bluuebunny/crossref_metadata_2025 huggingface dataset:
Aggregate health and economic burden of herpes zoster in the United States: illustrative example of a pain condition
Authors: Harvey Michael , Prosser Lisa A. , Rose Angela M. , Ortega-Sanchez Ismael R. , Harpaz Rafael
Published: October 2019

Our objective was to develop comprehensive national estimates of the total burden of herpes zoster (HZ) among U.S. adults, including direct (ie, medical costs) and indirect (ie, productivity losses) costs, as well as its psychosocial impact (ie, quality of life losses). Using a patient-level microsimulation model, we projected health and economic outcomes among U.S. adults aged 18 years and older using a 10-year time horizon. We conducted a comprehensive systematic literature review to generate parameter values and conducted simulation modeling to generate our outcomes, including numbers of cases of uncomplicated HZ, postherpetic neuralgia (PHN), and ocular complications, productivity losses, and losses in quality-adjusted life years (QALYs). We used a societal perspective for outcomes; the costing year was 2015. Projected outcomes for an unvaccinated population included 1.1 million HZ cases, 114,000 PHN cases, and 43,000 ocular complications annually, resulting in approximately 67,000 QALYs lost. HZ and its complications would incur costs of $2.4 billion in direct medical costs and productivity losses annually. Projected QALY losses were most sensitive to HZ and PHN health utility values in the model. Cost estimates were most sensitive to the probability of HZ and to the costs per episode of PHN. The national burden of direct, indirect, and psychosocial HZ costs is substantial. Our results can inform economic analyses for HZ vaccines. Comprehensive, national assessments of the total burden of other painful conditions would be very informative.
Does Aggressive Variant Histology Without Invasive Features Predict Overall Survival in Papillary Thyroid Cancer?
Authors: Limberg Jessica , Ullmann Timothy M. , Stefanova Dessislava , Buicko Jessica L. , Finnerty Brendan M. , Zarnegar Rasa , Fahey Thomas J. , Beninato Toni
Published: October 2019

Objective:

We aimed to clarify whether aggressive histology of papillary thyroid cancer (PTC) impacts overall survival (OS).

Summary Background Data:

Aggressive variants of PTC (AVPTC) are associated with invasive features. However, their behavior in the absence of these features is not well characterized.

Methods:

Patients treated from 2004 to 2015 for classic PTC (cPTC) or AVPTCs were identified from the National Cancer Database. Patients were further stratified based on presence of at least 1 invasive feature—extrathyroidal extension, multifocality, lymphovascular invasion, nodal or distant metastasis. Demographics, treatments, and OS were compared.

Results:

A total of 170,778 patients were included—162,827 cPTC and 7951 AVPTC. Invasive features were more prevalent in AVPTC lesions compared to cPTC (70.7% vs 59.7%, P < 0.001). AVPTC included tall cell/columnar cell (89.5%) and diffuse sclerosing (10.5%) variants. Patients with invasive features had worse OS irrespective of histology. Furthermore, when controlling for demographics, tumor size, and treatment variables in patients with noninvasive lesions, AVPTC histology alone was not associated with worse OS compared to cPTC (P = 0.209). In contrast, among patients who had at least 1 invasive feature, AVPTC histology was independently predictive of worse OS (P < 0.05) {TCV/Columnar hazard ratio [HR] 1.2; [95% confidence interval (CI) 1.1–1.3] and diffuse sclerosing HR 1.3; 95% CI 1.0–1.7]}. All invasive features, except multifocality, were independently associated with worse OS, with metastasis being the most predictive [HR 2.9 (95% CI 2.6–3.2) P < 0.001].

Conclusions:

In the absence of invasive features, AVPTC histology has similar OS compared to cPTC. In contrast, diffuse sclerosing and tall cell/columnar variants are associated with worse OS when invasive features are present.
Reduction of Postoperative Wound Infections by Antiseptica (RECIPE)?
Authors: Strobel Rahel M. , Leonhardt Marja , Krochmann Anika , Neumann Konrad , Speichinger Fiona , Hartmann Lisa , Lee Lucas D. , Beyer Katharina , Daum Severin , Kreis Martin E. , Lauscher Johannes C.
Published: October 2019

Objective:

To evaluate whether intraoperative subcutaneous wound irrigation with 0.04% polyhexanide can reduce surgical site infection (SSI) in elective laparotomies compared to saline.

Background:

SSI is a common complication after gastrointestinal surgery. To date, there is a lack of evidence whether subcutaneous wound irrigation is beneficial in terms of reduction of SSI.

Methods:

The RECIPE trial was an investigator initiated single-center, single-blind prospective, randomized controlled trial with 2 parallel treatment groups, comparing wound irrigation with 0.9% saline to antiseptic 0.04% polyhexanide solution in elective laparotomies. Primary endpoint was the rate of SSI within 30 days postoperatively according to Centers for Disease Control and Prevention criteria.

Results:

Between February 02, 2015, and May 23, 2018, 456 patients were randomly assigned to saline (n = 228) or polyhexanide (n = 228). Final cohort for analysis comprised 393 patients (202 in the saline and 191 in the polyhexanide group). Overall rate of SSI was 28.2%, n = 111. Simple analysis with cross tabulation revealed that significantly fewer SSIs occurred in the polyhexanide group: n = 70 (34.7%) versus n = 41 (21.5%); P = 0.004. In a multiple logistic regression model the factor wound irrigation with polyhexanide [odds ratio (OR) 0.44; 95% confidence interval (CI) 0.27–0.72; P = 0.001) was associated with risk reduction of SSI. Preoperative anemia (OR 2.08; 95% CI 1.27–3.40; P = 0.004) and more than 5 prior abdominal operations compared to none (OR 8.51; 95% CI 2.57–28.21; P < 0.001) were associated with SSI.

