bluuebunny/crossref_metadata_2025 huggingface dataset:
Radiation associated brain image changes after proton therapy for skull base head and neck cancers
Authors: Engeseth Grete May , Stieb Sonja , Radwan Mohamed Abdallah Sherif , He Renjie , Stokkevåg Camilla Hanquist , Brydøy Marianne , Fuller Clifton Dave , Garden Adam S , Rosenthal David I , Phan Jack , Morrison William H , Reddy Jay P , Wu Richard , Zhang Xiaodong , Frank Steven Jay , Gunn Gary Brandon
Published: February 2020

Background and purpose

To characterize patterns and outcomes of brain MR image changes after proton therapy (PT) for skull base head and neck cancer (HNC).

Material and methods

127 patients treated with PT for HNC who had received at least 40 Gy(RBE) to the brain and had ≥ 1 follow-up MRI > 6 months after PT were analyzed. MRIs were reviewed for radiation- associated image changes (RAIC). MRIs were rigidly registered to planning CTs, and RAIC were contoured on T1 (post-contrast) and T2 weighted sequences, and dose-volume parameters extracted. Probability of RAIC over time was calculated using multistate analysis. Univariate/multivariate analyses were performed using Cox Regression. Recursive partitioning analysis was used to investigate dose-volume correlates of RAIC development.

Results

17.3% developed RAIC. All RAIC events were asymptomatic and occurred in the temporal lobe (14), frontal lobe (6) and cerebellum (2). The median volume of the RAIC on post-contrast T1 was 0.5 cc at their maximum size. The RAIC spontaneously resolved in 27.3%, progressed in 27.3% and improved or were stable in 29.6% of patients. The 3-year actuarial rate of developing RAIC was 14.3%. Brain and RAIC lesion doses were generally higher for temporal lobe RAIC compared to frontal lobe RAIC. RAIC was observed in 63% of patients when V67 Gy(RBE) of the brain ≥ 0.17 cc.

Conclusion

RAIC lesions after PT were asymptomatic and either resolved or regressed in the majority of the patients. The estimated dose–volume correlations confirm the importance of minimizing focal high doses to brain when achievable.
Analysis of the epidemic growth of the early 2019-nCoV outbreak using internationally confirmed cases
Authors: Zhao Qingyuan , Chen Yang , Small Dylan S
Published: February 2020

Background

On January 23, 2020, a quarantine was imposed on travel in and out of Wuhan, where the 2019 novel coronavirus (2019-nCoV) outbreak originated from. Previous analyses estimated the basic epidemiological parameters using symptom onset dates of the confirmed cases in Wuhan and outside China.

Methods

We obtained information on the 46 coronavirus cases who traveled from Wuhan before January 23 and have been subsequently confirmed in Hong Kong, Japan, Korea, Macau, Singapore, and Taiwan as of February 5, 2020. Most cases have detailed travel history and disease progress. Compared to previous analyses, an important distinction is that we used this data to informatively simulate the infection time of each case using the symptom onset time, previously reported incubation interval, and travel history. We then fitted a simple exponential growth model with adjustment for the January 23 travel ban to the distribution of the simulated infection time. We used a Bayesian analysis with diffuse priors to quantify the uncertainty of the estimated epidemiological parameters. We performed sensitivity analysis to different choices of incubation interval and the hyperparameters in the prior specification.

Results

We found that our model provides good fit to the distribution of the infection time. Assuming the travel rate to the selected countries and regions is constant over the study period, we found that the epidemic was doubling in size every 2.9 days (95% credible interval [CrI], 2 days—4.1 days). Using previously reported serial interval for 2019-nCoV, the estimated basic reproduction number is 5.7 (95% CrI, 3.4—9.2). The estimates did not change substantially if we assumed the travel rate doubled in the last 3 days before January 23, when we used previously reported incubation interval for severe acute respiratory syndrome (SARS), or when we changed the hyperparameters in our prior specification.

Conclusions

Our estimated epidemiological parameters are higher than an earlier report using confirmed cases in Wuhan. This indicates the 2019-nCoV could have been spreading faster than previous estimates.
Clinical characteristics of 2019 novel coronavirus infection in China
Authors: Guan Wei-jie , Ni Zheng-yi , Hu Yu , Liang Wen-hua , Ou Chun-quan , He Jian-xing , Liu Lei , Shan Hong , Lei Chun-liang , Hui David S.C. , Du Bin , Li Lan-juan , Zeng Guang , Yuen Kwok-Yung , Chen Ru-chong , Tang Chun-li , Wang Tao , Chen Ping-yan , Xiang Jie , Li Shi-yue , Wang Jin-lin , Liang Zi-jing , Peng Yi-xiang , Wei Li , Liu Yong , Hu Ya-hua , Peng Peng , Wang Jian-ming , Liu Ji-yang , Chen Zhong , Li Gang , Zheng Zhi-jian , Qiu Shao-qin , Luo Jie , Ye Chang-jiang , Zhu Shao-yong , Zhong Nan-shan
Published: February 2020

Background

Since December 2019, acute respiratory disease (ARD) due to 2019 novel coronavirus (2019-nCoV) emerged in Wuhan city and rapidly spread throughout China. We sought to delineate the clinical characteristics of these cases.

Methods

We extracted the data on 1,099 patients with laboratory-confirmed 2019-nCoV ARD from 552 hospitals in 31 provinces/provincial municipalities through January 29th, 2020.

