bluuebunny/crossref_metadata_2025 huggingface dataset:
EXPLORING EMPATHY IN PEDIATRICS RESIDENTS AT AN URBAN CHILDREN’S HOSPITAL IN CANADA
Authors: Rawal Surabhi , Nimmon Laura , Strahlendorf Caron
Published: May 2018

BACKGROUND

Empathy is fundamental to the physician-patient relationship, promoting both patient compliance and increased treatment efficacy. Studies attempting to quantify changes in empathy during residency are inconsistent in their findings; those examining paediatrics training specifically, are no more definitive. The mixed conclusions may stem from the use of self-reporting scores, which may fail to capture the essence of the effect.

OBJECTIVES

This study aimed to explore the state, and map a trajectory, of empathy in paediatrics residents, to identify factors influencing the learning and retention of empathy.

DESIGN/METHODS

This qualitative descriptive study was conducted at an urban children’s hospital in Canada. A constructivist phenomenological approach was used. Participants were recruited for semi-structured interviews via a purposive sampling strategy; thereafter, a thematic analysis was employed. Emerging themes were discussed at research meetings. Sufficiency was felt to be achieved after ten interviews.

RESULTS

Senior residents reported an overall increase in empathy, in part attributed to a better understanding of paediatric illnesses and greater perspective of the impact on families. There appeared to be a reconciliation with the changing shape of their empathy: managerial and administrative responsibilities could be performed empathically if patient priorities remained a central objective. Challenges to the retention of empathy correlated with published literature: time constraints, compassion fatigue and burnout with poor coping, and the hidden curriculum. Empathy was learned from role modelling by peers, preceptors, and other health care providers. Resident resilience, as a product of personal adversity, was protective against the loss of empathy; this could be considered in the postgraduate admissions process, and should be fostered with resident wellness strategies. Residents advocated for increased autonomy and patient ownership, and fuller exposure to longitudinal care, including the patient’s social context and home life, both of which could be considered as additions to residency training curricula to increase resident empathy.

CONCLUSION

Residents demonstrated an increase in empathy during training. Resident resilience is valuable in protecting empathy and could be considered in admissions processes. Longitudinal clinics and home visits should be considered as additions to residency training curricula.
VALIDITY OF PARENT-COMPLETED DEVELOPMENTAL SCREENING IN CHILDREN WITH NEW-ONSET EPILEPSY BELOW THE AGE OF 3
Authors: Barton Madelyn , Simard Marie-Noëlle , Reiter-Campeau Sandra , Lupien Genevieve , Lamothe Marie-Pierre , Chartrand Dominic , Saint-Louis Marie-Eve , Lortie Anne , Major Philippe , Diadori Paola , Birca Ala , Rossignol Elsa , Carmant Lionel
Published: May 2018

BACKGROUND

Infants with childhood-onset epilepsies, including epileptic encephalopathies, are at high risk of developmental challenges such as motor and language delays. There has been a growing focus on developmental screening instruments due to the association between delayed development and long-term adverse outcomes, including negative impacts on health-related quality of life, school achievement and social participation. Therefore, children with developmental delays should be referred as early as possible to rehabilitation services such as occupational, physical, or speech therapy. Developmental screening using standardized tools is recommended in order to identify the high-risk children that require additional developmental assessments. The Ages and Stages Questionnaires (ASQ), a parent-completed developmental screening tool, is one of the more cited and recommended developmental screening tools. However, its utility in children with early-onset epilepsy has yet to be validated.

OBJECTIVES

This study aimed to determine the validity of the ASQ for identifying children with new-onset epilepsy who require further professional developmental rehabilitation.

DESIGN/METHODS

Fifty infants (25 males) with seizure onset under 3 years of age were prospectively recruited. Parents completed the ASQ-3 before the first clinic appointment. The ASQ-3 evaluates 5 domains of development. An ASQ score below 2 standard deviations (SD) on any one of the domains was considered abnormal. Once completed, all infants were evaluated by a multidisciplinary team including neurologists, occupational therapists, and physical therapists to determine if they should be referred for further rehabilitation interventions. Accuracy of the ASQ was calculated in terms of sensibility, specificity, positive predictive value (PPV) and negative predictive value (NPV).

RESULTS

Mean age at the initial evaluation was 13.1 months (SD=8.22). Among the 50 infants, 36 (72%) received a score <-2 SD in at least one domain of the ASQ and 43 (86%) were referred for further rehabilitation services after the multidisciplinary assessment. The ASQ had a sensitivity of 81%, a specificity of 71%, a PPV of 93% and a NPV of 36% in identifying children with new-onset epilepsy who would require further rehabilitation services.

CONCLUSION

The ASQ, a well-known parent-completed developmental screening tool, when abnormal shows adequate validity for the identification of children with early-onset epilepsy who require developmental assessments and interventions by rehabilitation professionals. Our results also provide further evidence that development delay is the rule rather than the exception in infants with new onset epilepsy.
IMPLEMENTATION OF A PEDIATRIC PATIENT NAVIGATOR FOR CHILDREN WITH DEVELOPMENTAL OR MENTAL HEALTH CONCERNS
Authors: Suleman Shazeen , Milone Francine , Rollins Meaghen , Vojvoda Dorjana , Barozzino Tony
Published: May 2018

BACKGROUND

Nearly 1 in 5 Canadians will suffer from a mental health condition, with most of these diagnoses beginning in childhood and adolescence. Few children and youth with developmental and mental health conditions have adequate access to necessary clinical, community and social services. Patient navigator programs can bridge this gap by facilitating connections to social services, supporting family coping strategies and advocating for patient clinical services, yet there remain few programs in Canada for this patient population.

