bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictive visuo-motor communication through neural oscillations
Authors: Benedetto Alessandro , Binda Paola , Costagli Mauro , Tosetti Michela , Morrone Maria Concetta
Published: July 2020

The mechanisms coordinating action and perception over time are poorly understood. The sensory cortex needs to prepare for upcoming changes contingent on action, and this requires temporally precise communication that takes into account the variable delays between sensory and motor processing. Several theorists1,2have proposed synchronization of the endogenous oscillatory activity observed in most regions of the brain3as the basis for an efficient and flexible communication protocol between distal brain areas2,4, a concept known as “communication through coherence”. Synchronization of endogenous oscillations5,6occurs after a salient sensory stimulus, such as a flash or a sound7–11, and after a voluntary action12–18, and this impacts directly on perception, causing performance to oscillate rhythmically over time. Here we introduce a novel fMRI paradigm to probe the neural sources of oscillations, based on the concept of perturbative signals, which overcomes the low temporal resolution of BOLD signals. The assumption is that a synchronized endogenous rhythm will modulate cortical excitability rhythmically, which should be reflected in the BOLD responses to brief stimuli presented at different phases of the oscillation cycle. We record rhythmic oscillations of V1 BOLD synchronized by a simple voluntary action, in phase with behaviourally measured oscillations in visual sensitivity in the theta range. The functional connectivity between V1 and M1 also oscillates at the same rhythm. By demonstrating oscillatory temporal coupling between primary motor and sensory cortices, our results strongly implicate communication through coherence to achieve precise coordination and to encode sensory-motor timing.
Unimodal effects of pigment richness on niche and fitness differences explain species richness and ecosystem function in light-limited phytoplankton communities
Authors: Spaak Jurg Werner , De Laender Frederik
Published: July 2020

Trait diversity is traditionally seen as promoting species richness and ecosystem function. Species with dissimilar traits would partition available resources, increasing niche differences, facilitating coexistence and increasing ecosystem function. Here we first show, using theory and simulations for light-limited phytoplankton, that combing photosynthetic pigments is indeed a necessary condition for coexistence and stimulates ecosystem function. However, pigment richness does mostly not permit the coexistence of more than two species, and increases productivity at most 60% compared to single-pigment communities. Surprisingly, combining all nine pigments known to date leads to a 2.5% probability that four species would coexist, illustrating that the coexistence of a high number of species along a continuous niche axis is constrained by limiting similarity. We explain these constraints by unimodal effects of pigment richness on niche and fitness differences, which jointly limit the positive effect of pigment on species richness. Empirical data and additional simulations suggest that pigment richness effects can be stronger during transient dynamics but inevitably weaken with time, i.e. pigment richness effects on species richness and function are likely short-lived. Our results highlight the need to apply coexistence theory to understand the long-term effects of trait diversity on biodiversity and ecosystem function.

Statement of authorship

J.W.S. and F.dL. developed the ideas and wrote the manuscript. J.W.S developed the mathematics and the python code to conduct the study. J.W.S conducted the literature review.
MAGIC: A label-free fluorescence method for 3D high-resolution reconstruction of myelinated fibers in large volumes
Authors: Costantini Irene , Baria Enrico , Sorelli Michele , Matuschke Felix , Giardini Francesco , Menzel Miriam , Mazzamuto Giacomo , Silvestri Ludovico , Cicchi Riccardo , Amunts Katrin , Axer Markus , Pavone Francesco Saverio
Published: July 2020

Analyzing the structure of neuronal fibers with single axon resolution, in large volumes, remains an unresolved challenge in connectomics. Here, we propose MAGIC (Myelin Autofluorescence imaging by Glycerol Induced Contrast enhancement), a simple tissue preparation method to perform label-free fluorescence imaging of myelinated fibers. We demonstrate its broad applicability by performing mesoscopic reconstruction at sub-micron resolution of mouse, rat, monkey, and human brain samples and by quantifying the different fiber organization in Control and Reeler mouse’s hippocampal sections.
Confirmation bias is adaptive when coupled with efficient metacognition
Authors: Rollwage Max , Fleming Stephen M.
Published: July 2020

Biases in the consideration of evidence can reduce the chances of consensus between people with different viewpoints. While such altered information processing typically leads to detrimental performance in laboratory tasks, the ubiquitous nature of confirmation bias makes it unlikely that selective information processing is universally harmful. Here we suggest that confirmation bias is adaptive to the extent that agents have good metacognition, allowing them to downweight contradictory information when correct but still able to seek new information when they realise they are wrong. Using simulation-based modelling, we explore how the adaptiveness of holding a confirmation bias depends on such metacognitive insight. We find that the behavioural consequences of selective information processing are systematically affected by agents’ introspective abilities. Strikingly, we find that selective information processing can even improve decision-making when compared to unbiased evidence accumulation, as long as it is accompanied by good metacognition. These results further suggest that interventions which boost people’s metacognition might be efficient in alleviating the negative effects of selective information processing on issues such as political polarisation.
Generalizing HMMs to Continuous Time for Fast Kinetics: Hidden Markov Jump Processes
Authors: Kilic Zeliha , Sgouralis Ioannis , Pressé Steve
Published: July 2020