Conclusions:

Intraoperative subcutaneous wound irrigation with antiseptic 0.04% polyhexanide solution is effective in reducing SSI after elective laparotomies.
Musical training sharpens behavioral tuning more saliently than peripheral tuning
Authors: Gong Qin , Wang Yao
Published: October 2019

Musical training appears to enhance performance at both peripheral and central auditory sites. We compared behavioral and peripheral frequency tuning in normal-hearing musicians and nonmusicians, whose native language is Mandarin. The results indicate that, at higher probe frequencies, musical training sharpens behavioral tuning more saliently than peripheral tuning. The improved peripheral tuning for musician appears to result principally from efferent top-down control rather than local cochlear changes.
Isolated night cough in children: how does it differ from wheeze?
Authors: Jurca Maja , Goutaki Myrofora , Latzin Philipp , Gaillard Erol A. , Spycher Ben D. , Kuehni Claudia E.
Published: October 2019

Background

Children with night cough but no wheeze might have a mild form of asthma (cough variant asthma), sharing risk factors with children who wheeze, and possibly developing wheeze later.

Methods

We compared risk factors of children with isolated night cough and children with wheeze in the Leicester Respiratory Cohort study at ages 1, 4, 6, and 9 years. We also compared prognoses of children with isolated night cough, children with wheeze, and asymptomatic children.

Results

Among 4,101 children at age 1 year, 2,854 at 4, 2,369 at 6, and 1,688 at 9 years, the prevalence of isolated night cough was 10% at age 1 and 18% in older children, while prevalence of wheeze decreased from 35% at 1 year to 13% at age 9. Although many risk factors were the same for cough and wheeze, day care, reflux, and family history of bronchitis were more strongly associated with cough, and male sex and family history of asthma with wheeze. Over one-third of pre-schoolers with cough continued to cough at school age, but their risk of developing wheeze was similar to that of children asymptomatic at earlier surveys. Wheeze tracked more strongly throughout childhood than cough.

Conclusions

Some risk factors for cough and wheeze were shared and some were not; there was little evidence that children with isolated night cough have an increased risk of future wheeze. This suggests that only a fraction of children with isolated night cough might have a variant of asthma, if at all.
Quaternary Prevention: Is this Concept Relevant to Public Health? A Bibliometric and Descriptive Content Analysis
Authors: Depallens Miguel Andino , Guimarães Jane Mary de Medeiros , Filho Naomar Almeida
Published: October 2019

Objective

To measure and map research output on Quaternary Prevention (P4) and outline research trends; to assess the papers content, mainly regarding methods and subjects approached in order to contribute to the improvement of global knowledge about P4 and to evaluate its relevance for public health.

Design

Bibliometric and descriptive content analysis.

Articles reviewed

Scientific articles about P4 recorded in Pubmed, LILACS, Scielo or CINAHL published until August 2018, with correspondent full articles available in Portuguese, English, Spanish, German or French.

Main outcome measures

Year of publication, first authors’ name and nationality, journals’ name, country and ranking, publication language, used methods and main reported subjects.

Results

65 articles were included, published in 33 journals of 16 countries between 2003 and 2018 with a peak of publications in 2015. The first authors came from 17 different countries, 23% of them were Brazilian and Uruguay was the leading nation according to the scientific production per capita. 40% of all the selected articles were in English, 32% in Portuguese, 26% in Spanish. 28% of the papers were published in Q1 or Q2 journals. The research outputs on P4 begun first in the South of Europe, went to South America and then expanded worldwide. 88% of the articles were bibliographic research and 38% of all focused on specific examples of medical overuse (including several screening tests).

Conclusions

Quaternary prevention represents an ethical and valid approach to prevent occurence of iatrogenic events and to achieve equal and fair access to health services. Conceptual, geographical and linguistic elements, as well as WONCA conferences and type of healthcare systems in the authors’ country were fundamental factors that affected research output. The quality and quantity of available studies is still limited, therefore further investigations are recommended to assess the effective impact of P4 on public health.
Joint modelling of individual trajectories, within-individual variability and a later outcome: systolic blood pressure through childhood and left ventricular mass in early adulthood
Authors: Parker Richard M.A. , Leckie George , Goldstein Harvey , Howe Laura D. , Heron Jon , Hughes Alun D. , Phillippo David M. , Tilling Kate
Published: October 2019

Within-individual variability of repeatedly-measured exposures may predict later outcomes: e.g. blood pressure (BP) variability (BPV) is an independent cardiovascular risk factor above and beyond mean BP. Since two-stage methods, known to introduce bias, are typically used to investigate such associations, we introduce a joint modelling approach, examining associations of both mean BP and BPV across childhood to left ventricular mass (indexed to height; LVMI) in early adulthood with data from the UK’s Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Using multilevel models, we allow BPV to vary between individuals (a “random effect”) as well as to depend on covariates (allowing for heteroscedasticity). We further distinguish within-clinic variability (“measurement error”) from visit-to-visit BPV. BPV was predicted to be greater at older ages, at higher bodyweights, and in females, and was positively correlated with mean BP. BPV had a positive association with LVMI (10% increase in SD(BP) was predicted to increase LVMI by mean = 0.42% (95% credible interval: −0.47%, 1.38%)), but this association became negative (mean = −1.56%, 95% credible interval: −5.01%, 0.44%)) once the effect of mean BP on LVMI was adjusted for. This joint modelling approach offers a flexible method of relating repeatedly-measured exposures to later outcomes.
Inconsistent Addiction Treatment for Patients Undergoing Cardiac Surgery for Injection Drug Use-Associated Infective endocarditis
Authors: Tiako Max Jordan Nguemeni , Hong Seong , Mahmood Syed Usman Bin , Mori Makoto , Mangi Abeel , Yun James , Juthani-Mehta Manisha , Geirsson Arnar
Published: October 2019