OBJECTIVES

To use a health behaviour change paradigm to develop and implement a paediatric patient navigator program for vulnerable children and youth living in a large urban centre in Canada

DESIGN/METHODS

A needs assessment was performed to identify navigation needs from the perspective of paediatric healthcare providers in an urban, inner-city district in Canada. Using these results, a referral and intake form were developed and pilot tested. To change provider behaviour with respect to utilization of the new navigation service, all providers, including paediatricians and allied health, participated in a workshop prior to implementation of the referral program and text reminders were posted throughout the clinic.

RESULTS

Patient navigation to access therapy services for children with developmental or mental health conditions, community services and assistance with completing funding information were identified as key services a paediatric patient navigator should offer. Participation in the workshop resulted in a significant increase in knowledge uptake for the role of the patient navigator and the referral process (p=0.01, 2-tailed T-test). 51 new referrals were received within one month of launching the paediatric patient navigation program, of which only 2 did not meet criteria

CONCLUSION

Patient navigation for children and youth with developmental and mental health diagnoses can be successfully implemented in an inner-city setting in a large urban centre. More research is needed to demonstrate the impact of patient navigation on patient health outcomes.
CANADIAN EARLY CAREER PAEDIATRICIANS ON THEIR TRANSITION TO PRACTICE EXPERIENCE
Authors: Rowan-Legg Anne
Published: May 2018

BACKGROUND

The Canadian Paediatric Society (CPS) is the national professional paediatric organization representing over 3000 child and youth health care providers. As future leaders, early career paediatricians (ECP, defined as those in their first 5 years of practice) are highly valued CPS members, and facilitating their active engagement is a key organizational priority. ECPs comprise 15% of the current CPS membership, and previous analysis has shown that this group’s membership rate drops by nearly one-third in the first 5 years of practice. This lack of engagement may be due in part to the intense amount of activity on multiple fronts during the transition to independent practice. We sought to better identify and understand these challenges, and determine how the CPS might better support this period of a paediatrician’s professional life.

OBJECTIVES

To better characterize the demographics of ECPs in Canada; to identify the challenges of transition to independent paediatric practice, and to inform future CPS initiatives to support them.

DESIGN/METHODS

Following iterative discussion, we created a 23-question survey with either closed-ended or free text responses. It was distributed, in English and French, via e-mail link to 481 Canadian ECPs across the country in September 2017. This group included both general and subspecialty paediatricians who had qualified for their Royal College certification in 2011 or later. Survey information was obtained by an online electronic tool (Survey Monkey). All responses remained confidential. Responses were collated, and descriptive statistics were used to analyze the data.

RESULTS

The survey response rate was 42% (200/481). 172/407 answered the English questionnaire, and 28/74 answered the French questionnaire. 68% self-identified as general paediatricians and 21% as subspecialists. Nearly three-quarters work in urban settings, with 35% at an academic/tertiary hospital. ECPs spend most of their working hours in a clinical setting (mean 80%), with less time in research and administration/leadership domains. Most (78%) were satisfied with their practice type and setting. Three-quarters reported good work-life balance. Identified challenges during the transition to practice included: financial and billing management; learning institutional processes and available resources; and achieving work-life balance. One third reported difficulty with continuing professional development.

CONCLUSION

These findings indicate that ECPs are more likely to be practising in urban settings and at academic centres. They describe some common challenges with transition to practice and would like the CPS to provide more practice management resources, mentorship, and career counseling. As a result, there is a clear opportunity for CPS to engage them in the organization, support their transition to practice, and offer accessible continuing professional education.
The impact of epidermal growth factor supernatant on pig performance and ileal microbiota1
Authors: Levesque Crystal L , Akhtar Nadeem , Huynh Evanna , Walk Carrie , Wilcock Pete , Zhang Zhengxiao , Dyce Paul W , de Lange Cornelius F M , Khafipour Ehsan , Li Julang
Published: May 2018

