bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of the common PRSS1-PRSS2 haplotype in alcoholic and non-alcoholic chronic pancreatitis: meta- and re-analyses
Authors: Herzig Anthony F. , Génin Emmanuelle , Cooper David N. , Masson Emmanuelle , Férec Claude , Chen Jian-Min
Published: October 2020

The association between a common PRSS1-PRSS2 haplotype and alcoholic chronic pancreatitis (ACP), which was revealed by the first genome-wide association study of chronic pancreatitis (CP), has been consistently replicated. However, the association with non-ACP (NACP) has been controversial. Herein, we sought to clarify this basic issue by means of an allele-based meta-analysis of currently available studies. We then used studies informative for genotype distribution to explore the biological mechanisms underlying the association data and to test for gene-environment interaction between the risk haplotype and alcohol consumption by means of a re-analysis. A literature search was conducted to identify eligible studies. Meta-analysis was performed using the Review Manager software. The association between the risk genotypes and NACP or ACP was tested for the best-fitting genetic model. Gene-environment interaction was estimated by both case-only and multinomial approaches. Five and eight studies were employed for the meta-analysis of ACP and NACP findings, respectively. The risk allele was significantly associated with both ACP (pooled OR 1.67, 95% CI 1.56–1.78; P<0.00001) and NACP (pooled OR 1.28, 95% CI 1.17–1.40; P<0.00001). Consistent with a dosage effect of the risk allele on PRSS1/PRSS2 mRNA expression in human pancreatic tissue, both ACP and NACP association data were best explained by an additive genetic model. Finally, the risk haplotype was found to interact synergistically with ACP.
SARS-CoV-2 S protein ACE2 interaction reveals novel allosteric targets
Authors: Raghuvamsi Palur , Tulsian Nikhil , Samsudin Firdaus , Qian Xinlei , Purushotorman Kiren , Yue Gu , Kozma Mary , Lescar Julien , Bond Peter , MacAry Paul , Anand Ganesh
Published: October 2020

The Spike (S) protein is the main handle for SARS-CoV-2 to enter host cells through surface ACE2 receptors. How ACE2 binding activates proteolysis of S protein is unknown. Here, we have mapped the S:ACE2 interface and uncovered long-range allosteric propagation of ACE2 binding to sites critical for viral host entry. Unexpectedly, ACE2 binding enhances dynamics at a distal S1/S2 cleavage site and flanking protease docking site ~27 Å away while dampening dynamics of the stalk hinge (central helix and heptad repeat) regions ~ 130 Å away. This highlights that the stalk and proteolysis sites of the S protein are dynamic hotspots in the pre-fusion state. Our findings provide a mechanistic basis for S:ACE2 complex formation, critical for proteolytic processing and viral-host membrane fusion and highlight protease docking sites flanking the S1/S2 cleavage site, fusion peptide and heptad repeat 1 (HR1) as allosterically exposed cryptic hotspots for potential therapeutic development.

One Sentence Summary

SARS-CoV-2 spike protein binding to receptor ACE2 allosterically enhances furin proteolysis at distal S1/S2 cleavage sites
Robotic Multi-Probe-Single-Actuator Inchworm Neural Microdrive
Authors: Smith R. D. , Kolb I. , Tanaka S. , Lee A. K. , Harris T. D. , Barbic M.
Published: October 2020

Electrophysiology is one of the major experimental techniques used in neuroscience. The favorable spatial and temporal resolution as well as the increasingly larger site counts of brain recording electrodes contribute to the popularity and importance of electrophysiology in neuroscience. Such electrodes are typically mechanically placed in the brain to perform acute or chronic freely moving animal measurements. The micro positioners currently used for such tasks employ a single translator per independent probe being placed into the targeted brain region, leading to significant size and weight restrictions. To overcome this limitation, we have developed a miniature robotic multi-probe neural microdrive that utilizes novel phase-change-material-filled resistive heater micro-grippers. The microscopic dimensions, gentle gripping action, independent electronic actuation control, and high packing density of the grippers allow for micrometer-precision independent positioning of multiple arbitrarily shaped parallel neural electrodes with only a single piezo actuator in an inchworm motor configuration. This multi-probe-single-actuator design allows for significant size and weight reduction, as well as remote control and potential automation of the microdrive. We demonstrate accurate placement of multiple independent recording electrodes into the CA1 region of the rat hippocampusin vivoin acute and chronic settings. Thus, our robotic neural microdrive technology is applicable towards basic neuroscience and clinical studies, as well as other multi-probe or multi-sensor micro-positioning applications.

One Sentence Summary

Miniature robotic multi-probe single-actuator microdrive utilizing phase change material based micro-grippers.
Analysis of Collective Response Reveals that COVID-19-Related Activities Start From the End of 2019 in Mainland China
Authors: Liu Ji , Huang Tongtong , Xiong Haoyi , Huang Jizhou , Zhou Jingbo , Jiang Haiyan , Yang Guanhua , Wang Haifeng , Dou Dejing
Published: October 2020