Results

The median age was 47.0 years, and 41.90% were females. Only 1.18% of patients had a direct contact with wildlife, whereas 31.30% had been to Wuhan and 71.80% had contacted with people from Wuhan. Fever (87.9%) and cough (67.7%) were the most common symptoms. Diarrhea is uncommon. The median incubation period was 3.0 days (range, 0 to 24.0 days). On admission, ground-glass opacity was the typical radiological finding on chest computed tomography (50.00%). Significantly more severe cases were diagnosed by symptoms plus reverse-transcriptase polymerase-chain-reaction without abnormal radiological findings than non-severe cases (23.87% vs. 5.20%, P<0.001). Lymphopenia was observed in 82.1% of patients. 55 patients (5.00%) were admitted to intensive care unit and 15 (1.36%) succumbed. Severe pneumonia was independently associated with either the admission to intensive care unit, mechanical ventilation, or death in multivariate competing-risk model (sub-distribution hazards ratio, 9.80; 95% confidence interval, 4.06 to 23.67).

Conclusions

The 2019-nCoV epidemic spreads rapidly by human-to-human transmission. Normal radiologic findings are present among some patients with 2019-nCoV infection. The disease severity (including oxygen saturation, respiratory rate, blood leukocyte/lymphocyte count and chest X-ray/CT manifestations) predict poor clinical outcomes.
Apathy is not associated with reduced ventral striatal volume in patients with schizophrenia
Authors: Burrer Achim , Caravaggio Fernando , Manoliu Andrei , Plitman Eric , Gütter Karoline , Habermeyer Benedikt , Stämpfli Philipp , Abivardi Aslan , Schmidt André , Borgwardt Stefan , Chakravarty Mallar , Lepage Martin , Dagher Alain , Graff-Guerrero Ariel , Seifritz Erich , Kaiser Stefan , Kirschner Matthias
Published: February 2020

Background

A growing body of neuroimaging research has revealed a relationship between blunted activation of the ventral striatum (VS) and apathy in schizophrenia. In contrast, the association between reduced striatal volume and apathy is less well established, while the relationship between VS function and structure in patients with schizophrenia remains an open question. Here, we aimed to replicate previous structural findings in a larger independent sample and to investigate the relationship between VS hypoactivation and VS volume.

Methods

We included brain structural magnetic resonance imaging (MRI) data from 60 patients with schizophrenia (SZ) that had shown an association of VS hypoactivation with apathy during reward anticipation and 58 healthy controls (HC). To improve replicability, we applied analytical methods developed in two previously published studies: Voxel-based morphometry and the Multiple Automatically Generated Templates (MAGeT) algorithm. VS and dorsal striatum (DS) volume were correlated with apathy correcting for age, gender and total brain volume. Additionally, left VS activity was correlated with left VS volume.

Results

We failed to replicate the association between apathy and reduced VS volume and did not find a correlation with DS volume. Functional and structural left VS measures exhibited a trend-level correlation (rs=0.248, p=0.067, r2=0.06).

Conclusions

Our present data suggests that functional and structural striatal neuroimaging correlates of apathy can occur independently. Replication of previous findings may have been limited by other factors (medication, illness duration, age) potentially related to striatal volume changes in SZ. Finally, associations between reward-related VS function and structure should be further explored.
Incorporating Human Movement Data to Improve Epidemiological Estimates for 2019-nCoV
Authors: Cao Zhidong , Zhang Qingpeng , Lu Xin , Pfeiffer Dirk , Wang Lei , Song Hongbing , Pei Tao , Jia Zhongwei , Zeng Daniel Dajun
Published: February 2020

Estimating the key epidemiological features of the novel coronavirus (2019-nCoV) epidemic proves to be challenging, given incompleteness and delays in early data reporting, in particular, the severe under-reporting bias in the epicenter, Wuhan, Hubei Province, China. As a result, the current literature reports widely varying estimates. We developed an alternative geo-stratified debiasing estimation framework by incorporating human mobility with case reporting data in three stratified zones, i.e., Wuhan, Hubei Province excluding Wuhan, and mainland China excluding Hubei. We estimated the latent infection ratio to be around 0.12% (18,556 people) and the basic reproduction number to be 3.24 in Wuhan before the city’s lockdown on January 23, 2020. The findings based on this debiasing framework have important implications to prioritization of control and prevention efforts.

One Sentence Summary

A geo-stratified debiasing approach incorporating human movement data was developed to improve modeling of the 2019-nCoV epidemic.
Genetic overlap and causal associations between smoking behaviours and psychiatric traits and disorders in adolescents and adults
Authors: Barkhuizen Wikus , Dudbridge Frank , Ronald Angelica
Published: February 2020

Background

Epidemiological research shows that smoking is associated with psychiatric disorders and psychotic experiences, even after controlling for confounds such as cannabis use and sleep problems. We investigated degree of genetic overlap and tested for causal associations between smoking and psychiatric traits and disorders using genetic data. We tested whether genetic associations existed beyond genetic influences shared with confounding variables.

Methods

Genetic correlations were estimated with LD-score regression between smoking behaviours (N=262,990-632,802) and psychiatric disorders (schizophrenia, bipolar disorder and depression; N=41,653-173,005), psychotic experiences in adolescents (N=6,297-10,098) and adults (N=116,787-117,794) and adult schizotypy (N=3,967-4,057). Genomic Structural Equation Modelling was performed to explore the associations while accounting for genetic influences of confounders (cannabis and alcohol use, risk-taking and insomnia). Causal associations were tested using Generalized Summary-based Mendelian Randomization (GSMR).

