bluuebunny/crossref_metadata_2025 huggingface dataset:
Strategically Applying New Criteria for Use Improves Management of Peripheral Intravenous Catheters
Authors: Loudermilk Ryan A. , Steffen Layne E. , McGarvey Jeremy S.
Published: August 2018

Peripheral intravenous catheters (PIVCs) are common devices used across many healthcare settings. This quality improvement project aims to proactively remove PIVCs as soon as possible by empowering nurses and providers to clinically evaluate the necessity of every PIVC on a daily basis on a general hospital medical unit. Specific criteria were established to assess PIVC necessity. Cases of PIVCs not meeting established criteria are escalated to providers for a decision point. The PIVC removal times documented within the electronic medical record were analyzed to compare precriteria PIVC dwell times to postcriteria dwell times. The time between removal of a patient's last PIVC and patient discharge was analyzed to determine if more PIVCs are being removed sooner after becoming clinically unnecessary. Significantly fewer PIVCs (decrease of 14.4%) are being removed on the day of discharge in the postintervention time frame, whereas more PIVCs are being removed one (increase of 5.5%) or two (increase of 4.0%) days before the day of discharge. A strategic project to critically evaluate PIVCs on a daily basis and remove PIVCs not meeting criteria for use was successful in proactively removing PIVCs. Hospitals should evaluate PIVC practice, monitor daily usage, and strategically intervene to remove unneeded PIVCs.
Designing Large-Scale Improvement: Using an Academic–Practice Partnership to Enhance Care Transitions
Authors: Polancich Shea , Selleck Cynthia S. , Poe Terri , Miltner Rebecca , Shirey Maria R.
Published: August 2018

This department column highlights translation of research into healthcare quality practice. Achieving the highest quality in healthcare requires organizations to understand care delivery and to develop and design process efficiencies. The improvement process may be enhanced through a partnership between the healthcare facility and an affiliated school of nursing. The purpose of this article was to describe the process for developing a large-scale improvement project focused on enhancing care transitions within an academic medical center using an academic–practice partnership model.
Hearing Restoration During Vestibular Schwannoma Surgery With Transcanal Approach: Anatomical and Functional Preliminary Report
Authors: Marchioni Daniele , Veronese Sheila , Carner Marco , Sacchetto Andrea , Sacchetto Luca , Masotto Barbara , Bianconi Luca
Published: August 2018

Objective:

Hearing restoration has always been a dream in vestibular schwannoma (VS) surgery. The aim of this study is to describe an endoscopic assisted transcanal retrocochlear approach to the internal auditory canal (IAC) with total removal of the VS; simultaneously we assessed the anatomical and functional aspects of hearing restoration with cochlear implant (CI).

Study Design:

A retrospective case series.

Setting:

Tertiary referral center.

Patients:

Six patients affected by VS involving the fundus of the IAC (Koos stage I–II) were included in this study. The patients already demonstrated symptoms of IAC involvement by the neuroma, with severe to profound hearing loss.

Interventions:

Transcanal microscopic, endoscopic assisted, approach was chosen for total tumor removal. Preoperative and intraoperative electrophysiological monitoring was performed using electrically evoked auditory brainstem responses (EABR) to evaluate preservation of cochlear function.

Main Outcome and Measures:

A retrospective evaluation of electrophysiological data collected during surgeries has been conducted; clinical outcomes, surgical complications, and postoperative radiological evaluations were also considered.

Results:

Total tumor removal was achieved in all patients with no major complications. One patient showed temporary facial palsy (HB stage II). We were able to preserve cochlear function in five out of six patients. In those patients intraoperative monitoring with EABR was performed after tumor removal with good responses.

Conclusions:

Transcanal retrocochlear approach for VS removal allows preservation of cochlea and cochlear nerve function. This is the first step towards developing an effective surgical technique for VS removal and hearing rehabilitation with CI.
Use of Biosimilars in Pediatric Inflammatory Bowel Disease
Authors: de Ridder Lissy , Assa Amit , Bronsky Jiri , Romano Claudio , Russell Richard K. , Afzal Nadeem A. , Hauer Almuthe C. , Knafelz Daniela , Lionetti Paolo , Strisciuglio Caterina , Veres Gábor , Winter Harland , Wolters Victorien M. , Sladek Malgorzata , Vulto Arnold G. , Dias Jorge A. ,   Paediatric IBD Porto group of ESPGHAN
Published: August 2018

Biologic therapies have changed the outcome of both adult and pediatric patients with Inflammatory Bowel Disease (IBD). In September 2013, the first biosimilar of infliximab was introduced into the pharmaceutical market. In 2015, a first position paper on the use of biosimilars in pediatric IBD was published by the ESPGHAN IBD Porto group. Since then, more data have accumulated for both adults and children demonstrating biosimilars are an effective and safe alternative to the originator. In this updated position statement, we summarize current evidence and provide joint consensus statements regarding the recommended practice of biosimilar use in children with IBD.
Field Expansion for Acquired Monocular Vision Using a Multiplexing Prism
Authors: Jung Jae-Hyun , Peli Eli
Published: August 2018

SIGNIFICANCE

Acquired monocular vision (AMV) is a common visual field loss. Patients report mobility difficulties in walking due to collisions with objects or other pedestrians on the blind side.

