bluuebunny/crossref_metadata_2025 huggingface dataset:
Minimal Residual Disease Assessment in CLL: Ready for Use in Clinical Routine?
Authors: Fürstenau Moritz , De Silva Nisha , Eichhorst Barbara , Hallek Michael
Published: August 2019

The introduction of chemoimmunotherapy and more recently the implementation of novel agents into first‐line and relapse treatment have substantially improved treatment outcomes in patients with chronic lymphocytic leukaemia (CLL). With longer progression‐free survival and more frequently observed deep remissions there is an emerging need for sensitive methods quantitating residual disease after therapy. Over the last decade, assessment of minimal residual disease (MRD) has increasingly been implemented in CLL trials. The predictive value of MRD status on survival outcomes has repeatedly been proven in the context of chemoimmunotherapy and cellular therapies. Recent data suggests a similar correlation for Bcl‐2 inhibitor‐based therapy. While the relevance of MRD assessment as a surrogate endpoint in clinical trials is largely undisputed, its role in routine clinical practice has not yet been well defined.

This review outlines current methods of MRD detection in CLL and summarizes MRD data from relevant trials. The significance of MRD testing in clinical studies and in routine patient care is assessed and new MRD‐guided treatment strategies are discussed.
Prevention of Infectious Complications in Acute Pancreatitis
Authors: Poropat Goran , Radovan Anja , Peric Marija , Mikolasevic Ivana , Giljaca Vanja , Hauser Goran , Milic Sandra , Stimac Davor
Published: August 2019

Objectives

This study aimed to investigate the efficiency of imipenem to prevent infectious complications in predicted severe acute pancreatitis (AP).

Methods

Consecutive AP patients were randomized to imipenem 3 × 500 mg intravenously daily or an identical placebo. Exclusion criteria were prior AP, chronic pancreatitis, active malignancy, immune deficiency, active infection, concomitant antibiotic treatment, pregnancy, and patients younger than 18 years. Infectious complications including infected pancreatic necrosis, pneumonia, urinary tract infection, positive blood cultures, sepsis, and other infections were assessed as the primary outcome. Secondary outcomes included mortality, persistent organ failure, systemic inflammatory response syndrome, local complications, serious adverse events, and need for surgical intervention.

Results

Forty-nine patients were randomized to each group. Infectious complications were present in 10 versus 12 of 49 patients (relative risk [RR], 0.833; 95% confidence interval [CI], 0.398–1.747). There were no significant differences in infected pancreatic necrosis (RR, 1.5; 95% CI, 0.262–8.588), pneumonia (RR, 1.5; 95% CI, 0.262–8.588), urinary tract infection (RR, 0.6; 95% CI, 0.152–2.374), positive blood cultures (RR, 0.5; 95% CI, 0.047–5.336), sepsis (RR, 0.333; 95% CI, 0.036–3.095), and other (RR, 1.333; 95% CI, 0.315–5.648). We found no significant differences in secondary outcomes.

Conclusions

Concordantly to available evidence, there is currently no ground to support prophylactic use of antibiotics in predicted severe AP.
Etiologic Distribution of Pancreatic Cystic Lesions Identified on Computed Tomography/Magnetic Resonance Imaging
Authors: Munigala Satish , Javia Siddharth B. , Agarwal Banke
Published: August 2019

Objectives

This study aimed to determine the distribution of etiology of pancreatic cysts using established criteria/markers from cyst fluid analysis and cytology that have been reported to have high specificity in published literature.

Methods

A retrospective study of pancreatic cysts using an endoscopic database from March 2002 and May 2013 was conducted. Pancreatic cysts <10 mm and cysts with a history of pancreatic cancer were excluded.

Results

In our cohort of 758 patients with pancreatic cyst(s), the cyst etiology was as follows: mucinous cyst/side-branch intraductal papillary mucinous neoplasms (SB-IPMNs)/mucinous cystic neoplasms (MCN; 48.2%), pseudocyst (27.6%), serous cystadenoma (11%), simple cysts (6.4%), mucinous cystadenocarcinoma (5.1%), and other (1%). Approximately 41% (n = 310) of the cysts were ≥3 cm in size and included the following: pseudocyst (39.7%), mucinous cysts/SB-IPMN/MCN (28.1%), serous cystadenoma (16.7%), mucinous cyst adenocarcinoma (9.7%), and simple cyst (4.8%). In 118 patients with a known history of acute pancreatitis, the cyst diagnoses included pseudocyst (68.7%), mucinous cyst/SB-IPMN/MCN (18.6%), benign/simple cyst (7.6%), and mucinous cystadenocarcinoma (2.5%).

