bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-time Estimation of Disease Activity in Emerging Outbreaks using Internet Search Information
Authors: Aiken Emily L. , McGough Sarah F. , Majumder Maimuna S. , Wachtel Gal , Nguyen Andre T. , Viboud Cecile , Santillana Mauricio
Published: November 2019

Understanding the behavior of emerging disease outbreaks in, or ahead of, real-time could help healthcare officials better design interventions to mitigate impacts on affected populations. Most healthcare-based disease surveillance systems, however, have significant inherent reporting delays due to data collection, aggregation, and distribution processes. Recent work has shown that machine learning methods leveraging a combination of traditionally collected epidemiological information and novel Internet-based data sources, such as disease-related Internet search activity, can produce meaningful “nowcasts” of disease incidence ahead of healthcare-based estimates, with most successful case studies focusing on endemic and seasonal diseases such as influenza and dengue. Here, we apply similar computational methods to emerging outbreaks in geographic regions where no historical presence of the disease of interest has been observed. By combining limited available historical epidemiological data available with disease-related Internet search activity, we retrospectively estimate disease activity in five recent outbreaks weeks ahead of traditional surveillance methods. We find that the proposed computational methods frequently provide useful real-time incidence estimates that can help fill temporal data gaps resulting from surveillance reporting delays. However, the proposed methods are limited by issues of sample bias and skew in search query volumes, perhaps as a result of media coverage.
PET markers of tau and neuroinflammation are co-localized in progressive supranuclear palsy
Authors: Malpetti Maura , Passamonti Luca , Rittman Timothy , Jones P. Simon , Vázquez Rodríguez Patricia , Bevan-Jones W. Richard , Hong Young T. , Fryer Tim D. , Aigbirhio Franklin I. , O’Brien John T. , Rowe James B.
Published: November 2019

Background

Progressive Supranuclear Palsy (PSP) is associated with tau-protein aggregation and neuroinflammation, but it remains unclear whether these pathogenic processes are relatedin vivo.

Objectives

We examined the relationship between tau pathology and microglial activation using [18F]AV-1451 (indexing tau burden) and [11C]PK11195 (microglial activation) PET in n=17 patients with PSP-Richardson’s syndrome.

Methods

Non-displaceable binding potential (BPND) for each ligand was quantified in 83 regions of interest (ROIs). [18F]AV-1451 and [11C]PK11195 BPNDvalues were correlated across all ROIs. The anatomical patterns of [18F]AV-1451 and [11C]PK11195 binding co-localization was determined across sets of regions derived from principal component analyses (PCAs). Finally, PCA-derived brain patterns of tau pathology and neuroinflammation were linked to clinical severity.

Results

[18F]AV-1451 and [11C]PK11195 binding were positively related across all ROIs (r=0.577, p<0.0001). PCAs identified four components for each ligand, reflecting the relative expression of tau pathology or neuroinflammation in distinct groups of brain regions. Positive associations between [18F]AV-1451 and [11C]PK11195 components were found in sub-cortical (r=0.769, p<0.0001) and cortical components(r=0.836, p<0.0001). PCA-derived components reflecting tau burden (r=0.599, p=0.011) and neuroinflammation (r=0.713, p=0.001) in sub-cortical areas related to disease severity.

Conclusions

We show that tau pathology and neuroinflammation co-localize in PSP, and that individual differences in subcortical tau pathology and neuroinflammation are linked to clinical severity. Although longitudinal studies are needed to determine how these molecular pathologies are causally linked, we suggest that the combination of tau- and immune-oriented strategies may be useful for effective disease-modifying treatments in PSP.
Per- and poly-fluoroalkyl substances and bone mineral density: results from the Bayesian weighted quantile sum regression
Authors: Colicino Elena , Pedretti Nicolo Foppa , Busgang Stefanie , Gennings Chris
Published: November 2019

Background

Per- and poly-fluoroalkyl substances (PFAS) are chemicals, detected in 95% of Americans, that induce osteotoxicity and modulate hormones thereby influencing bone health. Previous studies found associations between individual PFAS and bone mineral density but did not analyze their combined effects.

Objective

To extend weighted quantile sum (WQS) regression to a Bayesian framework (BWQS) and determine the association between a mixture of serum PFAS and mineral density in lumbar spine, total and neck femur in 499 adults from the 2013–2014 National Health and Nutrition Examination Survey (NHANES).

Methods

We used BWQS to assess the combined association of nine PFAS, as a mixture, with bone mineral density in adults. As secondary analyses, we focused on vulnerable populations (men over 50 years and postmenopausal women). Analyses were weighted according to NHANES weights and were adjusted for socio-demographic factors. Sensitivity analyses included bone mineral density associations with individual compounds and results from WQS regressions.

Results

The mean age was 55 years old (Standard Error [SE]=1) with average spine, total and neck femur mineral densities of 1.01 (SE=0.01), 0.95 (SE=0.01), and 0.78 (SE=0.01) gm/cm2, respectively. PFAS mixture levels showed no evidence of association with mineral density (spine: β=-0.004; 95% credible interval [CrI]=-0.04, 0.04; total femur: β=0.002; 95%CrI=-0.04, 0.05; femur neck: β=0.005; 95%CrI=-0.03, 0.04) in the overall population. Results were also null in vulnerable populations. Findings were consistent across sensitivity analyses.

