bluuebunny/crossref_metadata_2025 huggingface dataset:
Focus Your Screening Library: Rapid Identification of Novel PDE2 Inhibitors within silicoDriven Library Prioritization and MicroScale Thermophoresis
Authors: Kaiser Florian , Plach Maximilian G. , Schubert Thomas , Haupt V. Joachim
Published: April 2020

Accelerated development of lead structures is of high interest to the pharmaceutical industry in order to decrease development times and costs. We showcase how an intelligent combination of AI-based drug screening with state-of-the-art biophysics drives the rapid identification of novel inhibitor structures with high chemical diversity for cGMP-dependent 3’,5’-cyclic phosphodiesterase (PDE2). The starting point was an off-the-shelve chemical library of two million drug-like compounds. In a singlein silicoreduction step, we short-listed 125 compounds – the focused library – as potential binders to PDE2 and tested their binding behaviorin vitrousing MicroScale Thermophoresis (MST). Of this focused library, seven compounds indicated binding to PDE2, translating to a hit rate of 6%. Three of these compounds have affinities in the lower micromolar range. The compound with the highest affinity showed aKDof 10µMand is thus an excellent starting point for further medicinal chemistry optimization. The results show how innovative and structure-drivenin silicoapproaches and biophysics can be used to accelerate drug discovery and to obtain new molecular scaffolds at a fraction of the costs and time – compared with standard high-throughput screening.
Stearoyl-CoA desaturase mediated monounsaturated fatty acid availability supports humoral immunity
Authors: Zhou Xian , Zhu Xingxing , Li Chaofan , Li Yanfeng , Ye Zhenqing , Shapiro Virginia , Copland John A. , Hitosugi Taro , Bernlohr David , Sun Jie , Zeng Hu
Published: April 2020

Immune cells can metabolize glucose, amino acids, and fatty acids (FAs) to generate energy. The role of different FA species, and their impacts on humoral immunity remains poorly understood. Here we report that proliferating B cells require monounsaturated FAs (MUFA) to maintain mitochondrial metabolism and mTOR activity, and to prevent excessive autophagy and endoplasmic reticulum (ER) stress. Furthermore, B cell extrinsic Stearoyl-CoA desaturase (SCD) activity generates MUFA to support early B cell development and germinal center (GC) formationin vivoduring immunization and influenza infection. Thus, SCD-mediated MUFA production is critical for humoral immunity.
Representation of conscious percept without report in the macaque face patch network
Authors: Hesse Janis K. , Tsao Doris Y.
Published: April 2020

A powerful paradigm to identify the neural correlates of consciousness is binocular rivalry, wherein a constant visual stimulus evokes a varying conscious percept. It has recently been suggested that activity modulations observed during rivalry could represent the act of report rather than the conscious percept itself. Here, we performed single-unit recordings from face patches in macaque inferotemporal (IT) cortex using a no-report paradigm in which the animal’s conscious percept was inferred from eye movements. We found high proportions of IT neurons represented the conscious percept even without active report. Population activity in single trials, measured using a new 128-site Neuropixels-like electrode, was more weakly modulated by rivalry than by physical stimulus transitions, but nevertheless allowed decoding of the changing conscious percept. These findings suggest that macaque face patches encode both the physical stimulus and the animal’s conscious visual percept, and the latter encoding does not require active report.
Scalable unified framework of total and allele-specific counts for cis-QTL, fine-mapping, and prediction
Authors: Liang Yanyu , Aguet François , Barbeira Alvaro , Ardlie Kristin , Im Hae Kyung
Published: April 2020

Genome-wide association studies (GWAS) have been highly successful in identifying genomic loci associated with complex traits. However, identification of the causal genes that mediate these associations remains challenging, and many approaches integrating transcriptomic data with GWAS have been proposed. However, there currently exist no computationally scalable methods that integrate total and allele-specific gene expression to maximize power to detect genetic effects on gene expression. Here, we describe a unified framework that is scalable to studies with thousands of samples. Using simulations and data from GTEx, we demonstrate an average power gain equivalent to a 29% increase in sample size for genes with sufficient allele-specific read coverage. We provide a suite of freely available tools, mixQTL, mixFine, and mixPred, that apply this framework for mapping of quantitative trait loci, fine-mapping, and prediction.
Ontogeny and function of the circadian clock in intestinal organoids
Authors: Rosselot Andrew E. , Park Miri , Matsu-Ura Toru , Wu Gang , Flores Danilo E. , Subramanian Krithika R. , Lee Suengwon , Sundaram Nambirajan , Broda Taylor R. , McCauley Heather A. , Hawkins Jennifer A. , Chetal Kashish , Salomonis Nathan , Shroyer Noah F. , Helmrath Michael A. , Wells James M. , Hogenesch John B. , Moore Sean R. , Hong Christian I.
Published: April 2020