The hidden Markov model (HMM) is a framework for time series analysis widely applied to single molecule experiments. It has traditionally been used to interpret signals generated by systems, such as single molecules, evolving in a discrete state space observed at discrete time levels dictated by the data acquisition rate. Within the HMM framework, originally developed for applications outside the Natural Sciences, such as speech recognition, transitions between states, such as molecular conformational states, are modeled as occurring at the end of each data acquisition period and are described using transition probabilities. Yet, while measurements are often performed at discrete time levels in the Natural Sciences, physical systems evolve in continuous time according to transition rates. It then follows that the modeling assumptions underlying the HMM are justified if the transition rates of a physical process from state to state are small as compared to the data acquisition rate. In other words, HMMs apply to slow kinetics. The problem is, as the transition rates are unknown in principle, it is unclear,a priori, whether the HMM applies to a particular system. For this reason, we must generalize HMMs for physical systems, such as single molecules, as these switch between discrete states incontinuous time. We do so by exploiting recent mathematical tools developed in the context of inferring Markov jump processes and propose the hidden Markov jump process (HMJP). We explicitly show in what limit the HMJP reduces to the HMM. Resolving the discrete time discrepancy of the HMM has clear implications: we no longer need to assume that processes, such as molecular events, must occur on timescales slower than data acquisition and can learn transition rates even if these are on the same timescale or otherwise exceed data acquisition rates.
Deconvolution of cellular subsets in human tissue based on targeted DNA methylation analysis at individual CpG sites
Authors: Schmidt Marco , Maié Tiago , Dahl Edgar , Costa Ivan G. , Wagner Wolfgang
Published: July 2020

Background

The complex composition of different cell types within a tissue can be estimated by deconvolution of omics datasets. For example, DNA methylation (DNAm) profiles have been used to establish an atlas for multiple human tissues and cell types. In this study, we investigated if deconvolution is also feasible with individual cell-type-specific CG dinucleotides (CpG sites), which can be addressed by targeted analysis, such as pyrosequencing.

Results

We compiled and curated a dataset of 579 samples from Illumina 450k BeadChip technology that comprised 14 different purified and characterized human cell types. A training and validation strategy was applied to identify and test cell-type-specific CpGs. Initially, the amount of fibroblasts was estimated using two CpGs that were either hypermethylated or hypomethylated in fibroblasts. This FibroScore correlated with the state of fibrosis and was associated with overall survival in various types of cancer. Furthermore, we identified hypomethylated CpGs for leukocytes, endothelial cells, epithelial cells, hepatocytes, glia, neurons, fibroblasts and induced pluripotent stem cells. Using previously published BeadChip datasets with cell mixtures the accuracy of this eight CpG signature was comparable to previously published signatures based on several thousand CpGs. Finally, we established and validated pyrosequencing assays for the relevant CpGs that can be utilized for classification and deconvolution of cell types.

Conclusion

This proof of concept study demonstrates that DNAm analysis at individual CpGs reflects the cellular composition of cellular mixtures and different tissues. Targeted analysis of these genomic regions facilitates robust methods for application in basic research and clinical settings.
Unsupervised analysis of multi-experiment transcriptomic patterns with SegRNA identifies unannotated transcripts
Authors: Mendez Mickaël ,   FANTOM Consortium Main Contributors, Scott Michelle S. , Hoffman Michael M.
Published: July 2020

Background

Exploratory analysis of complex transcriptomic data presents multiple challenges. Many methods often rely on preexisting gene annotations, impeding identification and characterization of new transcripts. Even for a single cell type, comprehending the diversity of RNA species transcribed at each genomic region requires combining multiple datasets, each enriched for specific types of RNA. Currently, examining combinatorial patterns in these data requires time-consuming visual inspection using a genome browser.

Method

We developed a new segmentation and genome annotation (SAGA) method, SegRNA, that integrates data from multiple transcriptome profiling assays. SegRNA identifies recurring combinations of signals across multiple datasets measuring the abundance of transcribed RNAs. Using complementary techniques, SegRNA builds on the Segway SAGA framework by learning parameters from both the forward and reverse DNA strands. SegRNA’s unsupervised approach allows exploring patterns in these data without relying on pre-existing transcript models.

Results

We used SegRNA to generate the first unsupervised transcriptome annotation of the K562 chronic myeloid leukemia cell line, integrating multiple types of RNA data. Combining RNA-seq, CAGE, and PRO-seq experiments together captured a diverse population of RNAs throughout the genome. As expected, SegRNA annotated patterns associated with gene components such as promoters, exons, and introns. Additionally, we identified a pattern enriched for novel small RNAs transcribed within intergenic, intronic, and exonic regions. We applied SegRNA to FANTOM6 CAGE data characterizing 285 lncRNA knockdowns. Overall, SegRNA efficiently summarizes diverse multi-experiment data.
Substrate-induced clustering activates Trim-Away of pathogens and proteins
Authors: Zeng Jingwei , Santos Ana Filipa , Mukadam Aamir , Osswald Mariana , Luptak Jakub , Jacques David , Dickson Claire , Renner Nadine , Johnson Chris , Vaysburd Marina , McEwan William A. , Morais-de-Sá Eurico , Clift Dean , James Leo C.
Published: July 2020

