bluuebunny/crossref_metadata_2025 huggingface dataset:
Focus group testing of a mobile app for pharmacogenetic-guided dosing
Authors: Dodson Crystal Heath , Baker Elizabeth
Published: February 2020

Background:

A common barrier to implementation of precision medicine is the lack of use of published clinical practice guidelines. Consequently, a user-friendly mechanism to easily adopt these guidelines is imperative.

Purpose:

The purpose of this study was to evaluate the perceptions of a prototype of a clinical decision support tool through a mobile application for pharmacogenetics.

Methodological orientation:

A case study on a patient requiring pharmacogenetic testing was provided to the participants. The participants were given up to 30 minutes to identify the correct dosing in the clinical decision support tool based on clinical evidence-based guidelines. Immediately after the utilization of the mobile app, focus group interviews were conducted to identify the perceptions of the tool, obstacles associated with the tool, and suggestions for improvement of the tool.

Sample:

Focus group interviews with 23 nurse practitioners and nurse practitioner students were conducted. Field notes and audio recordings were taken.

Conclusions:

Specific feedback for improvement in the font and size of text, color contrast, use of drug calculator, automatic input, and desire for further development of education portal were found within the data. The findings revealed useful feedback to adjust the prototype to improve the ease of use among nurse practitioners.

Implications for practice:

The revision of this mobile app will improve user friendliness to increase applicability within health care. The mobile app can be used for future research to identify improvements in patient outcomes after implementing this tool.
Correlation of plasma soluble suppression of tumorigenicity-2 level with the severity and stability of coronary atherosclerosis
Authors: Zhang Ying , Fan Zixu , Liu Hua , Ma Jianwei , Zhang Min
Published: February 2020

Background

Soluble growth stimulation expressed gene 2 (sST2) is the receptor of interleukin (IL)-33. We hypothesized the IL-33/ST2 pathway may be closely related to the progression of coronary atherosclerotic lesions.

Methods

We analyzed 262 patients, including 63 with stable angina pectoris (SAP), 97 with acute coronary syndrome (ACS), and 102 control subjects. Plasma sST2 levels were determined using ELISA. Gensini scores were calculated. Patients with ACS and SAP were further divided according to the complexity of atherosclerotic lesions (simple/complex). Statistical analysis was performed on all data.

Results

The plasma sST2 levels were significantly higher in patients with coronary artery disease (CAD) than in the control group, and were significantly higher in ACS patients with complex lesions than in those with simple lesions. There were no correlations between plasma sST2 level and both the number of culprit vessels and Gensini score. Multivariate stepwise regression analysis revealed that angiographically detected complex lesions were independently correlated with plasma sST2 level. Logistic regression analyses showed that sST2 was an independent factor of both CAD and the lesion type (simple/complex) of ACS. For the diagnosis of ACS and complex lesions, the area under the receiver operating characteristic curve of sST2 was 0.651.

Conclusions

The plasma sST2 level was not correlated with the stenosis severity of coronary atherosclerosis. A relationship between the plasma sST2 level and the morphology of complex lesions was found for the first time, especially in ACS patients. It may be a new marker for assessing the stability and complexity of atherosclerotic plaques.
Teaching Father-Infant Massage during Postpartum Hospitalization
Authors: Suchy Carol , Morgan Gloria , Duncan Susan , Villar Susan , Fox Frieda , Rutledge Dana N.
Published: February 2020

Purpose:

The purpose of this study was to evaluate acceptability and impact of infant massage video instruction on fathers' behaviors in early postpartum.

Methods:

A randomized crossover design was used. Participants were fathers of healthy term infants born at a Magnet hospital in Southern California. Measures included a demographic survey, Father-to-Infant Bonding Scale, Father-Infant Observation Scale, and postdischarge phone interview. Study nurses observed father–infant interactions for 5 minutes. Fathers were randomized to one of two groups: fathers in group 1 saw the massage video before they were observed with their infants and fathers in group 2 saw the video after. Fathers completed the Bonding Scale at baseline in person and again within a week of discharge by phone. Statistics were descriptive and comparative. Responses to interview questions were categorized and described.

Results:

Ninety-eight fathers aged 18 to 44 years participated. Over half of fathers identified as Hispanic and the majority spoke English at home. Most fathers had positive responses to infants on individual Bonding Scale items. Fathers differed significantly in observed interactions with infants depending upon timing of massage instruction; fathers observed immediately after the video had more total interactions, specifically fingertip touching. Poststudy evaluations were predominantly positive.

Clinical Implications:

We found a brief infant massage instruction offered by video was well accepted by fathers and increased observed father–infant interactions.
A Qualitative Reexamination of the Key Features of Burnout
Authors: Tavella Gabriela , Parker Gordon
Published: February 2020

