bluuebunny/crossref_metadata_2025 huggingface dataset:
Tick Bite–Associated Morphea: A Case Report
Authors: George Eva , Nielson Colton B. , Vincek Vladimir
Published: October 2018

Borrelia burgdorferi, the causative organism of Lyme disease, has been linked to the development of scleroatrophic skin conditions including morphea, although this association remains controversial. The possibility that tick bite with or without concurrent Borrelia infection instigates that morphea development is important to recognize because this could prompt further workup for Lyme disease, or other tick-borne illness, which, when untreated, can have devastating consequences. Here, we report a case of a woman with a history of previous tick bite in the location of morphea. This prompted further workup, including serologies that were negative for borrelia. The patient declined empiric treatment with doxycycline. It is important to be aware that morphea may represent a consequence of tick bite because this can alter patient management.
Concurrent Microbial Keratitis and Nasolacrimal Duct Obstruction: Concordance, Etiopathogenesis, and Outcome
Authors: Nayak Arpita , Mitra Basu Sanchita , De Anuria , Mallick Aparajita , Das Sujata , Rath Suryasnata
Published: October 2018

Purpose:

Nasolacrimal duct obstruction (NLDO) is believed to be a risk factor for microbial keratitis (MK). The primary objective of this study was to look at microbiological concordance between corneal scraping and lacrimal sac flora in patients with concurrent MK and NLDO. The secondary objective was to compare microbiological isolates from MK and NLDO, MK alone, NLDO alone, and healthy subjects.

Methods:

A prospective comparative study of 146 subjects with standard microbiological analyses was performed between February 2014 and October 2017.

Results:

Of the 146 subjects, 35 had concurrent MK and NLDO, 35 had MK, 41 had NLDO, and 35 were healthy subjects. Overall, mean age and sex distribution among groups were similar. In the MK and NLDO group, coagulase-negative staphylococci (CNS) were the most common isolates from the corneal scraping (n = 12/35, 34%) and lacrimal sac (n = 10/35, 29%) with 58% concordance. CNS were also the most common isolates from the NLDO group and healthy subjects, fungus being the most common isolate in the MK group. Anatomical success was achieved in 31 patients (89%) after dacryocystorhinostomy (DCR) in the MK and NLDO group. The difference between the number of patients who had successful DCR surgery but failure of medical therapy for MK (1/31) versus those who failed DCR and medical therapy for MK (3/4) was statistically significant (P = 0.002, Fisher exact test).

Conclusions:

CNS are the most common organisms in concurrent MK and NLDO (58% concordance), in patients with NLDO alone, and as commensals in healthy subjects. Persistence of NLDO may be responsible for a poorer outcome of MK in a concurrent setting.
Extracorporeal Membrane Oxygenation for Adults With Refractory Septic Shock
Authors: Riera Jordi , Argudo Eduard , Ruiz-Rodríguez Juan Carlos , Ferrer Ricard
Published: October 2018

Because of a severe dysregulation of the host response to infection, septic shock may induce a profound imbalance between oxygen consumption and delivery, which in some cases may be refractory to conventional support measures. In this setting, extracorporeal membrane oxygenation (ECMO) may help to restore this ratio. Indeed, in neonates and children, this technique is already established as a valid salvage therapy. In spite of the rapid growth in the use of ECMO in recent years, the evidence of its benefits in adult patients is weak, particularly in cases of refractory septic shock. Nevertheless, several case series have reported good outcomes in selected cases with specific management. Here we explore the links between sepsis and ECMO, starting with the basic biology underlying the two entities. We then review the published literature on the use of extracorporeal support in adult patients with septic shock and finally conclude with a review of the key points of management that can optimize the results after this critical situation.
Outcomes and costs of treating hepatitis C patients with second-generation direct-acting antivirals: results from the German Hepatitis C-Registry
Authors: Krüger Kathrin , Krauth Christian , Rossol Siegbert , Mauss Stefan , Boeker Klaus H.W. , Müller Tobias , Klinker Hartwig , Pathil Anita , Heyne Renate , Stahmeyer Jona T.
Published: October 2018

Objective

Chronic hepatitis C virus infection is associated with a significant health burden. Long-term consequences are the development of liver cirrhosis and hepatocellular carcinoma. The introduction of direct-acting antivirals (DAA) has led to an increase in sustained virologic response rates (SVR), but is accompanied by higher treatment costs. The aim of this study was to assess the outcomes and costs of treating hepatitis C virus infected patients with DAAs in clinical practice in Germany.

Patients and methods

Data were derived from a noninterventional study including a pharmacoeconomic subset of 2673 patients with genotypes 1 and 3 who initiated and completed treatment between February 2014 and February 2017. Sociodemographic and clinical parameters as well as resource utilization were collected using a web-based data recording system. Costs were calculated using official remuneration schemes.

Results

The mean age of the patients was 54.6 years; 48% were men. 93.5% of all patients achieved an SVR. The average total treatment costs were €67 979 (€67 131 medication costs, €824 ambulatory care, €24 hospital costs). The average costs per SVR of €72 705 were calculated. Differences in SVR and costs according to genotype, treatment regimen, treatment experience, and cirrhosis were observed. Quality-of-life data showed no or a minimal decrease during treatment.