Conclusions

We introduced a Bayesian extension of WQS and found no evidence of the association between PFAS mixture and bone mineral density.
Determinants of normal haemoglobin concentration among children in Ghana: a positive deviance analysis of nationally representative cross-sectional survey data
Authors: Amugsi Dickson A.
Published: November 2019

Anaemia among children under 5, is a public health problem of serious concern. In Ghana, 8 out of every 10 children are anaemic. This study employed a novel approach to investigate the determinants of normal haemoglobin (Hb) concentration among children aged 6 to 59 months, using data from the Ghana Demographic and Health Surveys. The results showed that a year change in maternal education was positively associated with normal Hb concentration. Children of non-anaemic mothers were 1.67 (CI=1.32, 2.10; P<.001) times more likely to have normal Hb concentration relative to children of anaemic mothers. Compared to mothers who had less than 4 antenatal care (ANC) visits, mothers who had at least 4 ANC visits increased the odds of their children having a normal Hb concentration by 1.62 (CI=1.09, 2.40; P<.018). Children living in middle and rich households had respectively 1.48 (CI=1.06, 2.07; p<.021) and 1.59 (CI=1.08, 2.33; p<.018) increased odds of having a normal Hb concentration relative to those living in poor households. Maternal education, anaemia, ANC attendance, and household wealth index are strong determinants of normal Hb concentration among children in Ghana. Strategies aimed at addressing childhood anaemia should take into account maternal anaemia, education, poverty and ANC attendance.
Polygenic risk scores predict diabetic complications and their response to therapy
Authors: Tremblay J. , Haloui M. , Harvey F. , Tahir R. , Marois-Blanchet F.-C. , Long C. , Attaoua R. , Simon P. , Santucci L. , Hizel C. , Chalmers J. , Marre M. , Harrap S. , Cifkova R. , Krajcoviechova A. , Matthews D. , Williams B. , Poulter N. , Zoungas S. , Colagiuri S. , Mancia G. , Grobbee D.E. , Rodgers A. , Liu L. , Agbessi M. , Bruat V. , Favé M-J. , Harwood M. , Awadalla P. , Woodward M. , Hamet P.
Published: November 2019

Type 2 diabetes increases the risk of cardiovascular and renal complications, but early risk prediction can lead to timely intervention and better outcomes. Through summary statistics of meta-analyses of published genome-wide association studies performed in over 1.2 million of individuals, we combined 9 PRS gathering genomic variants associated to cardiovascular and renal diseases and their key risk factors into one logistic regression model, to predict micro- and macrovascular endpoints of diabetes. Its clinical utility in predicting complications of diabetes was tested in 4098 participants with diabetes of the ADVANCE trial followed during a period of 10 years and replicated it in three independent non-trial cohorts. The prediction model adjusted for ethnicity, sex, age at onset and diabetes duration, identified the top 30% of ADVANCE participants at 3.1-fold increased risk of major micro- and macrovascular events (p=6.3×10−21 and p=9.6×10−31, respectively) and at 4.4-fold (p=6.8×10−33) increased risk of cardiovascular death compared to the remainder of T2D subjects. While in ADVANCE overall, combined intensive therapy of blood pressure and glycaemia decreased cardiovascular mortality by 24%, the prediction model identified a high-risk group in whom this therapy decreased mortality by 47%, and a low risk group in whom the therapy had no discernable effect. Patients with high PRS had the greatest absolute risk reduction with a number needed to treat of 12 to prevent one cardiovascular death over 5 years. This novel polygenic prediction model identified people with diabetes at low and high risk of complications and improved targeting those at greater benefit from intensive therapy while avoiding unnecessary intensification in low-risk subjects.
Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes
Authors: Reiman Eric M. , Arboleda-Velasquez Joseph F. , Quiroz Yakeel T. , Huentelman Matthew J. , Beach Thomas G. , Caselli Richard J. , Chen Yinghua , Su Yi , Myers Amanda J. , Hardy John , Vonsattel Jean Paul , Younkin Steven G. , Bennett David A. , De Jager Philip L. , Larson Eric B. , Crane Paul K. , Keene C. Dirk , Kamboh M. Ilyas , Kofler Julia K. , Duque Linda , Gilbert John R. , Gwirtsman Harry E. , Buxbaum Joseph D. , Dickson Dennis W. , Frosch Matthew P. , Ghetti Bernardino , Lunetta Kathryn L. , Wang Li-San , Hyman Bradley T. , Kukull Walter A. , Foroud Tatiana , Haines Jonathan L. , Mayeux Richard P. , Pericak-Vance Margaret A. , Schneider Julie A. , Trojanowski John Q. , Farrer Lindsay A. , Schellenberg Gerard D. , Beecham Gary W. , Montine Thomas J. , Jun Gyungah R. ,   for the Alzheimer’s Disease Genetics Consortium
Published: November 2019

Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer’s dementia, such that APOE4 homozygotes have a particularly high risk. While the APOE2 allele is associated with a lower risk of Alzheimer’s dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer’s dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer’s dementia cases and controls. APOE2/2 was associated with exceptionally low Alzheimer’s dementia odds ratios compared to APOE2/3, 3/3 and 4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer’s disease could have a major impact on the understanding, treatment and prevention of this terrible disease.
Functional connectome fingerprinting accuracy in youths and adults is similar when examined on the same day and 1.5 years apart
Authors: Jalbrzikowski Maria , Liu Fuchen , Foran William , Klei Lambertus , Calabro Finnegan J. , Roeder Kathryn , Devlin Bernie , Luna Beatriz
Published: November 2019

Pioneering studies have shown that individual correlation measures from resting-state functional magnetic resonance imaging studies can identify another scan from that same individual. This method is known as “connectotyping” or functional connectome “fingerprinting”. We analyzed a unique dataset of 12-30 years old (N=140) individuals who had two distinct resting state scans on the same day and again 12-18 months later to assess the sensitivity and specificity of fingerprinting accuracy across different time scales (same day, ~1.5 years apart) and developmental periods (youths, adults). Sensitivity and specificity to identify one’s own scan was high (average AUC=0.94), although it was significantly higher in the same day (average AUC=0.97) than 1.5-year years later (average AUC=0.91). Accuracy in youths (average AUC=0.93) was not significantly different from adults (average AUC=0.96). Multiple statistical methods revealed select connections from the Frontoparietal, Default, and Dorsal Attention networks that enhanced the ability to identify an individual. Identification of these features generalized across datasets and improved fingerprinting accuracy in a longitudinal replication data set (N=208). These results provide a framework for understanding the sensitivity and specificity of fingerprinting accuracy in adolescents and adults at multiple time scales. Importantly, distinct features of one’s “fingerprint” contribute to one’s uniqueness, suggesting that cognitive and default networks play a primary role in the individualization of one’s connectome.
Regulation of yeast RPL22B splicing depends on intact pre-mRNA context of the intron
Authors: Abrhámová Kateřina , Folk Petr
Published: November 2019

Yeast RPL22A and RPL22B genes form an intergenic regulatory loop modulating the ratio of paralogous transcripts in response to changing levels of proteins. Gabunilas and Chanfreau (Gabunilas and Chanfreau, PLoS Genet 12, e1005999, 2016) and our group (Abrhámová et al., PLoS ONE 13, e0190685, 2018) described that Rpl22 proteins bound to the divergent introns of RPL22 paralogs and inhibited splicing in dosage dependent manner. Here, we continued to study the splicing regulation in more detail and designed constructs for in vivo analyses of splicing efficiency. We also tested Rpl22 binding to RPL22B intron in three-hybrid system. We were able to confirm the findings reported originally by Gabunilas and Chanfreau on the importance of a stem loop structure within the RPL22B intron. Mutations which lowered the stability of the structure abolished Rpl22-mediated inhibition. In contrast, we were not able to confirm the sequence specificity with respect to either Rpl22 binding or splicing inhibition within this region, which they reported. We contradict their results that the ‘RNA internal loop’ of RPL22Bi (nt 178CCCU181 and 221UGAA224) is crucial for mediating the Rpl22 effects. We assume that this discrepancy reflects the difference in constructs, as the reporters used by Gabunilas and Chanfreau lacked the alternative 5’ splice site as well as surrounding exons. Our own comparison confirms that deleting the sequence spanning alternative 5’ splice site lowers splicing efficiency, hinting to possible disturbances of the regulatory mechanism. We argue that the structural context of the ‘regulatory element’ may reach across the intron or into the surrounding sequences, similarly to what was found previously for other genes, such as RPL30. Apparently, more detailed analyses are needed to discern this intriguing example of splicing regulation.
Allele-specific DNA methylation is increased in cancers and its dense mapping in normal plus neoplastic cells increases the yield of disease-associated regulatory SNPs
Authors: Do Catherine , Dumont Emmanuel LP , Salas Martha , Castano Angelica , Mujahed Huthayfa , Maldonado Leonel , Singh Arunjot , DaSilva-Arnold Sonia C. , Bhagat Govind , Lehman Soren , Christiano Angela M. , Madhavan Subha , Nagy Peter L. , Green Peter H.R. , Feinman Rena , Trimble Cornelia , Illsley Nicholas P. , Marder Karen , Honig Lawrence , Monk Catherine , Goy Andre , Chow Kar , Goldlust Samuel , Kaptain George , Siegel David , Tycko Benjamin
Published: November 2019

Background

Mapping of allele-specific DNA methylation (ASM) can be a post-GWAS strategy for localizing regulatory sequence polymorphisms (rSNPs). However, the advantages of this approach, and the mechanisms underlying ASM in normal and neoplastic cells, remain to be clarified.