Conclusions

In patients with cystic pancreatic lesion noted on cross-sectional imaging, approximately half of the patients have lesions without malignancy or malignant potential and therefore not requiring surveillance. Endoscopic ultrasound/endoscopic ultrasound-guided fine-needle aspiration evaluation of the pancreatic cysts can help optimize their further management.
Mosquito and primate ecology predict human risk of yellow fever virus spillover in Brazil
Authors: Childs Marissa L. , Nova Nicole , Colvin Justine , Mordecai Erin A.
Published: August 2019

Many (re)emerging infectious diseases in humans arise from pathogen spillover from wildlife or livestock, and accurately predicting pathogen spillover is an important public health goal. In the Americas, yellow fever in humans primarily occurs following spillover from non-human primates via mosquitoes. Predicting yellow fever spillover can improve public health responses through vector control and mass vaccination. Here, we develop and test a mechanistic model of pathogen spillover to predict human risk for yellow fever in Brazil. This environmental risk model, based on the ecology of mosquito vectors and non-human primate hosts, distinguished municipality-months with yellow fever spillover from 2001 to 2016 with high accuracy (AUC = 0.72). Incorporating hypothesized cyclical dynamics of infected primates improved accuracy (AUC = 0.79). Using boosted regression trees to identify gaps in the mechanistic model, we found that important predictors include current and one-month lagged environmental risk, vaccine coverage, population density, temperature and precipitation. More broadly, we show that for a widespread human viral pathogen, the ecological interactions between environment, vectors, reservoir hosts and humans can predict spillover with surprising accuracy, suggesting the potential to improve preventive action to reduce yellow fever spillover and avert onward epidemics in humans.

This article is part of the theme issue ‘Dynamic and integrative approaches to understanding pathogen spillover’.
Cross-species pathogen spillover across ecosystem boundaries: mechanisms and theory
Authors: Borremans Benny , Faust Christina , Manlove Kezia R. , Sokolow Susanne H. , Lloyd-Smith James O.
Published: August 2019

Pathogen spillover between different host species is the trigger for many infectious disease outbreaks and emergence events, and ecosystem boundary areas have been suggested as spatial hotspots of spillover. This hypothesis is largely based on suspected higher rates of zoonotic disease spillover and emergence in fragmented landscapes and other areas where humans live in close vicinity to wildlife. For example, Ebola virus outbreaks have been linked to contacts between humans and infected wildlife at the rural-forest border, and spillover of yellow fever via mosquito vectors happens at the interface between forest and human settlements. Because spillover involves complex interactions between multiple species and is difficult to observe directly, empirical studies are scarce, particularly those that quantify underlying mechanisms. In this review, we identify and explore potential ecological mechanisms affecting spillover of pathogens (and parasites in general) at ecosystem boundaries. We borrow the concept of ‘permeability’ from animal movement ecology as a measure of the likelihood that hosts and parasites are present in an ecosystem boundary region. We then discuss how different mechanisms operating at the levels of organisms and ecosystems might affect permeability and spillover. This review is a step towards developing a general theory of cross-species parasite spillover across ecosystem boundaries with the eventual aim of improving predictions of spillover risk in heterogeneous landscapes.

This article is part of the theme issue ‘Dynamic and integrative approaches to understanding pathogen spillover’.
Improving risk assessment of the emergence of novel influenza A viruses by incorporating environmental surveillance
Authors: Pepin Kim M. , Hopken Matthew W. , Shriner Susan A. , Spackman Erica , Abdo Zaid , Parrish Colin , Riley Steven , Lloyd-Smith James O. , Piaggio Antoinette J.
Published: August 2019

Reassortment is an evolutionary mechanism by which influenza A viruses (IAV) generate genetic novelty. Reassortment is an important driver of host jumps and is widespread according to retrospective surveillance studies. However, predicting the epidemiological risk of reassortant emergence in novel hosts from surveillance data remains challenging. IAV strains persist and co-occur in the environment, promoting co-infection during environmental transmission. These conditions offer opportunity to understand reassortant emergence in reservoir and spillover hosts. Specifically, environmental RNA could provide rich information for understanding the evolutionary ecology of segmented viruses, and transform our ability to quantify epidemiological risk to spillover hosts. However, significant challenges with recovering and interpreting genomic RNA from the environment have impeded progress towards predicting reassortant emergence from environmental surveillance data. We discuss how the fields of genomics, experimental ecology and epidemiological modelling are well positioned to address these challenges. Coupling quantitative disease models and natural transmission studies with new molecular technologies, such as deep-mutational scanning and single-virus sequencing of environmental samples, should dramatically improve our understanding of viral co-occurrence and reassortment. We define observable risk metrics for emerging molecular technologies and propose a conceptual research framework for improving accuracy and efficiency of risk prediction.

This article is part of the theme issue ‘Dynamic and integrative approaches to understanding pathogen spillover’.
Confronting models with data: the challenges of estimating disease spillover
Authors: Cross Paul C. , Prosser Diann J. , Ramey Andrew M. , Hanks Ephraim M. , Pepin Kim M.
Published: August 2019

For pathogens known to transmit across host species, strategic investment in disease control requires knowledge about where and when spillover transmission is likely. One approach to estimating spillover is to directly correlate observed spillover events with covariates. An alternative is to mechanistically combine information on host density, distribution and pathogen prevalence to predict where and when spillover events are expected to occur. We use several case studies at the wildlife–livestock disease interface to highlight the challenges, and potential solutions, to estimating spatio-temporal variation in spillover risk. Datasets on multiple host species often do not align in space, time or resolution, and may have no estimates of observation error. Linking these datasets requires they be related to a common spatial and temporal resolution and appropriately propagating errors in predictions can be difficult. Hierarchical models are one potential solution, but for fine-resolution predictions at broad spatial scales, many models become computationally challenging. Despite these limitations, the confrontation of mechanistic predictions with observed events is an important avenue for developing a better understanding of pathogen spillover. Systems where data have been collected at all levels in the spillover process are rare, or non-existent, and require investment and sustained effort across disciplines.