Conclusion

This analysis confirms high SVR rates for newly introduced DAAs in a real-world setting. Costs per SVR estimated are comparable to first-generation DAA. Given the fact that the costs for the currently used treatment regimens have declined, it can be assumed that the costs per SVR have also decreased. Our insight into real-world outcomes and costs can serve as a basis for a comparison with the mentioned newly introduced treatment regimens.
Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer
Authors: Serrano Jose , Andersen Dana K. , Forsmark Christopher E. , Pandol Stephen J. , Feng Ziding , Srivastava Sudhir , Rinaudo Jo Ann S.
Published: October 2018

Research progress in diseases of the exocrine pancreas [chronic pancreatitis (CP), pancreatogenic diabetes mellitus, and pancreatic cancer] has been hampered by the disorders' heterogeneity, the limitations of previous small cross-sectional studies, the inability to safely obtain pancreatic tissue for study, and the lack of structured epidemiology tools, genetic testing, and biomarker development. Mechanism-based research of these diseases has suffered from the lack of systematically collected clinical measures in longitudinal cohort studies linked with biospecimens. Given the increasing incidence and prevalence of CP and its association to the development of pancreatic cancer, its complications, high mortality rate, and associated health care cost, the National Institute for Diabetes and Digestive and Kidney Diseases and the National Cancer Institute funded the Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer to identify research gaps and foster multidisciplinary collaborations to better diagnose, characterize, and manage CP and its sequelae. The CPDPC structure, governance, and research objectives are described in this article. Studies undertaken by the CPDPC are described in other articles in this journal's issue.
Accelerating the Drug Delivery Pipeline for Acute and Chronic Pancreatitis—Knowledge Gaps and Research Opportunities
Authors: Uc Aliye , Andersen Dana K. , Borowitz Drucy , Glesby Marshall J. , Mayerle Julia , Sutton Robert , Pandol Stephen J.
Published: October 2018

A workshop was sponsored by the Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, on July 25, 2018, in Pittsburgh, Penn. The workshop was designed to bring together a multidisciplinary group of experts to accelerate the development of therapeutics for clinical application in inflammatory diseases of the exocrine pancreas. Three separate working groups (acute pancreatitis, recurrent acute pancreatitis, and chronic pancreatitis) were formed to address the needs, gaps, and opportunities. The working groups included patients with pancreatic diseases, pharmaceutical company leaders, basic scientists, clinical researchers, and representatives from the US Food and Drug Administration to assist with regulatory considerations and to identify the unmet needs, research targets, and opportunities to provide direction for successful development of therapeutic agents in these diseases. This article represents the summary of the overview presentations at the National Institute of Diabetes and Digestive and Kidney Diseases workshop including an ongoing drug trial in acute pancreatitis; a successful drug development network developed by the Cystic Fibrosis Foundation; and considerations for subject selection in drug trials, incorporating Food and Drug Administration guidelines on clinical trial design and clinical outcome measures. The summaries of each working group follow separately in accompanying articles.
Chromogranin A in the Follow-up of Gastroenteropancreatic Neuroendocrine Neoplasms
Authors: Rossi Roberta Elisa , Ciafardini Clorinda , Sciola Valentina , Conte Dario , Massironi Sara
Published: October 2018

Objectives

Little is known about chromogranin A (CgA) during follow-up of gastroenteropancreatic neuroendocrine neoplasms. We hypothesized that serial CgA monitoring might be useful for the assessment of tumor progression, and we performed a systematic review of the literature and meta-analysis.

Methods

A bibliographical search was performed in PubMed using “chromogranin A” and “neuroendocrine tumors” and “follow-up” and “biomarker” to identify all pertinent articles published in the last 10 years.

Results

Eight studies were included in current meta-analysis. Chromogranin A as a follow-up marker shows sensitivity between 46% and 100% and specificity between 68% and 90%. The meta-analysis results showed an overall accuracy of 84% (95% confidence interval [CI], 81–86.6), a cumulative sensitivity of 74.6% (95% CI, 61.9–85.4), and a cumulative specificity of 84.7% (95% CI, 81.3–87.7). These data indicate that circulating CgA has a better overall accuracy in the follow-up setting; it can be used to rule the diagnosis of recurrence/progression in, rather than to rule it out.

Conclusions

Chromogranin A is more reliable when used to monitor disease progression and response to treatment and for the early detection of recurrence after treatment rather than in the diagnostic setting. It is more sensible to use this marker in those cases where the initial values were impaired.
Examining the Effectiveness of Year-Round School Calendars on Improving Educational Attainment Outcomes Within the Context of Advancement of Health Equity: A Community Guide Systematic Review
Authors: Finnie Ramona K. C. , Peng Yinan , Hahn Robert A. , Johnson Robert L. , Fielding Jonathan E. , Truman Benedict I. , Muntaner Carles , Fullilove Mindy T. , Zhang Xinzhi
Published: October 2018