Results

Significant genetic correlations were found between smoking and psychiatric disorders (rg = .10 - .38) and adult PE (rg = .33 - .40). After accounting for covarying genetic influences, genetic associations between most smoking phenotypes and schizophrenia and depression remained but not between smoking behaviours and bipolar disorder or most psychotic experiences. GSMR results supported a causal role of smoking initiation on psychiatric disorders and adolescent cognitive and negative psychotic experiences.

Conclusions

Pleiotropy between smoking behaviours and schizophrenia and depression exists beyond the common genetic basis of known confounders. Smoking also appears to be causally associated with psychiatric disorders and with cognitive PEs and negative symptoms during adolescence. Exploration of the biological links underlying smoking and psychiatric illness would be well-justified.
Epigenome-wide association study using prediagnostic bloods identifies a new genomic region (near TMEM204 and IFT140) associated with pancreatic cancer risk
Authors: Michaud Dominique S. , Ruan Mengyuan , Koestler Devin C. , Pei Dong , Marsit Carmen J. , De Vivo Immaculata , Kelsey Karl T.
Published: February 2020

Background

Epigenome-wide association studies (EWAS) using peripheral blood have identified specific sites of DNA methylation associated with risk of various cancers and may hold promise to identify novel biomarkers of risk; however, few studies have been performed for pancreatic cancer and none using a prospective study design.

Methods

Using a nested case-control study design, incident pancreatic cancer cases and matched controls were identified from participants who provided blood at baseline in three prospective cohort studies (Nurses’ Health Study, Health Professionals Follow-up Study and Physicians’ Health Study). DNA methylation levels were measured in DNA extracted from leukocytes using the Illumina MethylationEPIC array. Average follow-up period for this analysis was 13 years.

Results

A region in chromosome 16 near genesTMEM204 and IFT140 was identified as being differentially methylated in cases and controls. For some CpGs in the region, the associations were stronger with shorter time to diagnosis (e.g., OR= 5.95, 95% CI = 1.52-23.12, for top vs bottom quartile, for <5 years between blood draw and cancer diagnosis) but associations remained significantly higher even when cases were diagnosed over 10 years after blood collection. Statistically significant differences in DNA methylation levels were also observed in the gastric secretion pathway using GSEA analysis.

Conclusions

Changes in DNA methylation in peripheral blood may mark alterations in metabolic or immune pathways (potentially including alterations in immune subtypes) that play a role in pancreatic cancer. Identifying new biological pathways in carcinogenesis of pancreatic cancer using EWAS approach could provide new opportunities for improving treatment and prevention.
Negative selection on human genes causing severe inborn errors depends on disease outcome and both the mode and mechanism of inheritance
Authors: Rapaport Franck , Boisson Bertrand , Gregor Anne , Béziat Vivien , Boisson-Dupuis Stephanie , Bustamante Jacinta , Jouanguy Emmanuelle , Puel Anne , Rosain Jeremie , Zhang Qian , Zhang Shen-Ying , Gleeson Joseph G. , Quintana-Murci Lluis , Casanova Jean-Laurent , Abel Laurent , Patin Etienne
Published: February 2020

Background

Genetic variants underlying severe diseases are less likely to be transmitted to the next generation, and are thus gradually and selectively eliminated from the population through negative selection. Here, we study the determinants of this evolutionary process in genes underlying severe diseases in humans.

Results

We propose a novel approach, CoNeS, integrating known negative selection scores through principal component projection. We compare evidence for negative selection at 319 genes underlying inborn errors of immunity (IEI), which are life-threatening monogenic disorders. We find that genes underlying autosomal dominant (AD) or X-linked IEI are under stronger negative selection than those underlying autosomal recessive (AR) IEI, which are under no stronger selection than genes not known to be disease-causing. However, we find that genes with mutations causing AR IEI that are lethal before reproductive maturity and that display complete penetrance are under stronger negative selection than other genes underlying AR IEI. We also find that genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. Finally, we replicate these results in a study of 1,140 genes causing inborn errors of neurodevelopment.

Conclusions

These findings collectively show that the clinical outcomes of inborn errors, together with the mode and mechanism of inheritance of these errors, determine the strength of negative selection acting on severe disease-causing genes. These findings suggest that estimating the intensity of negative selection with CoNeS may facilitate the selection of candidate genes in patients suspected to carry an inborn error.
Genetic Adaptation in New York City Rats
Authors: Harpak Arbel , Garud Nandita , Rosenberg Noah A. , Petrov Dmitri A. , Combs Matthew , Pennings Pleuni S. , Munshi-South Jason
Published: February 2020