PURPOSE

The visual field of people with AMV extends more than 90° temporally on the side of the seeing eye but is restricted to approximately 55° nasally. We developed a novel field expansion device using a multiplexing prism (MxP) that superimposes the see-through and shifted views for true field expansion without apical scotoma. We present various designs of the device that enable customized fitting and improved cosmetics.

METHODS

A partial MxP segment is attached (base-in) near the nose bridge. To avoid total internal reflection due to the high angle of incidence at nasal field end (55°), we fit the MxP with serrations facing the eye and tilt the prism base toward the nose. We calculated the width of the MxP (the apex location) needed to prevent apical scotoma and monocular diplopia. We also consider the effect of spectacle prescriptions on these settings. The results are verified perimetrically.

RESULTS

We documented the effectivity of various prototype glasses designs with perimetric measurements. With the prototypes, all patients with AMV had field-of-view expansions up to 90° nasally without any loss of seeing field.

CONCLUSIONS

The novel and properly mounted MxP in glasses has the potential for meaningful field-of-view expansion up to the size of normal binocular vision in cosmetically acceptable form.
The Pediatric Critical Care Transfusion and Anemia Expertise Initiative Consensus Conference Methodology
Authors: Bembea Melania M. , Valentine Stacey L. , Bateman Scot T. , Wilson Lisa M. , Anton Blair , Harger Nancy , Robinson Karen A.
Published: August 2018

Objectives:

This article describes the methodology used for Pediatric Critical Care Transfusion and Anemia Expertise Initiative Consensus Conference.

Design:

Consensus conference of international experts in pediatric critical care and transfusion medicine, following standards set by the Institute of Medicine, using the Research and Development/UCLA Appropriateness Method, modeled after the Pediatric Acute Lung Injury Consensus Conference. Topics related to RBC transfusion in children with or at risk for critical illness were divided into nine subgroups with a systematic review of the literature.

Methods:

The panel of 38 content and four methodology experts met three times over the course of 2 years and collaborated to develop evidence-based and, when evidence was lacking, expert-based clinical recommendations as well as research priorities for RBC transfusions in critically ill children or those at risk for critical illness. Electronic searches were conducted using PubMed, Embase, and Cochrane Library databases from 1980 to May 2017. Agreement was obtained using the Research and Development/UCLA Appropriateness Method. We used a standardized data extraction form to construct evidence tables and graded the evidence using the Grading of Recommendations Assessment, Development, and Evaluation system.

Main Results:

The consensus conference resulted in 102 recommendation statements, of which 57 were clinical (20 evidence based and 37 based on expert consensus) and 45 detailed recommendations for future research. Dissemination was done via decision tree, a primary publication listing all statements, and separate publications for each subtopic that include supporting arguments for each recommendation.

Conclusions:

A consensus conference of experts from around the world developed recommendations for RBC transfusions in critically ill children or children at risk for critical illness, the identification of current research gaps, and future research priorities.
Recommendations on Selection and Processing of RBC Components for Pediatric Patients From the Pediatric Critical Care Transfusion and Anemia Expertise Initiative
Authors: Zantek Nicole D. , Parker Robert I. , van de Watering Leo M. , Josephson Cassandra D. , Bateman Scot T. , Valentine Stacey L. , Delaney Meghan
Published: August 2018

Objectives:

To present the recommendations and supporting literature for selection and processing of RBC products in critically ill children developed by the Pediatric Critical Care Transfusion and Anemia Expertise Initiative.

Design:

Consensus conference series of international, multidisciplinary experts in RBC transfusion management of critically ill children

Methods:

The panel of 38 experts developed evidence-based, and when evidence was lacking, expert-based clinical recommendations as well as research priorities for RBC transfusions in critically ill children. The RBC processing subgroup included five experts. Electronic searches were conducted using PubMed, EMBASE, and Cochrane Library databases from 1980 to May 2017. Agreement was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method.

Results:

Five recommendations reached agreement (> 80%). Irradiated cellular products are recommended for children at risk of transfusion-associated graft versus host disease due to severe congenital or acquired causes of immune deficiency or when the blood donor is a blood relative. Washed cellular blood components and avoidance of other plasma-containing products are recommended for critically ill children with history of severe allergic reactions or anaphylaxis to blood transfusions, although patient factors appear to be important in the pathogenesis of reactions. For children with history of severe allergic transfusion reactions, evaluation for allergic stigmata prior to transfusion is recommended. In children with severe immunoglobulin A deficiency with evidence of antiimmunoglobulin A antibodies and/or a history of a severe transfusion reaction, immunoglobulin A–deficient blood components obtained either from an immunoglobulin A–deficient donor and/or washed cellular components is recommended.

Conclusions:

The Transfusion and Anemia Expertise Initiative consensus conference developed recommendations for selection and processing of RBC units for critically ill children. Recommendations in this area are largely based on pediatric and adult case report data.
Do Patients With Inflammatory Bowel Disease Have a Higher Postoperative Risk of Venous Thromboembolism or Do They Undergo More High-risk Operations?
Authors: McKenna Nicholas P. , Bews Katherine A. , Behm Kevin T. , Mathis Kellie L. , Lightner Amy L. , Habermann Elizabeth B.
Published: August 2018

Objective:

To determine the relative or combined effects of Crohn disease (CD) and ulcerative colitis (UC) and the operation performed on postoperative venous thromboembolism (VTE) to better guide recommendations on extended VTE prophylaxis.