Burnout is generally defined as a triad of emotional exhaustion, lack of empathy, and reduced professional accomplishment constructs. We sought to determine in an exploratory, qualitative study whether these three constructs adequately represent burnout. Participants who self-identified as experiencing burnout completed a questionnaire that asked about their experiences of the condition. A qualitative thematic analysis was undertaken to determine the primary symptom constructs nominated by participants. The thematic analysis resulted in 12 symptom clusters or “themes” being identified as putative burnout features, with several of these themes overlapping with features identified in our independent quantitative analysis. Although we found emotional exhaustion, lack of empathy, and reduced professional accomplishment to be commonly nominated symptoms of burnout, the distinctive presence of several additional themes suggests that the burnout syndrome comprises a broader set of symptom constructs than those currently accepted as the defining features of the condition.
Opioid Use in Fibromyalgia Continues Despite Guidelines That Do Not Support Its Efficacy or Risk
Authors: Bruce Barbara K. , Allman Madeleine E. , Rivera Fernando A. , Abril Andy , Gehin Jessica M. , Oliphant Loretta M. , Nordan Lisa M. , White Launia J. , Martinez Dayana , Niazi Shehzad K.
Published: February 2020

Background/Objective

The aim of this cross-sectional study is to determine the prevalence of opioid use in a large sample of fibromyalgia (FM) patients and examine the factors associated with opioid prescription/use despite multiple clinical guidelines that do not recommend opioid use in this population.

Methods

Data were collected from a convenience sample of 698 patients admitted from August 2017 to May 2019 into an intensive 2-day Fibromyalgia Treatment Program at a tertiary medical center in the United States after FM diagnosis. Patients were administered the Fibromyalgia Impact Questionnaire–Revised, the Center for Epidemiologic Study of Depression Scale, and the Pain Catastrophizing Scale upon admission to the program. Demographic information and opioid use were self-reported. Logistic regression analysis was utilized to determine associations between patient-related variables and opioid use in this prospective study.

Results

Of 698 patients, 27.1% (n = 189) were taking opioids at intake. Extended duration of symptoms (>3 years), increased age, higher degree of functional impairment, and increased pain catastrophizing were significantly associated with opioid use.

Conclusions

Opioids are not recommended for the treatment of FM under current guidelines. Greater burden of illness appeared to be associated with the prescription and use of opioids in this population. These findings suggest that some providers may not be aware of current recommendations that have been found to be effective in the management of FM that are contained in guidelines. Alternative approaches to the management of FM that do not involve opioids are reviewed in an effort to improve care.
Evidence-Based Approach to Nerve Gap Repair in the Upper Extremity
Authors: Huayllani Maria T. , Boczar Daniel , Forte Antonio J. , Rinker Brian
Published: February 2020

The upper extremity is the most common site for nerve injuries. In most cases, direct repair can be performed, but when a critical gap occurs, special techniques must be used to enhance nerve regeneration and allow recovery of sensory and motor functions. These techniques include the use of autografts, processed nerve allografts, and conduits. However, surprisingly few studies have compared outcomes from the different methods of nerve gap repair in a rigorous fashion. There is a lack of evidence-based guidelines for the management of digital and motor and mixed nerve injuries with a nerve gap. The purpose of this study is to perform a comprehensive literature review and propose a rational algorithm for management of nerve injuries with a critical gap.
Design Thinking–Informed Simulation
Authors: Petrosoniak Andrew , Hicks Christopher , Barratt Lee , Gascon Dominic , Kokoski Candis , Campbell Doug , White Kari , Bandiera Glen , Lum-Kwong Margaret Moy , Nemoy Lori , Brydges Ryan
Published: February 2020

Introduction

Designing new healthcare facilities is complex and transitions to new clinical environments carry high risks, as unanticipated problems may arise resulting in inefficient care and patient harm. Design thinking, a human-centered design method, represents a unique framework to support the planning, testing, and evaluation of new clinical spaces throughout all phases of construction. Healthcare simulation has been used to test new clinical spaces, yet most report using simulation only in the late design stages. Moreover, healthcare design models have potentially underused human factors approaches calling for human-centered design. We applied a multimodal simulation-based approach underpinned by the principles of design thinking throughout the planning and construction stages of a newly renovated academic emergency department.

Methods

A multidisciplinary team developed and integrated 3 simulation strategies (table-top, mock-up, and in situ simulation) into the 5-step process of design thinking. Through end-user engagement, we identified potential challenges, prototyped solutions through table-top and mock-up simulations, and iteratively tested these solutions through in situ simulation within the actual clinical space.

Results

The team used end-user engagement and feedback to brainstorm and implement effective solutions to problems encountered before opening the new emergency department. The iterative steps and targeted use of simulation resulted in redesigning departmental processes and actual clinical space while mitigating anticipated safety threats and departmental deficiencies.

Conclusions

Design thinking coupled with multimodal simulation across all phases of construction enhanced the design and testing of new clinical infrastructure. Applying this approach early, thoroughly, and efficiently will help healthcare organizations plan changes to clinical spaces.
Teprotumumab in Thyroid-Associated Ophthalmopathy: Rationale for Therapeutic Insulin-Like Growth Factor–I Receptor Inhibition
Authors: Smith Terry J.
Published: February 2020

Thyroid-associated ophthalmopathy (TAO) is an autoimmune component of Graves' disease for which no currently available medical therapy provides reliable and safe benefit. Based on insights generated experimentally over the past several decades, the insulin-like growth factor–I receptor (IGF-IR) has been implicated in the pathogenesis of TAO. Furthermore, an IGF-IR inhibitor, teprotumumab, has emerged from 2 clinical trials as a promising treatment for active, moderate to severe TAO. This brief review intends to provide an overview of the rationale underlying the development of teprotumumab for this disease. It is possible that teprotumumab will soon take its place in our therapeutic armamentarium for active TAO.
Crossroads between transposons and gene regulation
Authors: Branco Miguel R. , Chuong Edward B.
Published: February 2020