Circadian rhythms regulate diverse aspects of gastrointestinal physiology ranging from the composition of microbiota to motility. However, development of the intestinal circadian clock and detailed molecular mechanisms regulating circadian physiology of the intestine remain largely unknown. The lack of appropriate human model systems that enable organ- and/or diseasespecific interrogation of clock functions is a major obstacle hindering advancements of translational applications using chronotherapy. In this report, we show that both pluripotent stem cell-derived human intestinal organoids engrafted into mice and patient-derived human intestinal enteroids (HIEs) possess robust circadian rhythms, and demonstrate circadian phase-dependent necrotic cell death responses toClostridium difficiletoxin B (TcdB). Intriguingly, mouse and human enteroids demonstrate anti-phasic necrotic cell death responses. RNA-Seq data show ~4% of genes are rhythmically expressed in HIEs. Remarkably, we observe anti-phasic gene expression ofRac1, a small GTPase directly inactivated by TcdB, between mouse and human enteroids. Importantly, the observed circadian time-dependent necrotic cell death response is abolished in both mouse enteroids and human intestinal organoids (HIOs) lacking robust circadian rhythms. Our findings uncover robust functions of circadian rhythms regulating critical clock-controlled genes (CCGs) in human enteroids governing organism-specific, circadian phasedependent necrotic cell death responses. Our data highlight unique differences between mouse and human enteroids, and lay a foundation for human organ- and disease-specific investigation of clock functions using human organoids for translational applications.
DNA micro-disk for the management of DNA-based data storage with index and write-once-read-many (WORM) memory features
Authors: Choi Yeongjae , Bae Hyung Jong , Lee Amos C. , Choi Hansol , Lee Daewon , Ryu Taehoon , Hyun Jinwoo , Kim Seojoo , Kim Hyeli , Song Suk-Heung , Kim Kibeom , Park Wook , Kwon Sunghoon
Published: April 2020

DNA-based data storage has attracted attention because of its higher physical density of the data and longer retention time than those of conventional digital data storage1–7. However, previous DNA-based data storage lacked index features and the data quality of storage after a single access is not preserved, obstructing its industrial use. Here, we propose DNA micro-disks, quick response (QR)-coded micro-sized disks that harbour data-encoded DNA molecules for the efficient management of DNA-based data storage. We demonstrate the two major features that previous DNA-based data storage studies could not achieve. One feature is accessing data items efficiently by indexing the data-encoded DNA library. Another is achieving write-once-read-many (WORM) memory through the immobilization of DNA molecules on the disk and their enrichment throughin situDNA production. Through these features, the reliability of DNA-based data storage was increased by allowing multiple accession of data-encoded DNA without data loss.
Rapid computations of spectrotemporal prediction error support perception of degraded speech
Authors: Sohoglu Ediz , Davis Matthew H.
Published: April 2020

Human speech perception can be described as Bayesian perceptual inference but how are these Bayesian computations instantiated neurally? We use magnetoencephalographic recordings of brain responses to degraded spoken words as a function of signal quality and prior knowledge to demonstrate that spectrotemporal modulations in speech are more clearly represented in neural responses than alternative speech representations (e.g. spectrogram or articulatory features). We found an interaction between speech signal quality and expectations from prior written text on the quality of neural representations; increased signal quality enhanced neural representations of speech that mismatched with prior expectations, but led to greater suppression of speech that matched prior expectations. This interaction is a unique neural signature of prediction error computations and already apparent in neural responses within 250 ms of speech input. Our findings contribute towards the detailed specification of a computational model of speech perception based on predictive coding frameworks.
Duplication accelerates the evolution of structural complexity in protein quaternary structure
Authors: Leonard Alexander S. , Ahnert Sebastian E.
Published: April 2020

Gene duplication, from single genes to whole genomes, has been observed in organisms across all taxa. Despite its prevalence, the evolutionary benefits of this mechanism are the subject of ongoing debate. Gene duplication can significantly alter the self-assembly of protein quaternary structures, impacting the dosage or interaction proclivity. Here we use a lattice model of self-assembly as a coarse-grained representation of protein complex assembly, and show that it can be used to examine potential evolutionary advantages of duplication. Duplication provides a unique mechanism for increasing the evolvability of protein complexes by enabling the transformation of symmetric homomeric interactions into heteromeric ones. This transformation is extensively observed inin silicoevolutionary simulations of the lattice model, with duplication events significantly accelerating the rate at which structural complexity increases. These coarse-grained simulation results are corroborated with a large-scale analysis of complexes from the Protein Data Bank.
Investigating an in-silico approach for prioritizing antidepressant drug prescription based on drug-induced expression profiles and predicted gene expression
Authors: Shoaib Muhammad , Giacopuzzi Edorado , Pain Oliver , Fabbri Chiara , Magri Chiara , Minelli Alessandra , Lewis Cathryn M. , Gennarelli Massimo
Published: April 2020

In clinical practice, antidepressant prescription is a trial and error approach, which is time consuming and discomforting for patients. This study investigated an in-silico approach for ranking antidepressants based on their hypothetical likelihood of efficacy.

We determined the transcriptomic profile of citalopram remitters by performing a transcriptomic-wide association study on STAR*D data (N =1163). The transcriptional profile of remitters was compared with 21 antidepressant-induced gene expression profiles in five human cell lines available in the connectivity map database. Spearman correlation, Pearson correlation, and the Kolmogorov Smirnov test were used to determine the similarity between antidepressant-induced profiles and remitter profiles, subsequently calculating the average rank of antidepressants across the three methods and a p-value for each rank by using a permutation procedure. The drugs with the top ranks were those having high positive correlation with the expression profiles of remitters and they may have higher chances of efficacy in the tested patients.