While the COVID-19 outbreak is making an impact at a global scale, the collective response to the pandemic becomes the key to analyzing past situations, evaluating current measures, and formulating future predictions. In this paper, we analyze the public reactions to the pandemic using search engine data and mobility data from Baidu Search and Baidu Maps respectively, where we particularly pay attentions to the early stage of pandemics and find early signals from the collective response to COVID-19. First, we correlate the number of confirmed cases per day to daily search queries of a large number of keywords through Dynamic Time Warping (DTW) and Detrended Cross-Correlation Analysis (DCCA), where the keywords top in the most critical days are believed the most relevant to the pandemic. We then categorize the ranking lists of keywords according to the specific regions of the search, such as Wuhan, Mainland China, the USA, and the whole world. Through the analysis on search, we succeed in identifying COVID-19 related collective response would not be earlier than the end of 2019 in Mainland China. Finally, we confirm this observation again using human mobility data, where we specifically compare the massive mobility traces, including the real-time population densities inside key hospitals and inter-city travels departing from/arriving in Wuhan, from 2018 to 2020. No significant changes have been witnessed before December, 2019.
A betacoronavirus multiplex microsphere immunoassay detects early SARS-CoV-2 seroconversion and controls for pre-existing seasonal human coronavirus antibody cross-reactivity
Authors: Laing Eric D. , Sterling Spencer L. , Richard Stephanie A. , Phogat Shreshta , Samuels Emily C. , Epsi Nusrat J. , Yan Lianying , Moreno Nicole , Coles Christian , Mehalko Jennifer , Drew Matthew , English Caroline , Chung Kevin K. , Clifton G. Travis , Munster Vincent J. , de Wit Emmie , Tribble David , Agan Brian K. , Esposito Dominic , Lanteri Charlotte , Mitre Edward , Burgess Timothy H. , Broder Christopher C.
Published: October 2020

With growing concern of persistent or multiple waves of SARS-CoV-2 in the United States, sensitive and specific SARS-CoV-2 antibody assays remain critical for community and hospital-based SARS-CoV-2 surveillance. Here, we describe the development and application of a multiplex microsphere-based immunoassay (MMIA) for COVD-19 antibody studies, utilizing serum samples from non-human primate SARS-CoV-2 infection models, an archived human sera bank and subjects enrolled at five U.S. military hospitals. The MMIA incorporates prefusion stabilized spike glycoprotein trimers of SARS-CoV-2, SARS-CoV-1, MERS-CoV, and the seasonal human coronaviruses HCoV-HKU1 and HCoV-OC43, into a multiplexing system that enables simultaneous measurement of off-target pre-existing cross-reactive antibodies. We report the sensitivity and specificity performances for this assay strategy at 98% sensitivity and 100% specificity for subject samples collected as early as 10 days after the onset of symptoms. In archival sera collected prior to 2019 and serum samples from subjects PCR negative for SARS-CoV-2, we detected seroprevalence of 72% and 98% for HCoV-HKU1 and HCoV-0C43, respectively. Requiring only 1.25 µL of sera, this approach permitted the simultaneous identification of SARS-CoV-2 seroconversion and polyclonal SARS-CoV-2 IgG antibody responses to SARS-CoV-1 and MERS-CoV, further demonstrating the presence of conserved epitopes in the spike glycoprotein of zoonotic betacoronaviruses. Application of this serology assay in observational studies with serum samples collected from subjects before and after SARS-CoV-2 infection will permit an investigation of the influences of HCoV-induced antibodies on COVID-19 clinical outcomes.
shinyCurves, a shiny web application to analyse multisource qPCR amplification data: a COVID 19 case study
Authors: Olaechea-Lázaro S. , García-Santisteban I. , Pineda JR. , Badiola I. , Alonso S. , Bilbao JR. , Fernandez-Jimenez N.
Published: October 2020

Quantitative, reverse transcription polymerase chain reaction (qRT-PCR) has been the gold-standard tool for viral detection during the SARS-CoV-2 pandemic. However, the desperate rush for a quick diagnosis led the use of very different types of machines and proprietary software, leading to an unbearable complexity of data analysis with a limited parameter setup. Here, we present shinyCurves, a shiny web application created to analyse multisource qPCR amplification data from independent multi-plate format. Furthermore, our automated system allows the classification of the results as well as the plot of both amplification and melting curves. Altogether, our web application is an automated qPCR analysis resource available to the research community.

Availability

The shinyCurves web application to analyze multisource qPCR amplification data is publicly available under CC license (CC BY-NC-SA 4.0) at https://biosol.shinyapps.io/shinycurves/ and https://github.com/biosol/shinyCurves.
Shark conservation risks associated with the use of shark liver oil in SARS-CoV-2 vaccine development
Authors: Macdonald Catherine , Soll Joshua
Published: October 2020

The COVID-19 pandemic may create new demand for wildlife-generated products for human health, including a shark-derived ingredient used in some vaccines. Adjuvants are a vaccine component that increases efficacy, and some adjuvants contain squalene, a natural compound derived from shark liver oil which is found most abundantly in deep-sea sharks. In recent decades, there has been growing conservation concern associated with the sustainability of many shark fisheries. The need for a potentially massive number of adjuvant-containing SARS-CoV-2 vaccines may increase global demand for shark-derived squalene, with possible consequences for shark conservation, especially of vulnerable and understudied deep-sea species. A shift to non-animal-derived sources of squalene, which are similar in cost and identical in effectiveness, or an emphasis on increasing traceability and sustainability of shark-derived squalene from existing well-managed fisheries, could better support conservation and public health goals.
Impact of a tarsonemid prey mite and its fungal diet on the reproductive performance of a predatory mite
Authors: Vangansbeke Dominiek , Duarte Marcus V. A. , Merckx Jonas , Benavente Alfredo , Magowski Wojciech L. , França Soraya C. , Bolckmans Karel , Wäckers Felix
Published: October 2020

