bluuebunny/crossref_metadata_2025 huggingface dataset:
RSVpredict: An Online Tool to Calculate the Likelihood of Respiratory Syncytial Virus Infection in Children Hospitalized With Acute Respiratory Disease
Authors: Manuel Britta , Hackbusch Matthes , Tabatabai Julia , Hoos Johannes , Peters Rebecca , Valerie Schnee Sarah , Marlene Ihling Clara , Schnitzler Paul , Pfeil Johannes
Published: February 2019

Background:

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infection in young children. Early detection of RSV infection can avoid unnecessary diagnostic and therapeutic intervention and is required to prevent the nosocomial spread of RSV infection in pediatric hospitals. We developed a web tool to calculate the probability of RSV infection in children hospitalized with acute respiratory tract infection (ARTI) (RSVpredict).

Methods:

During winter seasons 2014/2015 to 2017/2018, 1545 children hospitalized with clinical symptoms of ARTI at the University Hospital Heidelberg/Germany were prospectively included. Medical information was reported on a standardized data sheet, and nasopharyngeal swabs were obtained for multiplex real-time polymerase chain reaction analyses. We applied logistic regression to develop a prediction model and developed a web-based application to predict the individual probability of RSV infection.

Results:

Duration of clinical symptoms ≥2 days on admission, calendar month of admission, admission for lower respiratory tract infection, the presence of cough and rale and younger age were associated with RSV infection (P < 0.05). Those data were included in the prediction model (RSVpredict, https://web.imbi.uni-heidelberg.de/rsv/). RSVpredict is a web-based application to calculate the risk of RSV infection in children hospitalized with ARTI. The prediction model is based on easily accessible clinical symptoms and predicts the individual probability of RSV infection risk immediately.

Conclusions:

Pediatricians might use the RSVpredict to take informed decisions on further diagnostic and therapeutic intervention, including targeted RSV testing in children with relevant RSV infection risk.
Experience of Family Physicians in Practice Transformation Networks
Authors: Hansen Elizabeth Rose , Eden Aimee R. , Peterson Lars E. , Bishop Elizabeth M. , Phillips Robert L.
Published: February 2019

To help health care practices transition away from fee-for-service reimbursement and toward value-based payment, the Transforming Clinical Practice Initiative was launched in October 2015. It was designed to provide clinicians support through peer-based Practice Transformation Networks (PTNs). A group of American Board of Family Medicine board-certified family physicians enrolled in PTNs described their expectations of and experiences with PTN participation; we analyzed open-text comments. Physicians expected and experienced PTN support in informatics and data, team building, and workflow and care coordination; however, expectations regarding patient care and engagement, costs and payment reform, and population and panel health were described less frequently.
Impact of Pre-Analytical Conditions on the Antigenicity of Lung Markers: ALK and MET
Authors: Miller Rachel , Thorne-Nuzzo Trish , Loftin Isabell , McElhinny Abigail , Towne Penny , Clements June
Published: February 2019

Diagnostic assays for molecular alterations highly correlated with prognosis, predictive efficacy or safety of therapeutics are valuable clinical tools and in some cases approved as companion diagnostics (CDx) by the Federal Food and Drug Administration. For example, assays that determine echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) translocation status have been approved as CDx assay for therapies that target this molecular alteration. Characterizing the parameters that may compromise diagnostic accuracy for molecular biomarkers is critical for optimal patient care. To investigate the impact of pre-analytical handling and processing of tumor tissue on commonly used diagnostic immunohistochemistry-based assays for ALK and mesenchymal epithelial transition protein [c-mesenchymal epithelial transition (c-MET)], we investigated the effects of cold ischemia, fixative type, fixation time, and cut-slide age on staining consistency and intensity using human lung xenograft tumor tissue. Cold ischemia times for up to 5 to 6 hours for c-MET or ALK, respectively had minimal impact on staining. The optimal fixation conditions for both assays were found to be at least 6 hours and up to 48 hours for c-MET or 72 hours for ALK, in 10% neutral buffered formalin and Zinc formalin. The ALK antigen demonstrated marked staining intensity differences across non-neutral buffered formalin fixative types and times. Finally, cut-slide age influenced assay performance for both ALK and c-MET, with maximum stability observed when cut slides were stored at ambient temperatures (30°C) for no longer than 3, and 5 months, respectively. This study highlights the potential for pre-analytical factors to confound diagnostic test result interpretation.
Ultrasonography Features of Normal Submandibular Parenchyma and Incidental Diffuse Submandibular Disease
Authors: Kim Dong Wook
Published: February 2019

This study aimed to assess ultrasonography (US) features of normal submandibular parenchyma (NSP) and incidental diffuse submandibular disease (DSD). From January 2013 to December 2017, 39 patients underwent preoperative US of the submandibular gland before submandibular surgery in our hospital. Among them, 9 were excluded because of inadequate histopathologic data (n = 7) or poor US image quality (n = 2). The US features of the resected submandibular glands were retrospectively investigated by a single radiologist, blinded to clinicoserological information and the histopathologic result, using a picture archiving and communication system. Histopathologic analysis of the submandibular gland was retrospectively performed by a single pathologist. After histopathologic analysis, 11 of the 30 patients were classified as DSD and 19 as NSP. Of the individual US features, only parenchymal echotexture exhibited a statistically significant difference between NSP and DSD (P < 0.0001), whereas the other US features showed no significant differences (P > 0.05). There was no significant relationship between diffuse fibrosis and glandular size (P = 0.310) or the other US features (P = 1.000). In conclusion, US may be helpful for differentiating incidental DSD from NSP.
A Nomogram of Lateral Abdominal Wall Fat Thickness in Normal Third Trimester Fetuses
Authors: Dubinsky Theodore J. , O'Regan Jeremiah , Sonneborn Rachelle , Hippe Dan S. , Dighe Manjiri , Moshiri Mariam
Published: February 2019

Objectives

The objective of this study is to establish a nomogram of fetal abdominal wall fat thickness in fetuses with known normal neonatal outcomes.