Introduction

Cases of injection drug use-related infective endocarditis (IDU-IE) requiring surgery are rising in the setting of the current U.S. opioid epidemic. We thus aimed to determine the nature of addiction interventions in the perioperative period.

Methods

This is a retrospective review of surgical IDU-IE from 2011 to 2016 at a tertiary care center in New Haven, Connecticut. The data collected included substances consumed recreationally, consultations by social work (SW), psychiatry, pharmacotherapy for addiction, and evidence of enrollment in a drug rehabilitation program upon discharge.

Among patients with active drug use (ADU), we compared the 24-month survival of those who received at least one form of addiction intervention to that of those who did not.

Results

Forty-two patients (75%) had active drug use. Among them, 22 used heroin. Forty-one patients (73.2%) saw SW, 17 (30.4%) saw psychiatry; 14 (25%) saw neither SW nor psychiatry.

Twenty-one patients (37.5%) received methadone, 6 (10.7%) received buprenorphine, 1 (0.02%) received naltrexone; 26 (46.4%) did not receive any pharmacotherapy. Fifteen patients (26.8%) attended a drug rehabilitation program, 13 (86.7%) of whom had seen SW and 8 (53%) psychiatry. Among patients with ADU, there was no statistically significant difference in survival between those who received at least one intervention and those who did not (p=0.1 by log rank).

Conclusion

Addiction interventions are deployed inconsistently for patients with surgical IDU-IE. Untreated substance use disorder and recurrent endocarditis are the leading cause of death in this population. Studying best-practices for perioperative interventions in IDU-IE and establishing protocols are of the upmost importance.
Microbial signalling of Rhizobium bacteria as a method for cereal crop germination enhancement
Authors: Judge Ciara , Hickey Emer
Published: October 2019

1.

Rhizobiumnitrogen-fixing bacteria are a well studied microorganism family in the scientific community and it’s effects have been investigated thoroughly since its initial identification. This study aimed to research further the interactions of this bacteria with members of non-legume plant families, i.e. thepoaceaegrass species. This multi-year experimental series focuses on the germination stage of these plants, with varying treatments being applied to the seeds pre-germination in order to first test for a quantifiable effect taking place, and later to characterise the mechanism due to which an effect was noted. The identifier used to establish the presence of an effect was the germination rate of the seeds, which was found by examining the testa of each seed for the emergence of a radicle or plumule. Approximately 15,000 samples were tested during this process, the results of which were subsequently statistically analysed at a 95% confidence level. A conclusive increase of 40% (p<0.0001) was noted in the germination of barley seeds when treated withR. leguminosarum. Following tests which confirmed increase enzymatic activity, tests using a different bacterium (A. tumefaciens) and further review of existing literature, it was deemed likely that this effect was due to the release of lipo-chitooligosaccharides (LCOs) by the bacteria. It has been established that synthetically isolated LCO’s can positively effect barley germination. It is believed that this is the first time it has been demonstrated that freeRhizobiumbacteria in suspension can stimulate faster germination in thepoaceaespecies due to the natural release of LCO’s by the bacteria.
Effects of mutations in pigeonMc1rimplicate an expanded plumage color patterning regulatory network
Authors: Krishnan Shreyas , Cryberg Richard L.
Published: October 2019

Studies in mammals have shown that the Melanocortin 1 receptor occupies a pivotal role as a nexus for integrating paracrine and autocrine signals to regulate pigment production and type-switching between pheomelanin (red/yellow) and eumelanin (black/brown) pigment synthesis in melanocytes. Inactivating mutations in theMc1rgene are responsible for recessive pheomelanic reddening traits in several species, while mutations that increase activity cause dominant eumelanic darkening traits in mammals and birds. Previous efforts to associateMc1rcoding variants with color variation in pigeons (Columba livia) have yielded conflicting results. Applying a reverse genomic approach, we discovered a novel 500 base pair frameshifting deletion in pigeonMc1rthat likely inactivates the single-exon gene. Segregation analysis revealed complete cosegregation (LOD = 12.2) withsmoky(symbolsy), a recessive pigmentation trait reported in these pages by Willard F. Hollander 80 years ago. We coupled these findings with breeding tests to determine thatDirty(V), a dominant darkening trait, is allelic tosy, and identified two independentValleles, one of which is associated with melanic morphs of two other bird species. In contrast to observations thatMc1rinactivation results in uniform pheomelanic pelage in mammals, its loss in otherwise wild-type pigeons occurs without apparent pheomelanism, instead increasing plumage eumelanism while leaving black bar pattern elements of the tail and wing largely intact. These findings require reconsideration of Mc1r’s presumed role in pigment type-switching in birds, and suggest the existence of Mc1r-independent pathways for eumelanic pigmentation pattern regulation unknown in mammals.
Shared transcriptional responses to con- and heterospecific behavioral antagonists in a wild songbird
Authors: Louder Matthew I. M. , Lafayette Michael , Louder Amber A. , Uy Floria M. K. , Balakrishnan Christopher N. , Yasukawa Ken , Hauber Mark E.
Published: October 2019