Summary Background Data:

There is growing evidence to suggest patients with inflammatory bowel disease have an increased risk of postoperative VTE, but prior studies have not accounted for the operation performed nor acknowledged differences between CD and UC.

Methods:

The American College of Surgeons National Surgical Quality Improvement Project database from 2005 to 2016 was queried for patients with a diagnosis of CD, UC, malignancy, or benign disease (diverticular disease, Clostridium difficile) undergoing major abdominal surgery. Operations with a VTE rate >3% were designated high risk. Operation-specific univariate and multivariable logistic regression analyses were conducted.

Results:

A total of 231,718 operations were analyzed with 4426 patients experiencing a VTE (1.9%). The overall rate of VTE ranged widely based on the operation performed from 0.7% for enterostomy closure to 5.3% for open subtotal colectomy. Seven operations met our threshold of 3% to be considered high risk. For each operation, postoperative VTE rates were similar regardless of diagnostic indication when performed in the elective setting. However, when performed emergently, the same operations had significantly higher VTE rates. Compared with the malignancy and benign disease groups, neither CD nor UC was associated with increased odds of VTE after any operation.

Conclusions:

Postoperative VTE risk varies widely by the operation performed, and a diagnostic indication of CD or UC does not play a role. Extended duration VTE prophylaxis should be considered in all patients undergoing high-risk operations, regardless of their underlying diagnosis.
Comprehensive Modeling of Spinal Muscular Atrophy in Drosophila melanogaster
Authors: Spring Ashlyn M. , Raimer Amanda C. , Hamilton Christine D. , Schillinger Michela J. , Matera A. Gregory
Published: August 2018

Spinal muscular atrophy (SMA) is a neurodegenerative disorder that affects motor neurons, primarily in young children. SMA is caused by mutations in the Survival Motor Neuron 1 (SMN1) gene. SMN functions in the assembly of spliceosomal RNPs and is well conserved in many model systems including mouse, zebrafish, fruit fly, nematode, and fission yeast. Work in Drosophila has primarily focused on loss of SMN function during larval stages, primarily using null alleles or strong hypomorphs. A systematic analysis of SMA-related phenotypes in the context of moderate alleles that more closely mimic the genetics of SMA has not been performed in the fly, leading to debate over the validity and translational value of this model. We therefore examined fourteen Drosophila lines expressing SMA patient-derived missense mutations in Smn, with a focus on neuromuscular phenotypes in the adult stage. Animals were evaluated on the basis of organismal viability and longevity, locomotor function, neuromuscular junction structure, and muscle health. In all cases, we observed phenotypes similar to those of SMA patients, including progressive loss of adult motor function. The severity of these defects is variable, and forms a broad spectrum across the fourteen lines examined, recapitulating the full range of phenotypic severity observed in human SMA. This includes late-onset models of SMA, which have been difficult to produce in other model systems. The results provide direct evidence that SMA-related locomotor decline can be reproduced in the fly and support the use of patient-derived SMN missense mutations as a comprehensive system for modeling SMA.
Comparative genomics of ten newCaenorhabditisspecies
Authors: Stevens Lewis , Félix Marie-Anne , Beltran Toni , Braendle Christian , Caurcel Carlos , Fausett Sarah , Fitch David , Frézal Lise , Kaur Taniya , Kiontke Karin , Newton Matt D. , Noble Luke M. , Richaud Aurélien , Rockman Matthew V. , Sudhaus Walter , Blaxter Mark
Published: August 2018

The nematodeCaenorhabditis eleganshas been central to the understanding of metazoan biology. However,C. elegansis but one species among millions and the significance of this important model organism will only be fully revealed if it is placed in a rich evolutionary context. Global sampling efforts have led to the discovery of over 50 putative species from the genusCaenorhabditis, many of which await formal species description. Here, we present species descriptions for ten newCaenorhabditisspecies. We also present draft genome sequences for nine of these new species, along with a transcriptome assembly for one. We exploit these whole-genome data to reconstruct theCaenorhabditisphylogeny and use this phylogenetic tree to dissect the evolution of morphology in the genus. We show unexpected complexity in the evolutionary history of key developmental pathway genes. The genomic data also permit large scale analysis of gene structure, which we find to be highly variable within the genus. These new species and the associated genomic resources will be essential in our attempts to understand the evolutionary origins of theC. elegansmodel.
Origin of gibberellin-dependent transcriptional regulation by molecular exploitation of a transactivation domain in DELLA proteins
Authors: Hernández-García Jorge , Briones-Moreno Asier , Dumas Renaud , Blázquez Miguel A.
Published: August 2018