Weaning of pigs can lead to low-feed intake resulting in a lag in growth performance, reduced gut health, and diarrheal diseases. Epidermal growth factor (EGF), the most abundant growth factor in milk, increased weaned pig BW gain and feed efficiency in our previous work. It is believed that intestinal microbiota plays an important role in gut health and pig growth, but limited data are available on the impact of feed additives, such as EGF, on the microbial communities of the intestines. The objective of the study was to investigate if the positive influence of EGF supplementation on weight gain and gut health was related to differences in intestinal microbiota. To examine the efficacy of EGF, a 21-d animal trial was performed using 72 pigs (two equal blocks of 36 pigs with three barrows and three gilts/pen). Pigs were assigned to one of two dietary treatments at weaning (20 ± 2 d of age; n = 6 pens/treatment) balancing across treatment for litter, gender, and initial BW. Recombinant yeast supernatant containing EGF at 120 μg/kg BW/d and without EGF (control) was added to the feed for 21 d, followed by a common diet for 7 d. Pig performance was measured weekly and ileal digesta was collected at day 21 from six pigs/treatment for microbiome analysis. Pigs fed diets containing EGF fermentation supernatant had greater (P = 0.01) daily gain in week 3 and overall resulting in heavier (P = 0.029) BW at day 28, which was consistent to our previous finding. No difference in alpha-diversity (Chao1, Shanon, and Simpson indices) and beta-diversity (weighted and unweighted UniFrac distances) of ileal digesta microbiota between EGF supplemented and control pigs were observed. The relative abundances of bacterial taxa did not differ among treatment groups at the phylum level. The relative abundances of Corynebacterium (0.0 vs. 0.9%), Blautia (0.003 vs. 0.26%), and Coprococcus (0.0 vs. 0.05%) genera, and Rumminococcaceae family (0.001 vs. 0.08%) were decreased (P < 0.05) in EGF group compared to control and were negatively correlated (P < 0.05, r > 0.60) with growth performance. Pathways related to detoxification and carbohydrate metabolism were differentially represented in the luminal bacterial populations. The improved growth of pigs supplemented with EGF supernatant produced by Pichia pastoris may be related to changes in functional capacity of the gut microbial populations. However, the impact on mucosa-associated or large intestinal communities is still unknown.
A New Resistance Gene in Combination with Rmg8 Confers Strong Resistance Against Triticum Isolates of Pyricularia oryzae in a Common Wheat Landrace
Authors: Wang Shizhen , Asuke Soichiro , Vy Trinh Thi Phuong , Inoue Yoshihiro , Chuma Izumi , Win Joe , Kato Kenji , Tosa Yukio
Published: May 2018

The wheat blast fungus (Triticum pathotype of Pyricularia oryzae) first arose in Brazil in 1985 and has recently spread to Asia. Resistance genes against this new pathogen are very rare in common wheat populations. We screened 520 local landraces of common wheat collected worldwide with Br48, a Triticum isolate collected in Brazil, and found a highly resistant, unique accession, GR119. When F2 seedlings derived from a cross between GR119 and Chinese Spring (CS, susceptible control) were inoculated with Br48, resistant and susceptible seedlings segregated in a 15:1 ratio, suggesting that GR119 carries two resistance genes. When the F2 seedlings were inoculated with Br48ΔA8 carrying a disrupted allele of AVR-Rmg8 (an avirulence gene corresponding to a previously reported resistance gene, Rmg8), however, the segregation fitted a 3:1 ratio. These results suggest that one of the two genes in GR119 was Rmg8. The other, new gene was tentatively designated as RmgGR119. GR119 was highly resistant to all Triticum isolates tested. Spikes of GR119 were highly resistant to Br48, moderately resistant to Br48ΔA8 and a hybrid culture carrying avr-Rmg8 (nonfunctional allele), and highly resistant to its transformant carrying AVR-Rmg8. The strong resistance of GR119 was attributed to the combined effects of Rmg8 and RmgGR119.
High-Frequency Horizontal Semicircular Canal Function in Certain Menière’s Disease
Authors: Jerin Claudia , Maxwell Rebecca , Gürkov Robert
Published: May 2018

Objectives:

To characterize video head impulse testing (vHIT) in definitive Menière’s disease and to investigate the relationship between vHIT results and other audiovestibular function tests.

Design:

Fifty-four patients with certain Menière’s disease, that is, patients with clinically definite Menière’s disease and endolymphatic hydrops visualized by locally enhanced inner ear MR imaging, were recruited for this study. All patients underwent vHIT. The vestibular-ocular reflex gain at 60 ms and refixation saccades were the outcome parameters measured. Saccades were characterized by determining the saccade frequency, their mean latency, and their mean velocity.

Results:

Seven of 54 patients had bilateral normal vHITs. Clearly pathologically vHITs with decreased gain and refixation saccades were observed in further seven patients. The majority of patients exhibited vHITs with refixation saccades but normal gain. Saccades mostly occurred bilaterally. There was no correlation between vHIT gain or saccades and caloric irrigation, cervical vestibular evoked myogenic potential or audiometry for Menière’s ears. Furthermore, vHIT gain or saccades correlated neither with age nor with the duration of the disease.

Conclusions:

Pathological low vHIT gain values are rarely observed in patients with certain Menière’s disease, while refixation saccades occur very frequently. In the majority of patients, saccades occur bilaterally. In Menière’s disease, in contrast to vestibular neuritis, there is no compensatory decrease of saccade latency over time.
Preperitoneal or Subcutaneous Wound Catheters as Alternative for Epidural Analgesia in Abdominal Surgery
Authors: Mungroop Timothy H. , Bond Marinde J. , Lirk Philipp , Busch Olivier R. , Hollmann Markus W. , Veelo Denise P. , Besselink Marc G.
Published: May 2018

Objective:

To assess whether the location of wound catheters (ie, preperitoneal vs. subcutaneous) impacts outcomes, when compared with alternatives such as epidural analgesia.

Background:

Continuous wound infiltration is an alternative for epidural analgesia in abdominal surgery but studies have shown conflicting results. This difference could be explained by different efficacy of preperitoneal versus subcutaneous placement of the infiltrative catheters.