Transposons are mobile genetic elements that have made a large contribution to genome evolution in a largely species-specific manner. A wide variety of different transposons have invaded genomes throughout evolution, acting in a first instance as ‘selfish’ elements, whose success was determined by their ability to self-replicate and expand within the host genome. However, their coevolution with the host has created many crossroads between transposons and the regulation of host gene expression. Transposons are an abundant source of transcriptional modulatory elements, such as gene promoters and enhancers, splicing and termination sites, and regulatory non-coding RNAs. Moreover, transposons have driven the evolution of host defence mechanisms that have been repurposed for gene regulation. However, dissecting the potential functional roles of transposons remains challenging owing to their evolutionary path, as well as their repetitive nature, which requires the development of specialized analytical tools. In this special issue, we present a collection of articles that lay out current paradigms in the field and discuss a vision for future research.

This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.
Contribution of unfixed transposable element insertions to human regulatory variation
Authors: Goubert Clément , Zevallos Nicolas Arce , Feschotte Cédric
Published: February 2020

Thousands of unfixed transposable element (TE) insertions segregate in the human population, but little is known about their impact on genome function. Recently, a few studies associated unfixed TE insertions to mRNA levels of adjacent genes, but the biological significance of these associations, their replicability across cell types and the mechanisms by which they may regulate genes remain largely unknown. Here, we performed a TE-expression QTL analysis of 444 lymphoblastoid cell lines (LCL) and 289 induced pluripotent stem cells using a newly developed set of genotypes for 2743 polymorphic TE insertions. We identified 211 and 176 TE-eQTL acting
in cis
in each respective cell type. Approximately 18% were shared across cell types with strongly correlated effects. Furthermore, analysis of chromatin accessibility QTL in a subset of the LCL suggests that unfixed TEs often modulate the activity of enhancers and other distal regulatory DNA elements, which tend to lose accessibility when a TE inserts within them. We also document a case of an unfixed TE likely influencing gene expression at the post-transcriptional level. Our study points to broad and diverse
cis
-regulatory effects of unfixed TEs in the human population and underscores their plausible contribution to phenotypic variation.

This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.
Construction and characterization of a knock-down RNA interference line of
OsNRPD1
in rice (
Oryza sativa
ssp
japonica
cv Nipponbare)
Authors: Debladis Emilie , Lee Tzuu-Fen , Huang Yan-Jiun , Lu Jui-Hsien , Mathioni Sandra M. , Carpentier Marie-Christine , Llauro Christel , Pierron Davy , Mieulet Delphine , Guiderdoni Emmanuel , Chen Pao-Yang , Meyers Blake C. , Panaud Olivier , Lasserre Eric
Published: February 2020

In plants, RNA-directed DNA methylation (RdDM) is a silencing mechanism relying on the production of 24-nt small interfering RNAs (siRNAs) by RNA POLYMERASE IV (Pol IV) to trigger methylation and inactivation of transposable elements (TEs). We present the construction and characterization of
osnrpd1
, a knock-down RNA interference line of
OsNRPD1
gene that encodes the largest subunit of Pol IV in rice (
Oryza sativa
ssp
japonica
cv Nipponbare). We show that
osnrpd1
displays a lower accumulation of
OsNRPD1
transcripts, associated with an overall reduction of 24-nt siRNAs and DNA methylation level in all three contexts, CG, CHG and CHH. We uncovered new insertions of known active TEs, the LTR retrotransposons
Tos17
and
Lullaby
and the long interspersed nuclear element-type retrotransposon
Karma.
However, we did not observe any clear developmental phenotype, contrary to what was expected for a mutant severely affected in RdDM. In addition, despite the presence of many putatively functional TEs in the rice genome, we found no evidence of
in planta
global reactivation of transposition. This knock-down of
OsNRPD1
likely led to a weakly affected line, with no effect on development and a limited effect on transposition. We discuss the possibility that a knock-out mutation of
OsNRPD1
would cause sterility in rice.

This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.
Flavobacterium sandaracinum sp. nov., Flavobacterium caseinilyticum sp. nov., and Flavobacterium hiemivividum sp. nov., novel psychrophilic bacteria isolated from Arctic soil
Authors: Chaudhary Dhiraj Kumar , Dahal Ram Hari , Kim Dong-Uk , Kim Jaisoo
Published: February 2020

This study presents taxonomic description of strains LB-D12T, AT-3-2T, AT-3–7, and TSA-D2T isolated from Arctic soil. All strains were psychrophilic, Gram-stain-negative, aerobic, non-motile, and rod-shaped. Phylogenetic analysis showed that these strains belonged to the genus

Flavobacterium

. Strains LB-D12T, AT-3-2T and AT-3–7 were closest to

Flavobacterium psychrolimnae

LMG 22018T (98.5–98.8% sequence similarity). Strain TSA-D2T was closest to

Flavobacterium degerlachei

DSM 15718T (98.3 % sequence similarity). These strains shared common chemotaxonomic features comprising MK-6 as a sole quinone, phosphatidylethanolamine as the principal polar lipid, and summed feature 3 (iso-C15 : 0 2-OH and/or C16 : 1ω7c), iso-C16 : 0 3-OH, C15 : 1ω6c, iso-C16 : 0, and anteiso-C15 : 0 as the main fatty acids. The ANI and dDDH values between these novel isolates and their closest relatives were below the cut-off values of 95 and 70 %, respectively used for species demarcation. The DNA G+C content of all strains ranged from 34.2 to 34.6 mol%. The obtained polyphasic taxonomic data suggested that the isolated strains represent novel species within the genus