DELLA proteins are land-plant specific transcriptional regulators known to interact through their C-terminal GRAS domain with over 150 transcription factors in Arabidopsis thaliana. Besides, DELLAs from vascular plants can interact through the N-terminal domain with the gibberellin receptor encoded by GID1, through which gibberellins promote DELLA degradation. However, this regulation is absent in non-vascular land plants, which lack active gibberellins or a proper GID1 receptor. Current knowledge indicates that DELLAs are important pieces of the signalling machinery of vascular plants, especially angiosperms, but nothing is known about DELLA function during early land plant evolution or if they exist at all in charophytan algae. We have now elucidated the evolutionary origin of DELLA proteins, showing that algal GRAS proteins are monophyletic and evolved independently from those of land plants, which explains why there are no DELLAs outside land plants. DELLA genes have been maintained throughout land plant evolution with only two major duplication events kept among plants. Furthermore, we show that the features needed for DELLA interaction with the receptor were already present in the ancestor of all land plants, and propose that these DELLA N-terminal motifs have been tightly conserved in non-vascular land plants for their function in transcriptional co-activation, which allowed subsequent exaptation for the interaction with the GID1 receptor when vascular plants developed gibberellin synthesis and the corresponding perception module.
Bayesian arrival model for Atlantic salmon smolt counts powered by environmental covariates and expert knowledge
Authors: Pulkkinen Henni , Orell Panu , Erkinaro Jaakko , Mäntyniemi Samu
Published: August 2018

Annual run size and timing of Atlantic salmon smolt migration was estimated using Bayesian model framework and data from six years of a video monitoring survey. The model has a modular structure. It separates sub-processes of departing, traveling and observing, of which the first two together define the arrival distribution. The sub-processes utilize biological background and expert knowledge about the migratory behavior of smolts and about the probability to observe them from the video footage under varying environmental conditions. Daily mean temperature and discharge were used as environmental covariates. The model framework does not require assuming a simple distributional shape for the arrival dynamics and thus also allows for multimodal arrival distributions. Results indicate that 20% - 43% of smolts passed the Utsjoki monitoring site unobserved during the years of study. Predictive studies were made to estimate daily run size in cases with missing counts either at the beginning or in the middle of the run, indicating good predictive performance.
PathoLive – Real-time pathogen identification from metagenomic Illumina datasets
Authors: Tausch Simon H. , Loka Tobias P. , Schulze Jakob M. , Andrusch Andreas , Klenner Jeanette , Dabrowski Piotr W. , Lindner Martin S. , Nitsche Andreas , Renard Bernhard Y.
Published: August 2018

Motivation

Over the past years, NGS has become a crucial workhorse for open-view pathogen diagnostics. Yet, long turnaround times result from using massively parallel high-throughput technologies as the analysis can only be performed after sequencing has finished. The interpretation of results can further be challenged by contaminations, clinically irrelevant sequences, and the sheer amount and complexity of the data.

Results

We implemented PathoLive, a real-time diagnostics pipeline for the detection of pathogens from clinical samples hours before sequencing has finished. Based on real-time alignment with HiL-ive2, mappings are scored with respect to common contaminations, low-entropy areas, and sequences of widespread, non-pathogenic organisms. The results are visualized using an interactive taxonomic tree that provides an easily interpretable overview of the relevance of hits. For a human plasma sample that was spiked in vitro with six pathogenic viruses, all agents were clearly detected after only 40 of 200 sequencing cycles. For a real-world sample from Sudan the results correctly indicated the presence of Crimean-Congo hemorrhagic Fever Virus. In a second real-world dataset from the 2019 SARS-CoV-2 outbreak in Wuhan, we found the presence of a SARS Coronavirus as the most relevant hit without the novel virus reference genome being included in the database. For all samples, clinically irrelevant hits were correctly de-emphasized. Our approach is valuable to obtain fast and accurate NGS-based pathogen identifications and correctly prioritize and visualize them based on their clinical significance.

Availability

PathoLive is open source and available on GitLab (https://gitlab.com/rkibioinformatics/PathoLive) and BioConda (conda install –c bioconda patholive).

Contact

Bernhard.Renard@hpi.de, NitscheA@rki.de
Effect of cadmium accumulation on the performance of plants and of herbivores that cope differently with organic defences
Authors: Godinho Diogo Prino , Serrano Helena Cristina , Silva Anabela , Branquinho Cristina , Magalhães Sara
Published: August 2018

Some plants can accumulate in their shoots metals that are toxic to most other organisms. This ability may serve as a defence against herbivores. Although both metal accumulation and the production of organic defences may be costly to the plant, the two mechanisms may interact on their effect on herbivores. However, this interplay between metal-based and ‘classical’ organic defences remains overlooked.

To fill this gap, we studied the interactions between tomato (Solanum lycopersicum), a plant that accumulates cadmium, and two spider-mites,Tetranychus urticaeandT. evansithat respectively induce and suppress organic plant defences, measurable via the activity of trypsin inhibitors. We exposed plants to different concentrations of cadmium and measured their effect on mites and plants. The oviposition of both spider-mite species was higher on plants exposed to low concentrations of Cd than on control plants but decreased at concentrations above 0.5 mM. Therefore, herbivores with contrasting responses to organic defences responded similarly to metal accumulation by the plants. On the plant, despite clear evidence for Cd accumulation, we did not detect any effect of Cd on traits that reflect the general response of the plant, such as biomass, water content and carbon/nitrogen ratio. Still, we found an effect of Cd supply upon the quantity of soluble sugars and leaf reflectance changes that may reflect structural modifications in the cells. In turn, these changes in plant traits interfered with the performance of spider mites feeding on those plants.