Methods:

A systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines until April 3, 2017. Primary endpoints were pain scores in rest and when moving at 24 hours postoperatively. Secondary endpoints included postoperative pain scores at 12 and 48 hours, functional recovery, pain treatment-related complications, and patient satisfaction.

Results:

After screening 2283 studies, 29 randomized controlled trials (RCTs) with 2059 patients were included. Methodological quality of these RCTs ranged from moderate to high. In the one direct comparison (60 patients), preperitoneal catheters led to better pain control than subcutaneous catheters. Superiority of preperitoneal compared with subcutaneous placement was confirmed indirectly in placebo-controlled RCTs. Preperitoneal wound catheters provided comparable pain control compared with active controls, such as epidural analgesia. Recovery parameters, opioid consumption, incidence of hypotension, and patient satisfaction seemed to be in favor of preperitoneal wound catheters compared with active alternatives, as well as placebo.

Conclusion:

Continuous wound infiltration with preperitoneal wound catheters is an effective pain modality in abdominal surgery. Pain control is as effective as epidural analgesia, but could be favored based upon recovery parameters and patient satisfaction.
Analyzing Enzyme Kinetic Data Using the Powerful Statistical Capabilities of R
Authors: Huitema Carly , Horsman Geoff
Published: May 2018

We describe a powerful tool for enzymologists to use for typical non-linear fitting of common equations in enzyme kinetics using the statistical program R. Enzyme kinetics is a powerful tool for understanding enzyme catalysis, regulation, and inhibition but tools to perform the analysis have limitations. Software to perform the necessary nonlinear analysis may be proprietary, expensive or difficult to use, especially for a beginner. The statistical program R is ideally suited to analyzing enzyme kinetic data; it is free in two respects: there is no cost and there is freedom to distribute and modify. It is also robust, powerful and widely used in other fields of biology. In this paper we introduce the program R to enzymologists who want to analyze their data but are unfamiliar with R or similar command line statistical analysis programs. Data are inputted and examples of different non-linear models are fitted. Results are extracted and plots are generated to assist judging the goodness of fit. The instructions will allow users to create their own modifications to adapt the protocol to their own experiments. Because of the use of scripts, a method can be modified and used to analyze different datasets in less than one hour.
The genetic prehistory of the Greater Caucasus
Authors: Wang Chuan-Chao , Reinhold Sabine , Kalmykov Alexey , Wissgott Antje , Brandt Guido , Jeong Choongwon , Cheronet Olivia , Ferry Matthew , Harney Eadaoin , Keating Denise , Mallick Swapan , Rohland Nadin , Stewardson Kristin , Kantorovich Anatoly R. , Maslov Vladimir E. , Petrenko Vladimira G. , Erlikh Vladimir R. , Atabiev Biaslan Ch. , Magomedov Rabadan G. , Kohl Philipp L. , Alt Kurt W. , Pichler Sandra L. , Gerling Claudia , Meller Harald , Vardanyan Benik , Yeganyan Larisa , Rezepkin Alexey D. , Mariaschk Dirk , Berezina Natalia , Gresky Julia , Fuchs Katharina , Knipper Corina , Schiffels Stephan , Balanovska Elena , Balanovsky Oleg , Mathieson Iain , Higham Thomas , Berezin Yakov B. , Buzhilova Alexandra , Trifonov Viktor , Pinhasi Ron , Belinskiy Andrej B. , Reich David , Hansen Svend , Krause Johannes , Haak Wolfgang
Published: May 2018

Archaeogenetic studies have described the formation of Eurasian ‘steppe ancestry’ as a mixture of Eastern and Caucasus hunter-gatherers. However, it remains unclear when and where this ancestry arose and whether it was related to a horizon of cultural innovations in the 4thmillennium BCE that subsequently facilitated the advance of pastoral societies likely linked to the dispersal of Indo-European languages. To address this, we generated genome-wide SNP data from 45 prehistoric individuals along a 3000-year temporal transect in the North Caucasus. We observe a genetic separation between the groups of the Caucasus and those of the adjacent steppe. The Caucasus groups are genetically similar to contemporaneous populations south of it, suggesting that – unlike today – the Caucasus acted as a bridge rather than an insurmountable barrier to human movement. The steppe groups from Yamnaya and subsequent pastoralist cultures show evidence for previously undetected farmer-related ancestry from different contact zones, while Steppe Maykop individuals harbour additional Upper Palaeolithic Siberian and Native American related ancestry.
Disproportionate feedback interactions govern cell-type specific proliferation in mammalian cells
Authors: Sengupta Dola , Kompella Vijay Phanindra Srikanth , Kar Sandip
Published: May 2018