This article is part of the theme issue ‘Dynamic and integrative approaches to understanding pathogen spillover’.
Dose–response and transmission: the nexus between reservoir hosts, environment and recipient hosts
Authors: Lunn Tamika J. , Restif Olivier , Peel Alison J. , Munster Vincent J. , de Wit Emmie , Sokolow Sanna , van Doremalen Neeltje , Hudson Peter , McCallum Hamish
Published: August 2019

Dose is the nexus between exposure and all upstream processes that determine pathogen pressure, and is thereby an important element underlying disease dynamics. Understanding the relationship between dose and disease is particularly important in the context of spillover, where nonlinearities in the dose–response could determine the likelihood of transmission. There is a need to explore dose–response models for directly transmitted and zoonotic pathogens, and how these interactions integrate within-host factors to consider, for example, heterogeneity in host susceptibility and dose-dependent antagonism. Here, we review the dose–response literature and discuss the unique role dose–response models have to play in understanding and predicting spillover events. We present a re-analysis of dose–response experiments for two important zoonotic pathogens (Middle East respiratory syndrome coronavirus and Nipah virus), to exemplify potential difficulties in differentiating between appropriate models with small exposure experiment datasets. We also discuss the data requirements needed for robust selection between dose–response models. We then suggest how these processes could be modelled to gain more realistic predictions of zoonotic transmission outcomes and highlight the exciting opportunities that could arise with increased collaboration between the virology and epidemiology disciplines.

This article is part of the theme issue ‘Dynamic and integrative approaches to understanding pathogen spillover’.
Hospital-based zoonotic disease surveillance in Bangladesh: design, field data and difficulties
Authors: Das Pritimoy , Sazzad Hossain M. S. , Aleem Mohammad Abdul , Rahman M. Ziaur , Rahman Mahmudur , Anthony Simon J. , Lipkin W. Ian , Gurley Emily S. , Luby Stephen P. , Openshaw John J.
Published: August 2019

Early detection of zoonotic diseases allows for the implementation of early response measures, reducing loss of human life and economic disruption. We implemented a surveillance system in hospitals in Bangladesh to screen acutely ill hospitalized patients with severe respiratory infection and meningoencephalitis for zoonotic exposures. Patients were screened for the risk of zoonotic exposures with five questions covering vocational exposures, sick domestic animal and wild animal contact, and date palm sap consumption in the three weeks preceding illness onset. Patients giving at least one positive response were considered a potential zoonotic exposure. From September 2013 to March 2017, a total of 11 429 hospitalized patients across 14 participating hospitals were screened for exposures. Overall, 2% of patients reported a potential zoonotic exposure in the three-week period prior to becoming ill. Sixteen per cent of hospitalized patients with reported exposures died. After routine surveillance diagnostic testing, 88% of patients admitted to the hospital after a potential zoonotic exposure did not have a laboratory diagnosed aetiology for their illness. Hospital-based surveillance systems such as the Bangladeshi example presented here could play an important future role in the early detection of zoonotic spillover diseases.

This article is part of the theme issue ‘Dynamic and integrative approaches to understanding pathogen spillover’.
What is stirring in the reservoir? Modelling mechanisms of henipavirus circulation in fruit bat hosts
Authors: Glennon Emma E. , Becker Daniel J. , Peel Alison J. , Garnier Romain , Suu-Ire Richard D. , Gibson Louise , Hayman David T. S. , Wood James L. N. , Cunningham Andrew A. , Plowright Raina K. , Restif Olivier
Published: August 2019

Pathogen circulation among reservoir hosts is a precondition for zoonotic spillover. Unlike the acute, high morbidity infections typical in spillover hosts, infected reservoir hosts often exhibit low morbidity and mortality. Although it has been proposed that reservoir host infections may be persistent with recurrent episodes of shedding, direct evidence is often lacking. We construct a generalized SEIR (susceptible, exposed, infectious, recovered) framework encompassing 46 sub-models representing the full range of possible transitions among those four states of infection and immunity. We then use likelihood-based methods to fit these models to nine years of longitudinal data on henipavirus serology from a captive colony of
Eidolon helvum
bats in Ghana. We find that reinfection is necessary to explain observed dynamics; that acute infectious periods may be very short (hours to days); that immunity, if present, lasts about 1–2 years; and that recurring latent infection is likely. Although quantitative inference is sensitive to assumptions about serology, qualitative predictions are robust. Our novel approach helps clarify mechanisms of viral persistence and circulation in wild bats, including estimated ranges for key parameters such as the basic reproduction number and the duration of the infectious period. Our results inform how future field-based and experimental work could differentiate the processes of viral recurrence and reinfection in reservoir hosts.