The recognition of and differential responses to salient stimuli are among the main drivers of behavioral plasticity, yet, how animals evolve and modulate functional responses to novel classes of antagonistic stimuli remain poorly understood. We studied free-living male red-winged blackbirds (Agelaius phoeniceus) to test whether gene expression responses in blood are distinct or shared between patterns of aggressive behavioral responses directed at simulated conspecific versus heterospecific intruders. In this species, males defend territories against conspecific males and respond aggressively to female brown-headed cowbirds (Molothrus ater), a brood parasite that commonly lays eggs in blackbird nests. Both conspecific songs and parasitic calls elicited aggressive responses from focal subjects and caused a downregulation in genes associated with immune system response, relative to control calls of a second, harmless heterospecific species. In turn, only the conspecific song treatment elicited an increase in singing behavior and an upregulation of genes associated with metabolic processes relative to the two heterospecific calls. Our results suggest that aspects of antagonistic responses to both conspecifics and brood parasites can be based on similar physiological responses, suggestive of shared molecular and behavioral pathways involved in the recognition and reaction to both evolutionarily old and new enemies.
Proteome and phosphoproteome changes associated with prognosis in acute myeloid leukemia
Authors: Aasebø Elise , Berven Frode S. , Bartaula-Brevik Sushma , Stokowy Tomasz , Hovland Randi , Vaudel Marc , Døskeland Stein Ove , McCormack Emmet , Batth Tanveer S. , Olsen Jesper V. , Bruserud Øystein , Selheim Frode , Hernandez-Valladares Maria
Published: October 2019

Acute myeloid leukemia (AML) is a hematological cancer that mainly affects the elderly. Although complete remission (CR) is achieved for majority of the patients after induction and consolidation therapies, nearly two-thirds relapse within a short interval. Understanding biological factors that determine relapse has therefore become of major clinical interest in AML. We utilized liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify protein changes and protein phosphorylation events associated with AML relapse in primary cells from 41 AML patients at time of diagnosis. Patients were defined as relapse-free if they had not relapsed within a 5-year clinical follow-up after AML diagnosis. Relapse was associated with increased expression of RNA processing proteins and decreased expression of V-ATPase proteins. We also observed an increase in phosphorylation events catalyzed by cyclin-dependent kinases (CDKs) and casein kinase 2 (CSK2). The biological relevance of the proteome findings was supported by cell proliferation assays using inhibitors of V-ATPase (bafilomycin), CSK2 (CX-4945), CDK4/6 (abemaciclib) and CDK2/7/9 (SNS-032). While bafilomycin preferentially inhibited the cells from relapse patients, the kinase inhibitors were less efficient in these cells. This suggests that therapy against the upregulated kinases also could target the factors inducing their upregulation rather than their activity. In conclusion, our study presents markers that could help predict AML relapse and direct therapeutic strategies.
Predicting cellular position in the Drosophila embryo from Single-Cell Transcriptomics data
Authors: Tanevski Jovan , Nguyen Thin , Truong Buu , Karaiskos Nikos , Ahsen Mehmet Eren , Zhang Xinyu , Shu Chang , Xu Ke , Liang Xiaoyu , Hu Ying , Pham Hoang V.V. , Xiaomei Li , Le Thuc D. , Tarca Adi L. , Bhatti Gaurav , Romero Roberto , Karathanasis Nestoras , Loher Phillipe , Chen Yang , Ouyang Zhengqing , Mao Disheng , Zhang Yuping , Zand Maryam , Ruan Jianhua , Hafemeister Christoph , Qiu Peng , Tran Duc , Nguyen Tin , Gabor Attila , Yu Thomas , Glaab Enrico , Krause Roland , Banda Peter ,   DREAM SCTC Consortium, Stolovitzky Gustavo , Rajewsky Nikolaus , Saez-Rodriguez Julio , Meyer Pablo
Published: October 2019

Single-cell RNA-seq technologies are rapidly evolving but while very informative, in standard scRNAseq experiments the spatial organization of the cells in the tissue of origin is lost. Conversely, spatial RNA-seq technologies designed to keep the localization of the cells have limited throughput and gene coverage. Mapping scRNAseq to genes with spatial information increases coverage while providing spatial location. However, methods to perform such mapping have not yet been benchmarked. To bridge the gap, we organized the DREAM Single-Cell Transcriptomics challenge focused on the spatial reconstruction of cells from the Drosophila embryo from scRNAseq data, leveraging as gold standard genes with in situ hybridization data from the Berkeley Drosophila Transcription Network Project reference atlas. The 34 participating teams used diverse algorithms for gene selection and location prediction, while being able to correctly localize rare subpopulations of cells. Selection of predictor genes was essential for this task and such genes showed a relatively high expression entropy, high spatial clustering and the presence of prominent developmental genes such as gap and pair-ruled genes and tissue defining markers.
A 5’ UTR G-quadruplex controls localisation and translation of a potassium leak channel mRNA
Authors: Maltby Connor J. , Schofield James P. R. , Houghton Steven D. , O’Kelly Ita , Vargas-Caballero Mariana , Deinhardt Katrin , Coldwell Mark J.
Published: October 2019