Students may lose knowledge and skills achieved in the school year during the summer break, with losses greatest for students from low-income families. Community Guide systematic review methods were used to summarize evaluations (published 1965-2015) of the effectiveness of year-round school calendars (YRSCs) on academic achievement, a determinant of long-term health. In single-track YRSCs, all students participate in the same school calendar; summer breaks are replaced by short “intersessions” distributed evenly throughout the year. In multi-track YRSCs, cohorts of students follow separate calendar tracks, with breaks at different times throughout the year. An earlier systematic review reported modest gains with single-track calendars and no gains with multi-track calendars. Three studies reported positive and negative effects for single-track programs and potential harm with multi-track programs when low-income students were assigned poorly resourced tracks. Lack of clarity about the role of intersessions as simple school breaks or as additional schooling opportunities in YRSCs leaves the evidence on single-track programs insufficient. Evidence on multi-track YRSCs is also insufficient.
Mediastinal Duplication Cyst on 99mTc Pertechnetate Scan
Authors: Gupta Vanshika , Verma Ritu , Belho Ethel , Seniaray Nikhil
Published: October 2018

A 3-year-old boy presented with intermittent abdominal pain, melena, and anemia since 2 months. Upper gastrointestinal endoscopy did not reveal any significant abnormality. The child was then referred for 99mTc-pertechnetate scan to rule out the presence of ectopic functioning gastric mucosa. 99mTc-pertechnetate scan revealed abnormal tracer accumulation in the thoracic region, which persisted in the delayed images, suspicious for being ectopic gastric mucosa. Subsequently, ultrasound and contrast-enhanced CT (CECT) scans of the chest revealed a large multiseptate cystic lesion in the retrocardiac region, corresponding to the site of increased tracer uptake on 99mTc-pertechnetate scan.
Does Mesh Weight Affect Time to Failure After Robotic-Assisted Laparoscopic Sacrocolpopexy?
Authors: Askew Amy L. , Visco Anthony G. , Weidner Alison C. , Truong Tracy , Siddiqui Nazema Y. , Bradley Megan S.
Published: October 2018

Objective

The objective of this study was to compare time to anatomic failure after robotic sacrocolpopexy with use of ultralightweight versus heavier weight mesh types.

Methods

We performed a retrospective cohort study of women who underwent robotic sacrocolpopexy, from January 2012 to September 2016. We compared (1) sacrocolpopexy with ultralightweight mesh (≤20 g/m2) versus (2) sacrocolpopexy with heavier weight mesh (≤35 g/m2). Our primary outcome was time to anatomic failure, defined as recurrent prolapse beyond the hymen, or retreatment for prolapse with surgery or pessary. Secondary outcomes were compartment of failure and mesh exposure. Cox proportional hazards modeling was used to estimate the hazard of failure based on mesh type.

Results

Of 461 patients, 248 (53.8%) underwent sacrocolpopexy with ultralightweight mesh and 213 (46.2%) with heavier weight mesh. Failures occurred in 37 women, with 21 in the ultralightweight mesh group and 16 in the heavier weight mesh group. Time to failure was statistically significant between groups (P = 0.03). Ultralightweight mesh had twice the hazard of failure within 3 years compared with heavier weight mesh (hazard ratio, 2.15; 95% confidence interval, 1.10–4.21; P = 0.03). Among failures, use of ultralightweight mesh was associated with almost 5 times the hazard of anterior compartment failure (hazard ratio, 4.46; 95% confidence interval, 1.39–14.27; P = 0.01). There was no difference in time to posterior failure. Of 17 mesh exposures, there were fewer in the ultralightweight mesh group, although this group was followed for less time (1.6% ultralightweight vs 6.0% heavier weight, P = 0.01).

Conclusions

Women receiving ultralightweight mesh are more likely to experience earlier anatomic failure in the anterior compartment.
Global analysis of the RpaB regulon based on the positional distribution of HLR1 sequences and comparative differential RNA-Seq data
Authors: Riediger Matthias , Kadowaki Taro , Nagayama Ryuta , Georg Jens , Hihara Yukako , Hess Wolfgang R.
Published: October 2018

The transcription factor RpaB regulates the expression of genes encoding photosynthesis-associated proteins during light acclimation. The binding site of RpaB is the HLR1 motif, a pair of imperfect octameric direct repeats, separated by two random nucleotides. Here, we used high-resolution mapping data of transcriptional start sites (TSSs) in the modelSynechocystissp. PCC 6803 in conjunction with the positional distribution of HLR1 sites for the global prediction of the RpaB regulon. The results demonstrate that RpaB regulates the expression of more than 150 promoters, driving the transcription of protein-coding and non-coding genes and antisense transcripts under low light and upon the shift to high light when DNA binding activity is lost. Transcriptional activation by RpaB is achieved when the HLR1 motif is located 66 to 45 nt upstream, repression occurs when it is close to or overlapping the TSS. Selected examples were validated by multiple experimental approaches, including chromatin affinity purification, reporter gene, northern hybridization and electrophoretic mobility shift assays. We found that RpaB controlsssr2016/pgr5, which is involved in cyclic electron flow and state transitions; six out of nine ferredoxins; three of four FtsH proteases;gcvP/slr0293, encoding a crucial photorespiratory protein; andnirAandisiAfor which we suggest cross-regulation with the transcription factors NtcA or FurA, respectively. In addition to photosynthetic gene functions, RpaB contributes to the control of genes affiliated with nitrogen assimilation, cofactor biosyntheses, the CRISPR system and the circadian clock, making it one of the most versatile regulators in cyanobacteria.