Brown rats (Rattus norvegicus) thrive in urban environments by navigating the anthropocentric environment and taking advantage of human resources and by-products. From the human perspective, rats are a chronic problem that causes billions of dollars in damage to agriculture, health and infrastructure. Did genetic adaptation play a role in the spread of rats in cities? To approach this question, we collected whole-genome sequences from 29 brown rats from New York City (NYC) and scanned for genetic signatures of adaptation. We tested for (i) high-frequency, extended haplotypes that could indicate selective sweeps and (ii) loci of extreme genetic differentiation between the NYC sample and a sample from the presumed ancestral range of brown rats in northeast China. We found candidate selective sweeps near or inside genes associated with metabolism, diet, the nervous system and locomotory behavior. Patterns of differentiation between NYC and Chinese rats at putative sweep loci suggests that many sweeps began after the split from the ancestral population. Together, our results suggest several hypotheses on adaptation in rats living in close proximity to humans.
SlKIX8 and SlKIX9 are negative regulators of leaf and fruit growth in tomato
Authors: Swinnen Gwen , Mauxion Jean-Philippe , Baekelandt Alexandra , De Clercq Rebecca , Van Doorsselaere Jan , Inzé Dirk , Gonzalez Nathalie , Goossens Alain , Pauwels Laurens
Published: February 2020

Plant organ size and shape are major agronomic traits that depend on cell division and expansion, which are both regulated by complex gene networks. In several eudicot species belonging to the rosid clade, organ growth is controlled by a repressor complex consisting of PEAPOD (PPD) and KINASE-INDUCIBLE DOMAIN INTERACTING (KIX) proteins. The role of these proteins in asterids, which together with the rosids constitute most of the core eudicot species, is still unknown. We used CRISPR-Cas9 genome editing to targetSlKIX8andSlKIX9in the asterid model species tomato (Solanum lycopersicum) and analyzed loss-of-function phenotypes. We found that loss of function ofSlKIX8andSlKIX9led to the production of enlarged, dome-shaped leaves and that these leaves exhibited increased expression of putative SlPPD target genes. Unexpectedly,kix8 kix9mutants carried enlarged fruits with increased pericarp thickness due to cell expansion. At the molecular level, protein interaction assays indicated that SlKIX8 and SlKIX9 act as adaptors between the SlPPD and SlTOPLESS co-repressor proteins. Our results show that KIX8 and KIX9 are regulators of organ growth in asterids and can provide strategies to improve important traits in produce such as thickness of the fruit flesh.

One sentence summary

Two transcriptional repressors negatively regulate organ growth in tomato with loss-of-function lines producing enlarged fruits due to an appearance of more expanded cells in the fruit flesh.
High-fidelity base editor with no detectable genome-wide off-target effects
Authors: Zuo Erwei , Sun Yidi , Yuan Tanglong , He Bingbing , Zhou Changyang , Ying Wenqin , Liu Jing , Wei Wu , Zeng Rong , Li Yixue , Yang Hui
Published: February 2020

Base editors hold promise for correcting pathogenic mutations, while substantial single nucleotide variations (SNVs) on both DNA and RNA were generated by cytosine base editors (CBEs). Here we examined possibilities to reduce off-target effects by engineering cytosine deaminases. By screening 24 CBEs harboring various rAPOBEC1 (BE3) or human APOBEC3A (BE3-hA3A) mutations on the ssDNA or RNA binding domain, we found 8 CBE variations could maintain high on-target editing efficiency. Using Genome-wide Off-target analysis by Two-cell embryo Injection (GOTI) method and RNA sequencing analysis, we found DNA off-target SNVs induced by BE3 could be completely eliminated in BE3R126Ebut the off-target RNA SNVs was only slightly reduced. By contrast, BE3-hA3AY130Fabolished the RNA off-target effects while could not reduce the DNA off-target effects. Notably, BE3R132E, BE3W90Y+R126Eand BE3W90F+R126Eachieved the elimination of off-target SNVs on both DNA and RNA, suggesting the feasibility of engineering base editors for high fidelity deaminases.
ARF suppresses 5’-terminal oligopyrimidine mRNA translation
Authors: Cottrell Kyle A. , Chiou Ryan C. , Weber Jason D.
Published: February 2020

Tumor cells require nominal increases in protein synthesis in order to maintain high proliferation rates. As such, tumor cells must acquire enhanced ribosome production. How many of the mutations in tumor cells ultimately achieve this aberrant production is largely unknown. The gene encoding ARF is the most commonly deleted gene in human cancer. ARF plays a significant role in regulating ribosomal RNA synthesis and processing, ribosome export into the cytoplasm, and global protein synthesis. Utilizing ribosome profiling, we show that ARF is a major suppressor of 5’-terminal oligopyrimidine mRNA translation. Genes with increased translational efficiency following loss of ARF include many ribosomal proteins and translation factors. Knockout ofp53caused a similar increase in 5’-TOP mRNA translation. The 5’-TOP regulators mTORC1, eIF4G1 and LARP1 are dysregulated in ARF and p53 null cells.
Batch Equalization with a Generative Adversarial Network
Authors: Qian Wesley Wei , Xia Cassandra , Venugopalan Subhashini , Narayanaswamy Arunachalam , Peng Jian , Ando D. Michael
Published: February 2020

Advances in automation and imaging have made it possible to capture large image datasets for experiments that span multiple weeks with multiple experimental batches of data. However, accurate biological comparisons across the batches is challenged by the batch-to-batch variation due to uncontrollable experimental noise (e.g., different stain intensity or illumination conditions). To mediate the batch variation (i.e. the batch effect), we developed a batch equalization method that can transfer images from one batch to another while preserving the biological phenotype. The equalization method is trained as a generative adversarial network (GAN), using the StarGAN architecture that has shown considerable ability in doing style transfer for consumer images. After incorporating an additional objective that disentangles batch effect from biological features using an existing GAN framework, we show that the equalized images have less batch information as determined by a batch-prediction task and perform better in a biologically relevant task (e.g., Mechanism of Action prediction).
Economic Genome Assembly from Low Coverage Illumina and Nanopore Data
Authors: Gatter Thomas , von Löhneysen Sarah , Drozdova Polina , Hartmann Tom , Stadler Peter F.
Published: February 2020