In mammalian cells, the critical decision to maintain quiescence over proliferation commitment in and around the G1-S transition depends on more than one intertwined feedback interaction, and is highly cell-type dependent. However, the precise role played by these individual feedback regulations, in order to generate such diverse nature of proliferation commitment, is still poorly understood. Herein, we propose a generic mathematical model of G1-S transition in mammalian cells that not only reconciles distinct single cell experimental observations in a cell-type specific manner, but also makes experimentally testable non-intuitive predictions. Intriguingly, The model analysis reveals that the feedback motifs responsible for the G1-S transition act in a disparate fashion to organize the cell-type specific proliferation response in different mammalian cells. The proposed model, in principle, can be effectively tuned to explore proliferation dynamics in a cell-type specific way to gain crucial insights about novel therapeutic intervention to prevent unwanted cellular proliferation.
Supercharging enables organized assembly of synthetic biomolecules
Authors: Simon Anna J. , Ramasubramani Vyas , Glaser Jens , Pothukuchy Arti , Gerberich Jillian , Leggere Janelle , Morrow Barrett R. , Golihar Jimmy , Jung Cheulhee , Glotzer Sharon C. , Taylor David W. , Ellington Andrew D.
Published: May 2018

There are few methods for the assembly of defined protein oligomers and higher order structures that could serve as novel biomaterials. Using fluorescent proteins as a model system, we have engineered novel oligomerization states by combining oppositely supercharged variants. A well-defined, highly symmetrical 16-mer (two stacked, circular octamers) can be formed from alternating charged proteins; higher order structures then form in a hierarchical fashion from this discrete protomer. During SUpercharged PRotein Assembly (SuPrA), electrostatic attraction between oppositely charged variants drives interaction, while shape and patchy physicochemical interactions lead to spatial organization along specific interfaces, ultimately resulting in protein assemblies never before seen in nature.
Prefrontal co-expression of schizophrenia risk genes is associated with treatment response in patients
Authors: Pergola Giulio , Di Carlo Pasquale , Jaffe Andrew E. , Papalino Marco , Chen Qiang , Hyde Thomas M. , Kleinman Joel E. , Shin Joo Heon , Rampino Antonio , Blasi Giuseppe , Weinberger Daniel R. , Bertolino Alessandro
Published: May 2018

Gene co-expression networks are relevant to functional and clinical translation of schizophrenia (SCZ) risk genes. We hypothesized that SCZ risk genes may converge into coexpression pathways which may be associated with gene regulation mechanisms and with response to treatment in patients with SCZ. We identified gene co-expression networks in two prefrontal cortexpost-mortemRNA sequencing datasets (total N=688) and replicated them in four more datasets (total N=227). We identified and replicated (all p-values<.001) a single module enriched for SCZ risk loci (13 risk genes in 10 loci).In silicoscreening of potential regulators of the SCZ risk module via bioinformatic analyses identified two transcription factors and three miRNAs associated with the risk module. To translatepost-morteminformation into clinical phenotypes, we identified polymorphisms predicting co-expression and combined them to obtain an index approximating module co-expression (Polygenic Co-expression Index: PCI). The PCI-co-expression association was successfully replicated in two independent brain transcriptome datasets (total N=131; all p-values<.05). Finally, we tested the association between the PCI and short-term treatment response in two independent samples of patients with SCZ treated with olanzapine (total N=167). The PCI was associated with treatment response in the positive symptom domain in both clinical cohorts (all p-values<.05).

In summary, our findings in a large sample of humanpost-mortemprefrontal cortex show that coexpression of a set of genes enriched for schizophrenia risk genes is relevant to treatment response. This co-expression pathway may be co-regulated by transcription factors and miRNA associated with it.
Construction and analysis of mRNA, miRNA, lncRNA, and TF regulatory networks reveal the key genes in prostate cancer
Authors: Li Su-Liang , Ye Yun , Wang Sheng-Yu
Published: May 2018

Purpose: Prostate cancer (PCa) causes a common male urinary system malignant tumour, and the molecular mechanisms of PCa remain poorly understood. This study aims to investigate the underlying molecular mechanisms of PCa with bioinformatics.

Methods: Original gene expression profiles were obtained from the GSE64318 and GSE46602 datasets in the Gene Expression Omnibus (GEO). We conducted differential screens of the expression of genes (DEGs) between two groups using the R software limma package. The interactions between the differentially expressed miRNAs, mRNAs and lncRNAs were predicted and merged with the target genes. Co-expression of the miRNAs, lncRNAs and mRNAs were selected to construct the mRNA-miRNA and-lncRNA interaction networks. Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for the DEGs. The protein-protein interaction (PPI) networks were constructed, and the transcription factors were annotated. The expression of hub genes in the TCGA datasets was verified to improve the reliability of our analysis.

Results: The results demonstrated that 60 miRNAs, 1578 mRNAs and 61 lncRNAs were differentially expressed in PCa. The mRNA-miRNA-lncRNA networks were composed of 5 miRNA nodes, 13 lncRNA nodes, and 45 mRNA nodes. The DEGs were mainly enriched in the nuclei and cytoplasm and were involved in the regulation of transcription, related to sequence-specific DNA binding, and participated in the regulation of the PI3K-Akt signalling pathway. These pathways are related to cancer and focal adhesion signalling pathways. Furthermore, we found that 5 miRNAs, 6 lncRNAs, 6 mRNAs and 2 TFs play important regulatory roles in the interaction network. The expression levels of EGFR, VEGFA, PIK3R1, DLG4, TGFBR1 and KIT were significantly different between PCa and normal prostate tissue.