RNA G-quadruplexes (G4s) are non-canonical secondary structures that have been proposed to function as regulators of post-transcriptional mRNA localisation and translation. G4s within 3’ UTRs of some neuronal mRNAs are known to control their distal localisation and local translation, contributing to the distinct local proteomes that facilitate the synaptic remodelling attributed to normal cellular function. In this study, we characterise the G4 formation of a (GGN)13repeat found within the 5’ UTR of KCNK9 mRNA, encoding the potassium 2-pore domain leak channel Task3. Using circular dichroism, we show that this (GGN)13repeat forms a parallel G4 that exhibits the stereotypical potassium specificity of a G4, remaining thermostable under physiological ionic conditions. The G4 is inhibitory to translation of Task3, which can be overcome through the activity of the G4-specific helicase DHX36, consequently increasing K+leak currents and decreasing resting membrane potentials in HEK293 cells. Additionally, we observe that this G4 is fundamental to ensuring the delivery of Task3 mRNA to distal primary cortical neurites. It has previously been shown that abnormal Task3 expression correlates with neuronal dysfunction, we therefore posit that this G4 is required for regulated local expression of Task3 leak channels that maintain K+leak currents within neurons.
Deep learning of virus infections reveals mechanics of lytic cells
Authors: Andriasyan Vardan , Yakimovich Artur , Georgi Fanny , Petkidis Anthony , Witte Robert , Puntener Daniel , Greber Urs F.
Published: October 2019

Imaging across scales gives insight into disease mechanisms in organisms, tissues and cells. Yet, rare infection phenotypes, such as virus-induced cell lysis have remained difficult to study. Here, we developed fixed and live cell imaging modalities and a deep learning approach to identify herpesvirus and adenovirus infections in the absence of virus-specific stainings. Procedures comprises staining of infected nuclei with DNA-dyes, fluorescence microscopy, and validation by virus-specific live-cell imaging. Deep learning of multi-round infection phenotypes identified hallmarks of adenovirus-infected cell nuclei. At an accuracy of >95%, the procedure predicts two distinct infection outcomes 20 hours prior to lysis, nonlytic (nonspreading) and lytic (spreading) infections. Phenotypic prediction and live-cell imaging revealed a faster enrichment of GFP-tagged virion proteins in lytic compared to nonlytic infected nuclei, and distinct mechanics of lytic and nonlytic nuclei upon laser-induced ruptures. The results unleash the power of deep learning based prediction in unraveling rare infection phenotypes.
A multilayer network model of neuron-astrocyte populations in vitro reveals mGluR5inhibition is protective following traumatic injury
Authors: Schroeder Margaret E. , Bassett Danielle S. , Meaney David F.
Published: October 2019

Astrocytes communicate bidirectionally with neurons, enhancing synaptic plasticity and promoting the synchronization of neuronal microcircuits. Despite recent advances in understanding neuron-astrocyte signaling, little is known about astrocytic modulation of neuronal activity at the population level, particularly in disease or following injury. We used high-speed calcium imaging of mixed cortical culturesin vitroto determine how population activity changes after disruption of glutamatergic signaling and mechanical injury. We constructed a multilayer network model of neuron-astrocyte connectivity, which captured distinct topology and response behavior from single cell type networks. mGluR5inhibition decreased neuronal activity, but did not on its own disrupt functional connectivity or network topology. In contrast, injury increased the strength, clustering, and efficiency of neuronal but not astrocytic networks, an effect that was not observed in networks pre-treated with mGluR5inhibition. Comparison of spatial and functional connectivity revealed that functional connectivity is largely independent of spatial proximity at the microscale, but mechanical injury increased the spatial-functional correlation. Finally, we found that astrocyte segments of the same cell often belong to separate functional communities based on neuronal connectivity, suggesting that astrocyte segments function as independent entities. Our findings demonstrate the utility of multilayer network models for characterizing the multiscale connectivity of two distinct but functionally dependent cell populations.

AUTHOR SUMMARY

Astrocytes communicate bidirectionally with neurons, enhancing synaptic plasticity and promoting the synchronization of neuronal microcircuits. We constructed a multilayer network model of neuron-astrocyte connectivity based on calcium activity in mixed cortical cultures, and used this model to evaluate the effect of glutamatergic inhibition and mechanical injury on network topology. We found that injury increased the strength, clustering, and efficiency of neuronal but not astrocytic networks, an effect that was not observed in injured networks pre-treated with a glutamate receptor antagonist. Our findings demonstrate the utility of multilayer network models for characterizing the multiscale connectivity of two distinct but functionally dependent cell populations.
North American Birds Require Mitigation and Adaptation to Reduce Vulnerability to Climate Change
Authors: Bateman Brooke L. , Wilsey Chad , Taylor Lotem , Wu Joanna , LeBaron Geoffrey S. , Langham Gary
Published: October 2019