We describe a new approach to assemble genomes from a combination of low-coverage short and long reads.LazyBastardstarts from a bipartite overlap graph between long reads and restrictively filtered short-read unitigs, which are then reduced to a long-read overlap graphG. Edges are removed fromGto obtain first a consistent orientation and then a DAG. Using heuristics based on properties of proper interval graphs, contigs are extracted as maximum weight paths. These are translated into genomic sequence only in the final step. A prototype implementation ofLazyBastard, entirely written in python, not only yields significantly more accurate assemblies of the yeast and fruit fly genomes compared to state-of-the-art pipelines but also requires much less computational effort.

Funding

RSF / Helmholtz Association 18-44-06201; Deutsche Academische Austauschdienst, DFG STA 850/19-2 within SPP 1738; German Federal Ministery of Education an Research 031A538A, de.NBI-RBC
Optimal microbial pathway variants can be determined by large-scale bioenergetic evaluation in syntrophic propionate oxidation
Authors: Patón Mauricio , Hernández Héctor H. , Rodríguez Jorge
Published: February 2020

The complete understanding of microbial propionate oxidation in syntrophy with hydrogenotrophic methanogenesis remains elusive due to uncertainties in pathways and mechanisms for interspecies electron transfer (IET). Possible pathway variants differ in their intermediate metabolites, on which electron carriers are involved and in which steps are coupled to (and to how many) proton translocations. In this work, a systematic methodology was developed (based on sound biochemical, physiological and bioenergetic principles) to evaluate the feasibility and net ATP yield of large sets of pathway variants under different physiological and environmental conditions. A pathway variant is deemed feasible under given conditions only if all pathway reaction steps have non-positive Gibbs energy change and if all the metabolite concentrations remain within an acceptable physiological range (10−6to 10−2M). Several million combinations of pathway variants and parameters/conditions were evaluated for propionate oxidation, providing an unprecedented mechanistic insight into its biochemical and bioenergetic landscape. Propionate oxidation via lactate appeared as the most ATP yielding pathway under most of the conditions evaluated. Results under typical methanogenic conditions indicate that syntrophic propionate oxidation can sustain life only at hydrogen partial pressures within the range of 1.2 to 4 Pa. These extremely low concentrations constitute a kinetic impossibility and strongly suggest for IET mechanisms other than dissolved hydrogen.

Importance

In this work an original methodology was developed that quantifies the bioenergetically and physiologically feasible net ATP yields for large numbers of microbial metabolic pathways and their variants under different conditions. This ensures global optimality in finding the pathway variant(s) leading to the highest ATP yield. The methodology is especially relevant to hypothesise which microbial pathway variants are most likely to prevail in microbial ecosystems under high selective pressure for efficient metabolic energy conservation.

Syntrophic microbial oxidation of propionate to acetate has extremely low energy available and requires very high metabolic efficiency in order to sustain life. Our results bring mechanistic insights into the optimum pathway variants and the impact of environmental conditions on the ATP yields and other metabolic bottlenecks. Additionally, our results conclude that IET mechanisms other than hydrogen must exist to simultaneously sustain the growth of both propionate oxidisers and hydrogenotrophic methanogens.
Linear Embodied Saliency: a Model of Full-Body Kinematics-based Visual Attention
Authors: Abbott William W. , Harston J. Alex , Faisal A. Aldo
Published: February 2020

Gaze behaviour and motor actions are fundamentally interlinked in both a spatial and temporal manner. However, the vast majority of gaze behaviour research has focused to date on reductionist head-fixed screen viewing experiments and ignored the motor aspect of visuomotor behaviour, thereby neglecting a critical component of the perception-action loop. We address this with an experimental design to capture, rather than constrain, the full range of simultaneous gaze and motor behaviour in a range of natural daily life tasks. Through building autoregressive models and applying these to our novel datasets we find that beyond simple static regions of interest, we can predict visual attention shifts from freely-moving first person body kinematics, through explaining gaze dynamics in the context of body dynamics, on the timescale of freely moving interactive behaviour in individuals, expanding our understanding of natural visuomotor behaviour.
A non-invasive eDNA tool for detecting sea lamprey larvae in river sediments: analytical validation and field testing in a low abundance ecosystem
Authors: Baltazar-Soares Miguel , Pinder Adrian C. , Harrison Andrew J. , Oliver Will , Picken Jessica , Britton J. Robert , Andreou Demetra
Published: February 2020