Phytoseiid predatory mites are the most important group of biocontrol agents currently implemented in protected cultivations worldwide. The possibility to produce these predators at high densities on factitious prey mites is a crucial factor for their success. Commonly used factitious prey mites comprise mainly species belonging to the cohort of Astigmatina. In the present study, we investigated the potential of tarsonemid prey mites as a food source for the spider mite predatorNeoseiulus californicus(McGregor) (Acari: Phytoseiidae). The oviposition ofN. californicuson mixed stages ofTarsonemus fusariiCooreman (Acari: Tarsonemidae) was similar to that on its natural prey, the two-spotted spider miteTetranychus urticaeKoch (Acari: Tetranychidae). As most tarsonemids are specialized fungus-feeders, we tested the effect of different fungal species on the growth ofT. fusarii. Subsequently, we analysed the impact on the fungal growing medium on the oviposition ofN. californicus. The fungal growing medium ofT. fusariihad a significant effect on the reproductive output of the predatory mite, having a negative effect. WhenT. fusariiwas separated from the rearing medium, these detrimental effects were not observed. The present study shows the potential of using tarsonemid prey mites in the production of predatory mites.
Convergence of peptidergic and non-peptidergic protein markers in the human dorsal root ganglion and spinal dorsal horn
Authors: Shiers Stephanie , Sankaranarayanan Ishwarya , Jeevakumar Vivek , Cervantes Anna , Reese Jeffrey C. , Price Theodore J.
Published: October 2020

Peripheral sensory neurons are characterized by their size, molecular profiles, and physiological responses to specific stimuli. In mouse, the peptidergic and non-peptidergic subsets of nociceptors are distinct and innervate different lamina of the spinal dorsal horn. The unique molecular signature and neuroanatomical organization of these neurons supports a labeled line theory for certain types of nociceptive stimuli. However, long standing evidence supports the polymodal nature of nociceptors in many species. We have recently shown that the peptidergic marker, CGRP, and the non-peptidergic marker, P2X3R, show largely overlapping expression at the mRNA level in human dorsal root ganglion (DRG). Herein, our aim was to assess the protein distribution of nociceptor markers, including their central projections, in the human DRG and spinal cord. Using DRGs obtained from organ donors, we observed that CGRP and P2X3R were co-expressed by approximately 33% of human DRG neurons and TrpV1 was expressed in ~60% of human DRG neurons. In the dorsal spinal cord, CGRP, P2X3R, TrpV1 and Nav1.7 protein stained the entirety of lamina II, with only P2XR3 showing a gradient of expression. This was confirmed by measuring the size of the substantia gelatinosa using Hematoxylin and Eosin staining of adjacent sections. Our findings are consistent with the known polymodal nature of most primate nociceptors and indicate that the central projection patterns of nociceptors are different between mice and humans. Elucidating how human nociceptors connect to subsets of dorsal horn neurons will be important for understanding the physiological consequences of these species differences.
Simple muscle-lever systems are not so simple: The need for dynamic analyses to predict lever mechanics that maximize speed
Authors: Osgood A. C. , Sutton G.P. , Cox S. M.
Published: October 2020

Here we argue that quasi-static analyses are insufficient to predict the speed of an organism from its skeletal mechanics alone (i.e. lever arm mechanics). Using a musculoskeletal numerical model we specifically demonstrate that 1) a single lever morphology can produce a range of output velocities, and 2) a single output velocity can be produced by a drastically different set of lever morphologies. These two sets of simulations quantitatively demonstrate that it is incorrect to assume a one-to-one relationship between lever arm morphology and organism maximum velocity. We then use a statistical analysis to quantify what parameters are determining output velocity, and find that muscle physiology, geometry, and limb mass are all extremely important. Lastly we argue that the functional output of a simple lever is dependent on the dynamic interaction of two opposing factors: those decreasing velocity at low mechanical advantage (low torque and muscle work) and those decreasing velocity at high mechanical advantage (muscle force-velocity effects). These dynamic effects are not accounted for in static analyses and are inconsistent with a force-velocity tradeoff in lever systems. Therefore, we advocate for a dynamic, integrative approach that takes these factors into account when analyzing changes in skeletal levers.
Alzheimer’s pathology is associated with dedifferentiation of functional memory networks in aging
Authors: Cassady Kaitlin E. , Adams Jenna N. , Chen Xi , Maass Anne , Harrison Theresa M. , Landau Susan , Baker Suzanne , Jagust William
Published: October 2020

In presymptomatic Alzheimer’s disease (AD), beta-amyloid plaques (Aβ) and tau tangles accumulate in distinct spatiotemporal patterns within the brain, tracking closely with episodic memory decline. Here, we tested whether age-related changes in the segregation of the brain’s functional episodic memory networks - anterior-temporal (AT) and posterior-medial (PM) networks - are associated with the accumulation of Aβ, tau and memory decline using fMRI and PET. We found that AT and PM networks were less segregated in older than younger adults and this reduced specialization was associated with more tau and Aβ in the same regions. The effect of network dedifferentiation on memory depended on the amount of Aβ and tau, with low segregation and pathology associated with better performance at baseline and low segregation and high pathology related to worse performance over time. This pattern suggests a compensation phase followed by a degenerative phase in the early, preclinical phase of AD.
Loss of IL-10 signaling promotes IL-22 dependent host defenses against acuteClostridioides difficileinfection
Authors: Cribas Emily S. , Denny Joshua E. , Maslanka Jeffrey R. , Abt Michael C.
Published: October 2020