In MCF7 (breast cancer cell line), escitalopram had the highest average rank, with an average rank higher than expected by chance (p=0.0014). In A375 (human melanoma) and PC3 (prostate cancer) cell lines, escitalopram and citalopram emerged as the second highest ranked antidepressants, respectively (p=0.0310 and 0.0276, respectively). In HA1E (kidney) and HT29 (colon cancer) cell types, citalopram and escitalopram did not fall among top antidepressants.

The correlation between citalopram remitters’ and (es)citalopram-induced expression profiles in three cell lines suggests that our approach may be useful and with future improvements it can be applicable at the individual level to tailor treatment prescription.
Intrinsic, dynamic and effective connectivity among large-scale brain networks modulated by oxytocin
Authors: Jiang Xi , Ma Xiaole , Geng Yayuan , Zhao Zhiying , Zhou Feng , Zhao Weihua , Yao Shuxia , Yang Shimin , Zhao Zhongbo , Becker Benjamin , Kendrick Keith M.
Published: April 2020

The neuropeptide oxytocin is a key modulator of social-emotional behavior and its intranasal administration can influence the functional connectivity of brain networks involved in the control of attention, emotion and reward reported in humans. However, no studies have systematically investigated the effects oxytocin on dynamic or directional aspects of functional connectivity. The present study employed a novel computational framework to investigate these latter aspects in 15 oxytocin-sensitive regions using data from randomized placebo-controlled between-subject resting state functional MRI studies incorporating 200 healthy subjects. Results showed that oxytocin extensively modulated effective connectivity both between and within emotion, reward, salience and social cognition processing networks and their interactions with the default mode network, but had no effect on the frequency of dynamic changes. Top-down control over emotional processing regions such as the amygdala was particularly affected. Oxytocin effects were also sex-dependent, being more extensive in males. Overall, these findings suggest that modulatory effects of oxytocin on both within- and between-network interactions may underlie its functional influence on social-emotional behaviors, although in a sex-dependent manner. Furthermore, they demonstrate a useful approach to determining pharmacological influences on resting state effective connectivity and support oxytocin’s potential therapeutic use in psychiatric disorders.
Sex dependent gene activity in the human body
Authors: Hartman Robin J.G. , Mokry Michal , Pasterkamp Gerard , den Ruijter Hester M.
Published: April 2020

Many pathophysiological mechanisms in human health and disease are dependent on sex. Systems biology approaches are successfully used to decipher human disease etiology, yet the effect of sex on gene network biology is mostly unknown. To address this, we used RNA-sequencing data of over 700 individuals spanning 24 tissues from the Genotype-Tissue Expression project to generate a whole-body gene activity map and quantified the sex differences per tissue. We found that of the 13,787 genes analyzed in 24 tissues, 20.1% of the gene activity is influenced by sex. For example, skeletal muscle was predominantly enriched with genes more active in males, whereas thyroid primarily contained genes more active in females. This was accompanied by consistent sex differences in pathway activity, including hypoxia, epithelial-to-mesenchymal transition, and inflammation over the human body. Furthermore, multi-organ analyses revealed consistent sex-dependent gene activity over numerous tissues which was accompanied by enrichment of transcription factor binding motifs in the promoters of these genes. Finally, we show that many sex-biased genes are known druggable targets. This emphasizes sex as a biological variable and the need to incorporate sex in systems biology studies.
Extent of similarity between agricultural and natural land covers shapes how biodiversity responds to agricultural expansion at landscape scales
Authors: Wilson Scott , Alavi-Shoushtari Niloofar , Pouliot Darren , Mitchell Gregory W.
Published: April 2020

The impact of agriculture on biodiversity depends on the extent and types of agriculture and the degree to which agricultural land contrasts with the natural ecosystem. Most research on the latter comes from studies on the influence of different agricultural types within a single ecosystem with far less study on how the natural ecosystem context shapes the response of biodiversity to agricultural production. We used citizen science data from agricultural areas in Canada’s Eastern Hardwood-Boreal (forest ecosystem, n=108 landscapes) and Prairie Pothole (prairie ecosystem, n=99) regions to examine how ecosystem context shapes the response of avian species diversity, functional diversity and abundance to the amount of arable crop and pastoral agriculture at landscape scales. Avian surveys were conducted along 8km transects of Breeding Bird Survey routes with land cover assembled within a 20km2landscape around each transect. The amount of agriculture at which species diversity peaked differed between the forest (15%) and prairie (51%) ecosystems, indicating that fewer species tolerated the expansion of agriculture in the former. In both ecosystems, functional diversity initially increased with agriculture and peaked at higher amounts (forest: 42%, prairie: 77%) than species diversity suggesting that functional redundancy was lost first as agriculture increased. Species turnover with increasing agriculture was primarily among functional groups in forest where a shift from a low to a high agriculture landscape led to a decline in the percent of the community represented by Neotropical migrants, insectivores, upper foliage gleaners and bark foragers, and an increase in the percent of the community represented by short-distance migrants, granivores, omnivores and ground gleaners. There were few distinct shifts in the percent of the community represented by different functional groups in the prairie ecosystem. Total abundance was the least sensitive measure examined in both ecosystems and indicated that species losses with agriculture are likely followed by numerical compensation from agriculture tolerant species. Our results highlight the importance of ecosystem context for understanding how biodiversity is affected by agricultural production with declines in diversity occurring at lower agricultural extents in ecosystems with lower similarity between natural and agricultural land covers. These findings allow for more specific conservation recommendations including managing for species intolerant to agriculture in prairie ecosystems and limiting the expansion of high contrast agriculture and the loss of semi-natural habitat, such as hedge rows, in historically forested ecosystems.
Comparative proteomics analysis identifies L-FABP as a putative biomarker of graft injury during liver transplantation
Authors: Chen Maogen , Lin Xiaohong , Zhang Yixi , Zhao Qiang , Mei Peiming , Chen Yinghua , Guo Zhiyong , Wu Linwei , Ma Yi , Wang Dongping , Ju Weiqiang , He Xiaoshun
Published: April 2020

