bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preliminary report on SARS-CoV-2 Spike mutation T478K
Authors: Di Giacomo Simone , Mercatelli Daniele , Rakhimov Amir , Giorgi Federico M. 
Published: March 2021

AbstractSeveral SARS-CoV-2 variants have emerged, posing a renewed threat to COVID-19 containment and to vaccine and drug efficacy. In this study, we analyzed more than 1,000,000 SARS-CoV-2 genomic sequences deposited up to April 27, 2021 on the GISAID public repository, and identified a novel T478K mutation located on the SARS-CoV-2 Spike protein. The mutation is structurally located in the region of interaction with human receptor ACE2 and was detected in 11,435 distinct cases. We show that T478K has appeared and risen in frequency since January 2021, predominantly in Mexico and USA, but we could also detect it in several European countries.
Electron transfer parameters for Methemoglobin formation in mutant Hemoglobin α-chains
Authors: Dixit Vaibhav A. , Blumberger Jochen , Vyas Shivam Kumar 
Published: March 2021

AbstractHemoglobin mediated transport of dioxygen (O2) critically depends on the stability of the reduced (Fe2+) form of the Heme cofactors. Some protein mutations stabilize oxidized (Fe3+) state (Methemoglobin, Hb M) causing methemoglobinemia and can be lethal above 30 %. Majority of the analyses of factors influencing Hb oxidation are retrospective and give insights only for inner sphere mutations of Heme (His58, His87). Herein, we report the first all atom MD simulations on redox states and calculations of the Marcus ET parameters for the α-chain Hb oxidation and reduction rates for Hb M. The Hb (wild type), and most of the studied α-chain variants maintain globin structure except the Hb M Iwate (H87Y). Using linear response approximation we calculated average energy gaps (<ΔE>), total (λ), protein (λprot), solvent (λsolv) reorganization energies, and redox potentials (E°), and oxidation free energies (ΔG°). The total λ ranges from 0.685 – 0.730 eV in agreement with literature on Hb and similar Heme proteins. The mutants forming Hb M tend to lower theE° and thus stabilize the oxidized (Fe3+) state (e.g. the Hb Miyagi variant with K61E mutation). Solvent reorganization (λsolv73 – 96 %) makes major contributions to λ, while protein reorganization (λprot) accounts for 27 – 30 % except for the Miyagi and J-Buda variants (λprot∼ 4 %). Analysis of Heme-solvent H-bonding interactions among variants provide insights into the role of Lys61 residue in stabilizing Fe2+state and ET parameters. The ET parameters provide valuable insights into the Hb oxidation to Hb M in agreement with the experimental data. Thus our methodology explains the effect of mutations on the structure, stability and Hb oxidation, and has potential for the prediction of methemoglobinemia.
Paraburkholderia edwiniiprotectsAspergillussp. from phenazines by acting as a toxin sponge
Authors: Dahlstrom Kurt M. , Newman Dianne K. 
Published: March 2021

SummaryMany environmentally and clinically important fungi are sensitive to toxic, bacterially-produced, redox-active molecules called phenazines. Despite being vulnerable to phenazine-assault, fungi inhabit microbial communities that contain phenazine producers. Because many fungi cannot withstand phenazine challenge, but some bacterial species can, we hypothesized that bacterial partners may protect fungi in phenazine-replete environments. In the first soil sample we collected, we co-isolated several such physically associated pairings. We discovered the novel speciesParaburkholderia edwiniiand demonstrated it can protect a co-isolatedAspergillusspecies from phenazine-1-carboxylic acid (PCA) by sequestering it, acting as a toxin sponge; in turn, it also gains protection. When challenged with PCA,P. edwiniichanges its morphology, forming aggregates within the growing fungal colony. Further, the fungal partner triggersP. edwiniito sequester PCA and maintains conditions that limit PCA toxicity by promoting an anoxic and highly reducing environment. A mutagenic screen revealed this program depends on the stress-inducible transcriptional repressor HrcA. We show that one relevant stressor in response to PCA challenge is fungal acidification and that acid stress causesP. edwiniito behave as though the fungus were present. Finally, we reveal this phenomenon as widespread amongParaburkholderiawith moderate specificity among bacterial and fungal partners, including plant and human pathogens. Our discovery suggests a common mechanism by which fungi can gain access to phenazine-replete environments, and provides a tractable model system for its study. These results have implications for how rhizosphere microbial communities as well as plant and human infection sites are policed for fungal membership.
Predictors of zoonotic potential in helminths
Authors: Majewska Ania A. , Huang Tao , Han Barbara , Drake John M. 
Published: March 2021