Methods

After IRB approval (HSD-49496), 157 ultrasound examinations in 100 patients, 41 of whom had multiple examinations during the same pregnancy were reviewed. The thickness of the fetal lateral abdominal wall fat Interreader agreement was summarized using the intraclass correlation coefficient (ICC). Fat thickness growth curve equations were estimated to quantify the relationship between fat thickness and gestational age.

Results

The abdominal wall fat had an intraclass correlation coefficient of 0.93 (95% confidence interval, 0.90–0.96) for 2 readers. Fat thickness increased in all 41 fetuses with multiple examinations (P < 0.001). Fat thickness increased 0.19 mm per week on average (95% confidence interval, 0.17–0.21 mm; P < 0.001) from an average of 1.7 mm at 22 weeks and 4.3 mm at 36 weeks.

Conclusions

Lateral wall abdominal fat can be reproducibly measured with good inter observer correlation, and fat does increase with increasing gestational age in normal fetuses. We believe the utility of fetal fat is the documentation of its presence as a reassuring finding indicative of normal fetal health, particularly when prior dating is discrepant or not available during the third trimester.
Burn-Induced Microglia Activation is Associated With Motor Neuron Degeneration and Muscle Wasting in Mice
Authors: Ma Li , Zhou Yinhui , Khan Mohammed A.S. , Yasuhara Shingo , Martyn J. A. Jeevendra
Published: February 2019

Introduction:

Burn injury (BI) leads to both systemic and neuro-inflammation and is associated with muscle wasting and weakness, which increase morbidity and mortality. Disuse atrophy is concomitantly present in BI patients. Most studies have focused on muscle with little attention to role of central nervous system (CNS) in the neuromuscular changes. We tested the hypothesis that BI-induced muscle wasting stems from CNS microglia activation and cytokines and chemokine release, which is associated with spinal ventral horn motor neuron degeneration.

Methods:

Body surface (35%) BI, immobilization alone (Immob), BI with immobilization (BI + Immob), or Sham BI were administered to mice. Spinal cord (L3–L4 segments) and skeletal muscle tissues were harvested on days 7 and 14 after perturbations to examine microglia, motor neuron, and skeletal muscle changes.

Results:

BI and BI + Immob significantly (P < 0.05) activated microglia, evidenced by its increased density around motor neurons, upregulated neuroinflammation-marker, translocator protein 18 kDa expression and inflammatory cytokines (interleukin-1β, tumor necrosis factor-α) and/or chemokines (CXCL2) expression at days 7 and 14. Ventral horn motor neurons apoptosis and downregulation were observed at both periods after BI and was significantly magnified by concomitant BI + Immob. BI and more prominently BI + Immob disintegrated and fragmented the pretzel-shaped synapse and was associated with significantly decreased gastrocnemius, tibialis, and soleus muscle masses.

Conclusion:

BI induces microglia proliferation and activation (cytokine and chemokine release), degeneration of ventral horn motor neurons and muscle mass loss, all of which were accentuated by concomitant immobilization. The mechanisms connecting microglia activation and motor neuron degeneration to muscle mass loss require further delineation.
Different Bactericidal and Inflammatory Activities of Human and Mouse Blood
Authors: Lin Tian , Moorlag Simone J.C.F.M. , Liu Jialin , Ahmed Mohamed Yehia Hassan , Thundivalappil Sujatha R. , Riley Frank E. , Warren H. Shaw
Published: February 2019

We performed side-by-side experiments to compare the behavior of four strains of Escherichia coli and one strain of Pseudomonas aeruginosa in fresh human and mouse blood. Bacteria were multiplied in mouse whole blood and plasma but were killed in human whole blood and plasma. The percentage of granulocytes associated with fluorescence-labeled heat-killed E coli relative to total leukocytes counted was higher in human compared to mouse blood as assessed by flow cytometry analysis. Concentrations of proinflammatory cytokines were high in human blood, but undetectable in mouse blood despite high concentrations of bacteria. We conclude that bacterial killing, phagocytosis, and cytokine induction in blood during human bacteremia with these organisms are probably not mimicked in mouse models of bacterial challenge. Understanding the mechanisms for low cytokine induction with high bacterial loads in mouse blood may be helpful to interpret murine models of bacteremia and develop new approaches for treating sepsis in humans.
Effect of Pravastatin Pretreatment and Hypercapnia on Intestinal Microvascular Oxygenation and Blood Flow During Sepsis
Authors: Schulz Jan , Vollmer Christian , Truse Richard , Bauer Inge , Beck Christopher , Picker Olaf , Herminghaus Anna
Published: February 2019

Introduction:

In septic patients, adequate microvascular oxygenation (μHBO2) of the intestine is vital for their outcome. Recent studies suggest that statins can ameliorate septic microcirculation in a variety of tissues. However, the effect on intestinal microvascular oxygenation and blood flow is largely unknown. Furthermore, there are indications that statin therapy might not be beneficial in the presence of hypercapnia, as observed in septic acute respiratory distress syndrome (ARDS) patients. Therefore, the present study explores the effect of pravastatin with and without additional moderate acute hypercapnia on intestinal microvascular oxygenation and blood flow in experimental sepsis.