Anthropogenic activities are increasingly threatening aquatic biodiversity, especially anadromous species. Monitoring and conservation measures are thus required to protect, maintain, and restore imperilled populations. While many species can be surveyed using traditional capture and visual census techniques, species that use riverine habitats in a less conspicuous manner, such as sea lampreyPetromyzon marinus, can be more challenging to monitor. Sea lamprey larvae (ammocoetes) can spend several years in freshwater burrowed within soft sediments, inhibiting their detection and assessment. Here we present an environmental DNA (eDNA) assay to detect ammocoetes burrowed in the sediment. We performed a battery of tests that ensured both species-specificity of the assay as well as the capacity to detect ammocoetes when abundances are low. Experiments on burrowing activity suggested that most of the DNA released into the sediment occurs during burrowing. Overall, we demonstrated this new molecular-based tool is an efficient and effective complement to traditional monitoring activities targeting larval stages of sea lampreys.
Intra-articular AAV-PHP.S mediated chemogenetic targeting of knee-innervating dorsal root ganglion neurons alleviates inflammatory pain in mice
Authors: Chakrabarti Sampurna , Pattison Luke A. , Doleschall Balint , Rickman Rebecca H. , Blake Helen , Callejo Gerard , Heppenstall Paul A. , Smith Ewan St. John
Published: February 2020

Objective

Joint pain is the major clinical symptom of arthritis that affects millions of people. Controlling the excitability of knee-innervating dorsal root ganglion (DRG) neurons (knee neurons) could potentially provide pain relief. Therefore, our objective was to evaluate whether the newly engineered adeno-associated virus (AAV) serotype, AAV-PHP.S, can deliver functional artificial receptors to control knee neuron excitability following intra-articular knee injection.

Methods

AAV-PHP.S virus packaged with dTomato fluorescent protein and either excitatory (Gq) or inhibitory (Gi) designer receptors activated by designer drugs (DREADDs) was injected into the knee joint of adult mice. Labelling of DRG neurons by AAV-PHP.S from the knee was evaluated using immunohistochemistry. Functionality of Gq- and Gi-DREADDs was evaluated using whole-cell patch clamp electrophysiology on acutely cultured DRG neurons. Pain behavior in mice was assessed using a digging assay, dynamic weight bearing and rotarod, before and after intra-peritoneal administration of the DREADD activator, Compound 21.

Results

We show that AAV-PHP.S can deliver functional genes into the DRG neurons when injected into the knee joint in a similar manner to the well-established retrograde tracer, fast blue. Short-term activation of AAV-PHP.S delivered Gq-DREADD increases excitability of knee neurons in vitro, without inducing overt pain in mice when activated in vivo. By contrast, in vivo Gi-DREADD activation alleviated complete Freund’s adjuvant mediated knee inflammation-induced deficits in digging behavior, with a concomitant decrease in knee neuron excitability observed in vitro.

Conclusions

We describe an AAV-mediated chemogenetic approach to specifically control joint pain, which may be utilized in translational arthritic pain research.
Domestication reprogrammed the budding yeast life cycle
Authors: De Chiara Matteo , Barré Benjamin , Persson Karl , Chioma Amadi Onyetuga , Irizar Agurtzane , Schacherer Joseph , Warringer Jonas , Liti Gianni
Published: February 2020

Domestication of plants and animals is the foundation for feeding the world population. We report that domestication of the model yeastS. cerevisiaereprogrammed its life cycle entirely. We tracked growth, gamete formation and cell survival across many environments for nearly 1000 genome sequenced isolates and found a remarkable dichotomy between domesticated and wild yeasts. Wild yeasts near uniformly trigger meiosis and sporulate when encountering nutrient depletions, whereas domestication relaxed selection on sexual reproduction and favoured survival as quiescent cells. Domestication also systematically enhanced fermentative over respiratory traits while decreasing stress tolerance. We show that this yeast domestication syndrome was driven by aneuploidies and gene function losses that emerged independently in multiple domesticated lineages during the specie’s recent evolutionary history. We found domestication to be the most dramatic event in budding yeast evolution, raising questions on how much domestication has distorted our understanding of this key model species.
A novel role for cortical acetylcholine in object memory updating
Authors: Jardine Kristen H. , Wideman Cassidy E. , MacGregor Chelsea , Sgarbossa Cassandra , Orr Dean , Mitchnick Krista A. , Winters Boyer D.
Published: February 2020

Reactivated long-term memories can become labile and sensitive to modification. Memories in this destabilized state can be weakened or strengthened, but there is limited research characterizing the mechanisms underlying retrieval-induced qualitative updates (i.e., information integration). We have previously implicated cholinergic transmission in object memory destabilization. Here we present a novel rodent paradigm developed to assess the role of this cholinergic mechanism in qualitative memory updating. The post-reactivation object memory modification (PROMM) task exposes rats to contextual information following object memory reactivation. Subsequent object exploratory performance suggests that the contextual information is integrated with the original memory in a reactivation- and time-dependent manner. This effect is blocked by interference with M1muscarinic receptors and several downstream signals in perirhinal cortex. These findings therefore demonstrate a hitherto unacknowledged cognitive function for acetylcholine with important implications for understanding the dynamic nature of long-term memory storage in the normal and aging brain.
Boosting the biogenesis and secretion of mesenchymal stem cell-derived exosomes
Authors: Wang Jinli , Bonacquisti Emily , Nguyen J.
Published: February 2020