Results

We performed whole genome methyl-seq on diverse normal cells and tissues and three types of cancers (multiple myeloma, lymphoma, glioblastoma multiforme). After excluding imprinting, the data pinpointed 15,114 high-confidence ASM differentially methylated regions (DMRs), of which 1,842 contained SNPs in strong linkage disequilibrium or coinciding with GWAS peaks. ASM frequencies were increased 5 to 9-fold in cancers vs. matched normal tissues, due to widespread allele-specific hypomethylation and focal allele-specific hypermethylation in poised chromatin. Cancers showed increased allele switching at ASM loci, but disruptive SNPs in specific classes of CTCF and transcription factor (TF) binding motifs were similarly correlated with ASM in cancer and non-cancer. Rare somatic mutations affecting these same motif classes tracked with de novo ASM in the cancers. Allele-specific TF binding from ChIP-seq was enriched among ASM loci, but most ASM DMRs lacked such annotations, and some were found in otherwise uninformative “chromatin deserts”.

Conclusions

ASM is increased in cancers but occurs by a shared mechanism involving disruptive SNPs in CTCF and TF binding sites in both normal and neoplastic cells. Dense ASM mapping in normal plus cancer samples reveals candidate rSNPs that are difficult to find by other approaches. Together with GWAS data, these rSNPs can nominate specific transcriptional pathways in susceptibility to autoimmune, neuropsychiatric, and neoplastic diseases. Custom genome browser tracks with annotated ASM loci can be viewed at a UCSC browser session hosted by our laboratory (https://bit.ly/tycko-asm)
Simulating the human tumor microenvironment in colorectal cancer organoids in vitro and in vivo
Authors: Devarasetty Mahesh , Dominijanni Anthony , Herberg Samuel , Shelkey Ethan , Skardal Aleksander , Soker Shay
Published: November 2019

The tumor microenvironment (TME) plays a significant role in cancer growth and metastasis. Bioengineered models of the TME will advance our understanding of cancer progression and facilitate identification of novel anti-cancer therapeutics that target TME components such as extracellular matrix (ECM) and stromal cells. However, most current in vitro models fail to recapitulate the extensive features of the human tumor stroma, especially ECM architecture, and are not exposed to intact body physiology. On the other hand, in vivo animal models do not accurately capture human tumor architecture. Using the features of biopsied colorectal cancer (CRC) tissue as a guide, we address these deficiencies by creating human organoids containing a colonic stromal ECM layer and CRC spheroids. Organoids were studied in vitro and upon implantation in mice for 28 days. We show that the stromal ECM micro-architecture, generated in vitro, was maintained in vivo for at least 28 days. Furthermore, comparisons with biopsied CRC tumors revealed that organoids with orderly structured TMEs induce an epithelial phenotype in CRC cells, similar to low-grade tumors, compared to a mesenchymal phenotype observed in disordered TMEs, similar to high-grade tumors. Altogether, these results are the first demonstration of replicating the human tumor ECM architecture in biofabricated tumor organoids under ex vivo and in vivo conditions.
Photosynthesis and crop productivity is enhanced by glucose-functionalized fluorescent carbon dots
Authors: Swift Thomas A. , Fagan Daniel , Benito-Alifonso David , Hill Stephen A. , Yallop Marian L. , Oliver Thomas A. A. , Lawson Tracy , Galan M. Carmen , Whitney Heather M.
Published: November 2019

From global food security to textile production and biofuels, the demands currently made on plant photosynthetic productivity will continue to increase. Enhancing photosynthesis using designer, green and sustainable materials offers an attractive alternative to current genetic-based strategies and promising work with nanomaterials has recently started to emerge. Here we describe in planta use of carbon-based nanoparticles produced by low-cost renewable routes that are bioavailable to mature plants. Uptake of these functionalised nanoparticles from the soil improves photosynthesis and also increases crop production. We show for the first time that glucose-functionalization enhances nanoparticle uptake, photoprotection and pigment production, unlocking enhanced yields. This is demonstrated in Triticum aestivum ‘Apogee’ (dwarf bread wheat) and results in an 18% increase in grain yield. This establishes the viability of a functional nanomaterial to augment photosynthesis as a route to increased crop productivity.
Stochasticity in bacterial division control: Preliminary consequences for protein concentration
Authors: Nieto Acuna Cesar Augusto , Vargas Garcia Cesar Augusto , Pedraza Juan Manuel
Published: November 2019

The stochastic nature of protein concentration inside cells can have important consequences in their physiology and population fitness. Classical models of gene expression consider these processes as first-order reactions with little dependence with the cell size. However, the concentrations of the relevant molecules depend directly on the cellular volume. Here we model the cell size dynamics as exponential growth followed by division with occurrence rate proportional to the size. This framework, together with known models of chromosome replication and both protein and mRNA synthesis, lets us predict relationships between cell size and both protein number and concentration. As a main result, we find that protein production strategies (constant rate or rate proportional to either chromosome number, cell size or chromosome number times cell size) can be experimentally distinguished from the correlation between protein concentration and cell size.
Climate change and deforestation boost post-fire grass invasion of Amazonian forests
Authors: De Faria Bruno L. , Staal Arie , Martin Philip A. , Panday Prajjwal K. , Castanho Andrea D. , Dantas Vinícius L.
Published: November 2019