Infection with the bacterial pathogenClostridioides difficilecauses severe damage to the intestinal epithelium that elicits a robust inflammatory response. Markers of intestinal inflammation accurately predict clinical disease severity. However, determining the extent to which host-derived proinflammatory mediators drive pathogenesis versus promote host protective mechanisms remains elusive. In this report, we employedIl10-/-mice as a model of spontaneous colitis to examine the impact of constitutive intestinal immune activation, independent of infection, onC. difficiledisease pathogenesis. UponC. difficilechallenge,Il10-/-mice exhibited significantly decreased morbidity and mortality compared to littermateIl10heterozygote (Il10HET) control mice, despite a comparableC. difficileburden, innate immune response, and microbiota composition following infection. Similarly, antibody-mediated blockade of IL-10 signaling in wild-type C57BL/6 mice conveyed a survival advantage if initiated three weeks prior to infection. In contrast, no advantage was observed if blockade was initiated on the day of infection, suggesting that constitutive activation of inflammatory defense pathways prior to infection mediated host protection. IL-22, a cytokine critical in mounting a protective response againstC. difficileinfection, was elevated in the intestine of uninfected, antibiotic-treatedIl10-/-mice, and genetic ablation of the IL-22 signaling pathway inIl10-/-mice negated the survival advantage followingC. difficilechallenge. Collectively, these data demonstrate that constitutive loss of IL-10 signaling, via genetic ablation or antibody blockade, enhances IL-22 dependent host defense mechanisms to limitC. difficilepathogenesis.
Attention recruits frontal cortex in human infants
Authors: Ellis C. T. , Skalaban L. J. , Yates T. S. , Turk-Browne N. B.
Published: October 2020

Young infants learn about the world by overtly shifting their attention to perceptually salient events. In adults, attention recruits several brain regions spanning the frontal and parietal lobes. However, these regions are thought to have a protracted maturation and so it is unclear whether they are recruited in infancy and, more generally, how infant attention is supported by the brain. We used event-related fMRI with 24 awake behaving infants 3–12 months old while they performed a child-friendly attentional cuing task. A target was presented to either the left or right of the infant’s fixation and eye-tracking was used to measure the latency with which they saccaded to the target. To manipulate attention, a brief cue was presented before the target in three conditions: on the same side as the upcoming target (valid), on the other side (invalid), or on both sides (neutral). All infants were faster to look at the target on valid versus invalid trials, with valid faster than neutral and invalid slower than neutral, indicating that the cues effectively captured attention. We then compared the fMRI activity evoked by these trial types. Regions of adult attention networks activated more strongly for invalid than valid trials, particularly frontal regions such as anterior cingulate cortex. Neither behavioral nor neural effects varied by infant age within the first year, suggesting that these regions may function early in development to support the reorienting of attention. Together, this furthers our mechanistic understanding of how the infant brain controls the allocation of attention.
Cross-reactive anti-hemagglutinin (HA) IgG responses are shaped by previous long-interval monovalent H5 vaccination and highly correlated with HA antigenic distance
Authors: Wang Jiong , Li Dongmei , Perry Sheldon , Hilchey Shannon P. , Wiltse Alexander , Treanor John J. , Sangster Mark Y. , Zand Martin S.
Published: October 2020

Avian H5 influenza is an emerging influenza strain with the potential for human pandemic spread. One unresolved issue in pandemic vaccine preparedness is to what extent a vaccine recall response depends on the interval between the priming and boosting vaccinations. In this study, we analyzed the anti-H5 HA IgG responses to an H5 A/Indonesia/5/2005 boosting vaccination in three cohorts: (1) a short interval boosting cohort that received a prime and boost 28 days apart, (2) a long-interval boosting cohort that received an H5 A/Vietnam/203/2004 priming vaccination 5 years before boosting, and (3) a double long-boost cohort that received single doses of all three vaccines separated by 5-6 year intervals. Anti-HA IgG levels were measured using a multiple-plex assay against 21 H5 and 16 seasonal strains covering both influenza phylogenetic groups. We used the antigentic distance between the vaccine strain and each HA in the assay panel to de1ne the antibody response landscape. Both single and double long-interval boosting with the H5 variant vaccine elicited a broad antibody response to all H5 subtype strains, and double boosting resulted in sustained, vaccine-speci1c, anti-HA IgG levels over a six month period. Antibody-mediated immune responses were shaped by prior H5 exposure history, and the magnitude of both vaccine speci1c and cross-reactive anti-H5 HA IgG responses was highly correlated with the relative antigenic distance between the measured and the vaccine HAs. We conclude that the relative antibody landscape method can be used to quantify the phenomenon of antigenic imprinting on human influenza vaccine immune responses.