A limitation to using exosomes to their fullest potential is their limited secretion from cells, a major bottleneck to efficient exosome production and application. This is especially true for mesenchymal stem cell (MSCs), which can self-renew but have limited expansion capacity, undergoing senescence after only a few passages, with exosomes derived from senescent stem cells showing impaired regenerative capacity compared to young cells. Here we examined the effects of small molecule modulators capable of enhancing exosome secretion from MSCs. Treatment of MSCs with a combination of methyldopamine and norepinephrine robustly increased exosome production by three-fold without altering the ability of the MSC exosomes to induce angiogenesis, polarize macrophages to the anti-inflammatory phenotype, or inhibit fibrosis. These small molecule modulators provide a promising means to increase exosome production by MSCs.
Antisense ncRNAs during early vertebrate development are divided in groups with distinct features
Authors: Pillay Sanjana , Takahashi Hazuki , Carninci Piero , Kanhere Aditi
Published: February 2020

Long non-coding RNAs or lncRNAs are a broad class of non-protein coding RNAs that are >200nucleotides in length. A number of lncRNAs are shown to play an important role in gene expression regulation. LncRNAs antisense to a protein-coding gene can act either as positive or negative regulators of overlapping protein-coding mRNAs. Almost 50% of lncRNAs present during development of vertebrates such as zebrafish are of antisense lncRNA class. However, their role in gene expression regulation during development remains enigmatic. To understand the role of antisense lncRNAs in early vertebrate development, we took a computational biology approach to analyze existing as well as novel dataset. Our analysis of RNA sequencing data from zebrafish development indicates that antisense RNAs can be divided into two major classes based on their positive or negative co-expression patterns to the sense protein-coding genes. The ones with negative co-expression patterns or group-1 are maternal antisense lncRNAs that overlap mainly developmental genes. Group-2 with positive expression pattern overlap mainly house-keeping genes. Group-1 antisense lncRNAs are longer and more stable as compared to antisense lncRNAs in group-2. In addition, to answer if antisense RNAs in the two groups are differently localized in cell compartments, we deep-sequenced RNA from cytoplasmic and nuclear compartments during early developmental stages. The analysis of these compartment specific datasets revealed group-1 lncRNAs are cytosolic. Based on the cytosolic nature of group-1 RNAs and their higher complementarity to the overlapping developmental mRNAs, we speculate that the group-1 RNAs might function similar to microRNAs in silencing spurious expression of developmental genes. Group-1 and group-2 RNAs are also distinct in terms of their genomic configuration, conservation, length and transcriptional regulation. These results are not only important in understanding the role of antisense RNAs in development but also for predicting the nature of association between antisense lncRNA and overlapping protein-coding genes.
Domestication of the emblematic white cheese-making fungusPenicillium camembertiand its diversification into two varieties
Authors: Ropars Jeanne , Didiot Estelle , Rodríguez de la Vega Ricardo C. , Bennetot Bastien , Coton Monika , Poirier Elisabeth , Coton Emmanuel , Snirc Alodie , Le Prieur Stéphanie , Giraud Tatiana
Published: February 2020

Domestication involves recent adaptation under strong human selection and rapid diversification, and therefore constitutes a good model for studies of these processes. We studied the domestication of the emblematic white moldPenicillium camemberti, used for the maturation of soft cheeses, such as Camembert and Brie, about which surprisingly little was known, despite its economic and cultural importance. Whole genome-based analyses of genetic relationships and diversity revealed that an ancient domestication event led to the emergence of the gray-greenP. biformemold used in cheese-making, by divergence from the blue-green wildP. fuscoglaucumfungus. Another much more recent domestication event led to the generation of theP. camemberticlonal lineage as a sister group toP. biforme. Penicillium biformedisplayed signs of phenotypic adaptation to cheese-making relative toP. fuscoglaucum, in terms of whiter color, faster growth on cheese medium under cave conditions, lower levels of toxin production and greater ability to prevent the growth of other fungi. TheP. camembertilineage displayed even stronger signs of domestication for all these phenotypic features. We also identified two differentiatedP. camembertivarieties, apparently associated with different kinds of cheeses, and with contrasted phenotypic features in terms of color, growth, toxin production and competitive ability. We have, thus, identified footprints of domestication in these fungi, with genetic differentiation between cheese and wild populations, bottlenecks and specific phenotypic traits beneficial for cheese-making. This study has not only fundamental implications for our understanding of domestication but can also have important impacts on cheese-making.
A pyro-phosphodegron controls MYC polyubiquitination to regulate cell survival
Authors: Lolla Padmavathi , Shah Akruti , Unnikannan C.P. , Oddi Vineesha , Bhandari Rashna
Published: February 2020

The transcription factor MYC regulates cell survival and growth, and its level is tightly controlled in normal cells. Here, we report that serine pyrophosphorylation – an enigmatic posttranslational modification triggered by inositol pyrophosphate signaling molecules – controls MYC levels via regulated protein degradation. We find that endogenous MYC is stabilized and less polyubiquitinated in cells with reduced inositol pyrophosphates. We show that the inositol pyrophosphate 5-IP7transfers its high-energy beta phosphate moiety to pre-phosphorylated serine residues in the central PEST domain of MYC. Pyrophosphorylation of MYC promotes its interaction with the E3 ubiquitin ligase FBW7, thereby enhancing MYC polyubiquitination and degradation. FBW7 can bind directly to the PEST domain of MYC in a pyrophosphorylation-dependent manner. A stabilized, pyrophosphorylation-deficient form of MYC increases cell death during growth stress in untransformed cells, and promotes cell proliferation in response to mitogens. Thus, control of MYC stability through a novel pyro-phosphodegron provides unexpected insight into the regulation of cell survival in response to environmental cues.
Cotton leaf curl Multan virus βC1 Protein Induces Autophagy by Disrupting the Interaction of Autophagy-Related Protein 3 with Glyceraldehyde-3-Phosphate Dehydrogenases[OPEN]
Authors: Ismayil Asigul , Yang Meng , Haxim Yakupjan , Wang Yunjing , Li Jinlin , Han Lu , Wang Yan , Zheng Xiyin , Wei Xiang , Nagalakshmi Ugrappa , Hong Yiguo , Hanley-Bowdoin Linda , Liu Yule
Published: February 2020