Significance Statement

RpaB is a transcription factor in cyanobacteria and in the chloroplasts of several lineages of eukaryotic algae. Like other important transcription factors, the gene encoding RpaB cannot be deleted, making the study of deletion mutants impossible. Based on a bioinformatic approach, we increased the number of known genes controlled by RpaB by a factor of 5. Depending on the distance to the TSS, RpaB mediates transcriptional activation or repression. The high number and functional diversity among its target genes and co-regulation with other transcriptional regulators characterize RpaB as a regulatory hub.
Targeting MYC Overexpressing Leukemia with Cardiac Glycoside Proscillaridin Through Downregulation of Histone Acetyltransferases
Authors: Da Costa Elodie M. , Armaos Gregory , McInnes Gabrielle , Beaudry Annie , Moquin-Beaudry Gaël , Bertrand-Lehouillier Virginie , Caron Maxime , Richer Chantal , St-Onge Pascal , Johnson Jeffrey R. , Krogan Nevan , Sai Yuka , Downey Michael , Rafei Moutih , Boileau Meaghan , Eppert Kolja , Flores-Díaz Ema , Haman André , Hoang Trang , Sinnett Daniel , Beauséjour Christian , McGraw Serge , Raynal Noël J-M
Published: October 2018

Targeting MYC oncogene remains a major therapeutic goal in cancer chemotherapy. Here, we demonstrate that proscillaridin, a cardiac glycoside approved for heart failure treatment exhibit anticancer selectivity towards high MYC expressing leukemic cell lines and leukemia stem cells. At a clinically relevant concentration, proscillaridin induced a rapid downregulation of MYC protein level, due to a significant decrease in MYC protein half-life. Proscillaridin treatment induced a downregulation of gene sets involved in MYC pathway, and a concomitant upregulation of genes involved in hematopoietic differentiation. Proscillaridin induced a significant loss of lysine acetylation in histone H3 (K9, K14, K18 and K27) and in non-histone proteins such as MYC, MYC target proteins, and a series of histone acetylation regulators. Loss of lysine acetylation correlated with a rapid downregulation of histone acetyltransferase protein levels, involved in histone and MYC acetylation (CBP, P300, GCN5, TIP60, and MOZ), preferentially in MYC overexpressing leukemia as compared to other cancer cells. These results support the repurposing of proscillaridin in MYC overexpressing leukemia and propose a novel strategy to target MYC in cancer.
The influence of fluctuating population densities on evolutionary dynamics
Authors: Pisa Hanja , Hermisson Joachim , Polechova Jitka
Published: October 2018

The causes and consequences of fluctuating population densities are an important topic in ecological literature. Yet, the effects of such fluctuations on maintenance of variation in spatially structured populations have received little analytic treatment. We analyze what happens when two habitats coupled by migration not only differ in their trade-offs in selection but also in their demographic stability – and show that equilibrium allele frequencies can change significantly due to ecological feedback arising from locally fluctuating population sizes. When an ecological niche exhibits such fluctuations, these drive an asymmetry in the relative impact of gene flow, and therefore, the equilibrium frequency of the locally adapted type decreases. Our results extend the classic conditions on maintenance of diversity under selection and migration by including the effect of fluctuating population densities. We find simple analytic conditions in terms of the strength of selection, immigration, and the extent of fluctuations between generations in a continent-island model. Whereas weak fluctuations hardly affect coexistence, strong recurrent fluctuations lead to extinction of the type better adapted to the fluctuating niche – even if the invader is locally maladapted. There is a disadvantage to specialization to an unstable habitat, as it makes the population vulnerable to swamping from more stable habitats.
A simple approximation to bias in gene-environment interaction estimates when a case might not be the case
Authors: Lobach Iryna , Kim Inyoung , Alekseyenko Alexander , Lobach Siarhei , Zhang Li
Published: October 2018

Case-control genetic association studies are often used to examine the role of the genetic basis in complex diseases, such as cancer and neurodegenerative diseases. The role of the genetic basis might vary by non-genetic (environmental) measures, what is traditionally defined as gene-environment interactions (GxE). A commonly overlooked complication is that the set of clinically diagnosed cases might be contaminated by a subset with a nuisance pathologic state that presents with the same symptoms as the pathologic state of interest. The genetic basis of the pathologic state of interest might differ from that of the nuisance pathologic state. Often frequencies of the pathologically defined states within the clinically diagnosed set of cases vary by the environment. We derive a simple and general approximation to bias in GxE parameter estimates when presence of the nuisance pathologic state is ignored. We then perform extensive simulation studies to show that ignoring presence of the nuisance pathologic state can result in substantial bias in GxE estimates and that the approximation we derived is reasonably accurate in finite samples. We demonstrate the applicability of the proposed approximation in a study of Alzheimer’s disease.
ForestQC: quality control on genetic variants from next-generation sequencing data using random forest
Authors: Li Jiajin , Jew Brandon , Zhan Lingyu , Hwang Sungoo , Coppola Giovanni , Freimer Nelson B. , Sul Jae Hoon
Published: October 2018