Methods:

Forty male Wistar rats were randomized into four groups. Half of the animals received 0.2 mg • kg−1 pravastatin s.c., the other half received the same volume as vehicle (NaCl 0.9%). After 18 h, colon ascendens stent peritonitis surgery was conducted in all animals to induce sepsis. Twenty-four hours after surgery, baseline was established and the animals were subjected to either 120 min of normocapnic (pCO2 40 ± 6 mm Hg) or moderate hypercapnic (pCO2 72 ± 10 mm Hg) ventilation. Microcirculatory oxygenation (μHBO2) and perfusion (μflow) of the colon were continuously recorded using tissue reflectance spectrophotometry and laser Doppler, respectively.

Results:

In normocapnic septic animals μHBO2 decreased over time (−8.4 ± 8.7%; P < 0.05 vs. baseline), whereas after pravastatin pretreatment μHBO2 remained constant (−1.9 ± 5.7% vs. baseline). However, in hypercapnic septic animals pretreated with pravastatin μHBO2 declined significantly over time (−8.9 ± 11.8%; P < 0.05 vs. baseline) and was significantly lower compared with normocapnic pravastatin-pretreated animals. μflow did not change over time in any group.

Conclusion:

Pravastatin pretreatment ameliorates the intestinal microvascular oxygenation in sepsis and thus seems to prevent intestinal hypoxia. Furthermore, we demonstrated that additional hypercapnia abolishes this effect, indicating why septic ARDS patients might not benefit from pravastatin therapy.
The prion-like propagation hypothesis in Alzheimer's and Parkinson's disease
Authors: Duyckaerts Charles , Clavaguera Florence , Potier Marie-Claude
Published: February 2019

Purpose of review

This study, taking the example of Alzheimer's and Parkinson's diseases, presents the experimental and human data that support the hypothesis that Aβ, tau, and α-synuclein may seed and propagate the pathology and consider the potential clinical consequences.

Recent findings

Aβ aggregates transmit Aβ pathology to experimental animals. Interhuman transmission of Aβ pathology has also been observed in iatrogenic Creutzfeldt–Jakob disease, or after dural graft. Tau aggregates also transmit the pathology to mice when injected in the brain and propagates along neuronal pathways. Evidence of interhuman transmission is weak. Finally α-synuclein aggregates, when injected in specific areas of the brain may recapitulate Lewy pathology of Parkinson's disease but there is currently no hint of human to human transmission.

Since the first evidence that at least Aβ pathology of Alzheimer's disease could be transmitted to the animal, data have accumulated indicating that misfolded proteins characteristic of neurodegenerative diseases may seed and propagate pathology in a prion-like manner. The term propagon has been proposed to describe those proteins that act as prions at different levels. Taking the example of Alzheimer's and Parkinson's diseases, the experimental and human data supporting the hypothesis that Aβ, tau, and α-synuclein are indeed propagons are presented with their clinical consequences.
A Case of Buspirone Demonstrating Immediate and Sustained Benefit in a Man With Lifelong Non–Rapid-Eye-Movement Parasomnias
Authors: Mallapareddi Arun , Varghese Ranji
Published: February 2019

Background

Non–rapid-eye-movement (NREM) parasomnias are disorders of sleep ranging from confusional arousals to sleepwalking and sleep-related eating disorders. Historically, antidepressants and benzodiazepines were recommended in treatment of NREM parasomnias. In this case report, we are reporting the use of buspirone in a patient with NREM parasomnias, which produced substantial resolution of symptoms.

Case Presentation

A 38-year-old man presented with confusional arousals and somnambulism. In addition, the patient had significant anxiety with work-related stress. Given the patient's concerns of side effect profile of other medications indicated in NREM parasomnias and the patient's history of anxiety, we started the patient on buspirone. The patient had significant improvement in his symptoms immediately after starting the medication with sustained relief from symptoms.

Conclusion

Buspirone can be considered an effective alternate treatment option for NREM parasomnias when other medications are not preferred or cannot be prescribed.
The role of OPG/RANKL in the pathogenesis of diabetic cardiovascular disease
Authors: Forde Hannah , Davenport Colin , Harper Emma , Cummins Phil , Smith Diarmuid
Published: February 2019

Cardiovascular (CV) disease is the leading cause of mortality in patients with type 2 diabetes mellitus. A major factor in the pathogenesis of CV disease is vascular calcification (VC), which is accelerated in type 2 diabetes mellitus. Calcification of the vessel wall contributes to vascular stiffness and left ventricular hypertrophy whereas intimal calcification may predispose to plaque rupture and CV death. The pathogenesis of VC is complex but appears to be regulated by the osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL) signaling pathway, which is involved in bone remodeling. Within the bone, OPG prevents RANKL from binding to receptor activator of nuclear factor-κB and inhibiting bone resorption. Outside of the bone, the clinical significance of OPG blocking RANKL is not well understood, but OPG knockout mice that lack OPG develop early and severe VC. This minireview outlines some of the research on OPG/RANKL in the pathogenesis of VC and discusses potential therapies, which may reduce VC and CV burden in humans.
In-vivo metabolic studies of regional adipose tissue
Authors: Melvin Audrey , McQuaid Siobhán E.
Published: February 2019

