bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lipoproteome screening of the Lyme disease agent identifies novel inhibitors of antibody-mediated complement killing
Authors: Pereira Michael J. , Wager Beau , Garrigues Ryan J. , Gerlach Eva , Quinn Joshua D. , Dowdell Alex , Osburne Marcia S. , Zückert Wolfram R. , Kraiczy Peter , Garcia Brandon L. , Leong John M. 
Published: September 2021

AbstractSpirochetal pathogens such as the causative agent of Lyme disease, Borrelia burgdorferi sensu lato, encode an abundance of lipoproteins; however, due in part to their evolutionary distance from more well-studied bacteria such as Proteobacteria and Firmicutes, very few spirochetal lipoproteins have assigned functions. Indeed, B. burgdorferi devotes almost 8% of its genome to lipoprotein genes and interacts with its environment primarily through the production of at least eighty surface-exposed lipoproteins throughout its tick vector-vertebrate host lifecycle (57). Several B. burgdorferi lipoproteins have been shown to serve diverse roles, such as cellular adherence or immune evasion, but the functions for most B. burgdorferi surface lipoproteins remain unknown. In this study, we developed a B. burgdorferi lipoproteome screening platform utilizing intact spirochetes that enables the identification of previously unrecognized host interactions. As spirochetal survival in the bloodstream is essential for dissemination, we targeted our screen to C1, the first component of the classical (antibody-mediated) complement pathway. We identified two high-affinity C1 interactions by the paralogous lipoproteins, ErpB and ErpQ. Using biochemical, microbiological, and biophysical approaches, we demonstrated that ErpB and ErpQ inhibit the activated forms of the C1 proteases, C1r and C1s, and represent a new mechanistic class of C1 inhibitors that protect the spirochete from antibody-mediated complement killing by allosteric regulation. In addition to identifying a novel mode of complement inhibition, our study establishes a lipoproteome screening methodology as a discovery platform for identifying direct host-pathogen interactions that are central to the pathogenesis of spirochetes, such as the Lyme disease agent.Significance StatementSpirochetal pathogens encode an abundance of lipoproteins that can provide a critical interface with the host environment. For example, Borrelia burgdorferi, the model species for spirochetal biology, must survive an enzootic life cycle defined by fluctuations between vector (tick) and vertebrate host. While B. burgdorferi expresses over eighty surface lipoproteins— many of which likely contribute to host survival—the B. burgdorferi lipoproteome is poorly characterized. Here, we generated a platform to rapidly identify targets of B. burgdorferi surface lipoproteins and identified two orthologs that allosterically inhibit complement C1 subcomponents, conferring resistance to classical complement killing. This work expands our understanding of complement evasion mechanisms and points towards a discovery approach for identifying host-pathogen interactions that are central to spirochete pathogenesis.
Apixaban, an orally available anticoagulant, inhibits SARS-CoV-2 replication by targeting its major protease in a non-competitive way
Authors: Augusto Chaves Otávio , Sacramento Carolina Q. , Fintelman-Rodrigues Natalia , Temerozo Jairo Ramos , Pereira-Dutra Filipe , Mizurini Daniella M. , Monteiro Robson Q. , Vazquez Leonardo , Bozza Patricia T. , Castro-Faria-Neto Hugo Caire , Souza Thiago Moreno L. 
Published: September 2021