Additionally, we show that the induction and suppression of plant defences by spider mites was not affected by Cd supply to the plants. Furthermore, the effect of metal supply on spider-mite performance was not affected by previous infestation. Together, our results suggest no interaction between metal-based and organic plant defences, on our system. This may be useful for plants living in heterogeneous environments, as they may use one or the other defence mechanism, depending on their relative performance in each environment. This may be relevant to studies on the interactions between herbivores and plants, from physiology to ecology.
Formation of periodic pigment spots by the reaction-diffusion mechanism
Authors: Ding Baoqing , Patterson Erin L. , Holalu Srinidhi V. , Li Jingjian , Johnson Grace A. , Stanley Lauren E. , Greenlee Anna B. , Peng Foen , Bradshaw H. D. , Blackman Benjamin K. , Yuan Yao-Wu
Published: August 2018

Many organisms exhibit visually striking spotted or striped pigmentation patterns. Turing’s reaction-diffusion model postulates that such periodic pigmentation patterns form when a local autocatalytic feedback loop and a long-range inhibitory feedback loop interact. At its simplest, this network only requires one self-activating activator that also activates a repressor, which inhibits the activator and diffuses to neighboring cells. However, the molecular activators and repressors fully fitting this versatile model remain elusive. Here, we characterize an R2R3-MYB activator and an R3-MYB repressor in monkeyflowers that correspond to Turing’s model and explain how periodic anthocyanin spots form. Notably, disrupting this pattern impacts pollinator visitation. Thus, subtle changes in simple reaction-diffusion networks are likely essential contributors to the evolution of the remarkable diversity of periodic pigmentation patterns in flowers.
Leave-One-Trial-Out (LOTO): A general approach to link single-trial parameters of cognitive models to neural data
Authors: Gluth Sebastian , Meiran Nachshon
Published: August 2018

It has become a key goal of model-based neuroscience to estimate trial-by-trial fluctuations of cognitive model parameters for linking these fluctuations to brain signals. However, previously developed methods were limited by being difficulty to implement, time-consuming, or model-specific. Here, we propose an easy, efficient and general approach to estimating trial-wise changes in parameters: Leave-One-Trial-Out (LOTO). The rationale behind LOTO is that the difference between the parameter estimates for the complete dataset and for the dataset with one omitted trial reflects the parameter value in the omitted trial. We show that LOTO is superior to estimating parameter values from single trials and compare it to previously proposed approaches. Furthermore, the method allows distinguishing true variability in a parameter from noise and from variability in other parameters. In our view, the practicability and generality of LOTO will advance research on tracking fluctuations in latent cognitive variables and linking them to neural data.
Oscillatory infrasonic modulation of the cochlear amplifier by selective attention
Authors: Dragicevic Constantino D. , Marcenaro Bruno , Navarrete Marcela , Robles Luis , Delano Paul H.
Published: August 2018

Evidence shows that selective attention to visual stimuli modulates the gain of cochlear responses, probably through auditory-cortex descending pathways. At the cerebral cortex level, amplitude and phase changes of neural oscillations have been proposed as a correlate of selective attention. However, whether sensory receptors are also influenced by the oscillatory network during attention tasks remains unknown. Here, we searched for oscillatory attention-related activity at the cochlear receptor in humans. We used an alternating visual/auditory selective attention task and measured electroencephalographic activity simultaneously to distortion product otoacoustic emissions (a measure of cochlear receptor-cell activity). In order to search for cochlear oscillatory activity, the otoacoustic emission signal, was included as an additional channel in the electroencephalogram analyses. This method allowed us to study dynamic changes of cochlear oscillations in the same range of frequencies (1-35 Hz) in which cognitive effects are commonly observed in electroencephalogram works. We found the presence of low frequency (<10 Hz) brain and cochlear amplifier oscillations during periods of selective attention to visual and auditory stimuli. Notably, switching between auditory and visual attention modulates the amplitude and the temporal order of brain and inner ear oscillations. These results extend the role of the oscillatory activity network during cognition in neural systems to the receptor level.
Sex-Specific Protection Against Diet-Induced Non-Alcoholic Fatty Liver Disease in TRPV1 Null Mice
Authors: Connell Patrick J. , Bratz Ian N. , Andrei Spencer R. , Eusebio Luke , DelloStritto Daniel J. , Fahmy Joseph N. , Ferrell Jessica M. , Pathak Preeti , Chiang John Y.L. , Damron Derek S.
Published: August 2018

Objectives

TRPV1 channels have been linked to the development and progression of diabetes at multiple levels, including control of appetite and weight, regulation of pancreatic function, thermogenesis, metabolism and energy homeostasis. Despite this, little information is known regarding its role in liver homeostasis and nonalcoholic fatty liver disease (NAFLD).