This article is part of the theme issue ‘Dynamic and integrative approaches to understanding pathogen spillover’.
The problem of scale in the prediction and management of pathogen spillover
Authors: Becker Daniel J. , Washburne Alex D. , Faust Christina L. , Mordecai Erin A. , Plowright Raina K.
Published: August 2019

Disease emergence events, epidemics and pandemics all underscore the need to predict zoonotic pathogen spillover. Because cross-species transmission is inherently hierarchical, involving processes that occur at varying levels of biological organization, such predictive efforts can be complicated by the many scales and vastness of data potentially required for forecasting. A wide range of approaches are currently used to forecast spillover risk (e.g. macroecology, pathogen discovery, surveillance of human populations, among others), each of which is bound within particular phylogenetic, spatial and temporal scales of prediction. Here, we contextualize these diverse approaches within their forecasting goals and resulting scales of prediction to illustrate critical areas of conceptual and pragmatic overlap. Specifically, we focus on an ecological perspective to envision a research pipeline that connects these different scales of data and predictions from the aims of discovery to intervention. Pathogen discovery and predictions focused at the phylogenetic scale can first provide coarse and pattern-based guidance for which reservoirs, vectors and pathogens are likely to be involved in spillover, thereby narrowing surveillance targets and where such efforts should be conducted. Next, these predictions can be followed with ecologically driven spatio-temporal studies of reservoirs and vectors to quantify spatio-temporal fluctuations in infection and to mechanistically understand how pathogens circulate and are transmitted to humans. This approach can also help identify general regions and periods for which spillover is most likely. We illustrate this point by highlighting several case studies where long-term, ecologically focused studies (e.g. Lyme disease in the northeast USA, Hendra virus in eastern Australia,
Plasmodium knowlesi
in Southeast Asia) have facilitated predicting spillover in space and time and facilitated the design of possible intervention strategies. Such studies can in turn help narrow human surveillance efforts and help refine and improve future large-scale, phylogenetic predictions. We conclude by discussing how greater integration and exchange between data and predictions generated across these varying scales could ultimately help generate more actionable forecasts and interventions.

This article is part of the theme issue ‘Dynamic and integrative approaches to understanding pathogen spillover’.
Insomnia, excessive daytime sleepiness, anxiety, depression and socioeconomic status among customer service employees in Canada
Authors: Sosso FA Etindele
Published: August 2019

Objectives

The present study alerts on the potential effect of working full time in a call center as a risk factor for neuropsychiatric illnesses. It is the first study investigating deeply presence of anxiety, depression, insomnia and excessive daytime sleepiness among a large population of customer service employees. It has 3 specifics goals which were (1) document presence of sleep disorders among customer service advisors (2) document presence of anxiety and depression in this population (3) determine the influence of the socioeconomic status, duration in position and full time or part-time shift on the diseases above.

Findings

It was found that the majority of people working in customer service are undergraduate students or at a secondary/high school degree. They worked full time, are single and have reported at least two of the neuropsychiatric disorders assessed in the present study. Among customer service advisors enrolled in this study, all neuropsychiatric disorders investigated were present and significantly higher for those working full time. Perceived socioeconomic status (pSES) was almost similar for full time and part time workers with a mean score of 4.8 on the MacArthur scale of subjective social status. Results revealed that duration in position was an excellent predictor of insomnia, sleepiness and anxiety (respectively with R2=91,83%, R2=81,23% and R2=87,46%) but a moderate predictor of depression (R2=69,14%). The pSES was a moderate predictor of sleep disorders (respectively R2=62,04% for insomnia and R2=53,62% for sleepiness) but had a strong association with anxiety and depression (R2=82,95% for anxiety and R2=89,77% for depression). It was found that insomnia and anxiety are more prevalent for immigrants and international students compared to Canadians, while depression was similarly higher for Canadian and immigrants compared to international students. It was found that sleepiness has the same trend in the three subgroups.

Conclusion

Customer service employees are exposed to a continuous stimulation of their cognitive functions in addition to different stressors which can progressively and silently damage the nervous system. Investigations on mental and physical health of customer service advisors are worthy of interest, and understanding how their work, their rotating shifts and their socioeconomic status influence their resilience and their performance at work; may help comprehension of similar health issues emerging in similar populations with similar occupations.
Relationships between landscape structure and the prevalence of two tick-borne infectious agents, Anaplasma phagocytophilum and Borrelia burgdorferi sensu lato, in small mammal communities
Authors: Perez Grégoire , Bastian Suzanne , Chastagner Amélie , Agoulon Albert , Rantier Yann , Vourc’h Gwenaël , Plantard Olivier , Butet Alain
Published: August 2019

Context

By modifying ecosystems, land cover changes influence the emergence, the spread and the incidence of vector-borne diseases.

Objective

This study aimed at identifying associations between landscape structure and the prevalence of two tick-borne infectious agents, Anaplasma phagocytophilum and Borrelia burgdorferi s.l., in small mammal communities.

Methods

Small mammals were sampled in 24 sites along a gradient of woodland fragmentation and hedgerow network density, and screened for infectious agents with real-time PCR techniques. For each site, structural variables (composition and configuration) of the surrounding landscape at various scales (0-500 m) and variables of wooded habitats connectivity based on graph theory and least cost path distances for the two dominant species, bank voles (Myodes glareolus) and wood mice (Apodemus sylvaticus), were computed.

