bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional comparison of cancer incidence, mortality, and survival on the level of federal states in Germany using funnel plots
Authors: Geiss Karla , Meyer Martin
Published: April 2018

Population-based cancer registries allow the assessment of regional differences in cancer burden. Comparative cancer statistics are usually reported as ranked bar charts and choropleth maps, which can lead to misinterpretations of the presented figures. The aim of the present study is a regional comparison of cancer statistics in Germany on the level of federal states using funnel plots. Population-based cancer registry data on incidence, mortality, and survival on the level of federal states for the year 2011 were used. All cancer sites combined and the most common cancers were considered for the analysis. Funnel plots were used to compare the regional cancer statistics against the national estimates for Germany by sex, cancer site, and federal state. Cancer incidence and mortality showed large regional variation, which differed by sex and cancer site, whereas for cancer survival, essentially, no excess variation was observed. By taking into account statistical variation, funnel plots proved to be a suitable tool for assessing regional variation in cancer incidence, mortality, and survival and therefore can help improve population-based health management and eliminate cancer health disparities.
The Impact of Epidemiological Factors and Treatment Interventions on Survival in Patients With Signet Ring Cell Carcinoma of the Pancreas
Authors: Patel Mausam , Hans Harliv S. , Pan Kelsey , Khan Humza , Donath Elie , Caldera Humberto
Published: April 2018

Objectives:

Primary pancreatic signet ring cell carcinoma (SRCC) is a rare histologic variant of pancreatic carcinoma. A population-based analysis of pancreatic SRCC was performed to determine the predictive effects of epidemiological factors and treatment interventions on overall survival (OS) and disease-specific survival (DSS).

Materials and Methods:

The Surveillance, Epidemiology, and End Results registry was searched for pancreatic SRCC cases diagnosed between January 1, 1973 and December 31, 2013. Statistical analysis was performed using the Fisher exact test, χ2 analysis, Kaplan-Meier method, log-rank test, and Cox proportional hazards regression.

Results:

The mean age among 497 patients was 66.6 years (SD, 11.9). Most patients were white (82.7%) and male (54.5%). The 1-, 2-, and 5-year OS rates were 17%, 9%, and 4%, respectively, while the corresponding 1-, 2-, and 5-year rates for DSS were 18%, 10%, and 5%, respectively. On univariable analysis; age, site, grade, stage, and treatment were predictive of OS and DSS (P<0.05). On multivariable analysis; radiation improved OS and DSS (adjusted hazard ratio [aHR], 0.592 and 0.589, respectively), pancreatectomy improved OS and DSS (aHR, 0.360 and 0.355, respectively), and combination therapy improved OS and DSS (aHR, 0.295 and 0.286, respectively). Age, site, and stage were also independent predictors of OS and DSS. Subgroup analysis demonstrated treatment to be an independent predictor of OS and DSS in localized/regional disease, in distant disease, and in patients diagnosed between 2000 and 2013.

Conclusions:

Age, site, stage, and treatment independently predict OS and DSS in pancreatic SRCC.
Verrucous Plaque With Unusually Large Candida Blastoconidia: A Unique Clinicopathological Presentation of Systemic Mucocutaneous Candidiasis
Authors: Rozas-Muñoz Eduardo , Mozos Ana , Mir-Bonafé Juan F. , Cubiró Xavier , Sánchez-Reus Ferran , Monteagudo Carlos , Puig Lluís
Published: April 2018

Mucocutaneous candidiasis is a common infection affecting both immunocompetent and immunosuppressed individuals. Diversity in the clinical and histopathological presentation of mucocutaneous candidiasis is well known. However, the occurrence of cutaneous verrucous lesions and giant yeast-like structures has been rarely reported. In this article, we describe a case of disseminated mucocutaneous candidiasis in an immunosuppressed patient who presented as a verrucous plaque on the scrotum with giant Candida blastoconidia. This peculiar presentation expands the clinicopathological spectrum of mucocutaneous candidiasis and highlights the wide range of clinical manifestations and great morphologic variability of this common fungal infection.
Dyadic analysis of siblings' relationship quality, behavioural responses, and pain experiences during experimental pain
Authors: Schinkel Meghan G. , Chambers Christine T. , Corkum Penny , Jacques Sophie
Published: April 2018