Flavobacterium

, for which the names Flavobacterium sandaracinum sp. nov. (type strain LB-D12T=KEMB 9005-737T=KACC 21180T=NBRC 113784T), Flavobacterium caseinilyticum sp. nov. (type strain AT-3–2T=KEMB 9005-738T=KACC 21176T=NBRC 113785T), and Flavobacterium hiemivividum sp. nov. (type strain TSA-D2T=KEMB 9005-741T=KACC 21179T=NBRC 113788T) are proposed.
Tabrizicola piscis sp. nov., isolated from the intestinal tract of a Korean indigenous freshwater fish, Acheilognathus koreensis
Authors: Han Jeong Eun , Kang Woorim , Lee June-Young , Sung Hojun , Hyun Dong-Wook , Kim Hyun Sik , Kim Pil Soo , Tak Euon Jung , Jeong Yun-Seok , Lee Jae-Yun , Lee So-Yeon , Yun Ji-Hyun , Jung Mi-Ja , Shin Na-Ri , Whon Tae Woong , Kang Myung-Suk , Lee Ki-Eun , Lee Byoung-Hee , Bae Jin-Woo
Published: February 2020

A novel Gram-negative, obligately aerobic, rod-shaped and non-motile bacterium, designated strain K13M18T, was isolated from the intestinal tract of a Korean indigenous fish, oily bitterling (Acheilognathus koreensis). Strain K13M18T formed creamy-pink colonies on a marine agar plate. Results of phylogenetic analysis based on the 16S rRNA gene sequence similarity indicated that strain K13M18T was most closely related to

Tabrizicola sediminis

DRYC-M-16T, sharing 97.62 % similarity with that strain. Strain K13M18T belonged to the genus

Tabrizicola

, which formed a cluster with

Tabrizicola aquatica

RCRI19T,

Tabrizicola fusiformis

SY72T,

Tabrizicola sediminis

DRYC-M-16T and

Tabrizicola alkalilacus

DJCT in a phylogenetic tree based on the 16S rRNA gene sequences. Strain K13M18T grown optimally in 0 % (w/v) NaCl, at pH 7 and 30 °C, in a marine broth medium. The predominant cellular fatty acids were C18 : 1
ω7c and C18 : 1
ω6c. The major respiratory isoprenoid quinone was ubiquinone Q-10. Polar lipids of strain K13M18T contained phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, diphosphatidylglycerol, six unidentified aminophospholipids, one unidentified aminolipid and an unidentified lipid. Based on genome sequencing, the DNA G+C content of strain K13M18T was 64.08 mol %, with an average nucleotide identity value, calculated by a comparative genomic analysis of strains K13M18T and

T. sediminis

DRYC-M-16T, of 74.82 %. Based on the phylogenetic, genotypic, and phenotypic information, strain K13M18T is proposed to be a novel species of the genus

Tabrizicola

. The type strain is K13M18T (=KCTC 62659T=JCM 33230T).
EFFECT OF VISUAL-CUEING ON TWO-LEGGED HOPPING VARIABILITY IN CHILDREN WITH AUTISM SPECTRUM DISORDER: A PILOT STUDY
Authors: Lidstone Daniel E. , Dufek Janet S.
Published: February 2020

Background

Motor deficits in children with Autism Spectrum Disorder (ASD) are highly prevalent. High variability of motor output is commonly reported in children with ASD. Visual cueing using an exergame may be an effective intervention to reduce motor variability in children with ASD.

Aim

To examine the effect of visual cueing on two-legged hopping variability in children with ASD.

Methods

Four children with ASD and six age-matched TD controls performed three 20-s hopping trials with no visual cueing (no cue = NC) and with a 2 Hz visual cue (visual cue = VC). Three-dimensional kinematic data of the sacrum marker and ground reaction force were collected during each hopping trial. Variability was determined using the intra-trial coefficient of variation (CoV) of hopping frequency, hop height, and negative sacral displacement

Results

A marginally significant interaction between GROUP (ASD/TD) and CUE type (NC/VC) was observed for hopping frequency variability (p= 0.06) indicating greater impairment in the ASD group vs. TD group with visual vs. no-cueing. The main effect of group showed a statistically significant difference in hopping frequency (p= 0.037), hopping frequency variability (p= 0.008), and negative sacrum displacement variability (p= 0.04).