Background

To a large extent the success of liver transplantation depends on quality of allografts. The molecular basis of the susceptibility of different liver allografts to transplant injury remains undefined.

Methods

Transplanted liver samples were collected and divided into three groups: the optimal graft (OG) group, early allograft dysfunction (EAD) group, and primary nonfunction (PNF) group. iTRAQ comparative quantitative proteomic analysis and multiple reaction monitoring (MRM) verification was performed.

Results

More than 160 differentially expressed proteins were detected in the PNF group, compared to 54 and 36 proteins in the EAD and OG groups respectively. Liver-type fatty acid-binding protein (L-FABP) was found as differentially expressed in both cold preserved and reperfused liver. Serum L-FABP level in donors was higher in the PNF and EAD groups than in the OG group. A lower tissue expression of L-FABP was observed in the PNF groups than other groups after reperfusion, indicating incompetent liver donor quality. In mouse ischemia reperfusion injury (IRI) model, the serum levels and tissue expression of L-FABP corresponded to the ALT variation curve.

Conclusions

Suboptimal donor livers are more sensitive to ischemia reperfusion injury. L-FABP might be an effective biomarker for evaluating donor quality in liver transplantation.
Cognitive Deficits and Altered Functional Brain Network Organization in Pediatric Brain Tumor Patients
Authors: Anandarajah Hari , Seitzman Benjamin A. , McMichael Alana , Dworetsky Ally , Coalson Rebecca S. , Jiang Catherine , Gu Hongjie , Barbour Dennis L. , Schlaggar Bradley L. , Limbrick David D. , Rubin Joshua B. , Shimony Joshua S. , Perkins Stephanie M.
Published: April 2020

Pediatric brain tumor survivors experience significant cognitive sequelae from their diagnosis and treatment. The exact mechanisms of cognitive injury are poorly understood, and validated predictors of long-term cognitive outcome are lacking. Large-scale, distributed brain systems provide a window into brain organization and function that may yield insight into these mechanisms and outcomes.

Here, we evaluated functional network architecture, cognitive performance, and brain-behavior relationships in pediatric brain tumor patients. Patients ages 4-18 years old with diagnosis of a brain tumor underwent awake resting state fMRI during regularly scheduled clinical visits and were tested with the NIH Toolbox Cognition Battery. We observed that functional network organization was significantly altered in patients compared to age- and sex-matched healthy controls, with the integrity of the dorsal attention network particularly affected. Moreover, patients demonstrated significant impairments in multiple domains of cognitive performance, including attention. Finally, a significant amount of variance of age-adjusted total composite scores from the Toolbox was explained by changes in segregation between the dorsal attention and default mode networks.

Our results suggest that changes in functional network organization may provide insight into long-term changes in cognitive function in pediatric brain tumor patients.
Limitation by a shared mutualist promotes coexistence of multiple competing partners
Authors: Hammarlund Sarah P. , Gedeon Tomáš , Carlson Ross P. , Harcombe William
Published: April 2020

Although mutualisms are often studied as simple pairwise interactions, they typically involve complex networks of interacting species. How multiple mutualistic partners that provide the same service and compete for resources are maintained in mutualistic networks is an open question. We use a model bacterial community in which multiple ‘partner strains’ ofEscherichia colicompete for a carbon source and exchange resources with a ‘shared mutualist’ strain ofSalmonella enterica. In laboratory experiments, competingE. colistrains readily coexist in the presence ofS. enterica, despite differences in their competitive abilities. We use ecological modeling to demonstrate that a shared mutualist can create temporary resource niche differentiation by limiting growth rates, even if yield is set by a resource external to a mutualism. This mechanism can extend to maintain multiple competing partner species. Our results improve our understanding of complex mutualistic communities and aid efforts to design stable microbial communities.
Multi-centre, multi-vendor reproducibility of 7T QSM and R2* in the human brain: results from the UK7T study
Authors: Rua Catarina , Clarke William T , Driver Ian D , Mougin Olivier , Morgan Andrew T. , Clare Stuart , Francis Susan , Muir Keith , Wise Richard , Carpenter Adrian , Williams Guy , Rowe James B , Bowtell Richard , Rodgers Christopher T
Published: April 2020

We present the reliability of ultra-high field T2* MRI at 7T, as part of the UK7T Network’s “Travelling Heads” study. T2*-weighted MRI images can be processed to produce quantitative susceptibility maps (QSM) and R2* maps. These reflect iron and myelin concentrations, which are altered in many pathophysiological processes. The relaxation parameters of human brain tissue are such that R2* mapping and QSM show particularly strong gains in contrast-to-noise ratio at ultra-high field (7T) vs clinical field strengths (1.5 - 3T). We aimed to determine the inter-subject and inter-site reproducibility of QSM and R2* mapping at 7T, in readiness for future multi-site clinical studies.