AbstractAnticoagulants are associated with clinical benefit against the 2019 coronavirus disease (COVID-19), preventing COVID-19 associated coagulopathy. Blood coagulation factor Xa (FXa) and SARS-CoV-2 major protease (Mpro) share over 80% homology at the three-dimensional protein level. Thus, it is worth interrogating whether there is crosstalk between inhibitors and substrates between these enzymes. Here, we found that the clinically-approved FXa inhibitor apixaban targets SARS-CoV-2 Mpro with a 21-fold higher potency than boceprevir (GC376). Apixaban displayed a non-competitive mechanism of inhibition towards Mpro, since it targets the enzyme/substrate complex and the allosteric site onto the viral protease. Enzymatic assays were further validated in infected Calu-3 cells, which reveal that apixaban decreases the production of infectious viral particles in a dose-dependent manner, with an inhibitory potency in the micromolar range. Our results are in line with the proposed early use of anticoagulants, including FXa inhibitors, to improve clinical outcome of COVID-19 patients. In this context, apixaban may display a dual mechanism of action by targeting FXa to prevent coagulopathy and, at some level, SARS-CoV-2 Mpro.
Sieve tube structural variation inAustrobaileya scandensand its significance for lianescence
Authors: Losada Juan M. , He Zhe , Holbrook N. Michele 
Published: September 2021

ABSTRACTLianas are characterized by large leaf areas and slender stems, a combination of features that require an efficient vascular system. The only extant member of the Austrobaileyaceae, is an endemic twining liana of the tropical Australian forests with well-known xylem hydraulic traits. However, the vascular phloem continuum through aerial organs remains understudied.We analyzed the structure of phloem conduits across leaf veins and stems ofA. scandens, combining topological data obtained through light and electron microscopy, with current models of phloem transport.Leaves displayed a low xylem to phloem ratio compared with leaves of other angiosperms, with vascular elements invariant in diameter along the midrib, but tapered across vein hierarchies. Sieve plate pore radii were extremely small: 0.08 µm in minor veins, increasing to 0.12µm in the petiole and only to 0.20µm at the base of the stem, tens of meters away. Searcher branches contained tube shaped phloem conduits with a pectin-rich wall, whereas twining stems displayed sieve elements with tangential connections that displayed a greater fraction of the tubes populated with an astonishing number of sieve plates.Hydraulic segmentation of the leaves in Austrobaileyaceae correlate with vesseless leaves that benefit photoassimilate export through volumetric scaling of the sieve tube elements. Yet, compared with canopy dominant trees, the geometrical properties of the sieve tube in twining stems, restrict considerably energy distribution in the sub-canopy layers, potentially favoring the allocation of assimilates toward the elongating branches. Thus, the conductive xylem of twining stems contrasts with a poorly conductive phloem that meets the mechanical constraints of lianescence.
Transcriptional dynamics of methane-cycling microbiomes are linked to seasonal CH4 fluxes in two hydromorphic and organic-rich grassland soils
Authors: Täumer Jana , Marhan Sven , Groß Verena , Jensen Corinna , Kuss Andreas W. , Kolb Steffen , Urich Tim 
Published: September 2021

AbstractSoil CH4 fluxes are driven by CH4-producing and -consuming microorganisms that determine whether soils are sources or sinks of this potent greenhouse gas. Using quantitative metatranscriptomics, we linked CH4-cycling microbiomes to net surface CH4 fluxes throughout a year in two drained peatland soils differing in grassland land-use intensity and physicochemical properties. CH4 fluxes were highly dynamic; both soils were net CH4 sources in autumn and winter and sinks in spring and summer. Despite similar net CH4 emissions, methanogen and methanotroph loads, as determined by small subunit rRNA transcripts per gram soil, differed strongly between sites. In contrast, mRNA transcript abundances were similar in both soils and correlated well with CH4 fluxes. The methane monooxygenase to methanogenesis mRNA ratio was higher in spring and summer, when the soils were net CH4 sinks. CH4 uptake was linked to an increased proportion of USCα and γ and pmoA2 pmoA transcripts. We assume that methanogen transcript abundance may be useful to approximate changes in net surface CH4 emissions from drained peat soils; high methanotroph to methanogen ratios would indicate CH4 sink properties. Our study shows the strength of quantitative metatranscriptomics; mRNA transcript abundance holds promising indicator to link soil microbiome functions to ecosystem-level processes.
Aversive View Memory and Navigational Risk Sensitivity in the Desert Ant, Cataglyphis Velox
Authors: Freas Cody A , Wystrach Antoine , Schwarz Sebastian , Spetch Marcia L 
Published: September 2021