Conclusion

This pilot study confirmed high motor variability in the amplitude and frequency of repetitive movements in children with ASD. However, visual cueing was ineffective at reducing the variability of motor output in children with autism.
DKW basal salts improve micropropagation and callogenesis compared to MS basal salts in multiple commercial cultivars ofCannabis sativa
Authors: Page Serena R.G. , Monthony Adrian S. , Jones A. Maxwell P.
Published: February 2020

Micropropagation ofCannabis sativais an emerging area for germplasm storage and large-scale production of clean plants. Existing protocols use a limited number of genotypes and are often not reproducible. Previous studies reported MS + 0.5 μM TDZ to be optimal forCannabisnodal micropropagation, yet our preliminary studies using nodal explants suggested this media may not be optimal. It resulted in excessive callus formation, hyperhydricity, low multiplication rates, and high mortality rates. Following an initial screen of four commonly used basal salt mixtures (MS, B5, BABI, and DKW), we determined that DKW produced the healthiest plants. In a second experiment, the multiplication rate and canopy area of explants grown on MS + 0.5 μM TDZ and DKW + 0.5 μM TDZ were compared using five drug-type cultivars to determine if the preference for DKW was genotype-dependent. Four cultivars had significantly higher multiplication rates on DKW + 0.5 μM TDZ with the combined average being 1.5x higher than explants grown on MS + 0.5 μM TDZ. The canopy area was also significantly larger on DKW + 0.5 μM TDZ for four cultivars with the combined average being twice as large as the explants grown on MS + 0.5 μM TDZ. In the third experiment, callogenesis was compared using a range of 2,4-D concentrations (0-30 μM) on both MS and DKW and similarly, callus growth was superior on DKW. This study presents the largest comparison of basal salt compositions on the micropropagation of five commercially grownCannabiscultivars to date.
Model-based analysis of polymorphisms in an enhancer reveals cis-regulatory mechanisms
Authors: Khajouei F , Samper N , Djabrayan NJ , Lunt B , Jiménez G , Sinha S
Published: February 2020

It is challenging to predict the impact of small genetic changes such as single nucleotide polymorphisms on gene expression, since mechanisms involved in gene regulation and their cis-regulatory encoding are not well-understood. Recent studies have attempted to predict the functional impact of non-coding variants based on available knowledge of cis-regulatory encoding, e.g., transcription factor (TF) motifs. In this work, we explore the relationship between regulatory variants and cis-regulatory encoding from the opposite angle, using the former to inform the latter. We employ sequence-to-expression modeling to resolve ambiguities regarding gene regulatory mechanisms using information about effects of single nucleotide variations in an enhancer. We demonstrate our methodology using a well-studied enhancer of the developmental geneintermediate neuroblasts defective(ind) inD. melanogaster. We first trained the thermodynamics-based model GEMSTAT to relate the neuroectodermal expression pattern of ind to its enhancer’s sequence, and constructed an ensemble of models that represent different parameter settings consistent with available data for this gene. We then predicted the effects of every possible single nucleotide variation within this enhancer, and compared these to SNP data recorded in the Drosophila Genome Reference Panel. We chose specific SNPs for which different models in the ensemble made conflicting predictions, and tested their effect in vivo. These experiments narrowed in on one mechanistic model as capable of explaining the observed effects. We further confirmed the generalizability of this model to orthologous enhancers and other related developmental enhancers. In conclusion, mechanistic models of cis-regulatory function not only help make specific predictions of variant impact, they may also be learned more accurately using data on variants.

STATEMENT OF SIGNIFICANCE

A central issue in analyzing variations in the non-coding genome is to interpret their functional impact, and their connections to phenotype differences and disease etiology. Machine learning methods based on statistical modeling have been developed to associate genetic variants to expression changes. However, associations predicted by these models may not be functionally relevant, despite being statisticaly significant. We describe how mathematical modeling of gene expression can be employed to systematically study the non-coding sequence and its relationship to gene expression. We demonstrate our method in a well studied developmental enhancer of the fruitfly. We establish the efficacy of mathematical models in combination with the polymorphism data to reveal new mechanistic insights.
Exploring the selenium-over-sulfur substrate specificity and kinetics of a bacterial selenocysteine lyase
Authors: Johnstone Michael A. , Nelson Samantha J. , Van Groesbeck Christine , Self William T.
Published: February 2020

Selenium is a vital micronutrient in many organisms. While traces are required for utilization by the microbe, excess amounts are toxic; thus, selenium can be regarded as a biological “double-edged sword”. Selenium is chemically similar to the essential element sulfur, but curiously, evolution has selected the former over the latter for a subset of oxidoreductases. Enzymes involved in sulfur metabolism are less discriminate in terms of preventing selenium incorporation; however, its specific incorporation into selenoproteins reveals a highly discriminate process that is not completely understood. We have identified SclA, a selenocysteine lyase in the nosocomial pathogen,Enterococcus faecalis, and characterized its enzymatic activity and specificity for L-selenocysteine over L-cysteine. It is known that a single residue in the human selenocysteine lyase, D146, is considered to control selenocysteine specificity. Thus, using computational biology, we identified H100, a D146 ortholog in SclA, and generated mutant enzymes with site-directed mutagenesis. The proteins were overexpressed, purified, and characterized for their biochemical properties. All mutants exhibited varying levels of activity towards L-selenocysteine, suggesting a catalytic role for H100. Additionally, L-cysteine acted as a competitive inhibitor towards all enzymes with higher affinity than L-selenocysteine. Our findings offer key insight into the molecular mechanisms behind selenium-over-sulfur specificity and may further elucidate the role of selenocysteine lyasesin vivo.
Polymorphisms in human APOBEC3H differentially regulate ubiquitination and antiviral activity
Authors: Chesarino Nicholas M. , Emerman Michael
Published: February 2020