Next-generation sequencing technology (NGS) enables discovery of nearly all genetic variants present in a genome. A subset of these variants, however, may have poor sequencing quality due to limitations in sequencing technology or in variant calling algorithms. In genetic studies that analyze a large number of sequenced individuals, it is critical to detect and remove those variants with poor quality as they may cause spurious findings. In this paper, we present a statistical approach for performing quality control on variants identified from NGS data by combining a traditional filtering approach and a machine learning approach. Our method uses information on sequencing quality such as sequencing depth, genotyping quality, and GC contents to predict whether a certain variant is likely to contain errors. To evaluate our method, we applied it to two whole-genome sequencing datasets where one dataset consists of related individuals from families while the other consists of unrelated individuals. Results indicate that our method outperforms widely used methods for performing quality control on variants such as VQSR of GATK by considerably improving the quality of variants to be included in the analysis. Our approach is also very efficient, and hence can be applied to large sequencing datasets. We conclude that combining a machine learning algorithm trained with sequencing quality information and the filtering approach is an effective approach to perform quality control on genetic variants from sequencing data.

Author Summary

Genetic disorders can be caused by many types of genetic mutations, including common and rare single nucleotide variants, structural variants, insertions and deletions. Nowadays, next generation sequencing (NGS) technology allows us to identify various genetic variants that are associated with diseases. However, variants detected by NGS might have poor sequencing quality due to biases and errors in sequencing technologies and analysis tools. Therefore, it is critical to remove variants with low quality, which could cause spurious findings in follow-up analyses. Previously, people applied either hard filters or machine learning models for variant quality control (QC), which failed to filter out those variants accurately. Here, we developed a statistical tool, ForestQC, for variant QC by combining a filtering approach and a machine learning approach. We applied ForestQC to one family-based whole genome sequencing (WGS) dataset and one general case-control WGS dataset, to evaluate our method. Results show that ForestQC outperforms widely used methods for variant QC by considerably improving the quality of variants. Also, ForestQC is very efficient and scalable to large-scale sequencing datasets. Our study indicates that combining filtering approaches and machine learning approaches enables effective variant QC.
Cryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain (AL) amyloidosis patient
Authors: Swuec Paolo , Lavatelli Francesca , Tasaki Masayoshi , Paissoni Cristina , Rognoni Paola , Maritan Martina , Brambilla Francesca , Milani Paolo , Mauri Pierluigi , Camilloni Carlo , Palladini Giovanni , Merlini Giampaolo , Ricagno Stefano , Bolognesi Martino
Published: October 2018

Systemic light chain (AL) amyloidosis is a life-threatening disease caused by aggregation and deposition of monoclonal immunoglobulin light chains (LC) in target organs. Severity of heart involvement is the most important factor determining prognosis. Here, we report the 4.0 Å resolution cryo-electron microscopy (cryo-EM) map and structural model of amyloid fibrils extracted from the heart of an AL patient affected by severe amyloid cardiomyopathy. The fibrils are composed of one asymmetric protofilament, showing typical 4.9 Å stacking and parallel cross-β architecture. Two distinct polypeptide stretches belonging to the LC variable domain (Vl) could be modelled in the density (total of 77 residues), stressing the role of the Vl domain in fibril assembly and LC aggregation. Despite high levels of Vl sequence variability, residues stabilising the observed fibril core are conserved through several Vl domains, highlighting structural motifs that may be common to misfolded LCs. Our data shed first light on the architecture of life-threatening LC amyloid deposits, and provide a rationale for correlating LC amino acid sequences and fibril structures.
Pupillary dilations of mice performing a vibrotactile discrimination task reflect task engagement and response confidence
Authors: Ganea DA , Bexter A , Guenther M , Garderes PM , Kampa BM , Haiss F
Published: October 2018

Pupillometry, the measure of pupil size and reactivity, has been widely used to assess cognitive processes. As such, changes in pupil size have been shown to correlate with arousal, locomotion, cortical state and decision-making processes. In addition, pupillary responses have been linked to the activity of neuromodulatory systems that modulate attention and perception as the noradrenergic and cholinergic systems. Due to the extent of processes reflected by the pupil, we aimed at resolving pupillary responses in context of behavioral state and task performance while recording pupillary transients of mice performing a vibrotactile two-alternative forced choice task (2-AFC). We show that pre-stimulus pupil size differentiates between states of disengagement from task performance versus active engagement. In addition, when actively engaged, post-stimulus, pupillary dilations for correct responses are larger than for error responses with this difference reflecting response confidence. Importantly, in a delayed 2-AFC task version, we show that even though pupillary transients mainly reflect motor output or reward anticipation following the response of the animal, they also reflect animal decision confidence prior to its response. Finally, in a condition of passive engagement, when stimulus has no task relevance with reward provided automatically, pupillary dilations reflect stimulation and reward being reduced relative to a state of active engagement explained by shifts of attention from task variables. Our results provide further evidence for how pupillary dilations reflect cognitive processes in a task relevant context, showing that the pupil reflects response confidence and baseline pupil size encodes attentiveness rather than general arousal.