Research on family factors in paediatric pain has primarily focused on parents; the role of siblings has been largely ignored. This study examined whether sibling relationship quality was related to siblings' behaviours during experimental pain, and whether the behaviours of an observing sibling were related to children's pain outcomes. Ninety-two sibling dyads between 8 and 12 years old completed both observational and questionnaire measures of sibling relationship quality. Children took turns completing the cold-pressor task (CPT) in a counterbalanced order with their sibling present. Pain outcomes (intensity, fear, and tolerance) were recorded for each sibling, and the behaviour of the observing and participating siblings during the CPT were coded as attending, nonattending, and coping/encouragement. Structural equation modelling, using the actor–partner interdependence model, was conducted to analyse the dyadic data. While participating in the CPT with their sibling present, greater levels of warmth and positivity in the sibling relationship were related to children engaging in more nonattending behaviours and less attending behaviours. Greater levels of attending behaviours by the observing child was related to the sibling having a lower pain tolerance, and greater levels of coping/encouragement behaviours by the observing child was related to the sibling reporting greater pain intensity and fear during the CPT. Children with warmer/positive sibling relationships were more likely to respond to acute pain by shifting the focus away from their pain experience (eg, through distraction) when a sibling was present. Pain-focused behaviours by an observing sibling are related to greater child pain and fear during experimental pain.
Determinants of Severity in Acute Pancreatitis
Authors: Sternby Hanna , Bolado Federico , Canaval-Zuleta Héctor J. , Marra-López Carlos , Hernando-Alonso Ana I. , del-Val-Antoñana Adolfo , García-Rayado Guillermo , Rivera-Irigoin Robin , Grau-García Francisco J. , Oms Lluís , Millastre-Bocos Judith , Pascual-Moreno Isabel , Martínez-Ares David , Rodríguez-Oballe Juan A. , López-Serrano Antonio , Ruiz-Rebollo María L. , Viejo-Almanzor Alejandro , González-de-la-Higuera Belén , Orive-Calzada Aitor , Gómez-Anta Ignacio , Pamies-Guilabert José , Fernández-Gutiérrez-del-Álamo Fátima , Iranzo-González-Cruz Isabel , Pérez-Muñante Mónica E. , Esteba María D. , Pardillos-Tomé Ana , Zapater Pedro , de-Madaria Enrique
Published: April 2018

Objective:

The aim of this study was to compare and validate the different classifications of severity in acute pancreatitis (AP) and to investigate which characteristics of the disease are associated with worse outcomes.

Summary of Background Data:

AP is a heterogeneous disease, ranging from uneventful cases to patients with considerable morbidity and high mortality rates. Severity classifications based on legitimate determinants of severity are important to correctly describe the course of disease.

Methods:

A prospective multicenter cohort study involving patients with AP from 23 hospitals in Spain. The Atlanta Classification (AC), Revised Atlanta Classification (RAC), and Determinant-based Classification (DBC) were compared. Binary logistic multivariate analysis was performed to investigate independent determinants of severity.

Results:

A total of 1655 patients were included; 70 patients (4.2%) died. RAC and DBC were equally superior to AC for describing the clinical course of AP. Although any kind of organ failure was associated with increased morbidity and mortality, persistent organ failure (POF) was the most significant determinant of severity. All local complications were associated with worse outcomes. Infected pancreatic necrosis correlated with high morbidity, but in the presence of POF, it was not associated to higher mortality when compared with sterile necrotizing pancreatitis. Exacerbation of previous comorbidity was associated with increased morbidity and mortality.

Conclusion:

The RAC and DBC both signify an advance in the description and differentiation of AP patients. Herein, we describe the complications of the disease independently associated to morbidity and mortality. Our findings are valuable not only when designing future studies on AP but also for the improvement of current classifications.
Minimally Invasive Lobectomy Is Associated With Lower Noncancer-specific Mortality in Elderly Patients
Authors: Hristov Boris , Eguchi Takashi , Bains Sarina , Dycoco Joe , Tan Kay See , Isbell James M. , Park Bernard J. , Jones David R. , Adusumilli Prasad S.
Published: April 2018

Objective:

To investigate cancer- and noncancer-specific mortality following lobectomy by minimally invasive surgery (MIS) versus open thoracotomy in elderly patients with nonsmall cell lung cancer (NSCLC).

Background:

Two-thirds of patients with NSCLC are ≥65 years of age. As age increases, the risk of competing events, such as noncancer death, also increases.

Methods:

Elderly patients (≥65 yrs of age) who have undergone curative-intent lobectomy for stage I-III NSCLC without induction therapy (2002–2013) were included (n=1,303). Of those, 607 patients had undergone MIS and 696 had undergone thoracotomy. Propensity-score matching was performed to identify pairs of thoracotomy and MIS patients with comparable clinical characteristics (eg, year of surgery, comorbidities, and pulmonary function). Association between surgical approach (MIS vs thoracotomy) and lung cancer-specific and noncancer-specific cumulative incidence of death (CID) was analyzed using competing risks approach.

Results:

Following propensity score matching of patients who had undergone thoracotomy (n=338) versus MIS (n=338), MIS was associated with shorter length of stay (P<0.001), lower noncancer-specific 1-year mortality (P=0.027), and lower noncancer-specific CID (P=0.014) compared with thoracotomy; there was no difference in lung cancer-specific CID between surgical approaches. On multivariable analysis, thoracotomy was a significant risk factor for noncancer-specific death (subhazard ratio 2.45, 95% CI 1.18–5.06,P=0.016) independent of age, sex, and diffusion capacity of the lungs for carbon monoxide.

Conclusion:

In a propensity score-matched cohort, multivariable analysis has indicated that lobectomy performed by MIS is associated with lower incidence of noncancer-specific mortality compared with lobectomy performed by open thoracotomy in elderly patients with NSCLC.
Postoperative Surgical Site Infections
Authors: Ali-Mucheru Mariam N. , Seville Maria T. , Miller Vickie , Sampathkumar Priya , Etzioni David A.
Published: April 2018

Objective:

To characterize agreement in the ascertainment of surgical site infections (SSIs) between the National Surgical Quality Improvement Program (NSQIP), National Healthcare Safety Network (NHSN), and administrative data.

Background:

The NSQIP, NHSN, and administrative data are the primary systems used to monitor and report SSIs for the purpose of quality control and benchmarking of hospitals and surgeons. These systems have different methods for identifying SSIs.