Trim-Away is a powerful new technology that exploits off-the-shelf antibodies and the E3 RING ligase and cytosolic antibody receptor TRIM21 to carry out rapid protein depletion. How TRIM21 is catalytically-activated upon substrate engagement during either its normal immune function or when re-purposed for targeted protein degradation is unknown. Here we show that a mechanism of substrate-induced clustering triggers intermolecular dimerization of the RING domain to switch on the ubiquitination activity of TRIM21 and induce an antiviral response or drive Trim-Away. We harness this mechanism to expand the Trim-Away toolbox with highly-active TRIM21-nanobody chimeras that can also be controlled optogenetically. This work provides a mechanism for cellular activation of TRIM RING ligases and has important implications for targeted protein degradation technologies.
Association of Metabolic and DNA-repair gene polymorphisms with Longevity: a role forGSTT1, GSTPandXPCgenes
Authors: Scarfò Manuel , Sciandra Chiara , Santovito Alfredo
Published: July 2020

Aging and longevity are complex processes controlled at different levels, including genetic level. We evaluated the association of seven drug and DNA-repair gene polymorphisms with longevity in an Italian cohort. A sample of 756 subjects aged 18-98 was genotyped forCYP1A1 exon 7 A>G, GSTT1 null, GSTM1 null, GSTP A>G, XRCC1exon 6 C>T, XRCC1 exon 9 A> G and XPC exon 15 A>C gene polymorphisms. The association between the analyzed gene polymorphisms and longevity was evaluated by dividing the sample into three age groups: 10-50, 51-85, and 86-98.

We observed a significant decrease in the frequency of theGSTT1null,GSTPG andXPCC alleles in the oldest group with respect to the youngest one and with respect to 51-85 age group. We obtained the same results also subdividing the sample into 1-85 and 86-98 age groups. The general linear model analyses confirmed a significant decreasing trend of the above mentioned alleles with age. We hypothesized that these minor alleles, being important in the sensitivity against the development of different types of cancer, may reflect a reduced life-expectancy in carrier subjects and may explain their significantly lower frequency observed among subjects belonging to oldest age group.
Peripheral voltage-gated calcium channels in skin are essential for transient neurogenic thermal hyperalgesia in mice
Authors: DuBreuil Daniel M , Soto Eduardo Javier Lopez , Li Daniel , Lipscombe Diane
Published: July 2020

Voltage-gated CaV2.2 calcium channels are expressed in nociceptors, at pre-synaptic terminals, soma, and axons. CaV2.2 channel inhibitors applied to the spinal cord relieve pain in humans and rodents, especially during pathological pain, but a biological function of nociceptor CaV2.2 channels in processing of nociception, outside pre-synaptic terminals, is not explored. Here, we demonstrate that functional CaV2.2 channels in skin are required for thermal hyperalgesia following intraplantar capsaicin exposure. We provide evidence that CaV2.2 channels at nociceptor free endings release inflammatory signals, ATP and IL-1β. We assess the role of CaV2.2 splice isoforms to capsaicin-induced hyperalgesia measured by thermal and mechanical stimuli. Our data reveal a critical role for peripheral CaV2.2 channels in skin in neurogenic thermal hyperalgesia but not in mechanical hypersensitivity. Inhibition, or the complete lack, of peripheral CaV2.2 channels blunts the hyperalgesia responsein vivo.
Maize brace roots provide stalk anchorage
Authors: Reneau Jonathan W. , Khangura Rajdeep S. , Stager Adam , Erndwein Lindsay , Weldekidan Teclemariam , Cook Douglas D. , Dilkes Brian P. , Sparks Erin E.
Published: July 2020

Mechanical failure, known as lodging, negatively impacts yield and grain quality in crops. Limiting crop loss from lodging requires an understanding of the plant traits that contribute to lodging-resistance. In maize, specialized aerial brace roots are reported to reduce root lodging. However, their direct contribution to plant biomechanics has not been measured. In this manuscript, we find that brace roots establish a rigid base (i.e. stalk anchorage) to limit plant deflection in maize. The more brace root whorls that contact the soil, the greater the contribution of brace roots to anchorage. Previous studies have linked the number of brace root whorls to flowering time in maize. To determine if flowering time selection alters the brace root contribution to anchorage, a subset of the Hallauer’s Tusón tropical population was analyzed. Despite a significant change in flowering time, selection neither altered the number of brace root whorls in the soil nor the overall contribution of brace roots to anchorage. These results demonstrate that brace roots provide a rigid base in maize, but the contribution to anchorage is not linearly related to flowering time.
Long-range coupled motions underlie ligand recognition by a chemokine receptor
Authors: Sepuru Krishna Mohan , Nair Vinay , Prakash Priyanka , Gorfe Alemayehu A. , Rajarathnam Krishna
Published: July 2020

Chemokines are unusual class-A GPCR agonists because of their large size (∼10 kDa) and binding at two distinct receptor sites: N-terminal domain (Site-I, unique to chemokines) and a groove defined by extracellular loop/transmembrane helices (Site-II, shared with all small molecule class-A ligands). Whereas binding at Site-II triggers receptor activation, the role of Site-I is not known. Structures and sequence analysis reveal that the receptor N-terminal domains (N-domains) are flexible and contain intrinsic disorder. Using a hybrid NMR-MD approach, we characterized the role of Site-I interactions for the CXCL8-CXCR1 pair. NMR data indicate that the CXCR1 N-domain becomes structured on binding and that the binding interface is extensive with 30% of CXCL8 residues participating in this initial interaction. MD simulations indicate that CXCL8 bound at Site-I undergoes extensive reorganization on engaging Site-II with several residues initially engaged at Site-I also engaging Site-II. We conclude that structural plasticity of Site-I interactions plays an active role in driving ligand recognition by a chemokine receptor.
Role of substrate recognition in modulating strigolactone receptor selectivity in witchweed
Authors: Chen Jiming , White Alexandra , Nelson David C. , Shukla Diwakar
Published: July 2020