The accumulation of abdominal adipose tissue has long been associated with adverse cardiovascular outcomes. Paradoxically, increased gluteofemoral adipose tissue, which is predominantly subcutaneous fat, seems to play a protective role. There has been significant scientific interest in understanding how abdominal and gluteofemoral depots confer opposing metabolic risks. However, the study of regional adipose physiology in vivo remains challenging. We discuss some of the methodologies used. We focus specifically on the arteriovenous difference technique and present some insights into gluteofemoral adipose physiology.
Association between asymmetric dimethylarginine serum levels and left ventricular longitudinal deformation in patients with normal ejection fractions: a two-dimensional speckle-tracking echocardiography examination
Authors: Hosseinsabet Ali , Akavan-Khaleghi Niloofar , Mohseni-Badalabadi Reza
Published: February 2019

Objectives

Nitric oxide is an endogenous substance that preserves the myocardial function in patients with heart failure. Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of endogenous nitric oxide synthase. We sought to explore the association between the left ventricular (LV) function as assessed with two-dimensional echocardiography and the serum level of ADMA in nondiabetic patients without significant coronary artery disease.

Patients and methods

Eighty-seven consecutive patients with normal LV ejection fractions were included in this cross-sectional study. The ADMA serum level was measured, and the longitudinal deformation indices of the LV myocardium were evaluated using two-dimensional speckle-tracking echocardiography (2DSTE).

Results

The systolic strain, the systolic strain rate, and the early and late diastolic strain rates as evaluated with 2DSTE were not statistically significantly different between the patients with normal ADMA serum levels and those with increased ADMA serum levels. The two study groups were also not significantly different in terms of the systolic and diastolic myocardial velocities obtained with tissue Doppler.

Conclusion

Our findings showed no statistically significant correlations between the serum ADMA level and the 2DSTE-derived indices of the longitudinal deformation of the LV myocardium in our nondiabetic patients without significant coronary artery stenosis and with normal LV ejection fractions.
Recent trends over time in vascular disease in type 1 diabetes: insights from the Pittsburgh Epidemiology of Diabetes Complications study
Authors: Costacou Tina , Orchard Trevor J.
Published: February 2019

Aim

The aim of this study was to evaluate recent trends, by diagnosis year, in the cumulative incidence of vascular type 1 diabetes complications and their risk factors up to 35 years duration.

Participants and methods

Participants from the Epidemiology of Diabetes Complications study of childhood-onset type 1 diabetes were categorized into three-calendar year onset cohorts: 1965–1969, 1970–1974, and 1975–1980. All-cause, cardiovascular and renal mortality were determined both on the complete cohort (n=440) as well as in the subset with clinical examinations (n=363). Coronary artery disease (CAD, CAD death, myocardial infarction, revascularization, angina, and ischemic ECG abnormalities); lower extremity arterial disease (abnormal ankle brachial index/amputation/intermittent claudication); distal symmetric polyneuropathy (clinical exam); cardiac autonomic neuropathy (abnormal heart rate response to deep breathing); overt nephropathy (albumin excretion rate>200 μg/min); and proliferative retinopathy (fundus photography) were assessed on the subset with clinical examinations.

Results

While all-cause, cardiovascular and renal mortality improved with a more recent diagnosis in the overall cohort, no univariate differences were observed for complications requiring examination (CAD, distal symmetric polyneuropathy, cardiac autonomic neuropathy, and overt nephropathy), although a borderline trend toward improved complication-free survival with a more recent onset was observed for proliferative retinopathy (P=0.06). Lower extremity arterial disease incidence showed an anomalous pattern, being highest in the 1975–1980 and lowest in the 1970–1974 cohort (P=0.009). Allowing for risk factors over time did not materially change these results.

Conclusion

Despite declines in all-cause, cardiovascular and renal mortality in the total cohort, no improvements were observed in either mortality or complication incidence with a more recent onset in the examined cohort.
Competitive growth in a social fish
Authors: Reed Cymone , Branconi Rebecca , Majoris John , Johnson Cara , Buston Peter
Published: February 2019

Many animal societies have dominance hierarchies in which social rank is correlated with size. In such societies, the growth and size of individuals can be a strategic response to their social environment: in fishes, individuals may decrease their growth rate to remain small and retain a subordinate position; in mammals, individuals may increase their growth rate to become large and attain a dominant position—a strategy called competitive growth. Here, we investigate whether the clown anemonefish,
Amphiprion percula
, exhibits competitive growth also. We show that juvenile clownfish paired with a size-matched reproductive rival increase their growth rate and size relative to solitary controls. Remarkably, paired individuals achieved this, despite being provided with the same amount of food as solitary controls. Our results demonstrate that clownfish are able to increase their growth rate in response to social competition. This study adds to the growing body of evidence that the growth of social vertebrates can be a fine-tuned plastic response to their social environment.
Dead bacterial absorption of antimicrobial peptides underlies collective tolerance
Authors: Wu Fan , Tan Cheemeng
Published: February 2019