Results

The A. phagocytophilum prevalence increased with wooded habitats cover (0-500 m), likely through host population size, and increased slightly with bank vole abundance, which has a higher reservoir competence than wood mouse. The B. burgdorferi s.l. prevalence increased with wooded ecotones only at local scales (50-100 m). Wooded habitats connectivity measures did not improve models built with simple land cover variables. A more marked spatial pattern was observed for the prevalence of A. phagocytophilum than B. burgdorferi s.l..

Conclusions

This study highlights the interest of considering together the ecology of infectious agents (e.g. host specificity) and the host species community ecology to better understand the influence of the landscape structure on the spatial distribution of vector-borne infectious agents.
Comparison of RNA Isolation Methods on RNA-Seq: Implications for Differential Expression and Meta-Analyses
Authors: Scholes Amanda N. , Lewis Jeffrey A.
Published: August 2019

Technical variation across different batches of RNA-seq experiments can clearly produce spurious signals of differential expression and reduce our power to detect true differences. Thus, it is important to identify major sources of these so-called “batch effects” to eliminate them from study design. Based on the different chemistries of “classic” phenol extraction of RNA compared to common commercial RNA isolation kits, we hypothesized that specific mRNAs may be preferentially extracted depending upon method, which could masquerade as differential expression in downstream RNA-seq analyses. We tested this hypothesis and found that phenol extraction preferentially isolated membrane-associated mRNAs, thus resulting in spurious signals of differential expression. Within a self-contained experimental batch (e.g. control versus treatment), the method of RNA isolation had little effect on the ability to identify differentially expressed transcripts. However, we suggest that researchers performing meta-analyses across different experimental batches strongly consider the RNA isolation methods for each experiment.
Development of structure-function coupling in human brain networks during youth
Authors: Baum Graham L. , Cui Zaixu , Roalf David R. , Ciric Rastko , Betzel Richard F. , Larsen Bart , Cieslak Matthew , Cook Philip A. , Xia Cedric H. , Moore Tyler M. , Ruparel Kosha , Oathes Desmond , Alexander-Bloch Aaron , Shinohara Russell T. , Raznahan Armin , Gur Raquel E. , Gur Ruben C. , Bassett Danielle S. , Satterthwaite Theodore D.
Published: August 2019

The protracted development of structural and functional brain connectivity within distributed association networks coincides with improvements in higher-order cognitive processes such as working memory. However, it remains unclear how white matter architecture develops during youth to directly support coordinated neural activity. Here, we characterize the development of structure-function coupling using diffusion-weighted imaging and n-back fMRI data in a sample of 727 individuals (ages 8-23 years). We found that spatial variability in structure-function coupling aligned with cortical hierarchies of functional specialization and evolutionary expansion. Furthermore, hierarchy-dependent age effects on structure-function coupling localized to transmodal cortex in both cross-sectional data and a subset of participants with longitudinal data (n=294). Moreover, structure-function coupling in rostrolateral prefrontal cortex was associated with executive performance, and partially mediated age-related improvements in executive function. Together, these findings delineate a critical dimension of adolescent brain development, whereby the coupling between structural and functional connectivity remodels to support functional specialization and cognition.
Structured Reviews for Data and Knowledge Driven Research
Authors: Queralt-Rosinach Núria , Stupp Gregory S. , Li Tong Shu , Mayers Michael , Hoatlin Maureen E. , Might Matthew , Good Benjamin M. , Su Andrew I.
Published: August 2019

Motivation

Hypothesis generation is a critical step in research and a cornerstone in the rare disease field. Research is most efficient when those hypotheses are based on the entirety of knowledge known to date. Systematic review articles are commonly used in biomedicine to summarize existing knowledge and contextualize experimental data. But the information contained within review articles is typically only expressed as free-text, which is difficult to use computationally. Researchers struggle to navigate, collect and remix prior knowledge as it is scattered in several silos without seamless integration and access. This lack of a structured information framework hinders research by both experimental and computational scientists.

Results

To better organize knowledge and data, we built a structured review article that is specifically focused on NGLY1 Deficiency, an ultra-rare genetic disease first reported in 2012. We represented this structured review as a knowledge graph, and then stored this knowledge graph in a Neo4j database to simplify dissemination, querying, and visualization of the network. Relative to free-text, this structured review better promotes the principles of findability, accessibility, interoperability, and reusability (FAIR). In collaboration with domain experts in NGLY1 Deficiency, we demonstrate how this resource can improve the efficiency and comprehensiveness of hypothesis generation. We also developed a read-write interface that allows domain experts to contribute FAIR structured knowledge to this community resource. In contrast to traditional free-text review articles, this structured review exists as a living knowledge graph that is curated by humans and accessible to computational analyses. Finally, we have generalized this workflow into modular and repurposable components that can be applied to other domain areas. This NGLY1 Deficiency-focused network is publicly available athttp://ngly1graph.org/.

Availability and implementation

Source code and network data files are at:https://github.com/SuLab/ngly1-graphandhttps://github.com/SuLab/bioknowledge-reviewer.