IMPORTANCE

A signi1cant obstacle to development of a universal influenza vaccine is understanding the relationship between multidimensional host humoral immunity, prior antigen exposure, and viral antigenicity. In this study, we used a multiplexed antibody assay to measure antibody cross-reactivities against antigenically similar H5 influenza virus strains. This work uses a novel method, relative antibody landscapes, to analyze the relationship between immune response and antigenic distance between the target H5 vaccine HA and other HAs in the assay after a boosting vaccination. This method improves analysis of immune responses by relating antigen exposure history to the influenza vaccination antibody response. This study also revealed that multiple vaccine boosting over several years can generate high levels of long-lasting cross-reactive antibodies against the priming H5 strains vaccine that subjects received, suggesting the HA imprinting mechanism(s) have a strong influence in the adult antibody response to H5 MIV vaccination.
Poor protection of amphibian evolutionary history reveals opportunities for global protected areas
Authors: Upton Jasmin , Gray Claudia L. , Tapley Benjamin , Murray Kris A. , Gumbs Rikki
Published: October 2020

As habitat loss is a major driver of amphibian population declines, protected areas (PAs) can play a crucial role in amphibian conservation. Documenting how well the global PA network captures the evolutionary history of amphibians can inform conservation prioritisation and action. We conducted a phylogenetic gap analysis to assess the extent to which amphibian phylogenetic diversity (PD) is unprotected by the PA network and compared this to other terrestrial vertebrate groups. 78% of amphibian species and 64% of global amphibian PD remains unprotected, which is higher than corresponding figures for squamates, mammals and birds. Amongst amphibians, salamanders were the least well protected, with 78% of PD unprotected, compared with 64% for caecilians and 63% for frogs. We identify areas that offer the greatest opportunity to capture unprotected amphibian evolutionary history. We could capture an additional 29.4% of amphibian PD, representing 40 billion years of evolutionary history, by protecting an additional 1.9% of global amphibian distributions (1.74% of global land area) and increasing the restrictions in 0.6% of amphibian distributions to match the management objectives of PAs in IUCN categories I or II. Importantly, we found that the spatial distribution of unprotected PD was correlated across all groups, indicating that expanding the PA network to conserve amphibian PD can secure imperilled vertebrate diversity more generally.
Neuroprotective pentapeptide, CN-105, improves outcomes in translational models of intracerebral hemorrhage
Authors: Wang Haichen , Faw Timothy D. , Lin Yufeng , Huang Shan , Venkatraman Talaignair N. , Cantillana Viviana , Lascola Christopher D. , James Michael L. , Laskowitz Daniel T.
Published: October 2020

Background

Intracerebral hemorrhage (ICH) is a devastating form of cerebrovascular disease for which there are no approved pharmacological interventions that improve outcomes. Apolipoprotein E (apoE) has emerged as a promising therapeutic target given its neuroprotective properties and ability to modify neuroinflammatory responses. We developed a 5-amino acid peptide, CN-105, that mimics the polar face of the apoE helical domain involved in receptor interactions, readily crosses the blood-brain barrier, and improves outcomes in well-established preclinical ICH models. In the current study, we investigated the therapeutic potential of CN-105 in translational ICH models that account for hypertensive comorbidity, sex, species, and age.

Methods

In three separate experiments, we delivered three intravenous doses of CN-105 (up to 0.20 mg/kg) or vehicle to hypertensive male BPH/2J mice, spontaneously hypertensive female rats, or 11-month old male mice within 24-hours of ICH. Neuropathological and neurobehavioral outcomes were determined over 3, 7, and 9 days, respectively.

Results

In spontaneously hypertensive male mice, there was a significant dose-dependent effect of CN-105 on vestibulomotor function at 0.05 and 0.20 mg/kg doses (p < 0.05; 95% CI: 0.91 – 153.70 and p < 0.001; 95% CI: 49.54 – 205.62), while 0.20 mg/kg also improved neuroseverity scores (p < 0.05; 95% CI: 0.27 – 11.00) and reduced ipsilateral brain edema (p < 0.05; 95% CI:−0.037 –−0.001). In spontaneously hypertensive female rats, CN-105 (0.05 mg/kg) had a significant effect on vestibulomotor function (p < 0.01; η2= 0.093) and neuroseverity scores (p < 0.05; η2= 0.083), and reduced contralateral edema expansion (p < 0.01; 95% CI:−1.41 –−0.39). In 11-month old male mice, CN-105 had a significant effect on vestibulomotor function (p < 0.001; η2= 0.111) but not neuroseverity scores (p > 0.05; η2= 0.034).

Conclusions

Acute treatment with CN-105 improves outcomes in translational ICH models independent of sex, species, age, or hypertensive comorbidity.
Single-cell joint detection of chromatin occupancy and transcriptome enables higher-dimensional epigenomic reconstructions
Authors: Xiong Haiqing , Luo Yingjie , Wang Qianhao , Yu Xianhong , He Aibin
Published: October 2020