Methods:

We queried the NHSN, NSQIP, and administrative data systems for patients who had an operation at 1 of 4 hospitals within a single health system between January 2013 and September 2015. The detection of an SSI during a postoperative hospitalization was the outcome of analysis. Any SSI detected by one (or more) of these systems was analyzed by 2 reviewers to determine the presence of discrete elements of documentation constituting evidence of SSI. Concordance between the 3 systems (NHSN, NSQIP, and administrative data) was analyzed using Cohen's kappa.

Results:

After application of appropriate exclusion criteria, a cohort of 9447 inpatient operations was analyzed. In total, 130 SSIs were detected by 1 or more of the 3 systems, with reported SSI rates of 0.5% (NHSN), 0.7% (administrative data), and 1.0% (NSQIP). Of these 130 SSIs, only 17 SSIs were reported by all 3 systems. The concordance between these 3 systems was moderate (kappa values NSQIP-NHSN = 0.50 [0.40–0.60], administrative-NHSN = 0.36 [0.24–0.47], and administrative-NSQIP = 0.47 [0.38–0.57]). Chart review found that reasons for discordance were related to issues of different criteria as well as inaccuracies.

Conclusion:

There is significant discordance in the determination of SSIs reported by the NHSN, NSQIP, and administrative data. The differences and limitations of each of these systems have to be recognized, especially when using these data for quality reports and pay for performance.
Survival Implications of Increased Utilization of Local Excision for cT1N0 Esophageal Cancer
Authors: Sturm Emily C. , Zahnd Whitney E. , Mellinger John D. , Ganai Sabha
Published: April 2018

Objective:

We hypothesized that patients with cT1N0 esophageal cancer undergoing local excision would have lower survival compared with esophagectomy due to potential discordant staging.

Background:

Local excision has become an attractive alternative for management of early esophageal cancer, avoiding the morbidity of esophagectomy. It is uncertain if occult nodal metastasis impacts survival.

Methods:

An observational study was conducted using the National Cancer Database (1998–2012) for patients with clinical T1N0 esophageal cancer who underwent local excision (n = 1625) or esophagectomy (n = 3255).

Results:

The proportion of patients undergoing local excision increased from 12% in 1998 to 50% in 2012 (P < 0.001). After esophagectomy, 61% of cT1N0 cancers had concordant clinical and pathological staging, with 5.2% having positive nodal disease; 37% were staged concordant after local excision, with excess missing data (60%). Ninety-day mortality was 7.4% after esophagectomy compared with 2.8% after local excision (P < 0.001). While no significant difference was seen in unadjusted survival, adjusted Cox regression analysis indicated worse survival after esophagectomy compared with local excision for all cases [hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.27–1.95] and for patients with concordant staging (HR 1.68, 95% CI 1.23–2.28).

Conclusions:

Local excision for cT1N0 esophageal cancer has increased over time. Contrary to our hypothesis, despite incomplete nodal staging, patients undergoing local excision have favorable survival, particularly in the adenocarcinoma subgroup. This may reflect early differences in mortality due to differences in procedure-related complications and/or selection bias. As this study has limited power to compare outcomes between T1a and T1b cancers, further analysis is warranted.
Factors Associated With Prolonged Warm Ischemia Time Among Deceased Donor Kidney Transplant Recipients
Authors: Vinson Amanda J. , Rose Caren , Kiberd Bryce A. , Odutayo Ayodele , Kim S. Joseph , Alwayn Ian , Tennankore Karthik K.
Published: April 2018

Background

Prolonged warm ischemia time (WIT) is associated with graft failure and mortality, however less is known about factors associated with prolonged WIT.

Methods

In a cohort of United States deceased donor kidney transplant recipients identified using the Scientific Registry of Transplant Recipients (Jan 2005-Dec 2013), we identified factors associated with prolonged WIT (defined as ≥ 30 minutes versus 10-30 minutes) using hierarchical multilevel models adjusting for center effect, and WIT as a continuous variable using multiple linear regression of log-transformed data.

Results

Among 55 829 patients, potentially modifiable risk factors associated with prolonged WIT included increased recipient body mass index (BMI) (odds ratio [OR], 1.57; 95% confidence interval [CI], 1.44-1.72 for BMI > 35), right donor kidney (OR, 1.14; 95% CI, 1.08-1.19), and a prolonged cold ischemic time (OR, 1.23; 95% CI, 1.13-1.33 for cold ischemia time > 24 hours). Transplanting a right kidney into an obese recipient further prolonged WIT (OR, 1.75; 95% CI, 1.55-1.98; for BMI > 35), increasing overall WIT by 11.0%. There was no correlation between median WIT for a given center and annual center transplant rate (pairwise correlation coefficient, 0.0898).