Interactions among climate change, deforestation and fires are changing the stability of the Amazon forest, and may promote transitions to degraded grassy ecosystem states. However, our ability to predict the locations in the Amazon that are most vulnerable to these transitions is limited. In this study we used a dynamic carbon model to evaluate how drought, climate change and deforestation could affect the probability of post-fire grass invasion across the Amazon, and identify where grass-fire feedbacks may promote the persistence of species-poor degraded forests with savanna-like structure. Our results suggest that, under current climatic conditions, post-fire grass invasion could affect 11% of the Amazon, with the south-eastern Amazon at highest risk of invasion. We forecast that under business as usual climate change, by the end of the century areas with a high probability of post-fire grass invasion will increase to 20% of the Amazon. In 10% of the Amazon fire return interval will be shorter than the time required for canopy recovery, implying high risk of irreversible shifts to a fire-maintained degraded ecosystem state. Although resilience in canopy regeneration is evident in areas with low fire frequency, increased fire frequency could inhibit regeneration even in forests where grass is currently excluded, and push the Amazon forests towards a tipping point causing large areas of forest to transition to low tree cover state.
Unraveling Why We Sleep: Quantitative Analysis Reveals Abrupt Transition from Neural Reorganization to Repair in Early Development
Authors: Cao Junyu , Herman Alexander B. , West Geoffrey B. , Poe Gina , Savage Van M.
Published: November 2019

Sleep serves disparate functions, most notably neural repair, metabolite clearance and circuit reorganization, yet the relative importance of these functions remains hotly debated. Here, we create a novel mechanistic framework for understanding and predicting how sleep changes during ontogeny (why babies sleep twice as long as adults) and across phylogeny (why mice sleep roughly five times that of whales). We use this theory to quantitatively distinguish between sleep used for neural reorganization versus repair. We conduct a comprehensive, quantitative analysis of human sleep using total sleep time, cerebral metabolic rate, brain size, synaptic density, and REM sleep (used here to also refer to Active Sleep in infants and children). Our findings reveal an abrupt transition, between 2 and 3 years of age in humans. Specifically, our results show that differences in sleep across phylogeny and during late ontogeny (after 2 or 3 years in humans) are primarily due to sleep functioning for repair or clearance, while changes in sleep during early ontogeny (before 2 - 3 years in humans) primarily support neural reorganization and learning. Moreover, our analysis shows that neuroplastic reorganization occurs primarily in REM sleep but not in NREM. In accordance with the developmental role of neuroplasticity, the percent of time spent in REM sleep is independent of brain size across species but decreases dramatically as brain size grows through development. Furthermore, the ratio of NREM sleep time to awake time emerges as a new invariant across development. This developmental transition and fundamental shift across ontogeny and phylogeny suggests a complex interplay between developmental and evolutionary constraints on sleep.
The clinical drug candidate ebselen attenuates inflammation and promotes microbiome recovery after antibiotic treatment for Clostridium difficile infection
Authors: Garland Megan , Hryckowian Andrew J , Tholen Martina , Loscher Sebastian , Van Treuren William W. , Bender Kristina Oresic , Sonnenburg Justin L , Bogyo Matthew
Published: November 2019

Clostridium difficile infection (CDI) is an enteric bacterial disease that is increasing in prevalence worldwide. C. difficile capitalizes on gut inflammation and microbiome dysbiosis to establish infection, with symptoms ranging from watery diarrhea to toxic megacolon. We recently reported that the safe in human clinical drug candidate ebselen (NCT03013400, NCT01452607, NCT00762671, NCT02603081) has biochemical, cell-based and in vivo efficacy against the bacterial toxins of C. difficile. Here, we show that ebselen treatment reduces recurrence rates and decreases colitis in a hamster relapse model of CDI. Furthermore, ebselen treatment does not alter microbiome diversity but promotes its recovery back to that of healthy controls after antibiotic-induced dysbiosis in both healthy and C. difficile-infected mice. This increased microbiome recovery upon ebselen treatment correlates with a decrease in host-derived inflammatory markers suggesting that the anti-inflammatory properties of ebselen, combined with its anti-toxin function, help to mitigate the major clinical challenges of CDI, including recurrence, microbial dysbiosis, and colitis.
One-step Generation of Zebrafish Carrying a Conditional Knockout-Knockin Visible Switch via CRISPR/Cas9-Mediated Intron Targeting
Authors: Li Jia , Li Hong-yu , Gu Shan-ye , Zi Hua-Xing , Jiang Lai , Du Jiu-lin
Published: November 2019

The zebrafish has been becoming a popular vertebrate animal model in biomedical research. However, it is still challenging for making conditional gene knockout (CKO) zebrafish due to the low efficiency of homologous recombination (HR). Here we report an efficient non-HR-based method for generating zebrafish carrying a CKO and knockin (KI) switch (zCKOIS) coupled with dual-color fluorescent reporters. Using this strategy, we generated hey2zCKOIS which served as a hey2 KI reporter with EGFP expression. Upon Cre induction in targeted cells, the hey2zCKOIS was switched to a non-functional CKO allele hey2zCKOIS-inv associated with TagRFP expression, enabling to visualize CKO alleles. Thus, the simplification of the design, and the visibility and combination of both CKO and KI alleles’ engineering make our zCKOIS strategy an applicable CKO approach for zebrafish.
Preparatory delta phase response is correlated with naturalistic speech comprehension performance
Authors: Li Jiawei , Hong Bo , Nolte Guido , Engel Andreas K. , Zhang Dan
Published: November 2019