Contact

asu@scripps.edu
Empirically Constrained Network Models for Contrast-dependent Modulation of Gamma Rhythm in V1
Authors: Zachariou Margarita , Roberts Mark , Lowet Eric , De Weerd Peter , Hadjipapas Avgis
Published: August 2019

Here we present experimentally constrained computational models of gamma rhythm and use these to investigate gamma oscillation instability. To this end, we extracted empirical constraints for PING (Pyramidal Interneuron Network Gamma) models from monkey single-unit and LFP responses recorded during contrast variation. These constraints implied weak rather than strong PING, connectivity between excitatory (E) and inhibitory (I) cells within specific bounds, and input strength variations that modulated E but not I cells. Constrained models showed valid behaviours, including gamma frequency increases with contrast and power saturation or decay at high contrasts. The route to gamma instability involved increased heterogeneity of E cells with increasing input triggering a breakdown of I cell pacemaker function. We illustrate the model’s capacity to resolve disputes in the literature. Our work is relevant for the range of cognitive operations to which gamma oscillations contribute and could serve as a basis for future, more complex models.
Neurons expressing pathological Tau protein trigger dramatic changes in microglial morphology and dynamics
Authors: Hassan-Abdi Rahma , Brenet Alexandre , Bennis Mohamed , Yanicostas Constantin , Soussi-Yanicostas Nadia
Published: August 2019

Microglial cells, the resident macrophages of the brain, are important players in the pathological process of numerous neurodegenerative disorders, including tauopathies, a heterogeneous class of diseases characterized by intraneuronal Tau aggregates. However, microglia response in Tau pathologies remains poorly understood. Here we exploit a genetic zebrafish model of tauopathy, combined with live microglia imaging, to investigate the behaviour of microglia in vivo in the disease context. Results show that while microglia were almost immobile and displayed long and highly dynamic branches in a wild-type context, in presence of diseased neurons cells became highly mobile and displayed morphological changes, with highly mobile cell bodies together with fewer and shorter processes. We also imaged, for the first time to our knowledge, the phagocytosis of apoptotic tauopathic neurons by microglia in vivo and observed that microglia engulfed about as twice materials as in controls. Finally, genetic ablation of microglia in zebrafish tauopathy model significantly increased Tau hyperphosphorylation, suggesting that microglia provide neuroprotection to diseased neurons. Our findings demonstrate for the first time the dynamics of microglia in contact with tauopathic neurons in vivo and open perspectives for the real-time study of microglia in many neuronal diseases.
Musculoskeletal fat imaging and quantification by high-resolution metabolite cycling magnetic resonance spectroscopic imaging at 3 T: A fast method to generate separate distribution maps of lipid components
Authors: Alhulail Ahmad A. , Patterson Debra A. , Xia Pingyu , Zhou Xiaopeng , Lin Chen , Thomas M. Albert , Dydak Ulrike , Emir Uzay E.
Published: August 2019

Purpose

To provide a rapid, non-invasive fat quantification technique capable of producing separate lipid component maps.

Methods

The calf muscles in 5 healthy adolescents (age 12-16 years; BMI = 20 ± 3 Kg/m2) were scanned by two different fat fraction (FF) quantification methods. A high-resolution, density-weighted concentric ring trajectory (DW-CRT) metabolite cycling (MC) magnetic resonance spectroscopic imaging (MRSI) technique was implemented to collect data with 0.25 mL resolution within 3 minutes and 16 seconds. For comparative purposes, the standard Dixon technique was performed. The two techniques were compared using structural similarity (SSIM) analysis. Additionally, the difference in the distribution of each lipid over the adolescent calf muscles was assessed based on the MRSI data.

Results

The proposed MRSI technique provided individual FF maps for eight musculoskeletal lipids identified by LCModel analysis (L09, L11, L13, L15, L21, L23, L53, and L55) with mean SSIM indices of 0.19, 0.04, 0.03, 0.50, 0.45, 0.04, 0.07, and 0.12, respectively compared to that of Dixon’s FF map. Further analysis of voxels with zero SSIM demonstrated an increased sensitivity of FF lipid maps from data acquired using this MRSI technique over the standard Dixon technique. The trend of lipid spatial distribution over calf muscles was consistent with previously published findings in adults.

Conclusion

The advantages of this MRSI technique make it a useful tool when individual lipid FF maps are desired within a short scanning time.
Blockade of stromal Gas6 alters cancer cell plasticity, activates NK cells and inhibits pancreatic cancer metastasis
Authors: Ireland Lucy , Luckett Teifion , Schmid Michael C. , Mielgo Ainhoa
Published: August 2019

Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest cancers due to its aggressive and metastatic nature. PDA is characterized by a rich tumor stroma with abundant macrophages, fibroblasts and collagen deposition that can represent up to 90% of the tumor mass. Activation of the tyrosine kinase receptor AXL and expression of its ligand growth arrest-specific protein 6 (Gas6) correlate with a poor prognosis and increased metastasis in pancreatic cancer patients. Gas6 is a multifunctional protein that can be secreted by several cell types and regulates multiple processes, including cancer cell plasticity, angiogenesis and immune cell functions. However, the role of Gas6 in pancreatic cancer metastasis has not been fully investigated. In these studies we find that, in pancreatic tumors, Gas6 is mainly produced by tumor associated macrophages (TAMs) and cancer associated fibroblasts (CAFs) and that pharmacological blockade of Gas6 partially reverses epithelial-to-mesenchymal transition (EMT) of tumor cells and supports NK cell activation, thereby inhibiting pancreatic cancer metastasis. Our data suggest that Gas6 simultaneously acts on both the tumor cells and the NK cells to support pancreatic cancer metastasis. This study supports the rationale for targeting Gas6 in pancreatic cancer and use NK cells as a potential biomarker for response to anti-Gas6 therapy.
Chemistry of cation hydration and conduction in a skeletal muscle ryanodine receptor
Authors: Wu Zhaolong , Liu Congcong , Yu Hua , Kang Duan , Ma Yinping , Li Xuemei , Zhang Lei , Fan Chun , Li Xin-Zheng , Song Chen , Yin Chang-Cheng , Mao Youdong
Published: August 2019