Witchweed, or Strigahermonthica, is a parasitic weed that destroys billions of dollars worth of crops globally every year. Its germination is stimulated by strigolactones exuded by its host plants. Despite high sequence, structure, and ligand binding site conservation across different plant species, one strigolactone receptor in witchweed (ShHTL7) uniquely exhibits a picomolar EC50 for downstream signaling. Previous biochemical and structural analyses have hypothesized that this unique ligand sensitivity can be attributed to a large binding pocket volume inShHTL7 resulting in enhanced ability to bind substrates. Additional structural details of the substrate binding process can help explain its role in modulating the ligand selectivity. Using long-timescale molecular dynamics simulations, we demonstrate that mutations at the entrance of the binding pocket facilitate a more direct ligand binding pathway toShHTL7, whereas hydrophobicity at the binding pocket entrance results in a stable “anchored” state. We also demonstrate that several residues on the D-loop ofAtD14 stabilize catalytically inactive conformations. Finally, we show that strigolactone selectivity is not modulated by binding pocket volume. Our results indicate that while ligand binding is not the sole modulator of strigolactone receptor selectivity, it is a significant contributing factor. These results can be used to inform the design of selective antagonists for strigolactone receptors in witchweed.
Metabolism of glucose and glutamine is critical for skeletal muscle stem cell activation
Authors: Ahsan Sanjana , Raval Manmeet H. , Ederer Maxwell , Tiwari Rajiv , Chareunsouk Andrew , Rodgers Joseph T.
Published: July 2020

Injury to muscle tissue induces the resident, quiescent, skeletal muscle stem cells (MuSCs) to activate - to exit quiescence and enter the cell cycle. Previous work has shown that MuSC activation is associated with significant metabolic changes, however the substrates that MuSCs consume to support activation are poorly understood. Here, we show that MuSCs generate the majority of their energy through mitochondrial respiration, and that oxidative phosphorylation is required for MuSC activation. Furthermore, we have found that while glucose, glutamine, and fatty acids all significantly, and roughly equally, contribute to ATP production in MuSCs during activation, they do not have equal functional role in the dynamics of MuSC activation. Pharmacologic suppression of glycolysis, using 2-deoxy-D-glucose, or glutaminolysis, using BPTES, significantly impairs MuSC cell cycle entry. However, etomoxir-mediated inhibition of mitochondrial fatty acid transport has minimal effect on MuSC cell cycle progression. Our findings suggest that apart from their roles in fueling ATP production by the mitochondria, glucose and glutamine may generate metabolic intermediates needed for MuSC activation.
Mechanisms involved in the production of differently colored feathers in the structurally-colored Swallow Tanager (Tersina viridis; Aves: Thraupidae)
Authors: Bazzano Tomás , Lucas Mendicino , Inchaussandague Marina E. , Skigin Diana C. , García Natalia C. , Tubaro Pablo L. , Barreira Ana S.
Published: July 2020

Non-iridescent, structurally-based coloration in birds originates from the feather’s internal nanostructure (the keratin spongy matrix), but the presence of melanin and the characteristics of the barb’s cortex can affect the resulting color. Here we investigate how this nanostructure is regulated and combined with other elements in differently-colored plumage patches. To do so, we investigated the association between light reflectance and the morphology of feathers from the back and belly plumage patches of male Swallow Tanagers (Tersina viridis), which look greenish-blue and white, respectively. Both plumage patches have a reflectance peak around 550 nm, but the reflectance spectrum is much less saturated in the belly. The barbs of both types of feathers have similar spongy matrices at their tips which produce similar reflectance spectra. However, the color of the belly feather barbs changes from light green at the tip to white closer to the rachis. These barbs lack pigments and their morphology changes considerably: the spongy matrix is reduced, being almost hollow, and has a different shape towards the rachis. Instead, we observed deposition of melanin underneath the spongy matrix in the back feathers which had a much saturated coloration that was consistent along the barbs’ length. Overall, our results suggest that the color differences between the white and greenish-blue plumage are mostly due to the differential deposition of melanin and a reduction of the spongy matrix in some parts of the belly feather barbs, and not a result of changes in the periodicity of the spongy matrix.
SMAD2 Promotes Myogenin Expression and Terminal Myogenic Differentiation
Authors: Lamarche Émilie , AlSudais Hamood , Rajgara Rashida , Fu Dechen , Omaiche Saadeddine , Wiper-Bergeron Nadine
Published: July 2020

SMAD2 is a transcription factor whose activity is regulated by members of the Transforming Growth Factor beta (TGFβ) superfamily. While activation of SMAD2 and SMAD3 downstream of TGFβ or myostatin signaling is known to inhibit myogenesis, we find that SMAD2 in the absence of TGFβ signaling promotes terminal myogenic differentiation. We find that during myogenic differentiation, SMAD2 expression is induced. Knockout of SMAD2 expression in primary myoblasts did not affect the efficiency of myogenic differentiation but produced smaller myotubes with reduced expression of the terminal differentiation marker myogenin. Conversely, overexpression of SMAD2 stimulated myogenin expression, and enhanced both differentiation and fusion, and these effects were independent of classical activation by the TGFβ receptor complex. Loss ofSmad2in muscle satellite cellsin vivoresulted in decreased muscle fiber caliber and impaired regeneration after acute injury. Taken together, we demonstrate that SMAD2 is an important positive regulator of myogenic differentiation, in part through the regulation ofMyog.