The collective tolerance towards antimicrobial peptides (APs) is thought to occur primarily through mechanisms associated with live bacterial cells. In contrast to the focus on live cells, we discover that the LL37 antimicrobial peptide kills a subpopulation of
Escherichia coli
, forming dead cells that absorb the remaining LL37 from the environment. Combining mathematical modelling with population and single-cell experiments, we show that bacteria absorb LL37 at a timing that coincides with the permeabilization of their cytoplasmic membranes. Furthermore, we show that one bacterial strain can absorb LL37 and protect another strain from killing by LL37. Finally, we demonstrate that the absorption of LL37 by dead bacteria can be reduced using a peptide adjuvant. In contrast to the known collective tolerance mechanisms, we show that the absorption of APs by dead bacteria is a dynamic process that leads to emergent population behaviour.
Coasting in live-bearing fish: the drag penalty of being pregnant
Authors: Quicazan-Rubio Elsa M. , van Leeuwen Johan L. , van Manen Klaas , Fleuren Mike , Pollux Bart J. A. , Stamhuis Eize J.
Published: February 2019

Swimming performance of pregnant live-bearing fish is presumably constrained by the additional drag associated with the reproductive burden. Yet, it is still unclear how and to what extent the reproductive investment affects body drag of the females. We examined the effect of different levels of reproductive investment on body drag. The biggest measured increase in body volume due to pregnancy was about 43%, linked to a wetted area increase of about 16% and 69% for the frontal area. We printed three-dimensional models of live-bearing fish in a straight body posture representing different reproductive allocation (RA) levels. We measured the drag and visualized the flow around these models in a flow tunnel at different speeds. Drag grew in a power fashion with speed and exponentially with the increase of RA, thus drag penalty for becoming thicker was relatively low for low speeds compared to high ones. We show that the drag increase with increasing RA was most probably due to bigger regions of flow separation behind the enlarged belly. We suggest that the rising drag penalty with an increasing RA, possibly together with pregnancy-related negative effects on muscle- and abdominal bending performance, will reduce the maximum swimming speed.
Unmasking structural patterns in incidence matrices: an application to ecological data
Authors: Bramon Mora Bernat , Dalla Riva Giulio V. , Stouffer Daniel B.
Published: February 2019

Null models have become a crucial tool for understanding structure within incidence matrices across multiple biological contexts. For example, they have been widely used for the study of ecological and biogeographic questions, testing hypotheses regarding patterns of community assembly, species co-occurrence and biodiversity. However, to our knowledge we remain without a general and flexible approach to study the mechanisms explaining such structures. Here, we provide a method for generating ‘correlation-informed’ null models, which combine the classic concept of null models and tools from community ecology, like joint statistical modelling. Generally, this model allows us to assess whether the information encoded within any given correlation matrix is predictive for explaining structural patterns observed within an incidence matrix. To demonstrate its utility, we apply our approach to two different case studies that represent examples of common scenarios encountered in community ecology. First, we use a phylogenetically informed null model to detect a strong evolutionary fingerprint within empirically observed food webs, reflecting key differences in the impact of shared evolutionary history when shaping the interactions of predators or prey. Second, we use multiple informed null models to identify which factors determine structural patterns of species assemblages, focusing in on the study of nestedness and the influence of site size, isolation, species range and species richness. In addition to offering a versatile way to study the mechanisms shaping the structure of any incidence matrix, including those describing ecological communities, our approach can also be adapted further to test even more sophisticated hypotheses.
Combining the 5.8S and ITS2 gene regions to improve classification of fungi
Authors: Heeger Felix , Wurzbacher Christian , Bourne Elizabeth C. , Mazzoni Camila J. , Monaghan Michael T.
Published: February 2019

The internal transcribed spacer (ITS) is used in DNA metabarcoding of fungi. One disadvantage of its high variability may be a failure to classify OTUs when no similar reference sequence exists. We tested whether the 5.8S region, often sequenced with ITS2 but discarded before analysis, could provide OUT classifications when ITS fails.

We usedin silicoevaluation to compare classification success of 5.8S and ITS from the UNITE database when reference sequences of the same species, genus, or family were removed. We then developed an automated pipeline for a combined 5.8S - ITS2 analysis and applied it to mixed environmental samples containing many lineages that are underrepresented in databases.

ITS was clearly

superior for species-level classifications with a complete reference database, but 5.8S outperformed ITS at higher level classifications with an incomplete database. Our combined 5.8S-ITS2 pipeline classified 3x more fungal OTUs compared to ITS2 alone, particularly within Chytridiomycota (10x) and Rozellamycota (3x).