Biodiversity is being lost at an alarming rate across the globe, with extinction rates up to a hundred times greater than historical norms. Climate change will only exacerbate this crisis. The rapid pace of projected climate change is set to push birds to seek new locations, drastically reshuffling the avian communities of North America. In an emerging climate crisis, effective conservation requires both adaptation and mitigation to improve the resilience of species. However, the pledged reductions in greenhouse gas emissions outlined in the Paris Agreement framework would still lead to a 3.2°C or greater increase in global mean temperature by the end of this century. In this study, we use big data analytics to develop species distribution models and assess the vulnerability of 604 North American birds to multiple climate change scenarios. We assess how climate change mitigation can affect the number of species vulnerable to climate change, as well as the species and locations at risk if emissions continue unchecked. Our results indicate that over two-thirds of North American birds are moderately or highly vulnerable to climate change under a 3.0°C global warming scenario. Of these climate-vulnerable species, 76% would have reduced vulnerability and 38% of those would be considered non-vulnerable if warming were stabilized at 1.5°C. Thus, the current pledge in greenhouse gas reductions set by the Paris Agreement is inadequate to reduce vulnerability to birds. Additionally, if climate change proceeds on its current trajectory, arctic birds, waterbirds and boreal and western forest birds will be highly vulnerable to climate change; groups that are currently not considered of high conservation concern. Thus, there is an urgent need for both aggressive policies to mitigate emissions and focused conservation adaptation actions to protect birds and the places they need in a changing climate.
Priming enables a NEK7-independent route of NLRP3 activation
Authors: Schmacke Niklas A. , Gaidt Moritz M. , Szymanska Inga , O’Duill Fionan , Stafford Che A. , Chauhan Dhruv , Fröhlich Adrian L. , Nagl Dennis , Pinci Francesca , Schmid-Burgk Jonathan L. , Hornung Veit
Published: October 2019

The NLRP3 inflammasome plays a central role in antimicrobial defense, as well as in sterile inflammatory conditions. NLRP3 activity is governed by two independent signals. The first signal primes NLRP3, allowing it to respond to its activation signal. In the murine system, the mitotic spindle kinase NEK7 has been identified as a crucial factor in relaying the activation signal to NLRP3. Here we show that the requirement for NEK7 can be bypassed by TAK1-dependent post-translational priming. Under pro-inflammatory conditions that activate TAK1, NEK7 was dispensable for NLRP3 inflammasome formation in human and murine cells. Intriguingly, dissecting the NEK7 requirement in iPSC-derived primary human macrophages revealed that this NEK7-independent mechanism constitutes the predominant NLRP3 priming pathway in these cells. In summary, our results suggest that NEK7 functions as an NLRP3 priming – rather than activation – factor that can work in synergy or redundancy with other priming pathways to accelerate inflammasome activation.
Disinhibition-assisted LTP in the prefrontal-amygdala pathway via suppression of somatostatin-expressing interneurons
Authors: Ito Wataru , Fusco Brendon , Morozov Alexei
Published: October 2019

Natural brain adaptations often involve changes in synaptic strength. The artificial manipulations can help investigate the role of synaptic strength in a specific brain circuit not only in various physiological phenomena like correlated neuronal firing and oscillations but also in behaviors. High and low-frequency stimulation at presynaptic sites has been used widely to induce long-term potentiation (LTP) and depression (LTD), respectively. This approach is effective in many brain areas, but not in the basolateral amygdala (BLA), because the robust local GABAergic tone inside the BLA restricts synaptic plasticity. Here, we identified the subclass of GABAergic neurons that gate LTP in the BLA afferents from the dorsomedial prefrontal cortex (dmPFC). Chemogenetic suppression of somatostatin-positive interneurons (Sst-INs) enabled the ex vivo LTP by high-frequency stimulation of the afferent, but the suppression of parvalbumin-positive interneurons (PV-INs) did not. Moreover, optogenetic suppression of Sst-INs with Arch also enabled LTP of the dmPFC-BLA synapses both ex vivo and in vivo. These findings reveal that Sst-INs but not PV-INs gate LTP in the dmPFC-BLA pathway and provide a method for artificial synaptic facilitation in BLA.
Potent CRISPR-Cas9 inhibitors from Staphylococcus genomes
Authors: Watters Kyle E. , Shivram Haridha , Fellmann Christof , Lew Rachel J. , McMahon Blake , Doudna Jennifer A.
Published: October 2019

Anti-CRISPRs (Acrs) are small proteins that inhibit the RNA-guided DNA targeting activity of CRISPR-Cas enzymes. Encoded by bacteriophage and phage-derived bacterial genes, Acrs prevent CRISPR-mediated inhibition of phage infection and can also block CRISPR-Cas-mediated genome editing in eukaryotic cells. To identify Acrs capable of inhibiting Staphylococcus aureus Cas9 (SauCas9), an alternative to the most commonly used genome editing protein Streptococcus pyogenes Cas9 (SpyCas9), we used both self-targeting CRISPR screening and guilt-by-association genomic search strategies. Here we describe three new potent inhibitors of SauCas9 that we name AcrIIA13, AcrIIA14 and AcrIIA15. These inhibitors share a conserved N-terminal sequence that is dispensable for anti-CRISPR function, and have divergent C-termini that are required in each case for selective inhibition of SauCas9-catalyzed DNA cleavage. In human cells, we observe robust and specific inhibition of SauCas9-induced genome editing by AcrIIA13 and moderate inhibition by AcrIIA14 and AcrIIA15. We also find that the conserved N-terminal domain of AcrIIA13-15 binds to an inverted repeat sequence in the promoter of these Acr genes, consistent with its predicted helix-turn-helix DNA binding structure. These data demonstrate an effective strategy for Acr discovery and establish AcrIIA13-15 as unique bifunctional inhibitors of SauCas9.
Genome duplication inLeishmania majorrelies on DNA replication outside S phase
Authors: Damasceno Jeziel D. , Marques Catarina A. , Beraldi Dario , Crouch Kathryn , Lapsley Craig , Obonaga Ricardo , Tosi Luiz R. O. , McCulloch Richard
Published: October 2019