Ryanodine receptors (RyRs) are Ca2+-regulated Ca2+channels of 2.2-megadalton in muscles and neurons for calcium signaling. How Ca2+regulates ion conduction in the RyR channels remains elusive. We determined a 2.6-Å cryo-EM structure of rabbit skeletal muscle RyR1, and used multiscale dynamics simulations to elucidate cation interactions with RyR1. We investigated 21 potential cation-binding sites that may together rationalize biphasic Ca2+response of RyR1. The selectivity filter captures a cation hydration complex by hydrogen-bonding with both the inner and outer hydration shells of water molecules. Molecular dynamics simulations suggest that adjacent Ca2+ions moving in concert along ion-permeation pathway are separated by at least two cation-binding sites. Our analysis reveals that RyR1 has been evolved to favor its interactions with two hydration shells of cations.
E3 Ligase UBR5 HECT domain mutations in lymphoma control maturation of B cells via alternative splicing
Authors: Swenson Samantha A. , Gilbreath Tyler J. , Vahle Heather , Hynes-Smith R. Willow , Graham Jared H. , Law Henry Chun Hin , Woods Nicholas T. , Green Michael R. , Buckley Shannon M.
Published: August 2019

Coordination of a number of molecular mechanisms including transcription, alternative splicing, and class switch recombination are required to facilitate development, activation, and survival of B cells. Disruption of these pathways can result in malignant transformation. Recently, next generation sequencing has identified a number of novel mutations in mantle cell lymphoma (MCL) patients including the ubiquitin E3 ligase UBR5. Approximately 18% of MCL patients were found to have mutations in UBR5 with the majority of mutations within the HECT domain of the protein which can accept and transfer ubiquitin molecules to the substrate. Determining if UBR5 controls the maturation of B cells is important to fully understand malignant transformation to MCL. To elucidate the role of UBR5 in B cell maturation and activation we generated a conditional mutant disrupting UBR5’s C-terminal HECT domain. Loss of the UBR5 HECT domain leads to a block in maturation of B cells in the spleen and up-regulation of proteins associated with mRNA splicing via the spliceosome. Our studies reveal a novel role of UBR5 in B cell maturation by regulating alternative splicing of key transcripts during B cell development and suggests UBR5 mutations may promote mantle cell lymphoma initiation.

KEY POINTS

Utilizing a novel mouse model mimicking MCL patient mutations, the loss of UBR5’s HECT domain causes alterations in B cell development.

UBR5 mutations lead to stabilization of UBR5 and aberrant splicing.
vH+-ATPase-induced intracellular acidification is critical to glucose-stimulated insulin secretion
Authors: Naik Akshata R. , Formosa Brent J. , Pulvender Rishika G. , Liyanaarachchi Asiri G. , Jena Bhanu P.
Published: August 2019

Swelling of secretory vesicles is critical for the regulated expulsion of intra-vesicular contents from cells during secretion. At the secretory vesicle membrane of the exocrine pancreas and neurons, GTP-binding G proteins, vH+-ATPase, potassium channels and AQP water channels, are among the players implicated in vesicle volume regulation. Here we report in insulin secreting MIN6 cells, the requirement of vH+-ATPase-mediated intracellular acidification, on glucose-stimulated insulin release. MIN6 cells exposed to the vH+-ATPase inhibitor Bafilomycin A show decreased acidification of the cytosolic compartment that include insulin-carrying granules. Additionally, a loss of insulin granule association with the cell plasma membrane is demonstrated and results in a decrease in glucose-stimulated insulin secretion and accumulation of intracellular insulin. These results suggest that vH+-ATPase-mediated intracellular acidification is required both at the level of secretory vesicles and the cell plasma membrane for cell secretion.
Predicting the global mammalian viral sharing network using phylogeography
Authors: Albery Gregory F , Eskew Evan A , Ross Noam , Olival Kevin J
Published: August 2019

Understanding interspecific viral transmission is key to understanding viral ecology and evolution, disease spillover into humans, and the consequences of global change. Prior work has demonstrated that macroecological factors drive viral sharing in some mammalian groups, but analyses have never attempted to predict viral sharing in a pan-mammalian context. Here we show that host phylogenetic similarity and geographic range overlap are strong, nonlinear predictors of viral sharing among species across the entire mammal class. Using these traits, we predict global viral sharing patterns across 4196 mammal species and show that our simulated network successfully predicts viral sharing and reservoir host status using internal validation and an external dataset. We predict high rates of mammalian viral sharing in the tropics, particularly among rodents and bats, and that within- and between-order sharing differs geographically and taxonomically. Our results emphasize the importance of macroecological factors in shaping mammalian viral communities, and provide a robust, general model to predict viral host range and guide pathogen surveillance and conservation efforts.
Intraspecific genomic variation and local adaptation in a young hybrid species
Authors: Cuevas Angélica , Ravinet Mark , Sætre Glenn-Peter , Eroukhmanoff Fabrice
Published: August 2019