Methods

Ten healthy volunteers were scanned with harmonised single- and multi-echo T2*-weighted gradient echo pulse sequences. Participants were scanned five times at each “home” site and once at each of four other sites. The five sites had 1x Philips, 2x Siemens Magnetom, and 2x Siemens Terra scanners. QSM and R2* maps were computed with the Multi-Scale Dipole Inversion (MSDI) algorithm (https://github.com/fil-physics/Publication-Code). Results were assessed in relevant subcortical and cortical regions of interest (ROIs) defined manually or by the MNI152 standard space.

Results and Discussion

Mean susceptibility (χ) and R2* values agreed broadly with literature values in all ROIs. The inter-site within-subject standard deviation was 0.001 – 0.005 ppm (χ) and 0.0005 – 0.001 ms-1(R2*). For χ this is 2.1-4.8 fold better than 3T reports, and 1.1-3.4 fold better for R2*. The median ICC from within- and cross-site R2* data was 0.98 and 0.91, respectively. Multi-echo QSM had greater variability vs single-echo QSM especially in areas with large B0inhomogeneity such as the inferior frontal cortex. Across sites, R2* values were more consistent than QSM in subcortical structures due to differences in B0-shimming. On a between-subject level, our measured χ and R2* cross-site variance is comparable to within-site variance in the literature, suggesting that it is reasonable to pool data across sites using our harmonised protocol.

Conclusion

The harmonized UK7T protocol and pipeline delivers on average a 3-fold improvement in the coefficient of reproducibility for QSM and R2* at 7T compared to previous reports of multi-site reproducibility at 3T. These protocols are ready for use in multi-site clinical studies at 7T.
Rapid, sensitive, full genome sequencing of Severe Acute Respiratory Syndrome Virus Coronavirus 2 (SARS-CoV-2)
Authors: Paden Clinton R , Tao Ying , Queen Krista , Zhang Jing , Li Yan , Uehara Anna , Tong Suxiang
Published: April 2020

SARS-CoV-2 recently emerged, resulting a global pandemic. Rapid genomic information is critical to understanding transmission and pathogenesis. Here, we describe validated protocols for generating high-quality full-length genomes from primary samples. The first employs multiplex RT-PCR followed by MinION or MiSeq sequencing. The second uses singleplex, nested RT-PCR and Sanger sequencing.
Development ofmPing-based Activation Tags for Crop Insertional Mutagenesis
Authors: Johnson Alexander , Mcassey Edward , Diaz Stephanie , Reagin Jacob , Parrilla Daymond R. , Nguyen Hanh , Stec Adrian , McDaniel Lauren A. L. , Clemente Thomas E. , Stupar Robert M. , Parrott Wayne A. , Hancock C. Nathan
Published: April 2020

Modern plant breeding increasingly relies on genomic information to guide crop improvement. Although some genes are characterized, additional tools are needed to effectively identify and characterize genes associated with crop traits. To address this need, themPingelement from rice was modified to serve as an activation tag to induce expression of nearby genes. Embedding promoter sequences inmPingresulted in a decrease in overall transposition rate; however, this effect was negated by using a hyperactive version ofmPingcalledmmPing20. Transgenic soybean events carryingmPing-based activation tags and the appropriate transposase expression cassettes showed evidence of transposition. Expression analysis of a line that contained a heritable insertion of themmPing20Factivation tag indicated that the activation tag induced overexpression of the nearby soybean genes. This represents a significant advance in gene discovery technology as activation tags have the potential to induce more phenotypes than the originalmPingelement, improving the overall effectiveness of the mutagenesis system.
Mask, the Drosophila Ankyrin Repeat and KH domain-containing protein, regulates microtubule dynamics
Authors: Martinez Daniel , Zhu Mingwei , Guidry Jessie J. , Majeste Niles , Mao Hui , Yanofsky Sarah , Tian Xiaolin , Wu Chunlai
Published: April 2020

Proper regulation of microtubule (MT) dynamics is vital for essential cellular processes and neuronal activities, including axonal transport as well as synaptic growth and remodeling. Here we demonstrate that Mask negatively regulates MT stability and maintains a balanced dynamics of MT length and architecture in both fly larval muscles and motor neurons. In larval muscles, loss of mask increases MT length, and genetically altering mask levels modifies the Tau-induced MT fragmentation. In motor neurons, loss of mask function reduces the number of End-Binding Protein 1 (EB1)-positive MT plus-end structures in the axons and also results in overexpansion of the presynaptic terminal at larval neuromuscular junctions (NMJs). mask shows strong genetic interaction with stathmin (stai), a neuronal modulator of MT dynamics, in regulation of axon transportation and synaptic terminal stability. Our structure/function analysis on Mask revealed that truncated Mask transgenes carrying only its N-terminal portion that contains the two Ankyrin repeats domains is able to rescue the MT-related mask loss-of-function defects in larval muscles and NMJs, suggesting an essential role of the Ankyrin repeats domains in mediating Mask’s MT stability-regulating function. Furthermore, we discovered that Mask negatively regulates the abundance of the microtubule-associated protein Jupiter in motor neuron axons, and that neuronal knocking down of Jupiter partially suppresses mask loss of function phenotypes at the larval NMJs. Together, our study identified Mask as a novel regulator for microtubule stability and dynamics.