Once every cell cycle, DNA replication takes place to allow cells to duplicate their genome and segregate the two resulting copies into offspring cells. In eukaryotes, the number of DNA replication initiation loci, termed origins, is proportional to chromosome size. However, previous studies have suggested that inLeishmania, a group of single-celled eukaryotic parasites, DNA replication starts from just a single origin per chromosome, which is predicted to be insufficient to secure complete genome duplication within S phase. Here, we show that the paucity of origins activated in early S phase is balanced by DNA synthesis activity outside S phase. Simultaneous recruitment of acetylated histone H3 (AcH3), modified base J and the kinetochore factor KKT1 is exclusively found at the origins used in early S phase, while subtelomeric DNA replication can only be linked to AcH3 and displays persistent activity through the cell cycle, including in G2/M and G1 phases. We also show that subtelomeric DNA replication, unlike replication from the previously mapped origins, is sensitive to hydroxyurea and dependent on subunits of the 9-1-1 complex. Our work indicates thatLeishmaniagenome transmission relies on an unconventional DNA replication programme, which may have implications for genome stability in this important parasite.
CIC is a Critical Regulator of Neuronal Differentiation
Authors: Hwang Inah , Pan Heng , Yao Jun , Elemento Olivier , Zheng Hongwu , Paik Jihye
Published: October 2019

Capicua (CIC), a member of the high mobility group (HMG)-box superfamily of transcriptional repressors, is frequently mutated in human oligodendrogliomas. But its function in brain development and tumorigenesis remains poorly understood. Here, we report that brain-specific deletion of Cic compromises developmental transition of neuroblast to immature neurons in mouse hippocampus and compromises normal neuronal differentiation. Combined gene expression and ChIP-seq analyses identified VGF as an important CIC-repressed transcriptional surrogates involved in neuronal lineage regulation. Aberrant VGF expression promotes neural progenitor cell proliferation by suppressing their differentiation. Mechanistically, we demonstrated that CIC represses VGF expression by tethering SIN3-HDAC to form a transcriptional corepressor complex. Mass spectrometry analysis of CIC-interacting proteins further identified BRG1 containing mSWI/SNF complex of which function is necessary for transcriptional repression by CIC. Together, this study uncovers a novel regulatory pathway of CIC-dependent neuronal differentiation and provides molecular insights into the etiology of CIC-dependent brain tumors.
Age-linked heterogeneity among oligodendrocyte precursor cells in the cerebral cortex of mice and human
Authors: Bribián A , Medina-Rodríguez EM , Josa-Prado F , García-Álvarez I , Machín-Díaz I , Murcia-Belmonte V , Vega-Zelaya L , Pastor J , Garrido L , de Castro F
Published: October 2019

Oligodendrocyte precursor cells (OPCs) are responsible for spontaneous remyelination after a demyelinating lesion. They are present in large parts of the mouse and human central nervous system, both during development and in adulthood, yet how their physiological behaviour is modified throughout life remains largely unknown. Moreover, the activity of adult human OPCs is still not fully understood. Significantly, most of the molecules involved in OPC-mediated remyelination are also involved in their development, a phenomenon that may be clinically relevant. In this article, we have systematically analyzed the intrinsic properties of OPCs isolated from the cerebral cortex of neonatal, postnatal and adult mice, as well as those recovered from neurosurgical adult human cerebral cortex tissue. We also analyze the response of these cells to two molecules that have known effects on OPC biology during development and that are overexpressed in individuals with Multiple Sclerosis (MS): FGF2 and anosmin-1. By analyzing intact OPCs for the first time with H-1 HR-MAS NMR spectroscopy, we show that these cells behave distinctly and that they have different metabolic patterns in function of their stage of maturity. Moreover, their response to FGF-2 and anosmin-1 differs in relation to their developmental stage and in function of the species. Our data reveal that the behaviour of adult human and mouse OPCs differs in a very dynamic way that should be considered when testing drugs and for the proper design of effective pharmacological and/or cell therapies for MS.
A dual role for shape skeletons in human vision: perceptual organization and object recognition
Authors: Ayzenberg Vladislav , Kamps Frederik S. , Dilks Daniel D. , Lourenco Stella F.
Published: October 2019

Shape perception is crucial for object recognition. However, it remains unknown exactly how shape information is represented, and, consequently, used by the visual system. Here, we hypothesized that the visual system represents “shape skeletons” to both (1) perceptually organize contours and component parts into a shape percept, and (2) compare shapes to recognize objects. Using functional magnetic resonance imaging (fMRI) and representational similarity analysis (RSA), we found that a model of skeletal similarity explained significant unique variance in the response profiles of V3 and LO, regions known to be involved in perceptual organization and object recognition, respectively. Moreover, the skeletal model remained predictive in these regions even when controlling for other models of visual similarity that approximate low- to high-level visual features (i.e., Gabor-jet, GIST, HMAX, and AlexNet), and across different surface forms, a manipulation that altered object contours while preserving the underlying skeleton. Together, these findings shed light on the functional roles of shape skeletons in human vision, as well as the computational properties of V3 and LO.
Bacterial cell cycle control by citrate synthase independent of enzymatic activity
Authors: Bergé Matthieu , Pezzatti Julian , González-Ruiz Víctor , Degeorges Laurence , Rudaz Serge , Viollier Patrick H.
Published: October 2019