Missing reference sequences led to the failure of ITS to classify many fungal OTUs at all, and to a significant underestimation of environmental fungal diversity. Using 5.8S to complement ITS classification will likely provide better estimates of diversity in lineages for which database coverage is poor.
Fuzzysplit: Demultiplexing and Trimming Sequenced DNA With a Declarative Language
Authors: Liu Daniel
Published: February 2019

Next-generation sequencing technologies create large, multiplexed DNA sequences that require preprocessing before any further analysis. Part of this preprocessing includes demultiplexing and trimming sequences. Although there are many existing tools that can handle these preprocessing steps, they cannot be easily extended to new sequence schematics when new pipelines are developed. We present Fuzzysplit, a tool that relies on a simple declarative language to describe the schematics of sequences, which makes it incredibly adaptable to different use cases. In this paper, we explain the matching algorithms behind Fuzzysplit and we provide a preliminary comparison of its performance with other well-established tools. Overall, we find that its matching accuracy is comparable to previous tools.
Brain-enriched coding and long non-coding RNA genes are overrepresented in recurrent autism spectrum disorder CNVs
Authors: Alinejad-Rokny Hamid , Heng Julian I.T. , Forrest Alistair R.R.
Published: February 2019

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with substantial phenotypic and etiological heterogeneity. It is estimated that 10-20% of cases are due to copy number variations (CNVs). Here we apply a newly developed CNV association tool (SNATCNV) to reanalyse CNV data from 19,663 autistic and 6,479 control subjects from the AutDB database. We demonstrate that SNATCNV outperforms existing CNV association methods by finding smaller genomic regions that better discriminate cases and controls. By integrating data from the FANTOM5 expression atlas we show that both known ASD causal genes identified by the SFARI and MSSNG consortia and genes within the CNVs identified by SNATCNV have brain enriched expression patterns; both brain-enriched coding and long-non-coding RNA genes are over-represented. We provide full lists of these brain enriched coding and lncRNA genes as a resource to the research community. We also go on to show that each CNV region is associated with a distinct set of phenotypes, that some are sex biased and highlight one deleted region where a brain-enriched lncRNA is the only gene present. Our analyses identify 47 high confidence ASD associated CNV regions and identifies brain-enriched genes which underlie this neurodevelopmental disorder.
A dynamical motif comprising the interactions between antigens and CD8 T cells may underlie the outcomes of viral infections
Authors: Baral Subhasish , Antia Rustom , Dixit Narendra M.
Published: February 2019

Some viral infections culminate in very different outcomes in different individuals. They can be rapidly cleared in some, cause persistent infection in others, and mortality from immunopathology in yet others. The conventional view is that the different outcomes arise as a consequence of the complex interactions between a large number of different factors (virus, different immune cells and cytokines). Here, we identify a simple dynamical motif comprising the essential interactions between antigens and CD8 T cells and posit it as predominantly determining the outcomes. Antigen can activate CD8 T cells, which in turn can kill infected cells. Sustained antigen stimulation, however, can cause CD8 T cell exhaustion, compromising effector function. Using mathematical modelling, we show that the motif comprising these interactions recapitulates all the outcomes observed. The motif presents a new conceptual framework to understand the variable outcomes of infection. It also explains a number of confounding experimental observations, including the variation in outcomes with the viral inoculum size, the evolutionary advantage of exhaustion in preventing lethal pathology, the ability of NK cells to act as rheostats tuning outcomes, and the role of the innate immune response in the spontaneous clearance of hepatitis C. Interventions that modulate the interactions in the motif may present novel routes to clear persistent infections or limit immunopathology.
GNI-A1mediates trade-off between grain number and grain weight in tetraploid wheat
Authors: Golan Guy , Ayalon Idan , Perry Aviad , Zimran Gil , Ade-Ajayi Toluwanimi , Mosquna Assaf , Distelfeld Assaf , Peleg Zvi
Published: February 2019

Grain yield is a highly polygenic trait determined by the number of grains per unit area, as well as by grain weight. In wheat, grain number and grain weight are usually negatively correlated. Yet, the genetic basis underlying trade-off between the two is mostly unknown. Here, we fine-mapped a grain weight QTL using wild emmer introgressions in a durum wheat background, and showed that grain weight is associated with theGNI-A1gene, a regulator of floret fertility. In-depth characterization of grain number and grain weight indicated that suppression of distal florets by the wild emmerGNI-A1allele increase weight of proximal grains in basal and central spikelets due to alteration in assimilate distribution. Re-sequencing ofGNI-A1in tetraploid wheat demonstrated the rich allelic repertoire of the wild emmer gene pool, including a rare allele which was present in two gene copies and contained a non-synonymous mutation in the C-terminus of the protein. Using an F2population generated from a cross between wild emmer accessions Zavitan, which carries the rare allele, and TTD140, we demonstrated that this unique polymorphism is associated with grain weight, independent of grain number. Moreover, we showed, for the first time, thatGNI-A1proteins are transcriptional activators and that selection in domesticated wheat targeted compromised activity of the protein. Our finding expand the knowledge of the genetic basis underlying trade-off between key yield components and may contribute to breeding efforts for enhanced grain yield.
HMGB1 coordinates SASP-related chromatin folding and RNA homeostasis on the path to senescence
Authors: Sofiadis Konstantinos , Nikolic Milos , Kargapolova Yulia , Josipovic Natasa , Zirkel Anne , Papadakis Antonis , Papadionysiou Ioanna , Loughran Gary , Keanes James , Michel Audrey , Gusmao Eduardo G. , Mizi Athanasia , Georgomanolis Theodore , Altmüller Janine , Nürnberg Peter , Beyer Andreas , Papantonis Argyris
Published: February 2019