Methods and Results

To better understand the role of TRPV1 in liver metabolism, we explored the effects of a high fat/sugar diet (Western, 24-week regimen) in male and female wild type (WT) and TRPV1-null (V1KO) mice. Our data reveal that loss of the TRPV1 gene makes mice susceptible to diet-induced obesity and induces NAFLD. V1KO mice displayed gross phenotypic and gross morphological changes including insulin resistance, glucose intolerance, increased body mass and central adiposity on a western diet compared to WT counterparts. Western fed V1KO mice exhibited gross changes in liver morphology and size compared to western fed WT mice, which were supported with histological H&E and Oil Red O staining. Accompanying the liver changes, Western fed V1KO mice exhibited altered lipid profiles as demonstrated by elevated hepatic triglyceride, cholesterol and free fatty acid levels compared to western fed WT mice. Interestingly, female V1KO mice fed a western diet displayed significant protection against diet-induced obesity and the progression of NAFLD compared to their male counterparts. Taken together, these data suggest that loss of TRPV1 promotes fat accumulation, NAFLD development and changes in liver lipid profiles in male mice, the extent to which is less severe in female V1KO mice.

Conclusion

In conclusion, TRPV1 may be a protective therapeutic target for the prevention of NAFLD development in diet-induced obesity.
Chiral DNA sequences as commutable reference standards for clinical genomics
Authors: Deveson Ira W. , Madala Bindu Swapna , Blackburn James , Barker Chris , Wong Ted , Barton Kirston M. , Smith Martin A. , Watkins D. Neil , Mercer Tim R.
Published: August 2018

Chirality is a geometric property describing any object that is inequivalent to a mirror image of itself. Due to its 5’-3’ directionality, a DNA sequence is distinct from a mirrored sequence arranged in reverse nucleotide order, and is therefore chiral. A given sequence and its opposing chiral partner sequence share many properties, such as nucleotide composition and sequence entropy. Here we demonstrate that chiral DNA sequence pairs also perform equivalently during molecular and bioinformatic techniques that underpin modern genetic analysis, including PCR amplification, hybridization, whole-genome, target-enriched and nanopore sequencing, sequence alignment and variant detection. Given these shared properties, synthetic DNA sequences that directly mirror clinically relevant and/or analytically challenging regions of the human genome are ideal reference standards for clinical genomics. We show how the addition of chiral DNA standards to patient tumor samples can prevent false-positive and false-negative mutation detection and, thereby, improve diagnosis. Accordingly, we propose that chiral DNA standards can fulfill the unmet need for commutable internal reference standards in precision medicine.
The capsule regulatory network ofKlebsiella pneumoniaedefined by density-TraDISort
Authors: Dorman Matthew J. , Feltwell Theresa , Goulding David A. , Parkhill Julian , Short Francesca L.
Published: August 2018

Klebsiella pneumoniaeinfections affect infants and the immunocompromised, and the recent emergence of hypervirulent and multi-drug resistantK. pneumoniaelineages is a critical healthcare concern. Hypervirulence inK. pneumoniaeis mediated by several factors, including the overproduction of extracellular capsule. However, the full details of howK. pneumoniaecapsule biosynthesis is achieved or regulated are not known. We have developed a robust and sensitive procedure to identify genes influencing capsule production, density-TraDISort, which combines density gradient centrifugation with transposon-insertion sequencing. We have used this method to explore capsule regulation in two clinically-relevantKlebsiellastrains;K. pneumoniaeNTUH-K2044 (capsule type K1), andK. pneumoniaeATCC43816 (capsule type K2). We identified multiple genes required for full capsule production inK. pneumoniae, as well as putative suppressors of capsule in NTUH-K2044, and have validated the results of our screen with targeted knockout mutants. Further investigation of several of theK. pneumoniaecapsule regulators identified – ArgR, MprA/KvrB, SlyA/KvrA and the Sap ABC transporter – revealed effects on capsule amount and architecture, serum resistance and virulence. We show that capsule production inK. pneumoniaeis at the centre of a complex regulatory network involving multiple global regulators and environmental cues, and that the majority of capsule regulatory genes are located in the core genome. Overall our findings expand our understanding of how capsule is regulated in this medically-important pathogen, and provide a technology that can be easily implemented to study capsule regulation in other bacterial species.

Importance

Capsule production is essential forK. pneumoniaeto cause infections, but its regulation and mechanism of synthesis are not fully understood in this organism. We have developed and applied a new method for genome-wide identification of capsule regulators. Using this method, many genes that positively or negatively affect capsule production inK. pneumoniaewere identified, and we use these data to propose an integrated model for capsule regulation in this species. Several of the genes and biological processes identified have not previously been linked to capsule synthesis. We also show that the methods presented here can be applied to other species of capsulated bacteria, providing the opportunity to explore and compare capsule regulatory networks in other bacterial strains and species.
A tunable dual-input system for ‘on-demand’ dynamic gene expression regulation
Authors: Pedone Elisa , Rocca Dan L. , Postiglione Lorena , Aulicino Francesco , Montes-Olivas Sandra , Bernardo Diego di , Cosma Maria Pia , Marucci Lucia
Published: August 2018