AbstractHelminths are parasites that cause disease at considerable cost to public health and present a risk for emergence as novel human infections. Although recent research has elucidated characteristics conferring a propensity to emergence in other parasite groups (e.g. viruses), the understanding of factors associated with zoonotic potential in helminths remains poor. We applied an investigator-directed learning algorithm to a global dataset of mammal helminth traits to identify factors contributing to spillover of helminths from wild animal hosts into humans. We characterized parasite traits that distinguish between zoonotic and non-zoonotic species with greater than 88% accuracy. Results suggest that helminth traits relating to transmission (e.g. definitive and intermediate hosts) and geography (e.g. distribution) are more important to predicting zoonotic species than morphological or epidemiological traits. Whether or not a helminth causes infection in companion animals (cats and dogs) is the most important predictor of propensity to cause human infection. Finally, we identified helminth species with high modeled propensity to cause zoonosis (over 70%) that have not previously been deemed to be of risk. This work highlights the importance of prioritizing studies on the transmission of helminths that infect pets and points to the risks incurred by close associations with these animals.
A TBP-independent mechanism for RNA Polymerase II transcription
Authors: Kwan James Z.J. , Nguyen Thomas F. , Budzyński Marek A. , Cui Jieying , Price Rachel M. , Teves Sheila S. 
Published: March 2021

AbstractTranscription by RNA Polymerase II (Pol II) is initiated by the hierarchical assembly of the Pre-Initiation Complex onto promoter DNA. Decades ofin vitroand yeast research have shown that the TATA-box binding protein (TBP) is essential to Pol II initiation by triggering the binding of other general transcription factors, and ensuring proper Pol II loading. Here, we report instead that acute depletion of TBP in mouse embryonic stem cells (mESCs) has no global effect on ongoing Pol II transcription. Surprisingly, Pol II transcriptional induction through the Heat Shock Response or cellular differentiation also occurs normally in the absence of TBP. In contrast, acute TBP depletion severely impairs initiation by RNA Polymerase III. Lastly, we show that a metazoan-specific paralog of TBP is expressed in mESCs and that it binds to promoter regions of active Pol II genes even in the absence of TBP. Taken together, our findings reveal an unexplored TBP-independent process in mESCs that points to a diversity in Pol II transcription initiation mechanisms.
Endocervical regulatory T cells are associated with decreased genital inflammation and lower HIV target cell abundance
Authors: Ssemaganda Aloysious , Cholette Francois , Perner Michelle , Kambaran Cheli , Adhiambo Wendy , Wambugu Peter M. , Gebrebrhan Henok , Lee Amy , Nuhu Faisal , Mwatelah Ruth S. , Jahan Naima , Omole Tosin E. , Wanjiru Tabitha , Gitau Apollo , Kimani Joshua , McKinnon Lyle R. 
Published: March 2021