Author Summary

Microtubules (MTs) are an essential part of the cellular cytoskeleton, providing the structural basis for critical cellular processes and functionality. A series of factors are required to orchestrate the assembly and disassembly of MTs. Here, we identified Mask as a novel regulator of MT dynamics in Drosophila. Mask shows prominent interplay with two important modulators of MT, Tau and Stathmin (Stai). These findings not only support the role of Mask as a novel microtubule regulator but also provide the foundation to explore future therapeutic strategies in mitigating deficits related to dysfunction of Tau and/or Stai, both of which are linked to human neurodegenerative disorders. Further analyses on Mask demonstrated that Jupiter’s localization to the MTs in the axons is negatively affected by Mask, and that reducing Jupiter level is able to partially suppress synaptic defects caused by mask mutant. Together, these data imply that Mask’s function in regulating MT dynamics requires Jupiter.
SwabExpress: An end-to-end protocol for extraction-free COVID-19 testing
Authors: Srivatsan Sanjay , Heidl Sarah , Pfau Brian , Martin Beth K. , Han Peter D. , Zhong Weizhi , van Raay Katrina , McDermot Evan , Opsahl Jordan , Gamboa Luis , Smith Nahum , Truong Melissa , Cho Shari , Barrow Kaitlyn A. , Rich Lucille M. , Stone Jeremy , Wolf Caitlin R. , McCulloch Denise J. , Kim Ashley E. , Brandstetter Elisabeth , Sohlberg Sarah L. , Ilcisin Misja , Geyer Rachel E. , Chen Wei , Gehring Jase ,   Seattle Flu Study Investigators, Kosuri Sriram , Bedford Trevor , Rieder Mark J. , Nickerson Deborah A. , Chu Helen Y. , Konnick Eric Q. , Debley Jason S. , Shendure Jay , Lockwood Christina M. , Starita Lea M.
Published: April 2020

Structured Abstract

Background

The urgent need for massively scaled clinical testing for SARS-CoV-2, along with global shortages of critical reagents and supplies, has necessitated development of streamlined laboratory testing protocols. Conventional nucleic acid testing for SARS-CoV-2 involves collection of a clinical specimen with a nasopharyngeal swab in transport medium, nucleic acid extraction, and quantitative reverse transcription PCR (RT-qPCR) (1). As testing has scaled across the world, the global supply chain has buckled, rendering testing reagents and materials scarce (2). To address shortages, we developed SwabExpress, an end-to-end protocol developed to employ mass produced anterior nares swabs and bypass the requirement for transport media and nucleic acid extraction.

Methods

We evaluated anterior nares swabs, transported dry and eluted in low-TE buffer as a direct-to-RT-qPCR alternative to extraction-dependent viral transport media. We validated our protocol of using heat treatment for viral activation and added a proteinase K digestion step to reduce amplification interference. We tested this protocol across archived and prospectively collected swab specimens to fine-tune test performance.

Results

After optimization, SwabExpress has a low limit of detection at 2-4 molecules/uL, 100% sensitivity, and 99.4% specificity when compared side-by-side with a traditional RT-qPCR protocol employing extraction. On real-world specimens, SwabExpress outperforms an automated extraction system while simultaneously reducing cost and hands-on time.

Conclusion

SwabExpress is a simplified workflow that facilitates scaled testing for COVID-19 without sacrificing test performance. It may serve as a template for the simplification of PCR-based clinical laboratory tests, particularly in times of critical shortages during pandemics.
C. elegansepisodic swimming is driven by multifractal kinetics
Authors: Ikeda Yusaku , Jurica Peter , Kimura Hiroshi , Takagi Hiroaki , Zbigniew Struzik , Kiyono Ken , Arata Yukinobu , Sako Yasushi
Published: April 2020

Fractal scaling is a common property of temporal change in various modes of animal behavior. The molecular mechanisms of fractal scaling in animal behaviors remain largely unexplored. The nematodeC. elegansalternates between swimming and resting states in a liquid solution. Here, we report thatC. elegansepisodic swimming is characterized by scale-free kinetics with long-range temporal correlation and local temporal clusterization, which is characterized as multifractal kinetics. Residence times in actively-moving and inactive states were distributed in a power law-based scale-free manner. Multifractal analysis showed that temporal correlation and temporal clusterization were distinct between the actively-moving state and the inactive state. These results indicate thatC. elegansepisodic swimming is driven by transition between two behavioral states, in which each of two transition kinetics follows distinct multifractal kinetics. We found that a conserved behavioral modulator, cyclic GMP dependent kinase (PKG) may regulate the multifractal kinetics underlying an animal behavior. Our combinatorial analysis approach involving molecular genetics and kinetics provides a platform for the molecular dissection of the fractal nature of physiological and behavioral phenomena.
Optimal control of the COVID-19 pandemic with non-pharmaceutical interventions
Authors: Perkins T. Alex , España Guido
Published: April 2020