While human speech comprehension is thought to be an active process that involves top-down predictions, it remains unclear how predictive information is used to prepare for the processing of upcoming speech information. We aimed to identify the neural signatures of the preparatory processing of upcoming speech. Participants selectively attended to one of two competing naturalistic, narrative speech streams, and a temporal response function (TRF) method was applied to derive event-related-like neural responses from electroencephalographic data. The phase responses to the attended speech at the delta band (1–4 Hz) were correlated with the comprehension performance of individual participants, with a latency of -200–0 ms before onset over the fronto-central and left-lateralized parietal regions. The phase responses to the attended speech at the alpha band also correlated with comprehension performance, but with a latency of 650–980 ms post-onset over fronto-central regions. Distinct neural signatures were found for the attentional modulation, taking the form of TRF-based amplitude responses at a latency of 240–320 ms post-onset over the left-lateralized fronto-central and occipital regions. Our findings reveal how the brain gets prepared to process an upcoming speech in a continuous, naturalistic speech context.
A Small-Molecule Activity-Based Probe for Monitoring Ubiquitin C-terminal Hydrolase L1 (UCHL1) Activity in Live Cells and Zebrafish Embryos
Authors: Geurink Paul P. , Kooij Raymond , Sapmaz Aysegul , Liu Sijia , Xin Bo-Tao , Janssen George M. C. , van Veelen Peter A. , Dijke Peter ten , Ovaa Huib
Published: November 2019

Many reagents have been emerged to study the function of specific enzymesin vitro. On the other hand, target specific reagents are scarce or need improvement allowing investigations of the function of individual enzymes in a cellular context. We here report the development of a target-selective fluorescent small-molecule activity-based DUB probe that is active in live cells and whole animals. The probe labels active Ubiquitin Carboxy-terminal Hydrolase L1 (UCHL1), also known as neuron-specific protein PGP9.5 (PGP9.5) and parkinson disease 5 (PARK5), a DUB active in neurons that constitutes 1-2% of total brain protein. UCHL1 variants have been linked with the neurodegenerative disorders Parkinson’s and Alzheimer’s disease. In addition, high levels of UCHL1 also correlate often with cancer and especially metastasis. The function of UCHL1 or its role in cancer and neurodegenerative disease is poorly understood and few UCHL1 specific research tools exist. We show that the reagents reported here are specific for UCHL1 over all other DUBs detectable by competitive activity-based protein profiling and by mass spectrometry. Our probe, which contains a cyanimide reactive moiety, binds to the active-site cysteine residue of UCHL1 irreversibly in an activity-dependent manner. Its use is demonstrated by labelling of UCHL1 bothin vitroand in cells. We furthermore show that this probe can report UCHL1 activity during the development of zebrafish embryos.
Panoramic visual representation in the dorsal visual pathway and its role in reorientation
Authors: Li Tianyi , Arleo Angelo , Sheynikhovich Denis
Published: November 2019

While primates are primarily visual animals, how visual information is processed on its way to memory structures and contributes to the generation of visuospatial behaviors is poorly understood. Recent imaging data demonstrate the existence of scene-sensitive areas in the dorsal visual path that are likely to combine visual information from successive egocentric views, while behavioral evidence indicates the memory of surrounding visual space in extraretinal coordinates. The present work focuses on the computational nature of a panoramic representation that is proposed to link visual and mnemonic functions during natural behavior. In a spiking neural network model of the dorsal visual path it is shown how time-integration of spatial views can give rise to such a representation and how it can subsequently be used to perform memory-based spatial reorientation and visual search. More generally, the model predicts a common role of view-based allocentric memory storage in spatial and non-spatial mnemonic behaviors.
Geographic assessment of cancer genome profiling studies
Authors: Cordo Paula Carrio , Acheson Elise , Huang Qingyao , Baudis Michael
Published: November 2019

Cancers arise from the accumulation of somatic genome mutations, which can be influenced by inherited genomic variants and external factors such as environmental or lifestyle-related exposure. Due to the heterogeneity of cancers, precise information about the genomic composition of germline and malignant tissues has to be correlated with morphological, clinical and extrinsic features to advance medical knowledge and treatment options. With global differences in cancer frequencies and disease types, geographic data is of importance to understand the interplay between genetic ancestry and environmental influence in cancer incidence, progression and treatment outcome.

In this study, we analysed the current landscape of oncogenomic screening publications for geographic information content and quality, to address underrepresented study populations and thereby to fill prominent gaps in our understanding of interactions between somatic variations, population genetics and environmental factors in oncogenesis. We conclude that while the use of proxy derived geographic annotations can be useful for coarse-grained associations, the study of geo-correlated factors in cancer causation and progression will benefit from standardized geographic provenance annotations. Additionally, publication derived geographic provenance data allowed us to highlight stark inequality in the geographies of cancer genome profiling, with a near lack of sizeable studies from Africa and other large regions.
Diet induces parallel changes to the gut microbiota and problem solving performance in a wild bird
Authors: Davidson Gabrielle L. , Wiley Niamh , Cooke Amy C. , Johnson Crystal N. , Fouhy Fiona , Reichert Michael S. , de la Hera Iván , Crane Jodie M.S. , Kulahci Ipek G. , Ross R. Paul , Stanton Catherine , Quinn John L.
Published: November 2019