Significance Statement

For the last 60 years, pupillometry has been used to study various cognitive processes. Among which are mental load, arousal and various decision related components, linking pupil dilations to underlying neuromodulatory systems. Our results provide extensive evidence that in addition to reflecting attentiveness under task performance, pupil dilations also reflect the confidence of the subject in his ensuing response. This confidence coding is overlaid within a more pronounced pupil dilation that reflects motor output or other post-decision components such that are related to the response itself but not to the decision. Our results also provide evidence how different behavioral states, imposed by task demands, modulate what the pupil is reflecting, presumably showing what the underlying cognitive network is coding for.
Abundance compensates kinetics: Similar effect of dopamine signals on D1 and D2 receptor populations
Authors: Hunger Lars , Kumar Arvind , Schmidt Robert
Published: October 2018

The neuromodulator dopamine plays a key role in motivation, reward-related learning and normal motor function. The different affinity of striatal D1 and D2 dopamine receptor types has been argued to constrain the D1 and D2 signalling pathways to phasic and tonic dopamine signals, respectively. However, this view assumes that dopamine receptor kinetics are instantaneous so that the time courses of changes in dopamine concentration and changes in receptor occupation are basically identical. Here we developed a neurochemical model of dopamine receptor binding taking into account the different kinetics and abundance of D1 and D2 receptors in the striatum. Testing a large range of behaviorally-relevant dopamine signals, we found that the D1 and D2 dopamine receptor populations responded very similarly to tonic and phasic dopamine signals. Furthermore, due to slow unbinding rates, both receptor populations integrated dopamine signals over a timescale of minutes. Our model provides a description of how physiological dopamine signals translate into changes in dopamine receptor occupation in the striatum, and explains why dopamine ramps are an effective signal to occupy dopamine receptors. Overall, our model points to the importance of taking into account receptor kinetics for functional considerations of dopamine signalling.

Significance statement

Current models of basal ganglia function are often based on a distinction of two types of dopamine receptors, D1 and D2, with low and high affinity, respectively. Thereby, phasic dopamine signals are believed to mostly affect striatal neurons with D1 receptors, and tonic dopamine signals are believed to mostly affect striatal neurons with D2 receptors. This view does not take into account the rates for the binding and unbinding of dopamine to D1 and D2 receptors. By incorporating these kinetics into a computational model we show that D1 and D2 receptors both respond to phasic and tonic dopamine signals. This has implications for the processing of reward-related and motivational signals in the basal ganglia.
Development of a robust automated tool for the annotation of embryo morphokinetic parameters
Authors: Feyeux M , Reignier A , Mocaer M , Lammers J , Meistermann D , Vandormael-Pournin S , Cohen-Tannoudji M , Barrière P , Barrière P , Paul-Gilloteaux P , David L , Fréour T
Published: October 2018

Study Question

Is it possible to automatically annotate human embryo development in time-lapse devices, with results comparable to manual annotation?

Summary Answer

We developed an automated tool for the annotation of embryo morphokinetic parameters having a high concordance with expert manual annotation in a large scale-study.

What is Known Already

Morphokinetic parameters obtained with time-lapse devices are increasingly used for human embryo quality assessment. However, their annotation is timeconsuming and can be operator-dependent, highlighting the need of developing automated approaches.

Study Design, Size, Duration

This monocentric pilot study was conducted using 701 blastocysts originating from 584 couples undergoing IVF with embryo culture in a time-lapse device and on 4 mouse embryos.

Participants/Materials, Setting, Methods

An automated annotation tool was developed based on grey level coefficient of variation and detection of the thickness of the zona pellucida. The timings of cellular events obtained with the automated tool were compared with those obtained manually by 2 expert embryologists. The same procedure was applied on 4 mouse preimplantation embryos obtained with a different device in a different setting.

Main Results and the Role of Chance

Although some differences were found when embryos were considered individually, we found an overall excellent concordance between automated and manual annotation of human embryo morphokinetics from fertilization to expanded blastocyst stage (r2=0.94). Moreover, the automated annotation tool gave promising results across species (human, mice).

Limitations, Reasons for Caution

These results should undergo multi-centric external evaluation in order to test the overall performance of the annotation tool.

Wider Implications of the Findings

Our system performs significantly better than the ones reported in the literature and on a bigger cohort, paving the way for high-throughput analysis of multicentric morphokinetic databases, providing new insights into the clinical value of morphokinetics as predictor of embryo quality and implantation.

Study Funding/Competing Interest(s)

This study was partly funded by Finox Forward Grant 2016.

Trial Registration Number

NA
Connectional architecture of a mouse hypothalamic circuit node controlling social behavior
Authors: Lo Liching , Kim Dong-Wook , Yao Shenqin , Cetin Ali , Harris Julie , Zeng Hongkui , Anderson David J. , Weissbourd Brandon
Published: October 2018

Type 1 Estrogen receptor-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvlEsr1) play a causal role in the control of social behaviors including aggression. Here we use six different viral-genetic tracing methods to map the connectional architecture of VMHvlEsr1 neurons. These data reveal a high level of input convergence and output divergence (“fan-in/fan-out”) from and to over 30 distinct brain regions, with a high degree (~90%) of recurrence. Unlike GABAergic populations in other hypothalamic nuclei controlling feeding and parenting behavior, VMHvlEsr1 glutamatergic neurons collateralize to multiple targets. However, we identify two anatomically distinct subpopulations with anterior vs. posterior biases in their collateralization patterns. Surprisingly, these two subpopulations receive indistinguishable inputs. These studies suggest an overall system architecture in which an anatomically feed-forward sensory-to-motor processing stream is integrated with a dense, highly recurrent central processing circuit. This architecture differs from the “brain-inspired” feed-forward circuits used in certain types of artificial intelligence networks.