Hybridization increases genetic variation, hence hybrid species may have a strong evolutionary potential once their admixed genomes have stabilized and incompatibilities have been purged. Yet, little is known about how such hybrid lineages evolve at the genomic level following their formation, in particular the characteristics of their adaptive potential, i.e. constraints and facilitations of diversification. Here we investigate how the Italian sparrow (Passer italiae), a homoploid hybrid species, has evolved and locally adapted to its variable environment. Using restriction site-associated DNA sequencing (RAD-seq) on several populations across the Italian peninsula, we evaluate how genomic constraints and novel genetic variation have influenced population divergence and adaptation. We show that population divergence within this hybrid species has evolved in response to climatic variation. As in non-hybrid species, climatic differences may even reduce gene flow between populations, suggesting ongoing local adaptation. We report outlier genes associated with adaptation to climatic variation, known to be involved in beak morphology in other species. Most of the strongly divergent loci among Italian sparrow populations seem not to be differentiated between its parent species, the house and Spanish sparrow. Within the parental species, population divergence has occurred mostly in loci where different alleles segregate in the parent species, unlike in the hybrid, suggesting that novel combinations of parental alleles in the hybrid have not necessarily enhanced its evolutionary potential. Rather, our study suggests that constraints linked to incompatibilities may have restricted the evolution of this admixed genome, both during and after hybrid species formation.
A conjugation platform for CRISPR-Cas9 allows efficient β-cell engineering
Authors: Lim Donghyun , Sreekanth Vedagopuram , Cox Kurt J. , Law Benjamin K. , Wagner Bridget K. , Karp Jeffrey M. , Choudhary Amit
Published: August 2019

Genetically fusing protein domains to Cas9 has yielded several transformative technologies; however, these fusions are polypeptidic, limited to the Cas9 termini and lack multivalent display, and exclude diverse array of molecules. Here, we report a platform for the site-specific and multivalent display of a wide assortment of molecules on both the termini and internal sites on Cas9. Using this platform, we endow Cas9 with the functionality to effect precision genome edits, which involves efficient incorporation of exogenously supplied single-stranded oligonucleotide donor (ssODN) at the break site. We demonstrate that the multivalent display of ssODN on Cas9 significantly increased precision genome edits over those of Cas9 bearing one or no ssODN, and such display platform is compatible with large oligonucleotides and rapid screening of ssODNs. By hijacking the insulin secretion machinery and leveraging the ssODN display platform, we successfully engineer pancreatic β cells to secrete protective immunomodulatory factor interleukin-10.

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Piezo1 channel activates ADAM10 sheddase to regulate Notch1 and gene expression
Authors: Caolo Vincenza , Debant Marjolaine , Endesh Naima , Futers T Simon , Lichtenstein Laeticia , Parsonage Gregory , Jones Elizabeth AV , Beech David J
Published: August 2019

Mechanical force has emerged as a determinant of Notch signalling but the mechanisms of force sensing and coupling to Notch are unclear. Here we propose a role for Piezo1 channels, the recently identified mechanosensors of mammalian systems. Piezo1 channel opening in response to shear stress or a chemical agonist led to activation of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), a Ca2+-regulated transmembrane sheddase that mediates S2 Notch1 cleavage. Consistent with this observation there was increased Notch1 intracellular domain (NICD) that depended on ADAM10 and the downstream S3 cleavage enzyme, γ-secretase. Endothelial-specific disruption of Piezo1 in mice led to decreased Notch1-regulated gene expression in hepatic vasculature, consistent with prior evidence that Notch1 controls hepatic perfusion. The data suggest Piezo1 as a mechanism for coupling physiological force at the endothelium to ADAM10, Notch1, gene expression and vascular function.
Integrating Comprehensive Functional Annotations to Boost Power and Accuracy in Gene-Based Association Analysis
Authors: Quick Corbin , Wen Xiaoquan , Abecasis Gonçalo , Boehnke Michael , Kang Hyun Min
Published: August 2019

Gene-based association tests aggregate genotypes across multiple variants for each gene, providing an interpretable gene-level analysis framework for genome-wide association studies (GWAS). Early gene-based test applications often focused on rare coding variants; a more recent wave of gene-based methods, e.g. TWAS, use eQTLs to interrogate regulatory associations. Regulatory variants are expected to be particularly valuable for gene-based analysis, since most GWAS associations to date are non-coding. However, identifying causal genes from regulatory associations remains challenging and contentious. Here, we present a statistical framework and computational tool to integrate heterogeneous annotations with GWAS summary statistics for gene-based analysis, applied with comprehensive coding and tissue-specific regulatory annotations. We compare power and accuracy identifying causal genes across single-annotation, omnibus, and annotation-agnostic gene-based tests in simulation studies and an analysis of 128 traits from the UK Biobank, and find that incorporating heterogeneous annotations in gene-based association analysis increases power and performance identifying causal genes.