Conclusions

In conclusion, several modifiable factors are associated with prolonged WIT and may represent strategies to improve WIT and subsequent posttransplant outcomes.
Thermal niche evolution across replicatedAnolislizard adaptive radiations
Authors: Gunderson Alex R. , Mahler D. Luke , Leal Manuel
Published: April 2018

Elucidating how ecological and evolutionary mechanisms interact to produce and maintain biodiversity is a fundamental problem in evolutionary ecology. Here, we focus on how physiological evolution affects performance and species coexistence along the thermal niche axis in replicated radiations ofAnolislizards best known for resource partitioning based on morphological divergence. We find repeated divergence in thermal physiology within these radiations, and that this divergence significantly affects performance within natural thermal environments. Morphologically similar species that co-occur invariably differ in their thermal physiology, providing evidence that physiological divergence facilitates species coexistence within anole communities. Despite repeated divergence, phylogenetic comparative analyses indicate that physiological traits have evolved more slowly than key morphological traits related to the structural niche. Phylogenetic analyses also reveal that physiological divergence is correlated with divergence in broad-scale habitat climatic features commonly used to estimate thermal niche evolution, but that the latter incompletely predicts variation in the former. We provide comprehensive evidence for repeated adaptive evolution of physiological divergence withinAnolisadaptive radiations, including the complementary roles of physiological and morphological divergence in promoting community-level diversity. We recommend greater integration of performance-based traits into analyses of climatic niche evolution, as they facilitate a more complete understanding of the phenotypic and ecological consequences of climatic divergence.
Multi-omics analysis of thermal stress response in a zooxanthellate cnidarian reveals the importance of associating with thermotolerant symbionts
Authors: Cziesielski Maha J. , Liew Yi Jin , Cui Guoxin , Schmidt-Roach Sebastian , Campana Sara , Marondedze Claudius , Aranda Manuel
Published: April 2018

Corals and their endosymbiotic dinoflagellates of the genusSymbiodiniumhave a fragile relationship that breaks down under heat stress, an event known as bleaching. However, many coral species have adapted to high temperature environments such as the Red Sea (RS). To investigate mechanisms underlying temperature adaptation in zooxanthellate cnidarians we compared transcriptome- and proteome-wide heat stress response (24 h at 32°C) of three strains of the model organismAiptasia pallidafrom regions with differing temperature profiles; North Carolina (CC7), Hawaii (H2) and the RS. Correlations between transcript and protein levels were generally low but inter-strain comparisons highlighted a common core cnidarian response to heat stress, including protein folding and oxidative stress pathways. RS anemones showed the strongest increase in antioxidant gene expression and exhibited significantly lower reactive oxygen species (ROS) levelsin hospite. However, comparisons of antioxidant gene and protein expression between strains did not show strong differences, indicating similar antioxidant capacity across the strains. Subsequent analysis of ROS production in isolated symbionts confirmed that the observed differences of ROS levelsin hospitewere symbiont-driven. Our findings indicate that RS anemones do not show increased antioxidant capacity but may have adapted to higher temperatures through association with more thermally tolerant symbionts.
Biased generalization of salient traits drives the evolution of warning signals
Authors: Gamberale-Stille Gabriella , Kazemi Baharan , Balogh Alexandra , Leimar Olof
Published: April 2018

The importance of receiver biases in shaping the evolution of many signalling systems is widely acknowledged. Here, we show that receiver bias can explain which traits evolve to become warning signals. For warning coloration, a generalization bias for a signalling trait can result from predators learning to discriminate unprofitable from profitable prey. However, because the colour patterns of prey are complex traits with multiple components, it is crucial to understand which of the many aspects of prey appearance evolve into signals. We provide experimental evidence that the more salient differences in prey traits give rise to greater generalization bias, corresponding to stronger selection towards trait exaggeration. Our results are based on experiments with domestic chickens as predators in a Skinner-box-like setting, and imply that the difference in appearance between profitable and unprofitable prey that is most rapidly learnt produces the greatest generalization bias. As a consequence, certain salient traits of unprofitable prey are selected towards exaggeration to even higher salience, driving the evolution of warning coloration. This general idea may also help to explain the evolution of many other striking signalling traits found in nature.
Intra-tumor heterogeneity defines treatment-resistant HER2+ breast tumors
Authors: Rye Inga H. , Trinh Anne , Sætersdal Anna , Nebdal Daniel , Lingjærde Ole Christian , Almendro Vanessa , Polyak Kornelia , Børresen-Dale Anne-Lise , Helland Åslaug , Markowetz Florian , Russnes Hege G.
Published: April 2018

Targeted therapy for patients with HER2 positive (HER2+) breast cancer has improved the overall survival, but many patients still suffer relapse and death of the disease. Intra-tumor heterogeneity of both estrogen receptor (ER) and HER2 expression has been proposed to play a key role in treatment failure, but little work has been done to comprehensively study this heterogeneity at the single-cell level.

In this study, we explored the clinical impact of intra-tumor heterogeneity of ER protein expression, HER2 protein expression, and HER2 gene copy number alterations. Using combined immunofluorescence and in situ hybridization on tissue sections followed by a validated computational approach, we analyzed more than 13,000 single tumor cells across 37 HER2+ breast tumors. The samples were taken both before and after neoadjuvant chemotherapy plus HER2-targeted treatment, enabling us to study tumor evolution as well.

We found that intra-tumor heterogeneity for HER2 copy number varied substantially between patient samples. Highly heterogeneous tumors were associated with significantly shorter disease-free survival and fewer long-term survivors. Patients for which HER2 characteristics did not change during treatment had a significantly worse outcome.