SUMMARY STATEMENT

TGFβ and SMAD2 are normally associated with inhibition of myogenesis. Our work identifies a pro-myogenic role for SMAD2 during terminal myogenic differentiation, through regulation ofMyogandKlf4expression.
Environmental fluctuations reshape an unexpected diversity-disturbance relationship in a microbial community
Authors: Mancuso Christopher P. , Lee Hyunseok , Abreu Clare I. , Gore Jeff , Khalil Ahmad S.
Published: July 2020

Environmental disturbances have long been theorized to play a significant role in shaping the diversity and composition of ecosystems1,2. However, fundamental limitations in our ability to specify the characteristics of a disturbance in the field and laboratory have produced an inconsistent picture of diversity-disturbance relationships (DDRs) that shape the structure of ecosystems3. Here, using a recently developed continuous culture system with tunable environmental control4, we decomposed a dilution disturbance into intensity and fluctuation components5,6, and tested their effects on the diversity of a soil-derived bacterial community across hundreds of replicate cultures. We observed an unexpected U-shaped relationship between community diversity and disturbance intensity in the absence of fluctuations, an observation counter to classical intuition. Adding fluctuations erased the U-shape and increased community diversity across all disturbance intensities. All of these results are well-captured by a Monod consumer resource model, which further reveals how U-shaped DDRs emerge based on a novel “niche flip” mechanism in which competitive outcomes flip and coexistence regimes subsequently collapse at intermediate disturbance levels. Broadly, our results demonstrate how distinct features of an environmental disturbance can interact in complex ways to govern ecosystem assembly and produce all the major classes of DDRs, without invoking other organizational principles. With these findings, we construct a unifying framework that reconciles the disparate DDRs observed in nature, and propose strategies for predictively reshaping the compositional complexity of microbiomes and other ecosystems.
Direct exposure to SARS-CoV-2 and cigarette smoke increases infection severity and alters the stem cell-derived airway repair response
Authors: Purkayastha Arunima , Sen Chandani , Garcia Gustavo , Langerman Justin , Vijayaraj Preethi , Shia David W. , Meneses Luisa K. , Rickabaugh Tammy M. , Mulay A. , Konda B. , Sim Myung S. , Stripp Barry R. , Plath Kathrin , Arumugaswami Vaithilingaraja , Gomperts Brigitte N.
Published: July 2020

Most demographic studies are now associating current smoking status with increased risk of severe COVID-19 and mortality from the disease but there remain many questions about how direct cigarette smoke exposure affects SARS-CoV-2 airway cell infection. We directly exposed mucociliary air-liquid interface (ALI) cultures derived from primary human nonsmoker airway basal stem cells (ABSCs) to short term cigarette smoke and infected them with live SARS-CoV-2. We found an increase in the number of infected airway cells after cigarette smoke exposure as well as an increased number of apoptotic cells. Cigarette smoke exposure alone caused airway injury that resulted in an increased number of ABSCs, which proliferate to repair the airway. But we found that acute SARS-CoV-2 infection or the combination of exposure to cigarette smoke and SARS-CoV-2 did not induce ABSC proliferation. We set out to examine the underlying mechanism governing the increased susceptibility of cigarette smoke exposed ALI to SARS-CoV-2 infection. Single cell profiling of the cultures showed that infected airway cells displayed a global reduction in gene expression across all airway cell types. Interestingly, interferon response genes were induced in SARS-CoV-2 infected airway epithelial cells in the ALI cultures but smoking exposure together with SARS-CoV-2 infection reduced the interferon response. Treatment of cigarette smoke-exposed ALI cultures with Interferon β-1 abrogated the viral infection, suggesting that the lack of interferon response in the cigarette smoke-exposed ALI cultures allows for more severe viral infection and cell death. In summary, our data show that acute smoke exposure allows for more severe proximal airway epithelial disease from SARS-CoV-2 by reducing the mucosal innate immune response and ABSC proliferation and has implications for disease spread and severity in people exposed to cigarette smoke.
Estimating missing deaths in Delhi’s COVID-19 data
Authors: Chakravarty Shoibal
Published: July 2020

A sero-prevalence survey in Delhi measured an infection rate of 23.48% and an implied infection fatality rate (IFR) of 0.06%. Modeling using age group based IFRs from France, Spain and Lombardia project an average IFR that is significantly higher than currently estimated. We show that at least 1500-2500 COVID-19 deaths in the 60+ age group are missing.
Per1/Per2-Igf2 axis-mediated circadian regulation of myogenic differentiation
Authors: Katoku-Kikyo Nobuko , Paatela Ellen , Houtz Daniel L. , Lee Britney , Munson Dane , Wang Xuerui , Hussein Mohammed , Bhatia Jasmeet , Lim Seunghyun , Yuan Ce , Asakura Yoko , Asakura Atsushi , Kikyo Nobuaki
Published: July 2020