Coordination of cell cycle progression with central metabolism is fundamental to all cell types and likely underlies differentiation into dispersal cells in bacteria. How central metabolism is monitored to regulate cell cycle functions is poorly understood. A forward genetic selection for cell cycle regulators in the polarized alpha-proteobacteriumCaulobacter crescentusunearthed the uncharacterized CitA citrate synthase, a TCA (tricarboxylic acid) cycle enzyme, as unprecedented checkpoint regulator of the G1→S transition. We show that loss of the CitA protein provokes a (p)ppGpp alarmone-dependent G1-phase arrest without apparent metabolic or energy insufficiency. While S-phase entry is still conferred when CitA is rendered catalytically inactive, the paralogous CitB citrate synthase has no overt role other than sustaining TCA cycle activity when CitA is absent. With eukaryotic citrate synthase paralogs known to fulfill regulatory functions, our work extends the moonlighting paradigm to citrate synthase coordinating central (TCA) metabolism with development and perhaps antibiotic tolerance in bacteria.
Persons post-stroke restore step length symmetry by walking asymmetrically
Authors: Padmanabhan Purnima , Sreekanth Rao Keerthana , Gulhar Shivam , Cherry-Allen Kendra M. , Leech Kristan A. , Roemmich Ryan T.
Published: October 2019

Background

Restoration of step length symmetry is a common rehabilitation goal after stroke. Persons post-stroke often retain the capacity to walk with symmetric step lengths (“symmetric steps”); however, the resulting walking pattern remains effortful. Two key questions with direct implications for rehabilitation have emerged: 1) how do persons post-stroke generate symmetric steps, and 2) why do symmetric steps remain so effortful?

Objective

To understand how persons post-stroke generate symmetric steps and how the resulting gait pattern relates to the metabolic cost of transport.

Methods

Ten persons post-stroke walked on an instrumented treadmill under two conditions: preferred walking and symmetric stepping (using visual feedback). We recorded kinematic, kinetic, and metabolic data during both conditions.

Results

Persons post-stroke restored step length symmetry using energetically expensive, asymmetric patterns. Impaired paretic propulsion and abnormal vertical movement of the center of mass were evident during both preferred walking and symmetric stepping. These deficits contributed to diminished positive work performed by the paretic limb on the center of mass in both conditions. Decreased positive paretic work correlated with increased metabolic cost of transport, decreased self-selected walking speed, and increased asymmetry in limb kinematics.

Conclusions

It is important to consider the mechanics used to restore symmetric steps when designing interventions to improve walking after stroke. Facilitating symmetric steps via increased paretic propulsion or enabling paretic limb advancement without excessive vertical movement may enable persons post-stroke to walk with a less effortful, more symmetric gait pattern.
Microstructures amplify carotenoid plumage signals in colorful tanagers
Authors: McCoy Dakota E. , Shultz Allison J. , Vidoudez Charles , van der Heide Emma , Trauger Sunia A. , Haig David
Published: October 2019

Red, orange, and yellow carotenoid-colored plumages have been considered honest signals of condition. We comprehensively quantified carotenoid signals in the social, sexually-dimorphic tanager genusRamphocelususing scanning electron microscopy (SEM), finite-difference time-domain (FDTD) optical modeling, liquid chromatography–mass spectrometry (LC-MS), and spectrophotometry. Despite males having significantly more saturated color patches, males and females within a species have equivalent amounts and types of carotenoids. Male, but not female, feathers have elaborate microstructures which amplify color appearance. Expanded barbs enhance color saturation (for the same amount of pigment) by increasing the transmission of optical power through the feather. Dihedral barbules (vertically-angled, strap-shaped barbules) reduce total reflectance to generate “super black” plumage, an optical illusion to enhance nearby color. Dihedral barbules paired with red carotenoid pigment produce “velvet red” plumage. Together, our results suggest that a widely cited index of honesty—carotenoid pigments—cannot fully explain male appearance. We propose that males are selected to evolve amplifiers of honest signals—in this case, microstructures that enhance appearance —that are not necessarily themselves linked to quality.
A powerful subset-based gene-set analysis method identifies novel associations and improves interpretation in UK Biobank
Authors: Dutta Diptavo , VandeHaar Peter , Fritsche Lars G. , Zöllner Sebastian , Boehnke Michael , Scott Laura J. , Lee Seunggeun
Published: October 2019

Tests of association between a phenotype and a set of genes in a biological pathway can provide insights into the genetic architecture of complex phenotypes beyond those obtained from single variant or single gene association analysis. However, most existing gene set tests have limited power to detect gene set-phenotype association when a small fraction of the genes are associated with the phenotype, and no method exists which identifies the potentially “active” genes that might drive a gene-set-based association. To address these issues, we have developed Gene-set analysis Association Using Sparse Signals (GAUSS), a method for gene-set association analysis that requires only GWAS summary statistics. For each significantly associated gene set, GAUSS identifies the subset of genes that have the maximal evidence of association and can best account for the gene set association. Using pre-computed correlation structure among test statistics from a reference panel, our p-value calculation is substantially faster than other permutation or simulation-based approaches. In simulations with varying proportions of causal genes, we find that GAUSS effectively controls type 1 error rate and has greater power than several existing methods, particularly when a small proportion of genes account for the gene set signal. Using GAUSS, we analyzed UK Biobank GWAS summary statistics for 10,679 gene-sets and 1,403 binary phenotypes. We found that GAUSS is scalable and identified 13,466 phenotype and gene-set association pairs. Within these genes sets, we identify an average of 17.2 (max=405) genes that underlie these gene set associations.