SIGNIFICANCE

How the cellular heterogeneity of brain nuclei maps onto circuit connectivity, the relationship of this anatomical mapping to behavioral function, and whether there are general principles underlying this relationship, remains poorly understood. Here we systematically map the connectivity of estrogen receptor-1-expressing neurons in the ventromedial hypothalamus (VMHvlEsr1), which control aggression and other social behaviors. We find that a relatively sparse, anatomically feed-forward sensory-to-motor processing stream is integrated with a dense, highly recurrent central processing circuit. Further, the VMHvl contains at least two subpopulations of Esr1+ neurons with different cell body characteristics and locations, with distinct patterns of collateralization to downstream targets. Nevertheless, these projection-defined subpopulations receive similar inputs. This input-output organization appears distinct from those described in other hypothalamic nuclei.
Probe Sensitivity to Cortical versus Intracellular Cytoskeletal Network Stiffness
Authors: Vahabakashi Amir , Young Park Chan , Perkumas Kristin , Zhang Zhiguo , Deurloo Emily K. , Wu Huayin , Weitz David A. , Stamer W Daniel , Goldman Robert D. , Fredberg Jeffrey J. , Johnson Mark
Published: October 2018

In development, wound healing, and pathology, cell biomechanical properties are increasingly recognized as being of central importance. To measure these properties, experimental probes of various types have been developed, but how each probe reflects the properties of heterogeneous cell regions has remained obscure. To better understand differences attributable to the probe technology, as well as to define the relative sensitivity of each probe to different cellular structures, here we took a comprehensive approach. We studied two cell types --Schlemm’s canal (SC) endothelial cells and mouse embryonic fibroblasts (MEFs) – using four different probe technologies: 1) atomic force microscopy (AFM) with sharp-tip; 2) AFM with round-tip; 3) optical magnetic twisting cytometry (OMTC); and 4) traction microscopy (TM). Perturbation of SC cells with dexamethasone treatment, a-actinin overexpression, or Rho-A overexpression caused increases in traction reported by TM and stiffness reported by sharp-tip AFM, as compared to corresponding controls. By contrast, under these same experimental conditions, stiffness reported by round-tip AFM and by OMTC indicated little change. Knock out (KO) of vimentin in MEFs caused a diminution of traction reported by TM, as well as stiffness reported by sharp-tip and round-tip AFM. However, stiffness reported by OMTC in vimentin KO MEFs was greater than in wild-type. Finite element analysis demonstrated that this paradoxical OMTC result in vimentin KO MEFs could be attributed to reduced cell thickness. Our results also suggest that vimentin contributes not only to intracellular network stiffness but also cortex stiffness. Taken together, this evidence suggests that AFM sharp-tip and TM emphasize properties of the actin-rich shell of the cell whereas round-tip AFM and OMTC emphasize those of the non-cortical intracellular network.
A polyoxometalate-based metal–organic polyhedron constructed from a {V5O9Cl} building unit with rhombicuboctahedral geometry
Authors: Gong Ya-Ru , Su Zhong-Min , Wang Xin-Long
Published: October 2018

The design and construction of metal–organic polyhedra has received much attention by chemists due to the intriguing diversity of architectures and topologies that can be achieved. There are several crucial factors which should be considered for the construction of metal–organic polyhedra, such as the starting materials, reaction time and temperature, solvent and suitable organic ligands. Recently, polyoxometalates (POMs), serving as secondary building units to construct POM-based metal–organic polyhedra, have been the subject of much interest. The title compound, dodecakis(dimethylammonium) octakis(μ-benzene-1,3,5-tricarboxylato)hexa-μ-chlorido-tetracosa-μ-oxido-triacontaoxidotriacontavanadium, (NH2Me2)12[(V5O9Cl)6(C9H3O6)8], was synthesized successfully by self-assembly of VOCl3 and benzene-1,3,5-tricarboxylic acid under solvothermal conditions. The title polyhedron has an rdo topology when the {V5O9Cl} building unit and the benzene-1,3,5-tricarboxylate (BTC3−) ligand were simplified into 4-connected and 3-connected vertices. Interestingly, when the {V5O9Cl} building unit and the BTC3− ligand are considered as quadrangular and triangular faces, the structure displays rhombicuboctahedral geometry with an outer diameter of 21.88 Å. The packing of the polyhedra produces a circular channel with a diameter of 8.2 Å. The title compound was characterized by single-crystal X-ray diffraction, elemental analysis, IR spectroscopy, thermogravimetric analysis and powder X-ray diffraction.
Crystallization of ectonucleotide phosphodiesterase/pyrophosphatase-3 and orientation of the SMB domains in the full-length ectodomain
Authors: Döhler Christoph , Zebisch Matthias , Krinke Dana , Robitzki Andrea , Sträter Norbert
Published: October 2018