This work shows the impact of intra-tumor heterogeneity in molecular diagnostics for treatment selection in HER2+ breast cancer patients and the power of computational scoring methods to evaluate in situ molecular markers in tissue biopsies.
Container-based bioinformatics with Pachyderm
Authors: Novella Jon Ander , Khoonsari Payam Emami , Herman Stephanie , Whitenack Daniel , Capuccini Marco , Burman Joachim , Kultima Kim , Spjuth Ola
Published: April 2018

Motivation:

Computational biologists face many challenges related to data size, and they need to manage complicated analyses often including multiple stages and multiple tools, all of which must be deployed to modern infrastructures. To address these challenges and maintain reproducibility of results, researchers need (i) a reliable way to run processing stages in any computational environment, (ii) a well-defined way to orchestrate those processing stages, and (iii) a data management layer that tracks data as it moves through the processing pipeline.

Results:

Pachyderm is an open-source workflow system and data management framework that fulfills these needs by creating a data pipelining and data versioning layer on top of projects from the container ecosystem, having Kubernetes as the backbone for container orchestration. We adapted Pachyderm and demonstrated its attractive properties in bioinformatics. A Helm Chart was created so that researchers can use Pachyderm in multiple scenarios. The Pachyderm File System was extended to support block storage. A wrapper for initiating Pachyderm on cloud-agnostic virtual infrastructures was created. The benefits of Pachyderm are illustrated via a large metabolomics workflow, demonstrating that Pachyderm enables efficient and sustainable data science workflows while maintaining reproducibility and scalability.

Availability:

Pachyderm is available from https://github.com/pachyderm/pachyderm. The Pachyderm Helm Chart is available from https://github.com/kubernetes/charts/tree/master/stable/pachyderm. Pachyderm is available out-of-the-box from the PhenoMeNal VRE (https://github.com/phnmnl/KubeNow-plugin) and general Kubernetes environments instantiated via KubeNow. The code of the workflow used for the analysis is available on GitHub (https://github.com/pharmbio/LC-MS-Pachyderm).

Contact:

jon.novella@farmbio.uu.se
Deciphering hybrid larch reaction norms using random regression
Authors: Marchal Alexandre , Schlichting Carl D. , Gobin Rémy , Balandier Philippe , Millier Frédéric , Muñoz Facundo , Pâques Luc E. , Sánchez Leopoldo
Published: April 2018

The link between phenotypic plasticity and heterosis is a broad fundamental question, with stakes in breeding. We report a case-study evaluating temporal series of wood ring traits of hybrid larch (Larix decidua×L. kaempferiand reciprocal) in relation to soil water availability. Growth rings record the tree plastic responses to past environmental conditions, and we used random regressions to estimate the reaction norms of ring width and wood density with respect to water availability. We investigated the role of phenotypic plasticity on the construction of hybrid larch heterosis and on the expression of its quantitative genetic parameters. The data came from an intra-/interspecific diallel mating design between both parental species. Progenies were grown in two environmentally contrasted sites, in France. Ring width plasticity with respect to water availability was confirmed, as all three taxa produced narrower rings under the lowest water availability. Hybrid larch appeared to be the most plastic taxon as its superiority over its parental species increased with increasing water availability. Despite the low heritabilities of the investigated traits, we found that the quantitative genetic parameters varied along the water availability gradient. Finally, by means of a complementary simulation, we demonstrated that random regression can be applied to model the reaction norms of non-repeated records of phenotypic plasticity bound by a family structure. Random regression is a powerful tool for the modeling of reaction norms in various contexts, especially perennial species.
Cellular resolution imaging of vestibular processing across the larval zebrafish brain
Authors: Favre-Bulle Itia A. , Vanwalleghem Gilles , Taylor Michael A. , Rubinsztein-Dunlop Halina , Scott Ethan K.
Published: April 2018

The vestibular system, which reports on motion and gravity, is essential to postural control, balance, and egocentric representations of movement and space. The motion needed to stimulate the vestibular system complicates studying its circuitry, so we previously developed a method for fictive vestibular stimulation in zebrafish, using optical trapping to apply physical forces to the otoliths. Here, we combine this fictive stimulation with whole-brain calcium imaging at cellular resolution, delivering a comprehensive map of the brain regions and cellular responses involved in basic vestibular processing. We find these responses to be broadly distributed across the brain, with unique profiles of cellular responses and topography in each brain region. The most widespread and abundant responses involve excitation that is rate coded to the stimulus strength. Other responses, localized to the telencephalon and habenulae, show excitation that is only weakly rate coded and that is sensitive to weak stimuli. Finally, numerous brain regions contain neurons that are inhibited by vestibular stimuli, and these inhibited neurons are often tightly localised spatially within their regions. By exerting separate control over the left and right otoliths, we explore the laterality of brain-wide vestibular processing, distinguishing between neurons with unilateral and bilateral vestibular sensitivity, and revealing patterns by which conflicting vestibular signals from the two ears can be mutually cancelling. Our results show a broader and more extensive network of vestibular responsive neurons than has previously been described in larval zebrafish, and provides a framework for more targeted studies of the underlying functional circuits.
Reproducible functional connectivity alterations are associated with autism spectrum disorder
Authors: Holiga Štefan , Hipp Joerg F. , Chatham Christopher H. , Garces Pilar , Spooren Will , D’Ardhuy Xavier Liogier , Bertolino Alessandro , Bouquet Céline , Buitelaar Jan K , Bours Carsten , Rausch Annika , Oldehinkel Marianne , Bouvard Manuel , Amestoy Anouck , Caralp Mireille , Gueguen Sonia , Moal Myriam Ly-Le , Houenou Josselin , Beckmann Christian F. , Loth Eva , Murphy Declan , Charman Tony , Tillmann Julian , Laidi Charles , Delorme Richard , Beggiato Anita , Gaman Alexandru , Scheid Isabelle , Leboyer Marion , d’Albis Marc-Antoine , Sevigny Jeff , Czech Christian , Bolognani Federico , Honey Garry D. , Dukart Juergen
Published: April 2018