AbstractMany ants establish foraging routes through learning views of the visual panorama. Route models have focused primarily on attractive view use, which experienced foragers orient towards to return to known sites. However, aversive views have recently been uncovered as a key component of route learning. Here, Cataglyphis velox rapidly learned aversive views, when associated with a negative outcome, a period of captivity in brush, triggering an increase in hesitation behavior. These memories were based on the accumulation of experiences over multiple trips with each new experience regulating forager’s hesitancy. Foragers were also sensitive to captivity time differences, suggesting they possess some mechanism to quantify duration. Finally, we analyzed foragers’ perception of risky (i.e. variable) versus stable aversive outcomes by associating two sites along the route with distinct captivity schedules, a fixed or variable duration, with the same mean across training. Foragers exhibited significantly less hesitation to the risky outcome compared to the fixed, indicating they perceived risky outcomes as less severe. Results align with a logarithmic relationship between captivity duration and hesitations, suggesting that aversive stimulus perception is a logarithm of its actual value. We conclude by characterizing how these behaviors can be executed within the mushroom bodies’ neural circuitry.
Integrative analysis allows a global and precise identification of functional miRNA target genes in mESCs
Authors: Schäfer Moritz , Nabih Amena , Spies Daniel , Bodak Maxime , Wischnewski Harry , Stalder Patrick , Ngondo Richard Patryk , Liechti Luz Angelica , Sajic Tatjana , Aebersold Ruedi , Gatfield David , Ciaudo Constance 
Published: September 2021

SUMMARYMicroRNA (miRNA) loaded Argonaute (AGO) complexes regulate gene expression via direct base pairing with their mRNA targets. Current prediction approaches identified that between 20 to 60% of mammalian transcriptomes are regulated by miRNAs, but it remains largely unknown which fraction of these interactions are functional in a specific cellular context. Here, we integrated transcriptome data from a set of miRNA-depleted mouse embryonic stem cell (mESC) lines with published miRNA interaction predictions and AGO-binding profiles. This integrative approach, combined with molecular validation data, identified that only 6% of expressed genes are functionally and directly regulated by miRNAs in mESCs. In addition, analyses of the stem cell-specific miR-290-295 cluster target genes identified TFAP4 as an important transcription factor for early development. The extensive datasets developed in this study will support the development of improved predictive models for miRNA-mRNA functional interactions.
Inhibition of pyrimidine biosynthesis targets protein translation in AML
Authors: So Joan , Lewis Alexander C. , Smith Lorey K. , Stanley Kym , Pijpers Lizzy , Dominguez Pilar , Hogg Simon J. , Vervoort Stephin J. , Johnstone Ricky W. , McDonald Gabrielle , Ulanet Danielle B. , Murtie Josh , Gruber Emily , Kats Lev M. 
Published: September 2021

AbstractThe mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate-limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins and phospholipids. DHODH inhibitors (DHODHi) are clinically used for autoimmune diseases and are emerging as a novel class of anti-cancer agents, especially in acute myeloid leukemia (AML) where pyrimidine starvation was recently shown to reverse the characteristic differentiation block in AML cells. Herein we show that DHODH blockade rapidly shuts down protein translation in leukemic stem cells (LSCs) by down-regulation of the multi-functional transcription factor YY1, has potent activity against AML in vivo and is well tolerated with minimal impact on normal blood development. Moreover, we find that ablation of CDK5, a gene that is recurrently deleted in AML and related disorders, increases the sensitivity of AML cells to DHODHi. Our studies provide important molecular insights and identify a potential biomarker for an emerging strategy to target AML.
Mutations change excitability and the probability of re-entry in a computational model of cardiac myocytes in the sleeve of the pulmonary vein
Authors: Jæger Karoline Horgmo , Edwards Andrew G. , Giles Wayne R. , Tveito Aslak 
Published: September 2021