The APOBEC3 family of cytidine deaminases are an important part of the host innate immune defense against endogenous retroelements and retroviruses like human immunodeficiency virus (HIV).APOBEC3H(A3H) is the most polymorphic of the humanAPOBEC3genes, with four major haplotypes circulating in the population. Haplotype II is the only antivirally-active variant ofA3H, while the majority of the population possess independently destabilizing polymorphisms present in haplotype I (R105G) and haplotypes III and IV (N15del). Here, we show that instability introduced by either polymorphism is positively correlated with degradative ubiquitination, while haplotype II is protected from this modification. Inhibiting ubiquitination by mutating all of the A3H lysines increased expression of haplotypes III and IV, but these stabilized forms of haplotype III and IV had a strict nuclear localization, and did not incorporate into virions, nor exhibit antiviral activity, thus separating stabilization from function. On the other hand, the instability and functional deficiencies of haplotype III could be rescued by fusion to haplotype II, supporting a model by which antiviral A3H is actively stabilized through a cytoplasmic retention mechanism. Thus, the evolutionary loss of A3H activity in many humans involves functional deficiencies independent of protein stability.
An ERP index of real-time error correction within a noisy-channel framework of human communication
Authors: Ryskin Rachel , Stearns Laura , Bergen Leon , Eddy Marianna , Fedorenko Evelina , Gibson Edward
Published: February 2020

Recent evidence suggests that language processing is well-adapted to noise in the input (e.g., speech errors, mishearing) and readily corrects the input via rational inference over possible intended sentences and probable noise corruptions. However, it remains unclear whether this inference takes the form of an offline re-analysis or a rapid, real-time correction to the representations of the input. We hypothesize that noise inferences happen online during processing and that well-studied ERP components may serve as a useful index of this process. In particular, a reduced N400 effect and increased P600 effect appear to accompany sentences where the probability that the message was corrupted by noise exceeds the probability that it was produced intentionally and perceived accurately. Indeed, semantic violations that are attributable to noise—for example, in “The storyteller could turn any incident into an amusingantidote”, where the implausible word “antidote” is orthographically and phonologically close to the intended “anecdote”—elicit a reduced N400 effect and larger P600 effect. Further, the magnitude of this P600 effect is shown to relate to the probability that the comprehender will retrieve a plausible alternative. This work thus adds to the growing body of literature that suggests that many aspects of language processing are well-adapted to noise in the input and opens the door to electrophysiologic investigations of these processes
Data-driven models reveal mutant cell behaviors important for myxobacterial aggregation
Authors: Zhang Zhaoyang , Cotter Christopher R. , Lyu Zhe , Shimkets Lawrence J. , Igoshin Oleg A.
Published: February 2020

Single mutations frequently alter several aspects of cell behavior but rarely reveal whether a particular statistically significant change is biologically significant. To determine which behavioral changes are most important for multicellular self-organization, we devised a new methodology usingMyxococcus xanthusas a model system. During development, myxobacteria coordinate their movement to aggregate into spore-filled fruiting bodies. We investigate how aggregation is restored in two mutants,csgAandpilC, that cannot aggregate unless mixed with wild type (WT) cells. To this end, we use cell tracking to follow the movement of fluorescently labeled cells in combination with data-driven agent-based modeling. The results indicate that just like WT cells, both mutants bias their movement toward aggregates and reduce motility inside aggregates. However, several aspects of mutant behavior remain uncorrected by WT demonstrating that perfect recreation of WT behavior is unnecessary. In fact, synergies between errant behaviors can make aggregation robust.
T-ALL Proliferation Relies on Glutamine Uptake and EAAT1-dependent Conversion of Glutamine to Aspartate and Nucleotides
Authors: Stanulović Vesna S. , Omair Shorog Al , Reed Michelle A.C. , Potluri Sandeep , Roberts Jennie , Perry Tracey A. , Sarkar Sovan , Pratt Guy , Günther Ulrich L. , Ludwig Christian , Hoogenkamp Maarten
Published: February 2020

T-cell acute lymphoblastic leukaemia (T-ALL) is a cancer of the immune system. Approximately 20% of paediatric and 50% of adult T-ALL patients have refractory disease or relapse and die from the disease. To improve patient outcome new therapeutics are needed. With the aim to identify new therapeutic targets, we analysed the metabolic adaptations that T-ALL cells exhibit and found that glutamine uptake is essential for their proliferation. Isotope tracing experiments showed that glutamine fuels aspartate synthesis through the TCA cycle and that glutamine and glutamine-derived aspartate together supply three nitrogen atoms in purines and all but one atom in pyrimidine rings. We show that the glutamate-aspartate transporter EAAT1, which is normally only expressed in the CNS, is crucial for glutamine conversion to nucleotides and that T-ALL cell proliferation depends on EAAT1 function. Through this work, we identify EAAT1 as a novel therapeutic target for T-ALL treatment.
Recording the age of RNA with deamination
Authors: Rodriques Samuel G. , Chen Linlin M. , Liu Sophia , Zhong Ellen D. , Scherrer Joseph R. , Boyden Edward S. , Chen Fei
Published: February 2020