The COVID-19 pandemic has forced societies across the world to resort to social distancing to slow the spread of the SARS-CoV-2 virus. Due to the economic impacts of social distancing, there is growing desire to relax these measures. To characterize a range of possible strategies for control and to understand their consequences, we performed an optimal control analysis of a mathematical model of SARS-CoV-2 transmission. Given that the pandemic is already underway and controls have already been initiated, we calibrated our model to data from the US and focused our analysis on optimal controls from May 2020 through December 2021. We found that a major factor that differentiates strategies that prioritize lives saved versus reduced time under control is how quickly control is relaxed once social distancing restrictions expire in May 2020. Strategies that maintain control at a high level until summer 2020 allow for tapering of control thereafter and minimal deaths, whereas strategies that relax control in the short term lead to fewer options for control later and a higher likelihood of exceeding hospital capacity. Our results also highlight that the potential scope for controlling COVID-19 until a vaccine is available depends on epidemiological parameters about which there is still considerable uncertainty, including the basic reproduction number and the effectiveness of social distancing. In light of those uncertainties, our results do not constitute a quantitative forecast and instead provide a qualitative portrayal of possible outcomes from alternative approaches to control.
Suppression of HSF1 activity by wildtype p53 creates the driving force for p53 loss-of-heterozygosity, enabling mutant p53 stabilization and invasion
Authors: Sener Özge Cicek , Stender Adrian , Klemke Luisa , Stark Nadine , Isermann Tamara , Li Jinyu , Moll Ute M. , Schulz-Heddergott Ramona
Published: April 2020

A prerequisite for gain-of-function (GOF) p53 missense mutants (mutp53) is protein stabilization. Moreover, a prerequisite for mutp53 stabilization is loss of the remaining wildtype (WT) p53 allele (loss-of-heterozygosity, p53LOH) in mutp53/+ tumors. Thus, GOF, mutp53 stabilization and p53LOH are strictly linked. However, the driving force for p53LOH is unknown. Typically, heterozygous tumors are an instable transition state. Here we identify the repressive WTp53-HSF1 axis as the driver of p53LOH.

We find that the WTp53 allele in AOM/DSS-induced colorectal tumors (CRC) of p53R248Q/+mice retains its haploid transcriptional activity. Notably, WTp53 represses heat-shock factor 1 (HSF1) activity, the master transcription factor of the proteotoxic stress defense response (HSR) that is ubiquitously and constitutively activated in cancer tissues. HSR is critical for stabilizing oncogenic proteins including mutp53. WTp53-retaining murine CRC tumors and tumor-derived organoids and human CRC cells all suppress the tumor-promoting HSF1 transcriptional program.

Mechanistically, the retained WTp53 allele activates CDKN1A/p21, leading to cell cycle inhibition and suppression of the E2F target gene MLK3. MLK3 links cell cycle to the MAPK stress pathway to activate the HSR response. We show that in p53R248Q/+tumors WTp53 activation by constitutive stress (emanating from proliferative/metabolic stresses and genomic instability) represses MLK3, consequently inactivating the MAPK-HSF1 response necessary to ensure tumor survival. This creates strong selection pressure for p53LOH which eliminates the repressive WTp53-HSF1 axis and unleashes the tumor-promoting HSF1 functions, inducing mutp53 stabilization and enabling invasion.

HIGHLIGHTS

heterozygous p53R248Q/+tumors retain p53 transcriptional activity in a mouse model of colorectal cancer (CRC)

wildtype p53 actively represses the tumor-promoting HSF1-regulated chaperone system and proteotoxic stress response

the repressive WTp53 – HSF1 axis creates a selective pressure for WTp53 loss-of-heterozygosity in CRC tumors

p53 loss-of-heterozygosity enables stabilization of the gain-of-function p53R248Qmutant protein which in turn enables CRC invasion
Adaptive evolution of hybrid bacteria by horizontal gene transfer
Authors: Power Jeffrey J. , Pinheiro Fernanda , Pompei Simone , Kovacova Viera , Yüksel Melih , Rathmann Isabel , Förster Mona , Lässig Michael , Maier Berenike
Published: April 2020

Horizontal gene transfer is an important factor in bacterial evolution that can act across species boundaries. Yet, we know little about rate and genomic targets of cross-lineage gene transfer, and about its effects on the recipient organism’s physiology and fitness. Here, we address these questions in a parallel evolution experiment with twoBacillus subtilislineages of 7% sequence divergence. We observe rapid evolution of hybrid organisms: gene transfer swaps ~12% of the core genome in just 200 generations, and 60% of core genes are replaced in at least one population. By genomics, transcriptomics, fitness assays, and statistical modeling, we show that transfer generates adaptive evolution and functional alterations in hybrids. Specifically, our experiments reveal a strong, repeatable fitness increase of evolved populations in the stationary growth phase. By genomic analysis of the transfer statistics across replicate populations, we infer that selection on HGT has a broad genetic basis: 40% of the observed transfers are adaptive. At the level of functional gene networks, we find signatures of negative and positive selection, consistent with hybrid incompatibilities and adaptive evolution of network functions. Our results suggest that gene transfer navigates a complex cross-lineage fitness landscape, bridging epistatic barriers along multiple high-fitness paths.