Conclusion: Based on the current study, large-scale effects of interrelated mRNAs, miRNAs, lncRNAs, and TFs were revealed and a model for predicting the mechanism of PCa was provided. This study provides new insight for the exploration of the molecular mechanisms of PCa and valuable clues for further research.
Transient Overexpression of VEGF-A in Adipose Tissue Promotes Energy Expenditure via Activation of the Sympathetic Nervous System
Authors: Zhao Yueshui , Li Xin , Yanga Li , Eckel-Mahan Kristin , Tong Qingchun , Gu Xue , Kolonin Mikhail G. , Kai Sun
Published: May 2018

Adipose-derived VEGF-A stimulates functional blood vessel formation in obese fat pads which in turn facilitates healthy expansion of the adipose tissue. However, the detailed mechanism(s) governing the process remains largely unknown. Here, we investigated the role of sympathetic nervous system activation in the process. To this end, we induced overexpression of VEGF-A in an adipose-specific doxycycline (Dox)-inducible transgenic mouse model for a short period of time during high fat-diet (HFD) feeding. We found that local overexpression of VEGF-A in adipose tissue stimulated lipolysis and browning rapidly after Dox induction. Immunofluorescent staining against tyrosine hydroxylase (TH) indicated higher levels of sympathetic innervation in adipose tissue of transgenic mice. In response to the increased norepinephrine (NE) level, expression of β3-andrenoceptor was significantly upregulated and the downstream protein kinase A (PKA) pathway was activated, as indicated by the enhanced phosphorylation of the whole PKA substrates, in particular the hormone sensitive lipase (HSL) in adipocytes. As the result, the adipose tissue exhibited increased lipolysis, browning, and energy expenditure. Importantly, all these effects were abolished upon the treatment with β3-adrenoceptor antagonist SR59230A. Collectively, these results demonstrate that transient overexpressed VEGF-A activates sympathetic nervous system which hence promotes lipolysis and browning in adipose tissue.
Data-driven modeling of cholinergic modulation of neural microcircuits: bridging neurons, synapses, and network states
Authors: Ramaswamy Srikanth , Markram Henry
Published: May 2018

1

Neuromodulators, such as acetylcholine (ACh), control information processing in neural microcircuits by regulating neuronal and synaptic physiology. Computational models and simulations enable predictions on the potential role of ACh in reconfiguring network states. As a prelude into investigating how the cellular and synaptic effects of ACh collectively influence emergent network dynamics, we developed a data-driven framework incorporating phenomenological models of the anatomy and physiology of cholinergic modulation of the neocortex. The first-draft models were integrated into a biologically detailed tissue model of neocortical microcircuitry to predict how ACh affects different types of neurons and synapses, and consequently alters global network states. Preliminary simulations not only corroborate the long-standing notion that ACh desynchronizes network activity, but also reveal a potentially finegrained control over a spectrum of neocortical states. We show that low levels of ACh, such as those during sleep, drive microcircuit activity into slow oscillations and network synchrony, whereas high ACh concentrations, such as those during wakefulness, govern fast oscillations and network asynchrony. In addition, network states modulated by ACh levels shape spike-time cross-correlations across distinct neuronal populations in strikingly different ways. These effects are likely due to the differential regulation of neurons and synapses caused by increasing levels of ACh that enhances cellular excitability by increasing neuronal activity and decreases the efficacy of local synaptic transmission by altering neurotransmitter release probability. We conclude by discussing future directions to refine the biological accuracy of the framework, which will extend its utility and foster the development of hypotheses to investigate the role of neuromodulation in neural information processing.
A computational model to understand mouse iron physiology and diseases
Authors: Parmar Jignesh H. , Mendes Pedro
Published: May 2018

It is well known that iron is an essential element for life but is toxic when in excess or in certain forms. Accordingly there are many diseases that result directly from either lack or excess of iron. Iron has also been associated with a wide range of other diseases and may have an important role in aging. Yet many molecular and physiological aspects of iron regulation have only been discovered recently and others are still awaiting elucidation. In the last 18 years, after the discovery of the hormone hepcidin, many details of iron regulation have become better understood and a clearer picture is starting to emerge, at least in qualitative terms. However there is still no good quantitative and dynamic description of iron absorption, distribution, storage and mobilization that agrees with the wide array of phenotypes presented in several iron-related diseases. The present work addresses this issue by developing a mathematical model of iron distribution in mice that was calibrated with existing ferrokinetic data and subsequently validated against data from a series of iron disorders, such as hemochromatosis, β-thalassemia, atransferrinemia and anemia of inflammation. To adequately fit the ferrokinetic data required including the following mechanisms: a) the role of transferrin in deliving iron to tissues, b) the induction of hepcidin by high levels of transferrin-bound iron, c) the ferroportin-dependent hepcidin-regulated iron export from tissues, d) the erythropoietin regulation of erythropoiesis, and e) direct NTBI uptake by the liver. The utility of such a model to simulate disease interventions was demonstrated by using it to investigate the outcome of different schedules of transferrin treatment in β-thalassemia. The present model is a successful step towards a comprehensive mathematical model of iron physiology incorporating cellular and organ level details.
Acetylcholine inhibits platelet activation and regulates hemostasis
Authors: Bennett John A. , Ture Sara K. , Schmidt Rachel A. , Mastrangelo Michael A. , Cameron Scott J. , Terry Lara E. , Yule David I. , Morrell Craig N. , Lowenstein Charles J.
Published: May 2018

Platelets are key mediators of thrombosis. Many agonists of platelet activation are known, but there are fewer identified endogenous inhibitors of platelets, such as prostacyclin and nitric oxide (NO). Acetylcholinesterase inhibitors such as donepezil can cause bleeding in patients, but the underlying mechanisms are not well understood. We hypothesized that acetylcholine is an endogenous inhibitor of platelets.