Transcriptional programs implemented by cells often consist of complex temporal features, but current approaches to single-cell RNA sequencing only provide limited information about the dynamics of gene expression. Here, we present RNA timestamps, a method for inferring the age of individual RNAs in a sequencing-based readout by leveraging RNA editing. Timestamped RNAs include a RNA reporter motif that accumulates A to I edits over time, allowing the age of the RNA to be inferred with hour-scale accuracy. By combining observations of multiple timestamped RNAs driven by the same promoter, we are able to infer when in the past the promoter was active. We demonstrate that the system can infer the presence and timing of multiple past transcriptional events, with no prior knowledge. Finally, we apply this method to cluster single cells according to the times at which a particular transcriptional program was activated. RNA timestamps thus suggest a new approach for incorporating temporal information into RNA sequencing workflows.
ABCF1 regulates dsDNA-induced immune responses in human airway epithelial cells
Authors: Cao Quynh T. , Aguiar Jennifer A. , Tremblay Benjamin J-M , Abbas Nadin , Tiessen Nicholas , Revill Spencer , Makhdami Nima , Ayoub Anmar , Cox Gerard , Ask Kjetil , Doxey Andrew C. , Hirota Jeremy A.
Published: February 2020

Background

The airway epithelium represents a critical component of the human lung that helps orchestrate defences against respiratory tract viral infections, which are responsible for more than 2.5 million deaths/year globally. Innate immune activities of the airway epithelium rely Toll-like receptors (TLRs), nucleotide binding and leucine-rich-repeat pyrin domain containing (NLRP) receptors, and cytosolic nucleic acid sensors. ATP Binding Cassette (ABC) transporters are ubiquitous across all three domains of life – Archaea, Bacteria, and Eukarya – and expressed in the human airway epithelium. ABCF1, a unique ABC family member that lacks a transmembrane domain, has been defined as a cytosolic nucleic acid sensor that regulates CXCL10, interferon-β expression, and downstream type I interferon responses. We tested the hypothesis that ABCF1 functions as a dsDNA nucleic acid sensor in human airway epithelial cells important in regulating antiviral responses.

Methods

Expression and localization experiments were performed using in situ hybridization and immunohistochemistry in human lung tissue from healthy subjects, while confirmatory transcript and protein expression was performed in human airway epithelial cells. Functional experiments were performed with siRNA methods in human airway epithelial cells. Complementary transcriptomic analyses were performed to explore the contributions of ABCF1 to gene expression patterns.

Results

Using archived human lung and human airway epithelial cells, we confirm expression of ABCF1 gene and protein expression in these tissue samples, with a role for mediating CXCL10 production in response to dsDNA viral mimic challenge. Although, ABCF1 knockdown was associated with an attenuation of select genes involved in the antiviral responses, Gene Ontology analyses revealed a greater interaction of ABCF1 with TLR signaling suggesting a multifactorial role for ABCF1 in innate immunity in human airway epithelial cells.

Conclusion

ABCF1 is a candidate cytosolic nucleic acid sensor and modulator of TLR signaling that is expressed at gene and protein levels in human airway epithelial cells. The precise level where ABCF1 protein functions to modulate immune responses to pathogens remains to be determined but is anticipated to involve IRF-3 and CXCL10 production.
A taxonomy of seizure dynamotypes
Authors: Saggio Maria Luisa , Crisp Dakota , Scott Jared , Karoly Phillippa J. , Kuhlmann Levin , Nakatani Mitsuyoshi , Murai Tomohiko , Dümpelmann Matthias , Schulze-Bonhage Andreas , Ikeda Akio , Cook Mark , Gliske Stephen V. , Lin Jack , Bernard Christophe , Jirsa Viktor , Stacey William
Published: February 2020

Seizures are a disruption of normal brain activity present across a vast range of species, diseases, and conditions. Here we introduce an organizing principle that leads to the first objective Taxonomy of Seizure Dynamics (TSD) based on bifurcation theory, and applied it to the analysis of EEG data. The “dynamotype” of a seizure is the part of its dynamic composition that defines its observable characteristics, including how it starts, evolves and terminates. Analyzing over 2000 focal-onset seizures recorded from 7 epilepsy centers on five continents, we find evidence of all 16 dynamotypes predicted in TSD. We demonstrate that patients’ dynamotypes evolve during their lifetime and display complex but systematic variations including hierarchy (certain dynamotypes are more common), non-bijectivity (a patient may display multiple dynamotypes) and pairing preference (multiple dynamotypes may occur during one seizure). TSD not only provides a way to stratify patients in complement to present practical classifications but also guides biophysically based mechanistic approaches and provides a language to describe the most critical features of seizure dynamics.

Impact statement

Taxonomy of Seizure Dynamics (TSD) provides a rigorous method for classifying and quantifying seizures and a principled framework for understanding seizure initiation and propagation.
Neural correlates of newsvendor-based decision making in the human brain:An exploratory study to link neuroeconomics with neuroimaging using fNIRS
Authors: Wanniarachchi Hashini , Lang Yan , Wang Xinlong , Nerur Sridhar , Chen Kay-Yut , Liu Hanli
Published: February 2020

