance to targeted therapy in colon cancer, using data from a knock out and parental colon cancer cell line. We find that SHP2 is required for MAPK signalling, whereas AKT signalling only partially depends on SHP2.

Availability

An R-package is available at https://github.com/MathurinD/STASNet

Contact

nils.bluethgen@charite.de
TheRhodobacter sphaeroidesmethionine sulfoxide reductase MsrP can reduceR- andS-diastereomers of methionine sulfoxide from a broad-spectrum of protein substrates
Authors: Tarrago Lionel , Grosse Sandrine , Siponen Marina I. , Lemaire David , Alonso Béatrice , Miotello Guylaine , Armengaud Jean , Arnoux Pascal , Pignol David , Sabaty Monique
Published: January 2018

Methionine (Met) is prone to oxidation and can be converted to Met sulfoxide (MetO), which exists as R- and S-diastereomers. MetO can be reduced back to Met by the ubiquitous methionine sulfoxide reductase (Msr) enzymes. Canonical MsrA and MsrB were shown as absolutely stereospecific for the reduction of S- and R-diastereomer, respectively. Recently, the molybdenum-containing protein MsrP, conserved in all gram-negative bacteria, was shown to be able to reduce MetO of periplasmic proteins without apparent stereospecificity inEscherichia coli.Here, we describe the substrate specificity of theRhodobacter sphaeroidesMsrP. Proteomics analysis coupled to enzymology approaches indicate that it reduces a broad spectrum of periplasmic oxidized proteins. Moreover, using model proteins, we demonstrated that RsMsrP preferentially reduces unfolded oxidized proteins and we confirmed that this enzyme, like itsE. colihomolog, can reduce bothR-andS-diastereomers of MetO with similar efficiency.