Circadian rhythms regulate cell proliferation and differentiation but circadian control of tissue regeneration remains elusive at the molecular level. Here, we show that proper myoblast differentiation and muscle regeneration are regulated by the circadian master regulators Per1 and Per2. Depletion of Per1 or Per2 suppressed myoblast differentiationin vitroand muscle regenerationin vivo, demonstrating their non-redundant functions. Both Per1 and Per2 were required for the activation ofIgf2, an autocrine promoter of myoblast differentiation, accompanied by Per-dependent recruitment of RNA polymerase II, dynamic histone modifications at theIgf2promoter and enhancer, and the promoter-enhancer interaction. This circadian epigenetic priming created a preferred time window for initiating myoblast differentiation. Consistently, muscle regeneration was faster if initiated at night whenPer1,Per2, andIgf2were highly expressed compared with morning. This study reveals the circadian timing as a significant factor for effective muscle cell differentiation and regeneration.

eTOC Summary

Katoku-Kikyo et al. show that the circadian master regulators Per1 and Per2 control the efficiency of myoblast differentiation via Igf2 activation. This pathway creates a preferred circadian time window for myoblast differentiationin vitroand muscle regenerationin vivo.
Prediction of drug-protein interaction and drug repositioning using machine learning model
Authors: Lin Yu-Ting , Sheu Sheh-Yi , Lin Chen-Ching
Published: July 2020

Background

Traditional drug development is time-consuming and expensive, while computer-aided drug repositioning can improve efficiency and productivity. In this study, we proposed a machine learning pipeline to predict the binding interaction between proteins and marketed or studied drugs. We then extended the predicted interactions to construct a protein network that could be applied to discover the potentially shared drugs between proteins and thus predict drug repositioning.

Methods

Binding information between proteins and drugs from the Binding Database and the physicochemical properties of drugs from the ChEMBL database were used to build the machine learning models, i.e. support vector regression. We further measured proportionalities between proteins by the predicted binding affinity and introduced edge betweenness centrality to construct a protein similarity network for drug repositioning.

Results

As the proof of concept, we demonstrated our machine learning approach is capable of reflecting the binding strength between drugs and the target protein. When comparing coefficients of protein models, we found proteins SYUA and TAU that may share common ligand which were not in our training data. Using the edge betweenness centrality network based on the prediction proportionality of protein models, we found a potential target, AK1C2, of aspirin and of which the binding interaction had been validated.

Conclusions

Our study could not only be applied to drug repositioning by comparing protein models or searching the protein-protein network, but also to predict the binding strength once the sufficient experimental data was provided to train the protein models.
Heparin as an Anti-Inflammatory Agent
Authors: Litov Leandar , Petkov Peicho , Rangelov Miroslav , Ilieva Nevena , Lilkova Elena , Todorova Nadezhda , Krachmarova Elena , Malinova Kristina , Gospodinov Anastas , Hristova Rossitsa , Ivanov Ivan , Nacheva Genoveva
Published: July 2020

Timely control of the cytokine release syndrome (CRS) at the severe stage of COVID-19 is key to improving the treatment success and reducing the mortality rate. The inhibition of the activity of the two key cytokines, IFNγ and IL-6, can significantly reduce or even reverse the development of the cytokine storm. The objective of our investigations is to reveal the anti-inflammatory potential of heparin for prevention and suppression of the development of CRS in acute COVID-19 patients.

The effect of low-molecular-weight heparin (LMWH) on IFNγ signalling inside the stimulated WISH cells was investigated by measuring its antiproliferative activity and the translocation of phosphorylated STAT1 in the nucleus. The mechanism of heparin binding to IFNγ and IL-6 and therefore inhibition of their activity was studied by means of extensive molecular-dynamics simulations. We find that LMWH binds with high affinity to IFNγ and is able to inhibit fully the interaction with its cellular receptor. It also influences the biological activity of IL-6 by binding to either IL-6 or IL-6/IL-6Rα thus preventing the formation of the IL-6/IL-6Rα/gp130 signaling complex. Our conclusion is that heparin is a potent anti-inflammatory agent that can be used in acute inflammatory conditions, due to its potential to inhibit both IFN γ and IL-6 signalling pathways. Based on our results and available clinical observations, we suggest the administration of LMWH to COVID-19 patients in the initial stages of the acute phase. The beginning of the treatment and the dosage should be based on a careful follow-up of the platelet count and the D-dimer, IL-6, IFN, T-cells, and B-cells levels.
Mutational pressure drives differential genome conservation in two bacterial endosymbionts of sap feeding insects
Authors: Waneka Gus , Vasquez Yumary M. , Bennett Gordon M. , Sloan Daniel B.
Published: July 2020