AbstractAtrial fibrillation (AF) is a common health problem with substantial individual and societal costs. The origin of AF has been debated for more than a century, and the precise, biophysical mechanisms that are responsible for the initiation and maintenance of the chaotic electrochemical waves that define AF, remains unclear. It is well accepted that the outlet of the pulmonary veins is the primary anatomical site of AF initiation, and that electrical isolation of these regions remains the most effective treatment for AF. Furthermore, it is well known that certain ion channel or transporter mutations can significantly increase the likelihood of AF. Here, we present a computational model capable of characterizing functionally important features of the microanatomical and electrophysiological substrate that represents the transition from the pulmonary veins (PV) to the left atrium (LA) of the human heart. This model is based on a finite element representation of every myocyte in a segment of this (PV/LA) region. Thus, it allows for investigation a mix of typical PV and LA myocytes. We use the model to investigate the likelihood of ectopic beats and re-entrant waves in a cylindrical geometry representing the transition from PV to LA. In particular, we investigate and illustrate how six different AF- associated mutations can alter the probability of ectopic beats and re-entry in this region.
Bio-hybrid Soft Robotic Bioreactors for Mimicking Multi-Axial Femoropopliteal Artery Mechanobiology
Authors: Fell Cody , Brooks-Richards Trent L , Woodruff Maria Ann , Allenby Mark C 
Published: September 2021

AbstractThe emerging field of soft robotics aims to emulate dynamic physiological locomotion. Soft robotics’ mimicry of naturally complex biomechanics makes them ideal platforms for exerting mechanical stimuli for patient-specific tissue maturation and disease modeling applications. Such platforms are essential for emulating highly flexible tissues such as the kneecap’s femoropopliteal artery (FPA), one of the most flexible arteries in the body, which flexes and bends during walking, standing, and crouching movements. The FPA is a frequent site of disease, where 80% of all peripheral artery diseases manifest, affecting over 200 million people worldwide. The complex biomechanical and hemodynamic forces within the FPA have been implicated in the frequent occurrence of PAD and lead to debilitating morbidities, such as limb-threatening ischemia. To better mimic these complex biomechanics, we developed an in-vitro bio-hybrid soft robot (BSR). First, Platsil OO-20 was identified as an ideal hyperelastomer for both cell culture and BSR fabrication using 3D printed molds. Then, employing a simulation-based design workflow, we integrated pneumatic network (PneuNet) actuators cast with Platsil OO-20, which extend in angular, longitudinal, and radial dimensions. Pressurizing the BSR PneuNets enabled a range of mechanical stimuli to be dynamically applied during tissue culture to mimic normal and diseased FPA flexions during daily walking and sitting poses, the most extreme being radial distensions of 20% and angular flexions of 140°. Finally, these designed, manufactured, and programmed vascular BSRs were seeded with mesenchymal stem cells and conditioned for 24 hours to highlight the effect of dynamic conditioning on cultured cell alignment, as well as type IV collagen production and the upregulation of smooth muscle phenotypes. Soft robotic bioreactor platforms that accurately mimic patient-, disease-, and lifestyle-specific mechanobiology will develop fundamental disease understanding, preoperative laboratory simulations for existing therapeutics, and biomanufacturing platforms for tissue-engineered implants.
High-resolution mapping of DNA alkylation damage and base excision repair at yeast transcription factor binding sites
Authors: Duan Mingrui , Sivapragasam Smitha , Antony Jacob S. , Ulibarri Jenna , Hinz John M. , Poon Gregory M.K. , Wyrick John J. , Mao Peng 
Published: September 2021