Despite the high clinical burden little is known about pathophysiology underlying autism spectrum disorder (ASD). Recent resting state functional magnetic resonance imaging (rs-fMRI) studies have found atypical synchronization of brain activity in ASD. However, no consensus has been reached on the nature and clinical relevance of these alterations. Here we address these questions in the most comprehensive, large-scale effort to date comprising evaluation of four large ASD cohorts. We followed a strict exploration and replication procedure to identify core rs-fMRI functional connectivity (degree centrality) alterations associated with ASD as compared to typically developing (TD) controls (ASD: N=841, TD: N=984). We then tested for associations of these imaging phenotypes with clinical and demographic factors such as age, sex, medication status and clinical symptom severity. We find reproducible patterns of ASD-associated functional hyper- and hypo-connectivity with hypo-connectivity being primarily restricted to sensory-motor regions and hyper-connectivity hubs being predominately located in prefrontal and parietal cortices. We establish shifts in between-network connectivity from outside to within the identified regions as a key driver of these abnormalities. The magnitude of these alterations is linked to core ASD symptoms related to communication and social interaction and is not affected by age, sex or medication status. The identified brain functional alterations provide a reproducible pathophysiological phenotype underlying the diagnosis of ASD reconciling previous divergent findings. The large effect sizes in standardized cohorts and the link to clinical symptoms emphasize the importance of the identified imaging alterations as potential treatment and stratification biomarkers for ASD.
Network analysis reveals differential metabolic functionality in antibiotic-resistantPseudomonas aeruginosa
Authors: Dunphy Laura J. , Yen Phillip , Papin Jason A.
Published: April 2018

Metabolic adaptations accompanying the development of antibiotic resistance in bacteria remain poorly understood. To interrogate this relationship, we profiled the growth of lab-evolved antibiotic-resistant lineages of the opportunistic pathogenPseudomonas aeruginosaacross 190 unique carbon sources. We semi-automatically calculated growth dynamics (maximum growth density, growth rate, and time to mid-exponential phase) of over 2,800 growth curves. These data revealed that the evolution of antibiotic resistance resulted in systems-level changes to growth dynamics and metabolic phenotype. Drug-resistant lineages predominantly displayed decreased growth relative to the ancestral lineage; however, resistant lineages occasionally displayed enhanced growth on certain carbon sources, indicating that adaption to drug can provide a growth advantage in certain environments. A genome-scale metabolic network reconstruction (GENRE) ofP. aeruginosastrain UCBPP-PA14 was paired with whole-genome sequencing data of one of the drug-evolved lineages to predict genes contributing to observed changes in metabolism. Finally, we experimentally validatedin silicopredictions to identify genes mutated in resistantP. aeruginosaaffecting loss of catabolic function. Our results build upon previous mechanistic knowledge of drug-induced metabolic adaptation and provide a framework for the identification of metabolic limitations in antibiotic-resistant pathogens. Robust drug-driven changes in bacterial metabolism have the potential to be exploited to select against antibiotic-resistant populations in chronic infections.
A Coupled Network of Growth Transform Neurons for Spike-Encoded Auditory Feature Extraction
Authors: Gangopadhyay Ahana , Aono Kenji , Mehta Darshit , Chakrabartty Shantanu
Published: April 2018

This paper builds upon our previously reported growth transform based optimization framework to present a novel spiking neuron model and demonstrate its application for spike-based auditory signal processing. Unlike conventional neuromorphic approaches, the proposed Growth Transform (GT) neuron model is tightly coupled to a system objective function, which results in network dynamics that are always stable and interpretable; and the process of spike generation and population dynamics is the result of minimizing an energy functional. We then extend the model to include axonal propagation delays in a manner that the optimized solution of the system or network objective function remains unaffected. The paper characterizes the model for different types of stimuli, and explores how changing different aspects of the cost function can reproduce known single neuron dynamics. We then investigate the properties of a coupled GT neural network that can generate spike-encoded auditory features corresponding to the output of a gammatone filterbank. We show that the discriminatory information is not only encoded in the traditional spike-rates and interspike-interval statistics, but is also encoded in the subthreshold response of GT neurons for inputs that are not strong enough to elicit spikes. We also demonstrate that while different forms of coupling between the neurons could produce compact and energy-efficient representation of the auditory features, the classification performance for a speaker recognition task remains invariant across different types of coupling. Thus, we believe that the proposed GT neuron model provides a flexible neuromorphic framework to systematically design large-scale spiking neural networks with stable and interpretable dynamics.
Counting with DNA in metabarcoding studies: how should we convert sequence reads to dietary data?
Authors: Deagle Bruce E. , Thomas Austen C. , McInnes Julie C. , Clarket Laurence J. , Vesterinen Eero J. , Clare Elizabeth L. , Kartzinel Tyler R. , Eveson J. Paige
Published: April 2018

