bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

ABSTRACTVoltage-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

AbstractMechanical 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

AbstractChemokines 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.
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

ABSTRACTInjury 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

ABSTRACTNon-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

ABSTRACTSMAD2 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 STATEMENTTGFβ 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

SummaryEnvironmental 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

SUMMARYMost 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

AbstractA 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

AbstractCircadian 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 SummaryKatoku-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

AbstractBackgroundTraditional 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.MethodsBinding 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.ResultsAs 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.ConclusionsOur 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

ABSTRACTTimely 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

ABSTRACTCompared 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 STATEMENTTwo 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

AbstractMechanical 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.