Deciphering mechanisms in cell fate decisions requires single-cell holistic reconstructions of multi-dimensional epigenome in transcriptional regulation. Here we develop CoTECH, a combinatorial barcoding method allowing for high-throughput single-cell joint detection of chromatin occupancy and transcriptome. First, we used CoTECH to examine bivalent histone marks (H3K4me3 and H3K27me3) with transcription from naïve to primed mouse embryonic stem cells. Concurrent bivalent marks in pseudo-single cells linked via transcriptome were computationally derived, resolving pseudotemporal bivalency trajectories and disentangling a context-specific interplay between H3K4me3/H3K27me3 and transcription level. Next, CoTECH with H3K27ac, an active enhancer marker, revealed the regulatory basis of endothelial-to-hematopoietic transition in two waves of hematopoietic cells and distinctive enhancer-gene linking schemes guiding hemogenic endothelial cell (HEC) emergence, indicating a unique epigenetic control of transcriptional regulation for hematopoietic stem cell priming. Together, CoTECH provides an efficient framework for single-cell co-assay of chromatin occupancy and transcription, thus, enabling higher-dimensional epigenomic reconstructions.
Genome sequencing sheds light on the contribution of structural variants toBrassica oleraceadiversification
Authors: Guo Ning , Wang Shenyun , Gao Lei , Liu Yongming , Duan Mengmeng , Wang Guixiang , Li Jingjing , Yang Meng , Zong Mei , Han Shuo , Pei Yanzheng , Borm Theo , Sun Honghe , Miao Liming , Liu Di , Yu Fangwei , Zhang Wei , Ji Heliang , Zhu Chaohui , Xu Yong , Bonnema Guusje , Li Jianbin , Fei Zhangjun , Liu Fan
Published: October 2020

Brassica oleraceaincludes several morphologically diverse, economically important vegetable crops. Here we present high-quality chromosome-scale genome assemblies for twoB. oleraceamorphotypes, cauliflower and cabbage. Direct comparison of these two assemblies identifies ~120 K high-confidence structural variants (SVs). Population analysis of 271B. oleraceaaccessions using these SVs clearly separates different morphotypes, suggesting the association of SVs withB. oleraceaintraspecific divergence. Genes affected by SVs selected between cauliflower and cabbage are enriched with functions related to response to stress and stimulus and meristem and flower development. Furthermore, genes affected by selected SVs and involved in the switch from vegetative to generative growth that defines curd initiation, inflorescence meristem proliferation for curd formation, maintenance and enlargement, are identified, providing insights into the regulatory network of curd development. This study reveals the important roles of SVs in diversification of different morphotypes ofB. oleracea, and the newly assembled genomes and the SVs provide rich resources for future research and breeding.
Persistence of plant-mediated microbial soil legacy effects in soil and inside roots
Authors: Hannula S. Emilia , Heinen Robin , Huberty Martine , Steinauer Katja , De Long Jonathan R. , Jongen Renske , Bezemer T. Martijn
Published: October 2020

Plant-soil feedbacks are shaped by microbial legacies previous plants leave in the soil. We tested the persistence of such soil legacies after subsequent colonization by the same or other plant species, and whether the microbiome created by the previous plant explains current plant growth. Legacies of previous plants were detectable in soil fungal communities several months after their removal while concomitantly the effect of the current plant amplified in time. Remarkably, bacterial legacies faded away rapidly in the soil and bacterial communities were selected strongly by plant currently growing in the soil. Both fungal and bacterial legacies wrought by the previous plant were conserved inside the root endophytic compartment of the current plant and these endophytes affected significantly the plant growth. Hence, microbial soil legacies present at the time of plant establishment play a vital role in shaping plant growth even as the composition gradually changes in the soil after subsequent plant colonization, as they are taken up as endophytes in the plant. This suggests that plant-soil feedbacks may be partly mediated by a relatively stable endophytic community acquired in early ontogeny while the effects of previous plants detected on soil microbiomes vary between organisms studied. We further show that plants growing in their own soils harbor different endophytic microbiomes than plants growing in soils with legacy of other plants and that especially grasses are sensitive to species specific fungal pathogens while all plant species have less endophyticStreptomyceteswhen growing in their own soil. In conclusion, we show that soil legacies wrought by previous plants can remain present in the soils and inside the roots for months, even when subsequent plants colonize the soil and that these legacies also substantially modulate the plant growth.
Improving the sensitivity of differential-expression analyses for under-powered RNA-seq experiments
Authors: Kalinka Alex T.
Published: October 2020

High-throughput studies, in which thousands of hypothesis tests are conducted simultaneously, can be under-powered when effect sizes are small and there are few replicates. Here, I describe an approach to estimate the FDR for a given experiment such that the ground truth is known. A decision boundary between true and false positive calls can then be learned from the data itself along the axes of fold change and expression level. By excluding hits that fall into the false positive space, the FDR of any given method can be controlled providing a means to employ less conservative methods for detecting differential expression without incurring the usual loss of precision. I show that coupling this approach with a feature-selection method - an elastic-net logistic regression - can increase sensitivity 10-fold above what is achievable with the prevailing methods of the day. An R package implementing these methods is available athttps://github.com/alextkalinka/delboy.
Co-evolutionary Distance Prediction for Flexibility Prediction
Authors: Schwarz Dominik , Georges Guy , Kelm Sebastian , Shi Jiye , Vangone Anna , Deane Charlotte M.
Published: October 2020