The microbial community in the gut is influenced by environmental factors, especially diet, which can moderate host behaviour through the microbiome-gut-brain axis. However, the ecological relevance of microbiome-mediated behavioural plasticity in wild animals is unknown. We presented wild-caught great tits (Parus major) with a problem-solving task and showed that performance was weakly associated with variation in the gut microbiome. We then manipulated the gut microbiome by feeding birds one of two diets that differed in their relative levels of fat, protein and fibre content: an insect diet (low content), or a seed diet (high content). Microbial communities were less diverse among individuals given the insect compared to those on the seed diet. Individuals were less likely to problem-solve after being given the insect diet, and the same microbiota metrics that were altered as a consequence of diet were also those that correlated with variation in problem solving performance. Although the effect on problem-solving behaviour could have been caused by motivational or nutritional differences between our treatments, our results nevertheless raise the possibility that dietary induced changes in the gut microbiota could be an important mechanism underlying individual behavioural plasticity in wild populations.
A MAP of tumor-host interactions in glioma at single cell resolution
Authors: Caruso Francesca Pia , Garofano Luciano , D’Angelo Fulvio , Yu Kai , Tang Fuchou , Yuan Jinzhou , Zhang Jing , Cerulo Luigi , Bedognetti Davide , Sims Peter A. , Suvà Mario , Su Xiao-Dong , Lasorella Anna , Iavarone Antonio , Ceccarelli Michele
Published: November 2019

Single-cell RNA sequencing is the reference technique to characterize the heterogeneity of tumor microenvironment and can be efficiently used to discover cross-talk mechanisms between immune cells and cancer cells. We present a novel method, single cell Tumor-Host Interaction tool (scTHI), to identify significantly activated ligand-receptor interactions across clusters of cells from single-cell RNA sequencing data. We apply our approach to uncover the ligand-receptor interactions in glioma using six publicly available human glioma datasets encompassing 71 patients. We provide a comprehensive map of the signalling mechanisms between malignant cells and non-malignant cells in glioma uncovering potential novel therapeutic targets.
Spatially Resolved Estimation of Metabolic Oxygen Consumption From Optical Measurements in Cortex
Authors: Sætra Marte J. , Solbrå Andreas V. , Devor Anna , Dale Anders M. , Einevoll Gaute T.
Published: November 2019

The cerebral metabolic rate of oxygen (CMRO2) is an important indicator of brain function and pathology. Knowledge about its magnitude is also required for proper interpretation of the blood oxygenation level dependent (BOLD) signal measured with functional MRI (fMRI). The ability to measure CMRO2 with high spatial and temporal accuracy is thus highly desired. Traditionally the estimation of CMRO2 has been pursued with somewhat indirect approaches combining several different types of measurements with mathematical modeling of the underlying physiological processes. Given the numerous assumptions involved, questions have thus been raised about the accuracy of the resulting CMRO2 estimates. The recent ability to measure the level of oxygen (pO2) in cortex with high spatial resolution in in vivo conditions has provided a more direct way for estimating CMRO2. CMRO2 and pO2 are related via the Poisson partial differential equation. Assuming a constant CMRO2 and cylindrical symmetry around the blood vessel providing the oxygen, the so-called Krogh-Erlang formula relating the spatial pO2 profile to a constant CMRO2 value can be derived. This Krogh-Erlang formula has previously been used to estimate the average CMRO2 close to cortical blood vessels based on pO2 measurements in rats.

Here we introduce a new method, the Laplace method, to provide spatial maps of CMRO2 based on the same measured pO2 profiles. The method has two key steps: First the measured pO2 profiles are spatially smoothed to reduce effects of spatial noise in the measurements. Next, the Laplace operator (a double spatial derivative) in two spatial dimensions is applied on the smoothed pO2 profiles to obtain spatially resolved CMRO2 estimates. The smoothing introduces a bias, and a balance must be found where the effects of the noise are sufficiently reduced without introducing too much bias. In this model-based study we explore this balance in situations where the ground truth, that is, spatial profile of CMRO2 is preset and thus known, and the corresponding pO2 profiles are found by solving the Poisson equation, either numerically or by taking advantage of the Krogh-Erlang formula. MATLAB code for using the Laplace method is provided.
Data architecture for a large-scale neuroscience collaboration
Authors:   The International Brain Laboratory, Bonacchi Niccolò , Chapuis Gaelle , Churchland Anne , Harris Kenneth D. , Hunter Max , Rossant Cyrille , Sasaki Maho , Shen Shan , Steinmetz Nicholas A. , Walker Edgar Y. , Winter Olivier , Wells Miles
Published: November 2019