Advances in DNA sequencing technology have revolutionised the field of molecular analysis of trophic interactions and it is now possible to recover counts of food DNA barcode sequences from a wide range of dietary samples. But what do these counts mean? To obtain an accurate estimate of a consumer’s diet should we work strictly with datasets summarising the frequency of occurrence of different food taxa, or is it possible to use the relative number of sequences? Both approaches are applied in the dietary metabarcoding literature, but occurrence data is often promoted as a more conservative and reliable option due to taxa-specific biases in recovery of sequences. Here, we point out that diet summaries based on occurrence data overestimate the importance of food consumed in small quantities (potentially including low-level contaminants) and are sensitive to the count threshold used to define an occurrence. Our simulations indicate that even with recovery biases incorporated, using relative read abundance (RRA) information can provide a more accurate view of population-level diet in many scenarios. The ideas presented here highlight the need to consider all sources of bias and to justify the methods used to interpret count data in dietary metabarcoding studies. We encourage researchers to continue to addressing methodological challenges, and acknowledge unanswered questions to help spur future investigations in this rapidly developing area of research.
Efficient sorting of single-unit activity from midbrain cells using KiloSort is as accurate as manual sorting
Authors: Allen Madeleine , Chowdhury Tara , Wegener Meredyth , Moghaddam Bita
Published: April 2018

Extracting single-unit activity from in vivo extracellular neural electrophysiology data requires sorting spikes from background noise and action potentials from multiple cells in order to identify the activity of individual neurons. Typically this has been achieved by algorithms that employ principal component analyses followed by manual allocation of spikes to individual clusters based on visual inspection of the waveform shape. This method of manual sorting can give varying results between human operators and is highly time-consuming, especially in recordings with higher levels of background noise. To address these problems, automatic sorting algorithms have begun to gain popularity as viable methods for sorting electrophysiological data, although little is known about the use of these algorithms with neural data from midbrain recordings. KiloSort is a relatively new algorithm that automatically clusters raw data which can then be manually curated. In this report, we compare results of manually-sorted and KiloSort-processed recordings from the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Sorting with KiloSort required substantially less time to complete, while yielding comparable and consistent results. We conclude that the use of KiloSort to identify single units from multi-channel recording in the VTA and SNc is accurate and efficient.
Deep learning of quality control for stereotaxic registration of human brain MRI
Authors: Fonov Vladimir S. , Dadar Mahsa ,   The PREVENT-AD Research Group, Collins D. Louis
Published: April 2018

Linear registration to stereotaxic space is a common first step in many automated image-processing tools for analysis of human brain MRI scans. This step is crucial for the success of the following image-processing steps. Several well-established algorithms are commonly used in the field of neuroimaging for this task, but none of them has a 100% success rate. Manual assessment of the registration is commonly used as part of quality control.

We propose a completely automatic quality control method based on deep learning that replaces human rater and accurately performs quality control assessment for stereotaxic registration of T1w brain scans.

In a recently published study from our group comparing linear registration methods, we used a database of 9693 MRI scans from several publically available datasets and applied five linear registration tools. In this study, the resulting images that were assessed and labeled by a human rater are used to train a deep neural network to detect cases when registration failed.

Our method was able to achieve 88% accuracy and 11% false positive rate in detecting scans that should pass quality control, better than a manual QC rater.
Targeting glutamine metabolism and redox state for leukemia therapy
Authors: Gregory Mark A. , Nemkov Travis , Zaberezhnyy Vadym , Park Hae J. , Gehrke Sarah , Hansen Kirk C. , D’Alessandro Angelo , DeGregori James
Published: April 2018

Acute myeloid leukemia (AML) is a hematological malignancy characterized by the accumulation of immature myeloid precursor cells. AML is poorly responsive to conventional genotoxic chemotherapy and a diagnosis of AML is usually fatal. More effective and less toxic forms of therapy are desperately needed. AML cells are known to be highly dependent on the amino acid glutamine for their survival. Here, we show that blocking glutamine metabolism through the use of a glutaminase inhibitor (CB-839) significantly impairs antioxidant glutathione production in multiple types of AML, resulting in accretion of mitochondrial reactive oxygen species (mitoROS) and apoptotic cell death. Moreover, glutaminase inhibition makes AML cells susceptible to adjuvant drugs that further perturb mitochondrial redox state, such as arsenic trioxide (ATO) and homoharringtonine (HHT). Indeed, the combination of ATO or HHT with CB-839 exacerbates mitoROS and apoptosis, and leads to more complete cell death in AML cell lines, primary AML patient samples andin vivousing mouse models of AML. In addition, these redox-targeted combination therapies are effective in eradicating acute lymphoblastic leukemia cellsin vitroandin vivo. Thus, targeting glutamine metabolism in combination with drugs that perturb mitochondrial redox state represents an effective and potentially widely applicable therapeutic strategy for treating multiple types of leukemia.