Co-evolution analysis can be used to accurately predict residue-residue contacts from multiple sequence alignments. The introduction of machine-learning techniques has enabled substantial improvements in precision and a shift from predicting binary contacts to predicting distances between pairs of residues. These developments have significantly improved the accuracy ofde novoprediction of static protein structures. Here we examine the potential of these residue-residue distance predictions to predict protein flexibility rather than static structure. We used DMPfold to predict distance distributions for every residue pair in a set of proteins that showed both rigid and flexible behaviour. Residue pairs that were in contact in at least one reference structure were considered and classified as rigid, flexible or neither. The predicted distance distribution of each residue pair was analysed for local maxima of probability indicating the most likely distance or distances between a pair of residues. The average number of local maxima per residue pair was found to be different between the sets of rigid and flexible residue pairs. Flexible residue pairs more often had multiple local maxima in their predicted distance distribution than rigid residue pairs suggesting that the shape of predicted distance distributions is predictive of rigidity or flexibility of residue pairs.
Autocrine Signaling by Receptor Tyrosine Kinases in Urothelial Carcinoma of the Bladder
Authors: Lee Young H. , Lee Molly M. , De Silva Dinuka M. , Roy Arpita , Wright Cara , Wong Tiffany , Costello Rene , Olaku Oluwole , Grubb Robert L. , Agarwal Piyush K. , Apolo Andrea B. , Bottaro Donald P.
Published: October 2020

Comprehensive characterizations of bladder cancer (BCa) have established molecular phenotype classes with distinct alterations and survival trends. Extending these studies within the tyrosine kinase (TK) family to identify disease drivers could improve our use of TK inhibitors to treat specific patient groups or individuals. We examined the expression distribution of TKs as a class (n = 89) in The Cancer Genome Atlas (TCGA) muscle invasive BCa data set (n >400). Patient profiles of potentially oncogenic alterations (overexpression and/or amplification) clustered TKs into 3 groups; alterations of group 1 and 3 TKs were associated with significantly worse patient survival relative to those without alterations. Many TK pathways induce epithelial-to-mesenchymal transition (EMT), which promotes tumor invasiveness and metastasis. Overexpression and/or amplification among 9 EMT transcriptional activators occurred in 43% of TCGA cases. Co-occurring alterations of TKs and EMT transcriptional activators involved most group 1 TKs; 24% of these events were associated with significantly worse patient survival. Co-occurring alterations of receptor TKs and their cognate ligands occurred in 16% of TCGA cases and several BCa-derived cell lines. Suppression of GAS6, MST1 or CSF1, or their respective receptors (AXL, MST1R and CSF1R), in BCa cell lines was associated with decreased receptor activation, cell migration, cell proliferation and anchorage independent cell growth. These studies reveal the patterns and prevalence of potentially oncogenic TK pathway-related alterations in BCa and identify specific alterations associated with reduced BCa patient survival. Detection of these features in BCa patients could better inform TK inhibitor use and improve clinical outcomes.
DOT1L primarily acts as a transcriptional repressor in hematopoietic progenitor cells
Authors: Borosha Shaon , Ratri Anamika , Housami Sami M. , Rai Shubham , Ghosh Subhra , Malcom Carrie A. , Chakravarthi V. Praveen , Vivian Jay L. , Fields Timothy A. , Rumi M.A. Karim , Fields Patrick E.
Published: October 2020

DOT1L is essential for early hematopoiesis but the precise mechanisms remain largely unclear. The only known function of DOT1L is histone H3 lysine 79 (H3K79) methylation. We generated two mouse models; aDot1L-knockout (Dot1L-KO), and another possessing a point mutation in its methyltransferase domain (Dot1L-MM) to determine the role of its catalytic activity during early hematopoiesis. We observed thatDot1L-KO embryos suffered from severe anemia, whileDot1L-MM embryos showed minimal to no anemia. However,ex vivoculture ofDot1L-MM hematopoietic progenitors (HPCs) exhibited defective development of myeloid and mixed progenitors. DOT1L is a well-recognized, cell-type specific epigenetic regulator of gene expression. To elucidate the mechanisms underlying such diverse hematopoietic properties ofDot1L-KO andDot1L-MM HPCs, we examined their whole transcriptomes. Extensively self-renewing erythroblast (ESRE) cultures were established using yolk sac (YS) cells collected on embryonic day 10.5 (E10.5).Dot1l-KO andDot1l-MM cells expanded significantly less than the wildtype cells and showed slower progression through the cell cycle. Total RNA extracted from the wildtype andDot1l-mutant ESRE cells were subjected to RNA-seq analyses. We observed that the majority (~82%) of the differentially expressed genes (DEGs) were upregulated in both of theDot1L-mutants, which suggests that DOT1L predominantly acts as a transcriptional repressor in HPCs. We also observed that about ~40% of the DEGs were unique to either of the mutant group, suggesting that DOT1L possesses both methyltransferase domain-dependent and -independent functions. We further analyzed Gene Ontology and signaling pathways relevant to the DEGs common to both mutant groups and those that were unique to either group. Among the common DEGs, we observed upregulation of CDK inhibitors, which explains the cell cycle arrest in both of theDot1L-mutant progenitors.
High-throughput transcriptomic analysis of human primary hepatocyte spheroids exposed to per- and polyfluoroalkyl substances (PFAS) as a platform for relative potency characterization
Authors: Rowan-Carroll A. , Reardon A. , Leingartner K. , Gagné R. , Williams A. , Meier M.J. , Kuo B. , Bourdon-Lacombe J. , Moffat I. , Carrier R. , Nong A. , Lorusso L. , Ferguson S.S. , Atlas E. , Yauk C.
Published: October 2020