AbstractRegulatory T cells (Tregs) play important roles in tissue homeostasis, but few studies have investigated tissue Tregs in the context of genital inflammation, HIV target cell density, and vaginal microbiota in humans. In women from Nairobi (n=64), the proportion of CD4+ CD25+ CD127lowTregs in the endocervix correlated with those in blood (r=0.31, p=0.01), with a higher Treg frequency observed in the endocervix (median 3.8 vs 2.0%, p<0.0001). Most Tregs expressed FoxP3 in both compartments, and CTLA-4 expression was higher on endocervical Tregs compared to blood (median 50.8 vs 6.0%, p<0.0001). More than half (34/62, 55%) of participants displayed a non-Lactobacillusdominant vaginal microbiota, which was not associated with endocervical Tregs or CD4+ T cell abundance. In a multivariable linear regression, endocervical Treg proportions were inversely associated with the number of elevated pro-inflammatory cytokines (p=0.03). Inverse Treg associations were also observed for specific cytokines including IL-1β, G-CSF, Eotaxin, IL-1RA, IL-8, and MIP-1 β. Higher endocervical Treg proportions were associated with lower abundance of endocervical CD4+ T cells (0.30 log10CD4+ T cells per log10Treg, p=0.00028), with a similar trend for Th17 cells (p=0.09). Selectively increasing endocervical Tregs may represent a pathway to reduce genital tract inflammation in women.
An improved assembly of theAlbugo candidaAc2V genome reveals the expansion of the “CCG” class of effectors
Authors: Furzer Oliver J. , Cevik Volkan , Fairhead Sebastian , Bailey Kate , Redkar Amey , Schudoma Christian , MacLean Dan , Holub Eric B. , Jones Jonathan D.G. 
Published: March 2021

AbstractAlbugo candidais an obligate oomycete pathogen that infects many plants in the Brassicaceae family. We re-sequenced the genome of isolate Ac2V using PacBio long reads and constructed an assembly augmented by Illumina reads. The Ac2VPB genome assembly is 10% larger and more contiguous compared to a previous version. Our annotation of the new assembly, aided by RNASeq information, revealed a dramatic 250% expansion (40 to 110) in the CHxC effector class, which we redefined as “CCG” based on motif analysis. This class of effectors consist of arrays of phylogenetically related paralogs residing in gene sparse regions, and shows signatures of positive selection and presence/absence polymorphism. This work provides a resource that allows the dissection of the genomic components underlyingA. candidaadaptation and particularly the role of CCG effectors in virulence and avirulence on different hosts.
Critical contribution of 3’ non-seed base pairing to thein vivofunction of the evolutionarily conservedlet-7amicroRNA
Authors: Duan Ye , Veksler-Lublinsky Isana , Ambros Victor 
Published: March 2021

SummaryBase-pairing of the seed region (g2-g8) is essential for microRNA targeting, however, thein vivofunction of the 3’ non-seed region (g9-g22) are less well understood. Here we report the first systematic investigation of thein vivoroles of 3’ non-seed nucleotides in microRNAlet-7a,whose entire g9-g22 region is conserved among bilaterians. We found that the 3’ non-seed sequence functionally distinguisheslet-7afrom its family paralogs. The complete pairing of g11-g16 is essential forlet-7ato fully repress multiple key targets, including evolutionarily conservedlin-41,daf-12andhbl-1. Nucleotides at g17-g22 are less critical but may compensate for mismatches in the g11-g16 region. Interestingly, the 3’ non-seed pairing oflet-7acan be critically required with certain minimal complementarity for sites with perfect seed pairing. These results provide evidence that the specific configurations of both seed and 3’ non-seed base-pairing can critically influence microRNA-mediated gene regulationin vivo.
Gene expression in the developing nemertean brain indicates convergent evolution of complex brains in Spiralia
Authors: Gąsiorowski Ludwik , Børve Aina , Cherneva Irina A. , Orús-Alcalde Andrea , Hejnol Andreas 
Published: March 2021