Autophagy plays an important role in plant–pathogen interactions. Several pathogens including viruses induce autophagy in plants, but the underpinning mechanism remains largely unclear. Furthermore, in virus–plant interactions, viral factor(s) that induce autophagy have yet to be identified. Here, we report that the βC1 protein of Cotton leaf curl Multan betasatellite (CLCuMuB) interacts with cytosolic glyceraldehyde-3-phosphate dehydrogenase (GAPC), a negative autophagic regulator, to induce autophagy in Nicotiana benthamiana. CLCuMuB βC1 bound to GAPCs and disrupted the interaction between GAPCs and autophagy-related protein 3 (ATG3). A mutant βC1 protein (βC13A) in which I45, Y48, and I53 were all substituted with Ala (A), had a dramatically reduced binding capacity with GAPCs, failed to disrupt the GAPCs-ATG3 interactions and failed to induce autophagy. Furthermore, mutant virus carrying βC13A showed increased symptoms and viral DNA accumulation associated with decreased autophagy in plants. These results suggest that CLCuMuB βC1 activates autophagy by disrupting GAPCs–ATG3 interactions.
Status of lean construction implementation among small and medium building contractors (SMBCs) in Ghana
Authors: Ankomah Emmanuel Nsiah , Ayarkwa Joshua , Agyekum Kofi
Published: February 2020

Purpose

The purpose of this study is to ascertain the extent to which the practices of small and medium building contractors (SMBCs) conform to lean construction (LC) principles. Ultimately, practical results encourage a discourse on the true potentials and challenges to the holistic uptake of LC principles in the Ghanaian construction industry.

Design/methodology/approach

This research is based on a qualitative case study approach. The data was obtained through face-to-face structured interviews.

Findings

Across the cases, it was realized that there is a low-level application of LC principles among SMBCs. There was no indication that lean concepts were used on a company-wide basis in the Ghanaian construction industry. Furthermore, the study revealed that the traditional wasteful approach to managing construction projects was still prevalent among the firms.

Practical implications

This paper uses the 4P model as a foundation for assessing the extent to which the practices of SMBCs conform to LC principles. Practically, the study also created a certain level of awareness among the SMBCs about LC, LC principles and the benefits of the application of these principles within organizations.

Originality/value

This study contributes to the body of knowledge as it uncovers the status of LC implementation among SMBCs in the Ghanaian construction industry. The findings that are presented in this paper can be used as a starting point to disseminate the research and practice of LC among SMBCs.
Privatization and school mental health
Authors: Weist Mark , Franke Kathleen Blackburn , Lucio Rob , Bass Jefferson , Doan Terry , Blalock Deborah
Published: February 2020

Purpose

The purpose of this paper is to describe the relationship between privatization and school mental health (SMH) in the USA, as well as to present a case study of the SMH system in South Carolina.

Design/methodology/approach

The authors reviewed data regarding states’ mental health systems (e.g. public, private and hybrid of public and private), mental health budgets and percentages of schools with mental health clinicians.

Findings

The results demonstrate that the majority of states have public mental health systems. There is variability between states regarding general funding, as well as funding for SMH. Further, there was variability in the percentage of schools with SMH clinicians, with South Carolina reporting the greatest percentage. South Carolina’s mental health system, which is a public–private hybrid is reviewed, along with relevant history on the development of SMH programs in the state.

Originality/value

This paper contributes to the general knowledge by describing the provision and funding sources for SMH services within the USA. It yields important implications for integrating public mental health services within schools.
Potentially over 3 million children in EU Europe believed not to be receiving needed medical and dental treatment—and parents' reasons why
Authors: Rigby Michael J.
Published: February 2020

Background

Children have the right to health and countries a duty under the United Nations Convention on the Rights of the Child to facilitate this. The European Union has emphasized the importance of investing in children, but at times this seems more wish than pragmatism. Furthermore, European statistical systems do not provide any relevant data, and the degree of unmet need has hitherto been unknown. However, new ad hoc household survey data have now been published by Eurostat showing the percentage of children with a purported unmet medical or dental need and the expressed reasons for this.

Method

This paper critically reviews these data on children with a reported unmet medical or dental need to create an indication of the number of European children with unmet medical and dental needs, and the contributory factors.

Results

This paper calculates that some 1 million European children can be estimated to have an unmet medical need and 2 million children an unmet dental need, though the survey approach has some weaknesses. A probable overestimate of children affected in sample households offsets the likely failure to capture data about children in institutions, homeless, or in fractured families, or about multiple needs. The reported reasons for not obtaining treatments are a valuable first step in highlighting an important issue for Europe's children—measurement of service accessibility.

Conclusion

Potentially over 3 million European Union children are failing to have their health needs and their rights met. If the incoming European Commission is serious about its predecessor's promise to invest in children and to take seriously their rights, action is needed to improve quantification of unmet need and to reduce suffering and potential lasting damage.