Ectonucleotide phosphodiesterase/pyrophosphatase-3 (NPP3, ENPP3) is an ATP-hydrolyzing glycoprotein that is located in the extracellular space. The full-length ectodomain of rat NPP3 was expressed in HEK293S GntI−cells, purified using two chromatographic steps and crystallized. Its structure at 2.77 Å resolution reveals that the active-site zinc ions are missing and a large part of the active site and the surrounding residues are flexible. The SMB-like domains have the same orientation in all four molecules in the asymmetric unit. The SMB2 domain is oriented as in NPP2, but the SMB1 domain does not interact with the PDE domain but extends further away from the PDE domain. Deletion of the SMB domains resulted in crystals that diffracted to 2.4 Å resolution and are suitable for substrate-binding studies.
Crystal structures of the N-terminal domain of the Staphylococcus aureus DEAD-box RNA helicase CshA and its complex with AMP
Authors: Chen Xiaobao , Wang Chengliang , Zhang Xuan , Tian Tian , Zang Jianye
Published: October 2018

CshA is a DEAD-box RNA helicase that belongs to the DExD/H-box family of proteins, which generally have an RNA-dependent ATPase activity. In Staphylococcus aureus, CshA was identified as a component of the RNA degradosome and plays important roles in RNA turnover. In this study, the crystal structures of the N-terminal RecA-like domain 1 of S. aureus CshA (SaCshAR1) and of its complex with AMP (SaCshAR1–AMP) are reported at resolutions of 1.5 and 1.8 Å, respectively. SaCshAR1 adopts a conserved α/β RecA-like structure with seven parallel strands surrounded by nine α-helices. The Q motif and motif I are responsible for the binding of the adenine group and phosphate group of AMP, respectively. Structure comparison of SaCshAR1–AMP and SaCshAR1 reveals that motif I undergoes a conformational change upon AMP binding. Isothermal titration calorimetry assays further conformed the essential roles of Phe22 in the Q motif and Lys52 in motif I for binding ATP, indicating a conserved substrate-binding mechanism in SaCshA compared with other DEAD-box RNA helicases.
What drives spectators’ experiential loyalty? A case study of the Olympic Football Tournament Rio 2016
Authors: Wu Hung-Che , Cheng Ching-Chan
Published: October 2018

Purpose

The purpose of this paper is to examine the relationships among the experiential quality (EQ) dimensions, experiential satisfaction (ES), experiential involvement (EI), host city image (HCI), experiential equity (EE), spectator affection (SA) and experiential loyalty (EL) in the sport context.

Design/methodology/approach

The data used in this study were based on a sample of 674 spectators from the finals of the men’s and women’s football tournaments held at the Maracanã Stadium in Rio, indicating that the proposed model fitted the data.

Findings

Findings show that the six EQ dimensions physical environment quality, outcome quality, access quality (AQ), game quality, trip quality (TQ) and security quality (SQ), EI, EE, HCI and SA positively influence ES. Also, EI moderates the relationship between HCI and EL. Moreover, EL is influenced by EI, HCI, SA and ES.

Practical implications

Results will assist sport management in developing and implementing market-orientated service strategies to increase the EQ dimensions, ES, EI, EE, HCI and SA in order to increase EL.

Originality/value

This study provides data that result in a better understanding of the relationships among the EQ dimensions, ES, EI, HCI, EE, SA and EL in the sporting context.
Segmentation of financial clients by attitudes and behavior
Authors: Phan Thuy Chung , Rieger Marc Oliver , Wang Mei
Published: October 2018

Purpose

The purpose of this paper is to investigate segmentations by finance-related attitudes and behavior of financial consumers in Switzerland and Vietnam.

Design/methodology/approach

The authors replicated the questionnaire measuring attitudes toward financial affairs as used in the study of Fünfgeld and Wang (2009). In order to extract factors and identify profiles of financial customers, the authors applied the same techniques including factor analysis and a two-step cluster analysis (Ward and K-means) to both samples. Linear regressions were used to examine the impact of socio-demographic variables.

Findings

Factor analysis reveals surprisingly similar underlying dimensions of financial attitudes and behavior for participants in both countries. The five clusters based on these dimensions exhibit strikingly similar characteristics. The authors also find that socio-demographic variables such as gender, age and education significantly vary across groups.

Research limitations/implications

There are small differences in the composition of the revealed dimensions between the two countries, mainly a mixture of intuitive decisions and free-spending aspects. Future research may investigate more countries with comparable samples to further test the reliabilities and validities of the scales.

Practical implications

The findings suggest that the instruments as developed by Fünfgeld and Wang (2009) can be used not only in highly developed Western markets but also in non-Western and emerging markets. Such instruments can be very useful for offering financial advice based on market segmentation in a global market.

Originality/value

The study provides empirical evidence on universal segmentation variables that reflect financial consumers’ psychological traits and attitudes toward saving and spending. Furthermore, the study stresses the need for a broad use of those variables when studying consumer decision-making in international financial markets.