We measured the effect of acetylcholine or analogues of acetylcholine upon human platelet activation ex vivo. We characterized expression of components of the acetylcholine signaling pathway in human platelets. We tested the effect of a subunit of the acetylcholine receptor, CHRNA7, on acetylcholine signaling in platelets. Acetylcholine and analogues of acetylcholine inhibited platelet activation, as measured by P-selectin translocation and GPIIbIIIA conformational changes. Conversely, we found that antagonists of the acetylcholine receptor such as pancuronium enhance platelet activation. Furthermore, drugs inhibiting acetylcholinesterase such as donepezil also inhibit platelet activation, suggesting that platelets release acetylcholine. We found that NO mediates acetylcholine inhibition of platelets. Human platelets express members of the acetylcholine signaling pathway includingCHRNA2, CHRNA7, CHRNB1, andACHE. Platelets from mice lackingChrna7are hyperactive when stimulated by thrombin and resistant to inhibition by acetylcholine. Furthermore, acetylcholinesterase inhibitors prolonged bleeding in wild-type mice. Knockout mice lackingChrna7subunits of the acetylcholine receptor display prolonged bleeding as well.

Our data suggest that acetylcholine is an endogenous inhibitor of platelet activation. The cholinergic system may be a novel target for anti-thrombotic therapies.
Decoding Selective Attention to Context Memory: An Aging Study
Authors: Powell Patrick S. , Strunk Jonathan , James Taylor , Polyn Sean M. , Duarte Audrey
Published: May 2018

Emerging evidence has suggested that the tendency for older adults to bind too much contextual information during encoding (i.e., hyper-binding) may contribute to poorer memory for relevant contextual information during retrieval. While these findings are consistent with theories of age-related declines in selective attention and inhibitory control, the degree to which older adults are able to selectively attend to relevant contextual information during encoding is unknown. To better understand the neural dynamics associated with selective attention during encoding, the current study applied multivariate pattern analyses (MVPA) to oscillatory EEG in order to track moment-to-moment shifts of attention between relevant and irrelevant contextual information during encoding. Young and older adults studied pictures of objects in the presence of two contextual features: a color and a scene, and their attention was directed to the object’s relationship with one of those contexts (i.e., target context). Results showed that patterns of oscillatory power successfully predicted whether selective attention was directed to a scene or color, across age groups. Individual differences in overall classification performance were associated with individual differences in target context memory accuracy during retrieval. However, changes in classification performance within a trial, suggestive of fluctuations in selective attention, predicted individual differences in hyper-binding. To the best of our knowledge, this is the first study to use MPVA techniques to decode attention during episodic encoding and the impact of attentional shifts toward distracting information on age-related context memory impairments and hyper-binding. These results are consistent with the as-of-yet unsubstantiated theory that age-related declines in context memory may be attributable to poorer selective attention and/or greater inhibitory deficits in older adults.
Fast estimation of genetic relatedness between members of heterogeneous populations of closely related genomic variants
Authors: Tsyvina Viachaslau , Campo David S. , Sims Seth , Zelikovsky Alex , Khudyakov Yury , Skums Pavel
Published: May 2018

Many biological analysis tasks require extraction of families of genetically similar sequences from large datasets produced by Next-generation Sequencing (NGS). Such tasks include detection of viral transmissions by analysis of all genetically close pairs of sequences from viral datasets sampled from infected individuals or studying of evolution of viruses or immune repertoires by analysis of network of intra-host viral variants or antibody clonotypes formed by genetically close sequences. The most obvious naϊeve algorithms to extract such sequence families are impractical in light of the massive size of modern NGS datasets. In this paper, we present fast and scalable k-mer-based framework to perform such sequence similarity queries efficiently, which specifically targets data produced by deep sequencing of heterogeneous populations such as viruses. The tool is freely available for download at https://github.com/vyacheslav-tsivina/signature-sj
RefCell: Multi-dimensional analysis of image-based high-throughput screens based on ‘typical cells’
Authors: Shen Yang , Kubben Nard , Candia Julián , Morozov Alexandre V. , Misteli Tom , Losert Wolfgang
Published: May 2018

Background

Image-based high-throughput screening (HTS) reveals a high level of heterogeneity in single cells and multiple cellular states may be observed within a single population. Cutting-edge high-dimensional analysis methods are successful in characterizing cellular heterogeneity, but they suffer from the “curse of dimensionality” and non-standardized outputs.

Results

Here we introduce RefCell, a multi-dimensional analysis pipeline for image-based HTS that reproducibly captures cells with typical combinations of features in reference states, and uses these “typical cells” as a reference for classification and weighting of metrics. RefCell quantitatively assesses the heterogeneous deviations from typical behavior for each analyzed perturbation or sample.