Cellular systems have evolved numerous mechanisms to finely control signalling pathway activation and properly respond to changing environmental stimuli. This is underpinned by dynamic spatiotemporal patterns of gene expression. Indeed, in addition to gene transcription and translation regulation, modulation of protein levels, dynamics and localization are also essential checkpoints that govern cell functions. The introduction of tetracycline-inducible promoters has allowed gene expression control using orthogonal small molecules, facilitating rapid and reversible manipulation to study gene function in biological systems. However, differing protein stabilities means this solely transcriptional regulation is insufficient to allow precise ON-OFF dynamics, thus hindering generation of temporal profiles of protein levels seenin vivo. We developed an improved Tet-On based system augmented with conditional destabilising elements at the post-translational level that permits simultaneous control of gene expression and protein stability. Integrating these properties to control expression of a fluorescent protein in mouse Embryonic Stem Cells (mESCs), we found that adding protein stability control allows faster response times to changes in small molecules, fully tunable and enhanced dynamic range, and vastly improved microfluidic-basedin-silicofeedback control of gene expression. Finally, we highlight the effectiveness of our dual-input system to finely modulate levels of signalling pathway components in stem cells.
Mitotic chromosome binding predicts transcription factor properties in interphase
Authors: Raccaud Mahé , Alber Andrea B. , Friman Elias T. , Agarwal Harsha , Deluz Cédric , Kuhn Timo , Gebhardt J. Christof M. , Suter David M.
Published: August 2018

Mammalian transcription factors (TFs) differ broadly in their nuclear mobility and sequence-specific/non-specific DNA binding affinity. How these properties affect the ability of TFs to occupy their specific binding sites in the genome and modify the epigenetic landscape is unclear. Here we combined live cell quantitative measurements of mitotic chromosome binding (MCB) of 502 TFs, measurements of TF mobility by fluorescence recovery after photobleaching, single molecule imaging of DNA binding in live cells, and genome-wide mapping of TF binding and chromatin accessibility. MCB scaled with interphase properties such as association with DNA-rich compartments, mobility, as well as large differences in genome-wide specific site occupancy that correlated with TF impact on chromatin accessibility. As MCB is largely mediated by electrostatic, non-specific TF-DNA interactions, our data suggests that non-specific DNA binding of TFs enhances their search for specific sites and thereby their impact on the accessible chromatin landscape.
Effects ofP16DNA Methylation on Proliferation, Senescence, and Lifespan of Human Fibroblasts
Authors: Gan Ying , Cui Chenghua , Xiang Shengyan , Zhang Baozhen , Deng Dajun
Published: August 2018

The aim is to study the effects ofP16DNA methylation on lifespan of normal cells. An expression-controllable pTRIPZ vector expressing P26-specific zinc finger binding protein-based methyltransferase (P16-Dnmt) was used to induceP16methylation in primary CCD-I8C0 fibroblasts via stable transfection. Long-term dynamic IncuCyte analysis showed that CCD-I8C0 fibroblasts expressing baseline P16-Dnmt continued proliferating until passage-26 in the 53thpost-transfection week, while vector control cells stopped proliferating at passage-6 and completely died 2 weeks later. The proliferation rate of baseline P16-Dnmt cells was significantly higher than that of vector control cells. The proportion of P-galactosidase-positive staining cells was significantly decreased in baseline P16-Dnmt cells compared to vector control cells. The P16 expression was lost in baseline P16-Dnmt cells at and after passage-6. The average telomere length in baseline P16-Dnmt cells also gradually decreased. In conclusion,P16methylation could prevent senescence, promote proliferation, and expand lifespan of human fibroblasts, which may play a role in cancer development.

A zinc finger protein-based DNA methyltransferase (P16-Dnmt) expressed at the baseline level could specifically methylateP16promoter CpG islands.P16methylation induced by baseline P16-Dnmt could significantly prevent senescence, promote proliferation, and expand lifespan of primary human fibroblasts.
Assessing genomic admixture between cryptic Plutella moth species following secondary contact
Authors: Ward Christopher M. , Baxter Simon W.
Published: August 2018

Cryptic species are genetically distinct taxa without obvious variation in morphology and are occasionally discovered using molecular or sequence datasets of populations previously thought to be a single species. The world-wide Brassica pest, Plutella xylostella (diamondback moth), has been a problematic insect in Australia since 1882, yet a morphologically cryptic species with apparent endemism (P. australiana) was only recognized in 2013. Plutella xylostella and P. australiana are able to hybridize under laboratory conditions, and it was unknown whether introgression of adaptive traits could occur in the field to improve fitness and potentially increase pressure on agriculture. Phylogenetic reconstruction of 29 nuclear genomes confirmed P. xylostella and P. australiana are divergent, and molecular dating with 13 mitochondrial genes estimated a common Plutella ancestor 1.96±0.175 MYA. Sympatric Australian populations and allopatric Hawaiian P. xylostella populations were used to test whether neutral or adaptive introgression had occurred between the two Australian species. We used three approaches to test for genomic admixture in empirical and simulated datasets including i) the f3 statistic at the level of the population, ii) pairwise comparisons of Nei’s absolute genetic divergence (dXY) between populations and iii) changes in phylogenetic branch lengths between individuals across 50 kb genomic windows. These complementary approaches all supported reproductive isolation of the Plutella species in Australia, despite their ability to hybridize. Finally, we highlight the most divergent genomic regions between the two cryptic Plutella species and find they contain genes involved with processes including digestion, detoxification and DNA binding.
Ontology of RNA Sequencing (ORNASEQ) and its application
Authors: Fisher Stephen A , Kim Junhyong
Published: August 2018

Background:

Next-generation RNA sequencing is a rapidly developing technology with complex procedures encompassing different experimental modalities. As the technology evolves and its use expand, so does the need to capture the data provenance from these sequencing studies and the need to create new tools to manage and manipulate these provenance stores.