Effective data management is a major challenge for neuroscience labs, and even greater for collaborative projects. In the International Brain laboratory (IBL), ten experimental labs spanning 7 geographically distributed sites measure neural activity across the brains of mice making perceptual decisions. Here, we report a novel, modular architecture that allows users to contribute, access, and analyze data across this collaboration. Users contribute data using a web-based electronic lab notebook (Alyx), which automatically registers recorded data files and uploads them to a central server. Users access data with a lightweight interface, the Open Neurophysiology Environment (ONE), which searches data from all labs and loads it into MATLAB or Python. To analyze data, we have developed pipelines based on DataJoint, which automatically populate a website displaying a graphical summary of results to date. This architecture provides a new framework to contribute, access and analyze data, surmounting many challenges currently faced by neuroscientists.
Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis
Authors: Yang Jing , McGovern Amanda , Martin Paul , Duffus Kate , Ge Xiangyu , Zarrineh Peyman , Morris Andrew P , Adamson Antony , Fraser Peter , Rattray Magnus , Eyre Stephen
Published: November 2019

Genome-wide association studies have identified genetic variation contributing to complex disease risk. However, assigning causal genes and mechanisms has been more challenging because disease-associated variants are often found in distal regulatory regions with cell-type specific behaviours. Here, we collect ATAC-seq, Hi-C, Capture Hi-C and nuclear RNA-seq data in stimulated CD4+ T-cells over 24 hours, to identify functional enhancers regulating gene expression. We characterise changes in DNA interaction and activity dynamics that correlate with changes gene expression, and find that the strongest correlations are observed within 200 kb of promoters. Using rheumatoid arthritis as an example of T-cell mediated disease, we demonstrate interactions of expression quantitative trait loci with target genes, and confirm assigned genes or show complex interactions for 20% of disease associated loci, including FOXO1, which we confirm using CRISPR/Cas9.
A mathematical dissection of the adaptation of cell populations to fluctuating oxygen levels
Authors: Ardaševa Aleksandra , Gatenby Robert A , Anderson Alexander R A , Byrne Helen M , Maini Philip K , Lorenzi Tommaso
Published: November 2019

The disordered network of blood vessels that arises from tumour angiogenesis results in variations in the delivery of oxygen into the tumour tissue. This brings about regions of chronic hypoxia (i.e. sustained low oxygen levels) and regions with alternating phases of low and relatively higher oxygen levels within vascularised tumours, and makes it necessary for cancer cells to adapt to fluctuating environmental conditions. We use a phenotype-structured model to dissect the evolutionary dynamics of cell populations exposed to fluctuating oxygen levels. In this model, the phenotypic state of every cell is described by a continuous variable that provides a simple representation of its metabolic phenotype, ranging from fully oxidative to fully glycolytic, and cells are grouped into two competing populations that undergo heritable, spontaneous phenotypic variations at different rates. Model simulations indicate that, depending on the rate at which oxygen is consumed by the cells, nonlinear dynamic interactions between cells and oxygen can stimulate chronic hypoxia and cycling hypoxia. Moreover, the model supports the idea that under chronic-hypoxic conditions lower rates of phenotypic variation lead to a competitive advantage, whereas higher rates of phenotypic variation can confer a competitive advantage under cycling-hypoxic conditions. In the latter case, the numerical results obtained show that bet-hedging evolutionary strategies, whereby cells switch between oxidative and glycolytic phenotypes, can spontaneously emerge. We explain how these results can shed light on the evolutionary process that may underpin the emergence of phenotypic heterogeneity in vascularised tumours.
Mitochondria tether to Focal Adhesions during cell migration and regulate their size
Authors: Daniel Redaet , Mengeta Abebech , Bilodeau Patricia , Lee Jonathan M
Published: November 2019

Mitochondria are the key generators of ATP in a cell. Visually, they are highly dynamic organelles that undergo cellular fission and fusion events in response to changing cellular energy requirements. Mitochondria are now emerging as regulators of mammalian cell motility. Here we show that mitochondria infiltrate the leading edge of NIH3T3 fibroblasts during migration. At the leading edge, we find that mitochondria move to and tether to Focal Adhesions (FA). FA regulate cell migration by coupling the cytoskeleton to the Extracellular Matrix through integrin receptors. Importantly, we find that inhibition of mitochondrial ATP generation concomitantly inhibits FA size. This suggests that mitochondrial energy production regulates migration through FA control.
Biological sex and age shape melanoma tumour evolution
Authors: Lotz Martin , Furney Simon J. , Virós Amaya
Published: November 2019

Many cancer types display sex and age disparity in incidence and outcome. Here, we establish a mathematical approach using cancer mutational data to analyze how sex and age shape the tumour genome. We model how age-related (clock-like) somatic mutations that arise during cell division, and extrinsic (environmental) mutations accumulate in cancer genomes. As a proof-of-concept, we apply our approach to melanoma, a cancer driven by cell-intrinsic age-related mutations and extrinsic ultraviolet light-induced mutations, and show these mutation types differ in magnitude, chronology and by sex in the distinct molecular melanoma subtypes.

Our model confirms age and sex are determinants of cellular mutation rate, shaping the final mutation composition. We show mathematically for the first time how, similar to non-cancer tissues, melanoma genomes reflect a decline in cell division during ageing. We find clock-like mutations strongly correlate with the acquisition of ultraviolet light-induced mutations, but critically, males present a higher number and rate of cell division-linked mutations. These data indicate the contribution of environmental damage to melanoma likely extends beyond genetic damage to affect cell division.