AbstractBackgroundNemertea is a clade of worm-like animals, which belongs to a larger animal group called Spiralia (together with e.g. annelids, flatworms and mollusks). Many of the nemertean species possess a complex central nervous system (CNS) with a prominent brain, and elaborated chemosensory and neuroglandular cerebral organs, which have been suggested as homologues to the annelid mushroom bodies. In order to understand the developmental and evolutionary origins of complex nemertean brain, we investigated details of neuroanatomy and gene expression in the brain and cerebral organs of the juveniles of nemerteanLineus ruber.ResultsIn the hatched juveniles the CNS is already composed of all major elements present in the adults, including the brain (with dorsal and ventral lobes), paired longitudinal lateral nerve cords and an unpaired dorsal nerve cord. The TEM investigation of the juvenile cerebral organ revealed that the structure is already composed of several distinct cell types present also in the adults. We further investigated the expression of twelve transcription factors commonly used as brain and cell type markers in bilaterian brains, including genes specific for annelid mushroom bodies. The expression of the investigated genes in the brain is region-specific and divides the entire organ into several molecularly distinct areas, partially overlapping with the morphological compartments. Additionally, we detected expression of mushroom body specific genes in the developing cerebral organs.ConclusionsAt the moment of hatching, the juveniles ofL. ruberalready have a similar neuroarchitecture as adult worms, which suggests that further neural development is mostly related with increase in the size but not in complexity. Comparison in the gene expression betweenL. ruberand the annelidPlatynereis dumeriliiand other spiralians, indicates that the complex brains present in those two species evolved convergently by independent expansion of non-homologues regions of the simpler brain present in their common ancestor. The similarities in gene expression in mushroom bodies and cerebral organs might be a result of the convergent recruitment of the same genes into patterning of non-homologues organs or the results of more complicated evolutionary processes, in which conserved and novel cell types contribute to the non-homologues structures.
Dual control exerted by dopamine in blood-progenitor cell cycle regulation inDrosophila
Authors: Kapoor Ankita , Padmavathi A. , Mukherjee Tina 
Published: March 2021

AbstractInDrosophila, definitive hematopoiesis occurs in a specialized organ termed “lymph gland”, where multi-potent stem-like blood progenitor cells reside and their homeostasis is central to growth of this organ. Recent findings have implicated a reliance on neurotransmitters in progenitor development and function however, our understanding of these molecules is still limited. Here, we extend our analysis and show that blood-progenitors are self-sufficient in synthesizing dopamine, a well-established neurotransmitter and have modules for its sensing through receptor and uptake via, transporter. Modulating their expression in progenitor cells affects lymph gland growth. Progenitor cell cycle analysis revealed an unexpected requirement for intracellular dopamine in the progression of early progenitors from S to G2 phase of the cell cycle, while activation of dopamine-receptor later in development regulated progression from G2 to entry into mitosis. The dual capacity in which dopamine operates, both intra-cellular and extra-cellular, controls lymph gland growth. These data highlight a novel and non-canonical use of dopamine as a proliferative cue by the myeloid-progenitor system and reveals a functional requirement for intracellular dopamine in cell-cycle progression.
Alpha-synuclein alters the faecal viromes of rats in a gut-initiated model of Parkinson’s disease
Authors: Stockdale S. R. , Draper L. A. , O’Donovan S. M. , Barton W. , O’Sullivan O. , Volpicelli-Daley L. A. , Sullivan A. M. , O’Neill C. , Hill C. 
Published: March 2021

AbstractParkinson’s disease (PD) is a chronic neurological disorder associated with the misfolding of alpha-synuclein (α-syn) into Lewy body aggregates within nerve cells that contribute to their neurodegeneration. Recent evidence suggests α-syn aggregation may begin in the gut and travel to the brain along the vagus nerve, with microbes a potential trigger initiating the misfolding of α-syn. However, changes in the gut virome in response to α-syn alterations have not been investigated. In this study, we show longitudinal changes in the faecal virome of rats administered either monomeric or preformed fibrils (PFF) of α-syn directly into their enteric nervous system. Differential changes in rat viromes were observed when comparing monomeric and PFF α-syn. The virome β-diversity changes after α-syn treatment were compounded by the addition of LPS as an adjunct. Changes in the diversity of rat faecal viromes were observed after one month and did not resolve within the study’s five month observational period. Overall, these results suggest that microbiome alterations associated with PD may, partially, be reactive to host α-syn associated changes.
Distal and proximal cis-regulatory elements sense X-chromosomal dosage and developmental state at theXistlocus
Authors: Gjaltema Rutger A.F. , Schwämmle Till , Kautz Pauline , Robson Michael , Schöpflin Robert , Lustig Liat Ravid , Brandenburg Lennart , Dunkel Ilona , Vechiatto Carolina , Ntini Evgenia , Mutzel Verena , Schmiedel Vera , Marsico Annalisa , Mundlos Stefan , Schulz Edda G. 
Published: March 2021