Results:

Here we used the Ontology for Biomedical Investigations (OBI) and many other ontologies from the Open Biological and Biomedical Ontology (OBO) Foundry as a framework from which to create an application ontology (ORNASEQ: Ontology of RNA sequencing) to capture data provenance for next-generation RNA sequencing studies. Additionally, we provide an extensive real-life sample provenance data set for use in developing new provenance tools and additional sequencing data models.

Conclusions:

The Ontology of RNA Sequencing (ORNASEQ) provides core terms for use in building data models to capture the provenance from next-generation RNA sequencing studies. The supplied sample provenance data also exemplifies many of the complexities of RNA sequencing studies and underscores the need for potent workflow management systems.
Genetic control of the HDL proteome
Authors: Pamir Nathalie , Pan Calvin , Plubell Deanna L. , Hutchins Patrick M. , Tang Chongren , Wimberger Jake , Irwin Angela , Vallim Thomas Q. de Aguiar , Heinecke Jay W. , Lusis Aldons J.
Published: August 2018

High-density lipoproteins (HDL) are nanoparticles with >80 associated proteins, phospholipids, cholesterol and cholesteryl esters. A comprehensive genetic analysis of the regulation of proteome of HDL isolated from a panel of 100 diverse inbred strains of mice, Hybrid Mouse Diversity Panel (HMDP), revealed widely varied HDL protein levels across the strains. Some of this variation was explained by local, cis-acting regulation, termed cis-protein quantitative trait loci. Variations in apolipoprotein A-II and apolipoprotein C-3 affected the abundance of multiple HDL proteins indicating a coordinated regulation. We identified modules of co-varying proteins and define a protein-protein interaction network describing the protein composition of the naturally occurring subspecies of HDL in mice. Sterol efflux capacity varied up to 3-fold across the strains and HDL proteins displayed distinct correlation patterns with macrophage and ABCA1 specific cholesterol efflux capacity and cholesterol exchange, suggesting that subspecies of HDL participate in discrete functions. The baseline and stimulated sterol efflux capacity phenotypes associated with distinct QTLs with smaller effect size suggesting a multi genetic regulation. Our results highlight the complexity of HDL particles by revealing high degree of heterogeneity and intercorrelation, some of which is associated with functional variation, supporting the concept that HDL-cholesterol alone is not an accurate measure of HDL’s properties such as protection against CAD.
Acute Psychological Stress Triggers Circulating Cell-Free Mitochondrial DNA
Authors: Trumpff Caroline , Marsland Anna L. , Basualto-Alarcón Carla , Martin James L. , Carroll Judith E. , Sturm Gabriel , Vincent Amy E. , Mosharov Eugene V. , Gu Zhenglong , Kaufman Brett A. , Picard Martin
Published: August 2018

Intrinsic biological mechanisms transduce psychological stress into physiological adaptation, but the role of mitochondria and mitochondrial DNA (mtDNA) in this process has not been defined in humans. Here, we show that similar to physical injury, psychological stress triggers elevation in circulating cell- free mtDNA (ccf-mtDNA). Healthy midlife adults exposed on two separate occasions to a brief psychological challenge exhibit a 2-3-fold increase in ccf-mtDNA, with no change in nuclear DNA levels, establishing the magnitude and specificity to ccf-mtDNA. In cell-based studies, we show that glucocorticoid signaling – a consequence of psychological stress in humans – is sufficient to induce mtDNA extrusion in a time frame consistent with human psychophysiology. Collectively, these findings provide the first evidence that psychological stress induces ccf-mtDNA and implicate glucocorticoid signaling as a trigger for ccf-mtDNA release. Further work is needed to examine the functional significance of psychological stress-induced ccf-mtDNA as a mitokine in humans.
TF-TWAS: Transcription-factor polymorphism associated with tissue-specific gene expression
Authors: Tang Yi-Ching , Gottlieb Assaf
Published: August 2018

Transcriptional regulation is associated with a broad range of diseases. Methods associating genetic polymorphism with gene transcription levels offer key insights for understanding the transcriptional regulation plan. The majority of gene imputation methods focus on modeling polymorphism in the cis regions of the gene, partially owing to the large genetic search space. We hypothesize that polymorphism within transcription factors (TFs) may help explain transcription levels of their transcribed genes.

Here, we test this hypothesis by developing TF-TWAS: imputation models that integrate transcription factor information with transcription-wide association study methodology. By comparing TF-TWAS models to base models that use only gene cis information, we are able to estimate possible mechanisms of the TF polymorphism effect – TF expression or binding affinity within four tissues – whole blood, liver, brain hippocampus and coronary artery.

We identified 48 genes where the TF-TWAS models explain significantly better their expression than cis models alone in at least one of the four tissues. Sixteen of these genes are associated with various diseases, including cancer, neurological, psychiatric and rare genetic diseases. Our method is a new expansion to transcriptome-wide association studies and enables the identification of new associations between polymorphism in transcription factor and gene transcription levels.