Spatial organization and gene expression of mammalian chromosomes are maintained and regulated in conjunction with cell cycle progression. This is however disturbed once cells enter senescence and the highly abundant HMGB1 protein is depleted from senescent cell nuclei to act as an extracellular proinflammatory stimulus. Despite its physiological importance, we know little about the positioning of HMGB1 on chromatin or about its roles in the nucleus. To address this, we mapped HMGB1 binding genome-wide in different primary cells using a tailored protocol. We integrated ChIP-seq and Hi-C data with a graph theory approach to uncover HMGB1 demarcation of a subset of topologically-associating domains (TADs) that harbor genes required for paracrine senescence. Moreover, using sCLIP, knock-down and overexpression experiments, we now show that HMGB1 is abona fideRNA-binding protein (RBP) bound to senescence-relevant mRNAs and affecting splicing. HMGB1 also has an interactome rich in RBPs, many of which are implicated in senescence regulation. The mRNAs of many of these RBPs are directly bound by HMGB1 and concertedly regulate the availability of SASP-relevant transcripts. Our findings highlight a broader than hitherto assumed role for HMGB1. It coordinates chromatin folding and RNA homeostasis as part of a feedforward loop controlling both cell-autonomous and paracrine senescence inside and outside of cells.
Identification of a functional non-coding variant in the GABAA receptor α2 subunit of the C57BL/6J mouse reference genome: Major implications for neuroscience research
Authors: Mulligan Megan K. , Abreo Timothy , Neuner Sarah M. , Parks Cory , Watkins Christine E. , Houseal M. Trevor , Shapaker Thomas M. , Hook Michael , Tan Haiyan , Wang Xusheng , Ingels Jesse , Peng Junmin , Lu Lu , Kaczorowski Catherine C. , Bryant Camron D. , Homanics Gregg E. , Williams Robert W.
Published: February 2019

GABA type-A (GABA-A) receptors containing the α2 subunit (Gabra2) are expressed in most brain regions and are critical in modulating inhibitory synaptic function. Genetic variation at the GABRA2 locus has been implicated in epilepsy, affective and psychiatric disorders, alcoholism and drug abuse. Gabra2 expression varies as a function of genotype and is modulated by sequence variants in several brain structures and populations, including F2 crosses originating from C57BL/6J (B6J) and the BXD recombinant inbred family derived from B6J and DBA/2J. Here we demonstrate a global reduction of Gabra2 brain mRNA and protein in the B6J strain relative to other inbred strains, and identify and validate the causal mutation in B6J. The mutation is a single base pair intronic deletion located adjacent to a splice acceptor site that only occurs in the B6J reference genome. The deletion became fixed in B6J between 1976 and 1991 and is now pervasive in many engineered lines, BXD strains generated after 1991, the Collaborative Cross, and the majority of consomic lines. Repair of the deletion using CRISPR-Cas9 mediated gene editing on a B6J genetic background completely restored brain levels of Gabra2 mRNA and protein. Comparison of transcript expression in hippocampus, cortex, and striatum between B6J and repaired genotypes revealed alterations in GABA-A receptor subunit expression, especially in striatum. These results suggest that naturally occurring variation in GABRA2 levels between B6J and other substrains or inbred strains may also explain strain differences in anxiety-like or alcohol and drug response traits related to striatal function. Characterization of the B6J private mutation in the Gabra2 gene is of critical importance to molecular genetic studies in neurobiological research as this strain is widely used to generate genetically engineered mice and murine genetic populations, and is the most widely utilized strain for evaluation of anxiety-like, depression-like, pain, epilepsy, and drug response traits that may be partly modulated by Gabra2 function.
Reproducible Risk Loci and Psychiatric Comorbidities in Anxiety: Results from ~200,000 Million Veteran Program Participants
Authors: Levey Daniel F. , Gelernter Joel , Polimanti Renato , Zhou Hang , Cheng Zhongshan , Aslan Mihaela , Quaden Rachel , Concato John , Radhakrishnan Krishnan , Bryois Julien , Sullivan Patrick F. ,   Million Veteran Program, Stein Murray B.
Published: February 2019

We used GWAS in the Million Veteran Program sample (nearly 200,000 informative individuals) using a continuous trait for anxiety (GAD-2) to identify 5 genome-wide significant (GWS) signals for European Americans (EA) and 1 for African Americans. The strongest findings were on chromosome 3 (rs4603973, p=7.40×10−11) near the SATB1 locus, a global regulator of gene expression and on chromosome 6 (rs6557168, p=1.04×10−9) near ESR1 which encodes estrogen receptor α. A locus identified on chromosome 7 near MADIL1 (p=1.62×10−8) has been previously identified in GWAS of bipolar disorder and of schizophrenia and may represent a risk factor for psychiatric disorders broadly. SNP-based heritability was estimated to be ~6% for GAD-2. We also GWASed for self-reported anxiety disorder diagnoses (N=224,330) and identified two GWS loci, one (rs35546597, MAF=0.42, p=1.88×10−8) near the AURKB locus, and the other (rsl0534613, MAF=0.41, p=4.92×10−8) near the IQCHE and MADIL1 locus identified in the GAD-2 analysis. We demonstrate reproducibility by replicating our top findings in the summary statistics from the Anxiety NeuroGenetics Study (ANGST) and a UK Biobank neuroticism GWAS. We also replicated top findings from a large UK Biobank preprint, demonstrating stability of GWAS findings in complex traits once sufficient power is attained. Finally, we found evidence of significant genetic overlap between anxiety and major depression using polygenic risk scores, but also found that the main anxiety signals are independent of those for MDD. This work presents novel insights into the neurobiological risk underpinning anxiety and related psychiatric disorders.