Key Points

Glutaminase inhibition commonly impairs glutathione metabolism and induces mitochondrial oxidative stress in acute myeloid leukemia cells

A glutaminase inhibitor synergizes with pro-oxidant drugs in inducing apoptosis and eliminating leukemia cellsin vitroandin vivo
Comparative analysis of IgG Responses to recombinant Qβ phage displayed MSP3 and UB05 in Dual HIV-malaria infected adults living in areas differing in Malaria transmission intensities
Authors: Lissom Abel , Ouambo Herve F. , Megnekou Rosette , Okeke Malachy I. , Ngu Loveline N. , Netongo Palmer M. , Ngoh Apeh A. , Sanders Carrie A. , Bawage Swapnil , Tchouangueu Thibau F. , Tchadji Colince J. , Okoli Arinze S. , Priso Ghislain D. Njambe , Garcia Rosario , Gutiérrez Anna , Chukwuma George O. , Esimone Charles O. , Achidi Eric A. , Mbacham Wilfred F. , Kaptue Lazare , Leke Rose FG , Park Chae Gyu , Waffo Alain Bopda , Nchinda Godwin W.
Published: April 2018

Immunoglobulin G specific responses againstPlasmodium falciparummerozoite antigens such as the merozoite surface protein 3 (MSP3) and UB05 are known to play critical roles in parasitemia control and protection from symptomatic illness. However when there is intense perennial malaria transmission coupled with concurrent infection with the human immunodeficiency virus type 1 (HIV), knowledge of IgG antibody response profiles is limited. In this study we assessed the impact of dual HIV-Malaria infections on IgG subclass responses to MSP3 (QβMSP3) and UB05 (QβUB05) in individuals living in two areas of Cameroon differing in transmission intensity. We observed differences in antigen specific IgG and IgG subclass responses which was dependent upon the antigen type, malaria transmission intensity, HIV infection, malaria infection and dual HIV-malaria infections. Individuals living in high malaria transmission areas irrespective of HIV or malaria status had significantly higher IgG responses to both antigens (P=0.0001 for QβMSP3, P=0.0001 for QβUB05) than their counterpart from low transmission areas. When dual HIV-Malaria infection is considered significantly higher QβMSP3 specific IgG1 (P=0.0001) and IgG3 (P=0.04) responses in double negative individuals was associated with protection against malaria in low transmission areas. Superior QβUBO5 specific IgG1 responses (P=0.0001) in double negative individuals were associated with protection in high transmission areas in contrast to significantly higher IgG3 responses to QβUB05 (P=0.0001) which were more relevant to protection in low malaria transmission areas in the same population. Thus, understanding immune responses to QβUB05 and QβMSP3 could facilitate the development of immunotherapeutic strategies suitable for areas differing in malaria transmission intensity.
Nisin penetratesStaphylococcus aureusbiofilms but shows differences in killing effects against sessile and planktonic cells
Authors: Godoy-Santos Fernanda , Pitts Betsey , Stewart Philip S. , Mantovani Hilário Cuquetto
Published: April 2018

Biofilms may restrict antimicrobial penetration and contribute to the recalcitrance of bacterial infections. In this work, we investigated the penetration of nisin intoS. aureusbiofilms and compared the susceptibility ofS. aureusplanktonic and sessile cells to this lantibiotic. Biofilms were grown under continuous flow in CDC reactors and calcein fluorescence was used to monitor the effect of nisin on the cytoplasmic membrane ofS. aureuscells. Confocal scanning laser microscopy (CLSM) showed that calcein was lost within approximately 20 min in CDC biofilms, demonstrating that nisin penetrated to the bottom of the biofilm and caused membrane permeabilization. Viability analysis using PI staining showed that nisin was bactericidal againstS. aureussessile cells. Time-kill assays were performed againstS. aureusin the following conditions: homogenized exponential planktonic (HEP), homogenized stationary planktonic (HSP), homogenized CDC biofilm (HB) and intact CDC biofilm (IB). The mean viability reduction of HEP and HSP were 6.71 and 1.64 log CFU.ml-1, respectively, confirming that stationaryS. aureuscells were much less susceptible than exponential cells. The HB and IB treatments showed mean viability reductions of 1.25 and 0.50 log CFU.ml-1, respectively. Nisin activity againstS. aureuswas not limited by its ability to penetrate the bacterial biofilm, but the killing efficacy of the antimicrobial peptide was reduced by the physiological status of the biofilm-grown cells.

Importance

Biofilms represent a major problem to control microorganisms in industrial environments and medical devices. We developed a direct real-time microscopic visualization technique to demonstrate experimentally that the antimicrobial peptide nisin is able to penetrateS. aureusbiofilms. Our results confirmed that nisin caused membrane permeabilization of sessile bacteria and revealed qualitative agreement between viability loss and membrane integrity loss. This approach could improve the evaluation of antibacterial susceptibility breakpoints when testing the efficacy of standard and novel antimicrobials.
Stimulus Vignetting and Orientation Selectivity in Human Visual Cortex
Authors: Roth Zvi N. , Heeger David J. , Merriam Elisha P.
Published: April 2018

Neural selectivity to orientation is one of the simplest and most thoroughly-studied cortical sensory features. Here, we show that a large body of research that purported to measure orientation tuning may have in fact been inadvertently measuring sensitivity to second-order changes in luminance, a phenomenon we term ‘vignetting’. Using a computational model of neural responses in primary visual cortex (V1), we demonstrate the impact of vignetting on simulated V1 responses. We then used the model to generate a set of predictions, which we confirmed with functional MRI experiments in human observers. Our results demonstrate that stimulus vignetting can wholly determine the orientation selectivity of responses in visual cortex measured at a macroscopic scale, and suggest a reinterpretation of a well-established literature on orientation processing in visual cortex.