Significance statement

In a parallel evolution experiment, we probe lateral gene transfer between twoBacillus subtilislineages close to the species boundary. We show that laboratory evolution by horizontal gene transfer can rapidly generate hybrid organisms with broad genomic and functional alterations. By combining genomics, transcriptomics, fitness assays and statistical modeling, we map the selective effects underlying gene transfer. We show that transfer takes place under genome-wide positive and negative selection, generating a net fitness increase in hybrids. The evolutionary dynamics efficiently navigates this fitness landscape, finding viable paths with increasing fraction of transferred genes.
The genetic variation of lactase persistence alleles in northeast Africa
Authors: Hollfelder Nina , Babiker Hiba , Granehäll Lena , Schlebusch Carina M , Jakobsson Mattias
Published: April 2020

Lactase persistence (LP) is a well-studied example of a Mendelian trait under selection in some human groups due to gene-culture co-evolution. We investigated the frequencies of genetic variants linked to LP in Sudanese and South Sudanese populations. These populations have diverse subsistence patterns, and some are dependent on milk to various extents, not only from cows, but also from other livestock such as camels and goats. We sequenced a 316bp region involved in regulating the expression of theLCTgene on chromosome 2, which encompasses five polymorphisms that have been associated with LP. Pastoralist populations showed a higher frequency of LP-associated alleles compared to non-pastoralist groups, hinting at positive selection also in northeast African pastoralists. There was no incidence of the East African LP allele (−14010:C) in the Sudanese groups, and only one heterozygote individual for the European LP allele (−13910:T), suggesting limited recent admixture from these geographic regions. Among the LP variants, the −14009:G variant occurs at the highest frequency among the investigated populations, followed by the −13915:G variant, which is likely of Middle Eastern origin, consistent with Middle Eastern gene-flow to the Sudanese populations. The Beja population of the Beni Amer show three different LP-variants at substantial and similar levels, resulting in one of the greatest frequencies of LP-variants among all populations across the world.
Predictive coding as a unifying principle for explaining a broad range of brightness phenomena
Authors: Lerer Alejandro , Supèr Hans , S.Keil Matthias
Published: April 2020

The visual system is highly sensitive to spatial context for encoding luminance patterns. Context sensitivity inspired the proposal of many neural mechanisms for explaining the perception of luminance (brightness). Here we propose a novel computational model for estimating the brightness of many visual illusions. We hypothesize that many aspects of brightness can be explained by a predictive coding mechanism, which reduces the redundancy in edge representations on the one hand, while non-redundant activity is enhanced on the other (response equalization). Response equalization is implemented with a dynamic filtering process, which (dynamically) adapts to each input image. Dynamic filtering is applied to the responses of complex cells in order to build a gain control map. The gain control map then acts on simple cell responses before they are used to create a brightness map via activity propagation. Our approach is successful in predicting many challenging visual illusions, including contrast effects, assimilation, and reverse contrast.

Author summary

We hardly notice that what we see is often different from the physical world “outside” of the brain. This means that the visual experience that the brain actively constructs may be different from the actual physical properties of objects in the world. In this work, we propose a hypothesis about how the visual system of the brain may construct a representation for achromatic images. Since this process is not unambiguous, sometimes we notice “errors” in our perception, which cause visual illusions. The challenge for theorists, therefore, is to propose computational principles that recreate a large number of visual illusions and to explain why they occur. Notably, our proposed mechanism explains a broader set of visual illusions than any previously published proposal. We achieved this by trying to suppress predictable information. For example, if an image contained repetitive structures, then these structures are predictable and would be suppressed. In this way, non-predictable structures stand out. Predictive coding mechanisms act as early as in the retina (which enhances luminance changes but suppresses uniform regions of luminance), and our computational model holds that this principle also acts at the next stage in the visual system, where representations of perceived luminance (brightness) are created.
Body mass index trajectories and adiposity rebound during the first 6 years in Korean children: based on the National Health Information Database, 2008-2015
Authors: Hwang Il Tae , Ju Young-Su , Lee Hye Jin , Shim Young Suk , Jeong Hwal Rim , Kang Min Jae
Published: April 2020

Purpose

We analyzed the nationwide longitudinal data to explore body mass index (BMI) growth trajectories and the time of adiposity rebound (AR).

Methods

Personal data of 84,005 subjects born between 2008 and 2012 were obtained from infant health check-ups which were performed at 5, 11, 21, 33, 45, 57, and 69 months. BMI 00trajectories of each subject were made according to sex and birth weight (Bwt) and the timing of AR was defined as the lowest BMI occurred. Subjects were divided according to Bwt and AR timing as follows: very low birth weight (VLBW), 0.5 kg ≤ Bwt ≤ 1.5 kg; low birth weight (LBW), 1.5 kg < Bwt ≤ 2.5 kg; non-LBW, 2.5 kg < Bwt ≤ 5.0 kg; early AR, before 45 months; moderate AR, at 57 months; and late AR, not until 69 months.

Main results

Median time point of minimum BMI was 45 months, and the prevalence rates of early, moderate, and late AR were 63.0%, 16.6%, and 20.4%, respectively. BMI at the age of 57 months showed a strong correlation with AR timing after controlling for Bwt (P< 0.001). Sugar-sweetened beverage intake at 21 months (P= 0.02) and no-exercise habit at 57 months (P< 0.001) showed correlations with early AR. When VLBW and LBW subjects were analyzed, BMI at 57 months and breastfeeding at 11 months were correlated with rapid weight gain during the first 5 months (bothP< 0.001).

Conclusions

Based on this first longitudinal study, the majority of children showed AR before 57 months and the degree of obesity at the age of 57 months had a close correlation with early AR or early weight during infancy.