Per- and poly-fluoroalkyl substances (PFAS) are widely found in the environment because of their extensive use and persistence. Although several PFAS are well studied, most lack toxicity data to inform human health hazard and risk assessment. This study focussed on four model PFAS: perfluorooctanoic acid (PFOA; 8 carbon), perfluorobutane sulfonate (PFBS; 4 carbon), perfluorooctane sulfonate (PFOS; 8 carbon), and perfluorodecane sulfonate (PFDS; 10 carbon). Human primary liver cell spheroids (pooled from 10 donors) were exposed to 10 concentrations of each PFAS and analyzed at four time-points. The approach aimed to: (1) identify gene expression changes mediated by the PFAS; (2) identify similarities in biological responses; (3) compare PFAS potency through benchmark concentration analysis; and (4) derive bioactivity exposure ratios (ratio of the concentration at which biological responses occur, relative to daily human exposure). All PFAS induced transcriptional changes in cholesterol biosynthesis and lipid metabolism pathways, and predicted PPARα activation. PFOS exhibited the most transcriptional activity and had a highly similar gene expression profile to PFDS. PFBS induced the least transcriptional changes and the highest benchmark concentration (i.e., was the least potent). The data indicate that these PFAS may have common molecular targets and toxicities, but that PFOS and PFDS are the most similar. The transcriptomic bioactivity exposure ratios derived here for PFOA and PFOS were comparable to those derived using rodent apical endpoints in risk assessments. These data provide a baseline level of toxicity for comparison with other known PFAS using this testing strategy.
Numerical Uncertainty in Analytical Pipelines Lead to Impactful Variability in Brain Networks
Authors: Kiar Gregory , Chatelain Yohan , Castro Pablo de Oliveira , Petit Eric , Rokem Ariel , Varoquaux Gaël , Misic Bratislav , Evans Alan C. , Glatard Tristan
Published: October 2020

The analysis of brain-imaging data requires complex processing pipelines to support findings on brain function or pathologies. Recent work has shown that variability in analytical decisions, small amounts of noise, or computational environments can lead to substantial differences in the results, endangering the trust in conclusions1-7. We explored the instability of results by instrumenting a connectome estimation pipeline with Monte Carlo Arithmetic8,9to introduce random noise throughout. We evaluated the reliability of the connectomes, their features10,11, and the impact on analysis12,13. The stability of results was found to range from perfectly stable to highly unstable. This paper highlights the potential of leveraging induced variance in estimates of brain connectivity to reduce the bias in networks alongside increasing the robustness of their applications in the classification of individual differences. We demonstrate that stability evaluations are necessary for understanding error inherent to brain imaging experiments, and how numerical analysis can be applied to typical analytical workflows both in brain imaging and other domains of computational science. Overall, while the extreme variability in results due to analytical instabilities could severely hamper our understanding of brain organization, it also leads to an increase in the reliability of datasets.
Design of SARS-CoV-2 RBD mRNA Vaccine Using Novel Ionizable Lipids
Authors: Elia Uri , Ramishetti Srinivas , Dammes Niels , Bar-Haim Erez , Naidu Gonna Somu , Makdasi Efi , Cohen Ofer , Peer Dan
Published: October 2020

The novel coronavirus SARS-CoV-2 has been identified as the causal agent of COVID-19 and stands at the center of the current global human pandemic, with death toll exceeding one million. The urgent need for a vaccine has led to the development of various immunization approaches. mRNA vaccines represent a cell-free, simple and rapid platform for immunization, and therefore have been employed in recent studies towards the development of a SARS-CoV-2 vaccine. In this study, we present the design of a lipid nanoparticles (LNP)-encapsulated receptor binding domain (RBD) mRNA vaccine. Several ionizable lipids have been evaluatedin vivoin a luciferase mRNA reporter assay, and two leading LNPs formulation have been chosen for the subsequent RBD mRNA vaccine experiment. Intramuscular administration of LNP RBD mRNA elicited robust humoral response, high level of neutralizing antibodies and a Th1-biased cellular response in BALB/c mice. These novel lipids open new avenues for mRNA vaccines in general and for a COVID19 vaccine in particular.
Multiple glacial refugia across northern and southern China and unexpected patterns of spatial genetic diversity inBetula albosinensis: a widespread temperate deciduous tree species
Authors: Liu Lu , Gougherty Andrew V. , Ding Junyi , Li Kun , Wang Wenting , Wang Luwei , Wang Feifei , Wang Nian
Published: October 2020

The central-marginal hypothesis (CMH) predicts high genetic diversity at the species’ geographic centre and low genetic diversity at the species’ geographic margins. However, most studies examining the CMH have neglected potential effect of past climate. Here, we test six hypotheses, representing effects of past climate and contemporary range position, for their ability to explain the spatial patterns of genetic diversity in 37 populations ofBetula albosinensis. Ecological niche modelling (ENM) revealed large and continuous suitable habitats in north, southwest and southeast China during the last glacial maximum (LGM) but a contraction of suitable habitats since the LGM. Pollen records further confirmed the existence of multiple refugia in north and south China. The spatial pattern of genetic diversity (i.e., expected heterozygosity, gene diversity and allele richness) were best explained by distance to the southern edge and distance to the range edge but also showed longitudinal and latitudinal gradients. Hypotheses accounting for the effects of climate (climatic suitability, climatic stability and climatic variability) had comparatively little support. Our findings show partial support for the CMH and illustrates that the existence of multiple LGM refugia, and suggests species abundance and past species movement play a role in shaping genetic diversity across species’ ranges.