Conclusions

We apply RefCell to the analysis of data from a high-throughput imaging screen of a library of 320 ubiquitin protein targeted siRNAs selected to gain insights into the mechanisms of premature aging (progeria). RefCell yields results comparable to a more complex clustering based single cell analysis method, which both reveal more potential hits than conventional average based analysis.
Design of a de novo aggregating antimicrobial peptide and bacterial conjugation delivery system
Authors: Collins Logan T. , Otoupal Peter B. , Courtney Colleen M. , Chatterjee Anushree
Published: May 2018

Traditional antibiotics are reaching obsolescence as a consequence of antibiotic resistance; therefore novel antibiotic approaches are needed. A recent non-traditional approach involves formation of protein aggregates as antimicrobials to disrupt bacterial homeostasis. Previous work on protein aggregates has focused on genome mining for aggregation-prone sequences in bacterial genomes rather than on rational design of aggregating antimicrobial peptides. Here, we use a synthetic biology approach to design an artificial gene encoding the first de novo aggregating antimicrobial peptide. This artificial gene,opaL(overexpressed protein aggregator Lipophilic), disrupts bacterial homeostasis by expressing extremely hydrophobic peptides. When this hydrophobic sequence is disrupted by acidic residues, consequent aggregation and antimicrobial effect decreases. Further, to deliver this artificial gene, we developed a probiotic approach using RK2, a broad host range conjugative plasmid, to transferopaLfrom donor to recipient bacteria. We utilize RK2 to mobilize a shuttle plasmid carrying theopaLgene by adding the RK2 origin of transfer. We show thatopaLis non-toxic to the donor, allowing for maintenance and transfer since its expression is under control of a promoter with a recipient-specific T7 RNA polymerase. Upon mating of donor and recipientEscherichia coli, we observe selective growth repression in T7 polymerase expressing recipients. This technique could be used to target desired pathogens by selecting pathogen-specific promoters to controlopaLexpression. This system provides a basis for the design and delivery of novel antimicrobial peptides.

Importance

The growing threat of antibiotic resistance necessitates new treatment options for bacterial infections that are recalcitrant to traditional antimicrobials. Existing methods usually involve small-molecule compounds which interfere with essential processes in bacterial cells. By contrast, protein aggregates operate by causing widespread disruption of bacterial homeostasis and may provide a new method for combating infections. We used rational design to create and test an aggregating de novo antimicrobial peptide, OpaL. In addition, we employed bacterial conjugation to deliver theopaLgene from donor bacteria to recipient bacteria while using a strain-specific promoter to ensure that OpaL was only expressed in targeted recipients. To the best of our knowledge, this represents the first design for a de novo peptide with aggregation-mediated antimicrobial activity. We envision that OpaL’s design parameters could be used in developing a new class of antimicrobial peptides to help treat antibiotic resistant infections.
Isolation and characterization of antagonistic bacteria with the potential for biocontrol of soil-borne wheat diseases
Authors: Wang Xiaohui , Wang Changdong , Ji Chao , Li Qian , Zhang Jiamiao , Song Xin , Jun Kang Sui , Liu Zhaoyang , Du Jianfeng , Liu Xunli
Published: May 2018

Bacillus amyloliquefaciens subsp. plantarum XH-9 is a plant-beneficial rhizobacterium that shows good antagonistic potential against phytopathogens by releasing diffusible and volatile antibiotics, and secreting hydrolytic enzymes. Furthermore, the XH-9 strain possesses important plant growth-promoting characteristics, including nitrogen fixation (7.92 ± 1.05 mg/g), phosphate solubilization (58.67 ± 4.20 μg/L), potassium solubilization (10.07 ± 1.26 μg/mL), and the presence of siderophores (4.92 ± 0.46 μg/mL), indole-3-acetic acid (IAA) (7.76 ± 0.51 μg/mL) and 1-aminocyclopropane-1-carboxylic acid deaminase (ACC-deaminase) (4.67 ± 1.21 nmol/[mg•h]). Moreover, the XH-9 strain showed good capacities for wheat, corn, and chili root colonization, which are critical prerequisites for controlling soil-borne diseases as a bio-control agent. Real-time quantitative polymerase chain reaction experiments showed that the amount of Fusarium oxysporum DNA associated with the XH-9 strain after treatment significantly decreased compared with control group. Accordingly, wheat plants inoculated with the XH-9 strain showed significant increases in the plant shoot heights (14.20%), root lengths (32.25%), dry biomass levels (11.93%), and fresh biomass levels (16.28%) relative to the un-inoculated plants. The results obtained in this study suggest that the XH-9 strain has potential as plant-growth promoter and biocontrol agent when applied in local arable land to prevent damage caused by F. oxysporum and other phytopathogens.

Importance

Plant diseases, particularly soilborne pathogens, play a significant role in the destruction of agricultural resources. Although these diseases can be controlled to some extent with crop and fungicides, while these measures increase the cost of production, promote resistance, and lead to environmental contamination, so they are being phased out. Plant growth-promoting rhizobacteria are an alternative to chemical pesticides that can play a key role in crop production by means of siderophore and indole-3-acetic acid production, antagonism to soilborne root pathogens, phosphate and potassium solubilization, and nitrogen fixation. These rhizobacteria can also promote a beneficial change in the microorganism community by significantly reducing its pathogenic fungi component. Their use is fully in accord with the principles of sustainability.