Compared to free-living bacteria, endosymbionts of sap-feeding insects have tiny and rapidly evolving genomes. Increased genetic drift, high mutation rates, and relaxed selection associated with host control of key cellular functions all likely contribute to genome decay. Phylogenetic comparisons have revealed massive variation in endosymbiont evolutionary rate, but such methods make it difficult to partition the effects of mutation vs. selection. For example, the ancestor of auchenorrhynchan insects contained two obligate endosymbionts,Sulciaand a betaproteobacterium (BetaSymb; calledNasuiain leafhoppers) that exhibit divergent rates of sequence evolution and different propensities for loss and replacement in the ensuing ∼300 Ma. Here, we use the auchenorrhynchan leafhopperMacrosteles sp. nr. severini, which retains both of the ancestral endosymbionts, to test the hypothesis that differences in evolutionary rate are driven by differential mutagenesis. We used a high-fidelity technique known as duplex sequencing to measure and compare low-frequency variants in each endosymbiont. Our direct detection ofde novomutations reveals that the rapidly evolving endosymbiont (Nasuia) has a much higher frequency of single-nucleotide variants than the more stable endosymbiont (Sulcia) and a mutation spectrum that is even more AT-biased than implied by the 83.1% AT content of its genome. We show that indels are common in both endosymbionts but differ substantially in length and distribution around repetitive regions. Our results suggest that differences in long-term rates of sequence evolution inSulciavs.BetaSymb, and perhaps the contrasting degrees of stability of their relationships with the host, are driven by differences in mutagenesis.

SIGNIFICANCE STATEMENT

Two ancient endosymbionts in the same host lineage display stark differences in genome conservation over phylogenetic scales. We show the rapidly evolving endosymbiont has a higher frequency of mutations, as measured with duplex sequencing. Therefore, differential mutagenesis likely drives evolutionary rate variation in these endosymbionts.
The ciliary protein IFT88 controls post-natal cartilage thickness and influences development of osteoarthritis
Authors: Coveney CR , Zhu L , Miotla-Zarebska J , Stott B , Parisi I , Batchelor V , Duarte C , Chang E , McSorley E , Vincent TL , Wann AKT
Published: July 2020

Mechanical and biological cues drive cellular signalling in cartilage development, health, and disease. Proteins of the primary cilium, implicated in transduction of biophysiochemical signals, control cartilage formation during skeletal development, but their influence in post-natal cartilage remains unknown.Ift88fl/flandAggrecanCreERT2mice were crossed to create a cartilage-specific, inducible knockout mouseAggrecanCreERT2;Ift88fl/fl. Tibial articular cartilage (AC) thickness was assessed, through adolescence and adulthood, by histomorphometry and integrity by OARSI score.In situmechanisms were investigated by immunohistochemistry (IHC), RNA scope and qPCR of micro-dissected cartilage. OA was induced by surgical destabilisation (DMM). Mice voluntarily exercised using wheels. Deletion of IFT88 resulted in progressive reductions in medial AC thickness during adolescence, and marked atrophy in adulthood. At 34 weeks of age, medial thickness was reduced from 104.00μm, [100.30-110.50, 95% CI] inIft88fl/flto 89.42μm [84.00-93.49, 95% CI] inAggrecanCreERT2;Ift88fl/fl(p<0.0001), associated with reductions in calcified cartilage. Occasionally, atrophy was associated with complete, spontaneous, medial cartilage degradation. Following DMM,AggrecanCreERT2;Ift88fl/flmice had increased OA scores. Atrophy in mature AC was not associated with obvious increases in aggrecanase-mediated destruction or chondrocyte hypertrophy.Ift88expression positively correlated withTcf7l2, connective tissue growth factor (Ctgf) andEnpp1. RNA scope revealed increased hedgehog (Hh) signalling (Gli1), associated with reductions inIft88, inAggrecanCreERT2;Ift88fl/flcartilage. Wheel exercise restored both AC thickness and levels of Hh signalling inAggrecanCreERT2;Ift88fl/fl. Our results demonstrate that IFT88 is chondroprotective, regulating AC thickness, potentially by thresholding a Hh response to physiological loading that controls cartilage calcification.
Developmental asymmetries in learning to adjust to cooperative and uncooperative environments
Authors: Westhoff Bianca , Molleman Lucas , Viding Essi , van den Bos Wouter , van Duijvenvoorde Anna C. K.
Published: July 2020

Learning to successfully navigate social environments is a critical developmental goal, predictive of long-term wellbeing. However, little is known about how people learn to adjust to different social environments, and how this behaviour emerges across development. Here, we use a series of economic games to assess how children, adolescents, and young adults learn to adjust to social environments that differ in their level of cooperation (i.e., trust and coordination). Our results show an asymmetric developmental pattern: adjustment requiring uncooperative behaviour remains constant across adolescence, but adjustment requiring cooperative behaviour improves markedly across adolescence. Behavioural and computational analyses reveal that age-related differences in this social learning are shaped by age-related differences in the degree of inequality aversion and in the updating of beliefs about others. Our findings point to early adolescence as a phase of rapid change in cooperative behaviours, and highlight this as a key developmental window for interventions promoting well-adjusted social behaviour.
Recombinational repair of nuclease-generated mitotic double-strand breaks with different end structures in yeast
Authors: Gamble Dionna , Shaltz Samantha , Jinks-Robertson Sue
Published: July 2020