Neuroeconomics with neuroimaging is a novel approach involving economics and neuroscience. The newsvendor problem (NP) is a prevalent economics concept that may be used to map brain activations during NP-evoked risky decision making. In this study, we hypothesized that key brain regions responsible for NP are dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC). Twenty-seven human subjects participated in the study using 40 NP trials; the participants were randomly assigned to a group with a low-profit margin (LM) or high-profit margin (HM) treatment. Cerebral hemodynamic responses were recorded simultaneously during the NP experiments from all participants with a 77-channel functional Near-infrared Spectroscopy (fNIRS) system. After data preprocessing, general linear model was applied to generate brain activation maps, followed by statistical t-tests. The results showed that: (a) DLPFC and OFC were significantly evoked by NP versus baseline regardless of treatment types; (b) DLPFC and OFC were activated by HM versus baseline; and (c) DLPFC was activated during LM versus baseline. Furthermore, significant deactivation in right DLPFC was shown due to LM with respect to HM. This study affirms that DLPFC and OFC are two key cortical regions when solving NP. In particular, right DLPFC was found to be more deactivated under challenging risk decision making.
Decoding Attention Control and Selection in Visual Spatial Attention
Authors: Hong Xiangfei , Bo Ke , Meyyapan Sreenivasan , Tong Shanbao , Ding Mingzhou
Published: February 2020

Event-related potentials (ERPs) are used extensively to investigate the neural mechanisms of attention control and selection. The commonly applied univariate ERP approach, however, has left important questions inadequately answered. Here, we addressed two questions by applying multivariate pattern classification to multichannel ERPs in two spatial-cueing experiments (N= 56 in total): (1) impact of cueing strategies (instructional vs. probabilistic) and (2) neural and behavioral effects of individual differences. Following the cue onset, the decoding accuracy (cue left vs. cue right) began to rise above chance level earlier and remained higher in instructional cueing (∼80 ms) than in probabilistic cueing (∼160 ms), suggesting that unilateral attention focus leads to earlier and more distinct formation of the attentional set. A similar temporal sequence was also found for target-related processing (cued targets vs. uncued targets), suggesting earlier and stronger attention selection under instructional cueing. Across the two experiments, individuals with higher decoding accuracy during ∼460-660 ms post-cue showed higher magnitude of attentional modulation of target-evoked N1 amplitude, suggesting that better formation of anticipatory attentional state leads to better target processing. During target processing, individual difference in decoding accuracy was positively associated with behavioral performance (reaction time), suggesting that stronger selection of task-relevant information leads to better behavioral performance. Taken together, multichannel ERPs combined with machine learning decoding yields new insights into attention control and selection that are not possible with the univariate ERP approach, and along with the univariate ERP approach, provides a more comprehensive methodology to the study of visual spatial attention.
Mechanisms of Feature Selectivity and Invariance in Primary Visual Cortex
Authors: Almasi Ali , Meffin Hamish , Cloherty Shaun L. , Wong Yan , Yunzab Molis , Ibbotson Michael R.
Published: February 2020

Visual object identification requires both selectivity for specific visual features that are important to the object’s identity and invariance to feature manipulations. For example, a hand can be shifted in position, rotated, or contracted but still be recognised as a hand. How are the competing requirements of selectivity and invariance built into the early stages of visual processing? Typically, cells in the primary visual cortex are classified as either simple or complex. They both show selectivity for edge-orientation but complex cells develop invariance to edge position within the receptive field (spatial phase). Using a data-driven model that extracts the spatial structures and nonlinearities associated with neuronal computation, we show that the balance between selectivity and invariance in complex cells is more diverse than thought. Phase invariance is frequently partial, thus retaining sensitivity to brightness polarity, while invariance to orientation and spatial frequency are more extensive than expected. The invariance arises due to two independent factors: (1) the structure and number of filters and (2) the form of nonlinearities that act upon the filter outputs. Both vary more than previously considered, so primary visual cortex forms an elaborate set of generic feature sensitivities, providing the foundation for more sophisticated object processing.
Hyaluronan-NK cell Interaction Controls the Primary Vascular Barrier during Early Pregnancy
Authors: Hadas Ron , Gershon Eran , Cohen Aviad , Stroganov Sima , Atrakchi Ofir , Lazar Shlomi , Golani Ofra , Dassa Bareket , Elbaz Michal , Cohen Gadi , Kartvelishvily Elena , Eilam Raya , Dekel Nava , Neeman Michal
Published: February 2020

Successful implantation is associated with a unique spatial pattern of vascular remodeling, characterized by profound peripheral neo-vascularization surrounding a peri-embryo avascular niche. We hypothesized that hyaluronan controls the formation of the unique vascular pattern encompassing the embryo. This hypothesis was evaluated by genetic modification of hyaluronan metabolism specifically targeted to embryonic trophoblast cells. The outcome of altered hyaluronan deposition on uterine vascular remodeling and post-implantation development were analyzed by MRI, detailed histological examinations, and RNA-sequencing of uterine NK cells. Our experiments revealed that eliminating the anti-angiogenic hyaluronan, led to elevated expression of MMP-9, VEGF-A and its receptor VEGFR-2, accompanied by reduced recruitment of uterine NK cells. Further local decrease in VEGFR-3 resulted in impaired formation of vascular sinuous folds, ectopic angiogenesis and dysfunctional uterine NK cells. Conversely, enhanced deposition of hyaluronan caused the expansion of the maternal-embryo barrier, leading to an increased diffusion distance and aborted implantation. These results demonstrate a pivotal role for hyaluronan in successful pregnancy by fine-tuning the peri-embryo avascular niche and maternal vascular morphogenesis.