Significance

Anxiety disorders are common and often disabling. They are also frequently co-morbid with other mental disorders such as major depressive disorder (MDD); these disorders may share commonalities in their underlying genetic architecture. Using one of the largest homogenously phenotyped cohorts available, the Million Veteran Program sample, we investigated common variants associated with anxiety in genome-wide association studies (GWASes), using survey results from the GAD-2 anxiety scale (as a continuous trait, n=199,611), and self-reported anxiety disorder diagnosis (as a binary trait, n=224,330). This largest GWAS to date for anxiety and related traits identified numerous novel significant associations, several of which are replicated in other datasets, and allows inference of underlying biology.
Musashiexpression in intestinal stem cells attenuates radiation-induced decline in intestinal homeostasis and survival inDrosophila
Authors: Sharma Amit , Akagi Kazutaka , Pattavina Blaine , Wilson Kenneth A , Nelson Christopher , Watson Mark , Maksoud Elie , Ortega Mauricio , Brem Rachel , Kapahi Pankaj
Published: February 2019

Exposure to genotoxic stress by environmental agents or treatments, such as radiation therapy, can diminish health span and accelerate aging. We have developed aDrosophila melanogastermodel to study the molecular effects of radiation-induced damage and repair. Utilizing a quantitative intestinal permeability assay, we performed an unbiased GWAS screen (using ∼150 strains from the DGRP reference panel) to search for natural genetic variants that regulate radiation-induced gut permeability. From this screen, we identified the RNA binding protein,Musashi (msi).Msioverexpression promoted intestinal stem cell proliferation, which increased survival after irradiation and rescued radiation-induced gut permeability. We identified that a novel role ofMsi inISC proliferation a novel role forMsiin enhancing ISC function following radiation-induced gut damage, which identifiesMsias a potential therapeutic target.
Exploring the space of human exploration
Authors: Schulz Eric , Bertram Lara , Hofer Matthias , Nelson Jonathan D.
Published: February 2019

What drives people’s exploration in complex scenarios where they have to actively acquire information by making queries? How do people adapt their selection of queries to their environment? We explore these questions using Entropy Mastermind, a novel variant of the Mastermind code-breaking game, in which participants have to guess a secret code by making useful queries. Participants solved games more efficiently and more quickly if the entropy of the game environment was low; moreover, people adapted their initial queries to the scenario they were in. We also investigated whether it would be possible to predict participants’ queries within the generalized Sharma-Mittal information-theoretic framework. Although predicting individual queries is difficult, the modeling framework offered important insight on human behavior. Entropy Mastermind offers rich possibilities for modeling and behavioral research.
Selfish: Discovery of Differential Chromatin Interactions via a Self-Similarity Measure
Authors: Ardakany Abbas Roayaei , Ay Ferhat , Lonardi Stefano
Published: February 2019

Motivation

High-throughput conformation capture experiments such as Hi-C provide genome-wide maps of chromatin interactions, enabling life scientists to investigate the role of the three-dimensional structure of genomes in gene regulation and other essential cellular functions. A fundamental problem in the analysis of Hi-C data is how to compare two contact maps derived from Hi-C experiments. Detecting similarities and differences between contact maps is critical in evaluating the reproducibility of replicate experiments and identifying differential genomic regions with biological significance. Due to the complexity of chromatin conformations and the presence of technology-driven and sequence-specific biases, the comparative analysis of Hi-C data is analytically and computationally challenging.

Results

We present a novel method called Selfish for the comparative analysis of Hi-C data that takes advantage of the structural self-similarity in contact maps. We define a novel self-similarity measure to design algorithms for (i) measuring reproducibility for Hi-C replicate experiments and (ii) finding differential chromatin interactions between two contact maps. Extensive experimental results on simulated and real data show that Selfish is more accurate and robust than state-of-the-art methods.

Availability

https://github.com/ucrbioinfo/Selfish

Contact

aroay001@ucr.eduandstelo@cs.ucr.edu
Making ATP fast and slow: do yeasts play a mixed strategy to metabolise glucose?
Authors: Safdari Hadiseh , Sadeghi Mehdi , Kalirad Ata
Published: February 2019

The ability of some microorganisms to switch from respiration to fermentation in the presence of oxygen-the so-called Crabtree effect-has been a fascinating subject of study at the theoretical and experimental fronts. Game-theoretical approaches have been routinely used to examine and explain the way a microorganism, such as yeast, would switch between the two ATP-producing pathways, i.e., respiration and fermentation. Here we attempt to explain the switch between respiration and fermentation in yeast by constructing a simple metabolic switch. We then utilise an individual-based model, in which each individual is equipped with all the relevant chemical reactions, to see how cells equipped with such metabolic switch would behave in different conditions. We further investigate our proposed metabolic switch using the game-theoretical approach. Based on this model, we postulate that individuals play a mixed game of glucose metabolism in the population. This approach not only sheds some light in the varieties of metabolic regulations that can be utilised by the individual in the population in competition with others for a common resource, it would also allow a better understanding of the causes of the Warburg effect and similar phenomena observed in nature.