Mitotic recombination is the predominant mechanism for repairing double-strand breaks inSaccharomyces cerevisiae. Current recombination models are largely based on studies utilizing the enzyme I-SceI or HO to create a site-specific break, each of which generates broken ends with 3’ overhangs. In this study sequence-diverged ectopic substrates were used to assess whether the frequent Pol δ-mediated removal of a mismatch 8 nucleotides from a 3’ end affects recombination outcomes and whether the presence of a 3’versus5’ overhang at the break site alters outcomes. Recombination outcomes monitored were the distributions of recombination products into crossoversversusnoncrossovers, and the position/length of transferred sequence (heteroduplex DNA) in noncrossover products. A terminal mismatch that was 22 nucleotides from the 3’ end was rarely removed and the greater distance from the end did not affect recombination outcomes. To determine whether the recombinational repair of breaks with 3’versus5’ overhangs differs, we compared the well-studied 3’ overhang created by I-SceI to a 5’ overhang created by a ZFN (Zinc Finger Nuclease). Initiation with the ZFN yielded more recombinants, consistent with more efficient cleavage and potentially faster repair rate relative to I-SceI. While there were proportionally more COs among ZFN-than I-SceI-initiated events, NCOs in the two systems were indistinguishable in terms of the extent of strand transfer. These data demonstrate that the method of DSB induction and the resulting differences in end polarity have little effect on mitotic recombination outcomes despite potential differences in repair rate.
Straightforward and reproducible analysis of bacterial pangenomes using Pagoo
Authors: Ferrés Ignacio , Iraola Gregorio
Published: July 2020

Pangenome analysis is fundamental to explore evolutionary processes occurring in bacterial populations. However, the lack of standardized methods for handling diverse pangenomic datasets and complex metadata hinders more straightforward and reproducible downstream analyses. To fill this gap, we introduce Pagoo, a new framework that integrates pangenome data, analytical methods and visualization tools in a single object that can be easily stored, shared and responsively queried for improved biological interpretation of bacterial evolution.
Nuclear and cytoplasmic huntingtin inclusions exhibit distinct biochemical composition, interactome and ultrastructural properties
Authors: Riguet Nathan , Mahul-Mellier Anne-Laure , Maharjan Niran , Burtscher Johannes , Croisier Marie , Knott Graham , Hastings Janna , Patin Alice , Reiterer Veronika , Farhan Hesso , Nasarov Sergey , Lashuel Hilal A.
Published: July 2020

Despite the strong evidence linking the aggregation of the Huntingtin protein (Htt) to the pathogenesis of Huntington’s disease (HD), the mechanisms underlying Htt aggregation and neurodegeneration remain poorly understood. Herein, we investigated the ultrastructural properties and protein composition of Htt cytoplasmic and nuclear inclusions in mammalian cells and primary neurons overexpressing mutant exon1 of the Htt protein. Our findings provide novel insight into the ultrastructural properties of cytoplasmic and nuclear Htt inclusions and their mechanisms of formation. We show that Htt inclusion formation and maturation are complex processes that, although initially driven by polyQ-dependent Htt aggregation, also involve 1) polyQ and PRD domain-dependent sequestration of lipids and cytoplasmic and cytoskeletal proteins related to HD dysregulated pathways; 2) recruitment and accumulation of remodeled or dysfunctional membranous organelles, and 3) impairment of the protein quality control and degradation machinery. We also show that nuclear and cytoplasmic Htt inclusions exhibit distinct biochemical compositions and ultrastructural properties, suggesting different mechanisms of aggregation and toxicity.

Graphical Abstract

Schematic depictions and original electron micrographs of cytoplasmic inclusions formed by native (tag-free) mutant Huntingtin exon1 proteins (Httex1 72Q, left) and the corresponding GFP fusion protein (Httex1 72Q-GFP, right).
Validating gene-phenotype associations using relationships in the UMLS
Authors: Blumenfeld Andrew L , Gonzaga-Jauregui Claudia , Sharma Deepika ,   Geisinger-Regeneron DiscovEHR Collaboration,   Regeneron Genetics Center, Yadav Ashish , Khalid Shareef , Balasubramanian Suganthi , Reid Jeffrey G , Habegger Lukas , Cantor Michael N , Staples Jeffrey
Published: July 2020

Objective

Large scale next-generation sequencing of population cohorts paired with patients’ electronic health records (EHR) provides an excellent resource for the study of gene-disease associations. To validate those associations, researchers often consult databases that identify relationships between genes of interest and relevant disease phenotypes, which we refer to as simply “phenotypes”. However, most of these databases contain phenotypes that are not suited for automated analysis of EHR data, which often captured these phenotypes in the form of International Classification of Diseases (ICD) codes. There is a need for a resource that comprehensively provides gene-phenotype mappings in a format that can be used to evaluate phenotypes from EHR.

Methods

We built a directed graph database of genes, medical concepts and ICD codes based on a subset of the National Library of Medicine’s Unified Medical Language System (UMLS) and other resources. To obtain associations between genes and ICD codes, we traversed the defined relationships from gene, variant and disease concepts to ICD codes, resulting in a set of mappings that link specific genes and variants to these ICD codes.

Results

Our method created 249,764 mappings between genes and ICD codes, including 27,226 “disease” phenotypes and 222,538 “symptom” phenotypes, and provided mappings for 4,456 unique genes. Paths were validated by manual review of a diverse sample of paths. In a cohort of 92,455 samples, we used these mappings to validate gene-phenotype associations in 32,786 samples where a person had a potentially disease-causing genetic mutation and at least one corresponding diagnosis in their EHR.

Conclusion

The concepts and relationships in the UMLS can be used to generate gene-ICD phenotype mappings that are not explicit in the source vocabularies. We were able use these mappings to validate gene-disease associations in a large cohort of sequenced exomes paired with EHR.