AbstractDevelopmental genes such asXist, the master regulator of X-chromosome inactivation (XCI), are controlled by complexcis-regulatory landscapes, which decode multiple signals to establish specific spatio-temporal expression patterns.Xistintegrates information on X-chromosomal dosage and developmental stage to trigger XCI at the primed pluripotent state in females only. Through a pooled CRISPR interference screen in differentiating mouse embryonic stem cells, we identify functional enhancer elements ofXistduring the onset of random XCI. By quantifying how enhancer activity is modulated by X-dosage and differentiation, we find that X-dosage controls the promoter-proximal region in a binary switch-like manner. By contrast, differentiation cues activate a series of distal elements and bring them into closer spatial proximity of theXistpromoter. The strongest distal element is part of an enhancer cluster ∼200 kb upstream of theXistgene which is associated with a previously unannotatedXist-enhancing regulatory transcript, we namedXert. Developmental cues and X-dosage are thus decoded by distinct regulatory regions, which cooperate to ensure female-specificXistupregulation at the correct developmental time. Our study is the first step to disentangle how multiple, functionally distinct regulatory regions interact to generate complex expression patterns in mammals.
An investigation into decision-making and delivery activities following design-led events in collaborative planning
Authors: AlWaer Husam , Rintoul Susan , Cooper Ian 
Published: March 2021

PurposeThis paper is concerned with what should happen after design-led events have been held to promote co-decision-making, between professionals and local stakeholders, in collaborative planning of the built environment. Rather than being standalone, such events form one single step in a multi-stage collaborative planning process. What comes before and after them has to be acknowledged as important to their effective contribution to collaborative planning. This paper aims to make a case for giving more attention to the post-event stages of collaborative planning, to ensure that the involvement of the public produces real and tangible benefits.Design/methodology/approachContent analysis of both academic and grey literatures was undertaken to examine emerging advice on how to conduct decision-making, the implementation of outputs and the delivery of desired outcomes, after design-led events. A critical review of the post-event decision-making and delivery activities is offered, which aims to add to the current academic literature on the deployment of design-led events. An attempt is made to sketch out the characteristics of post-event stages, drawn from the literature and collated specific examples of collaborative planning investigated in Scotland.FindingsThree key factors are identified as affecting the successful implementation of decisions reached at design-led events: (1) a shared follow-on plan, (2) an agreed action programme for delivering this and (3) a properly constituted and resourced delivery vehicle that can monitor and evaluate progress. A research agenda to address questions raised but left unanswered is suggested dealing with how the decision-making and delivery activities following design-led events in collaborative planning might be improved.Originality/valueA research agenda to address questions raised but left unanswered is suggested dealing with how the decision-making and delivery activities following design-led events in collaborative planning might be improved.
How relationship quality, autonomous work motivation and socialization experience influence the adjustment of self-initiated expatriates in China
Authors: Jannesari Milad T. , Sullivan Sherry E. 
Published: March 2021

PurposeThe continued expansion of organizations outside China's planned economy due to the Belt-and-Road Initiative (BRI) is expected to increase recruitment of self-initiated expatriates (SIEs). Drawing on social capital, motivation and socialization theories, this study examines the experiences of SIEs in China, which is considered one of the most difficult locations for foreigners to work. While previous research has focused on the impact of individual characteristics on adjustment, this study explores the interplay among relationship quality (trust and shared vision), autonomous work motivation, socialization experience and adjustment.Design/methodology/approachBased on the developed theoretical framework, hypotheses are proposed and tested using data collected by surveying 274 SIEs in China.FindingsRelationship quality with host country nationals (HCNs) was positively associated with adjustment, and autonomous work motivation fully mediated this relationship. Socialization experience moderated the association between relationship quality and autonomous work motivation. Specifically, SIEs' socialization experience strengthened the associations of trust and shared vision with autonomous work motivation. However, socialization experiences failed to moderate the mediated effects of trust and shared vision on adjustment via autonomous work motivation.Originality/valueThis study answers repeated calls for more research on SIEs' adjustment and SIEs working in non-Western countries, especially China. The findings underscore the importance of studying SIE-HCN work relationships and the theoretical value of autonomous work motivation as an underlying mechanism by which the quality of an SIE's relationship with an HCN colleague influences adjustment.