AbstractDNA base damage arises frequently in living cells and needs to be removed by base excision repair (BER) to prevent mutagenesis and genome instability. Both the formation and repair of base damage occur in chromatin and are conceivably affected by DNA-binding proteins such as transcription factors (TFs). However, to what extent TF binding affects base damage distribution and BER in cells is unclear. Here, we used a genome-wide damage mapping method, N-methylpurine-sequencing (NMP-seq), to characterize alkylation damage distribution and BER at TF binding sites in yeast cells treated with the alkylating agent methyl methanesulfonate (MMS). Our data shows that alkylation damage formation was mainly suppressed at the binding sites of yeast TFs Abf1 and Reb1, but individual hotspots with elevated damage levels were also found. Additionally, Abf1 and Reb1 binding strongly inhibits BER in vivo and in vitro, causing slow repair both within the core motif and its adjacent DNA. The observed effects are caused by the TF-DNA interaction, because damage formation and BER can be restored by depletion of Abf1 or Reb1 protein from the nucleus. Thus, our data reveal that TF binding significantly modulates alkylation base damage formation and inhibits repair by the BER pathway. The interplay between base damage formation and BER may play an important role in affecting mutation frequency in gene regulatory regions.
The role of career shocks in contemporary career development: key challenges and ways forward
Authors: Akkermans Jos , Rodrigues Ricardo , Mol Stefan T. , Seibert Scott E. , Khapova Svetlana N. 
Published: September 2021

PurposeThis article aims to introduce the special issue entitled “the role of career shocks in contemporary career development,” synthesize key contributions and formulate a future research agenda.Design/methodology/approachThe authors provide an introduction of the current state-of-the-art in career shocks research, offer an overview of the key lessons learned from the special issue and present several important avenues for future research.FindingsThe authors discuss how the special issue articles contribute to a better understanding of career shocks' role in contemporary career development, focusing on (1) conceptual clarity of the notion of career shocks, (2) career outcomes of career shocks, (3) mechanisms that can explain the impact of career shocks and (4) interdisciplinary connectivity.Originality/valueThis article offers a synthesis of the critical contributions made within this special issue, thereby formulating key ways to bring the field of career shocks research forward. It also provides new avenues for research.
Risks of water and wastewater PPP projects: an investors’ perspective
Authors: Amiri Omid , Ayazi Amir , Rahimi Mahmoud , Khazaeni Garshasb 
Published: September 2021

Purpose
Water and wastewater (WW) projects are gaining attention in Iran because of shortages of water resources. However, these projects are lengthy and they are accompanied by numerous risks, such as lack of sufficient financial resources. Public–private partnerships (PPPs) are taken into account as a constructive approach to deal with the problem of insufficient government funds and they are increasingly being implemented to construct the required infrastructures in different countries. Although WW projects in PPPs can reduce the government’s debt, investors are still uncertain about this approach. Hence, this study aims to identify and evaluate the risk of all parties involved in WW-PPP projects, from the viewpoint of investor.

Design/methodology/approach
First, the risk factors which are involved in WW projects are identified by interviewing experts and reviewing the literature by means of fault tree analysis (FTA) tool. Second, the probability and effects of the risky factors which are related to specific event are evaluated and analyzed by hybridization of interval fuzzy Type-2 sets (IT2FS) and risk score formulation. Finally, some solutions are proposed to deal with the most challenging risks.

Findings
Six gate events, namely, risks which are related to investors such as investor’s consultant-related risks, risky conditions from engineering, procurement, and construction (EPC) contractors’ point of view, risk factors which public sector takes into account, public sector’s consultant-related risks which public sector’s consultant consider challenging and external factors were defined according to the literature. From FTA tool and by interviewing the experts, 94 basic events were identified. Finally, from hybridization of IT2FSs and risk score formulation, top five risks are determined as “Difficulty of injecting financial resources into the project,” “Fluctuation in inflation rate,” “Poor decision-making process” in public sector, “Difficulty of importing the equipment which are required for the project (such as pumps, grain catchers, garbage collectors, etc.) from other countries” and “Impact of risky conditions in other projects on operation of PPP project.”

Originality/value
In the absence of a constructive approach for risk identification and a reliable model for evaluating the identified risks in PPP projects, this research project is one of the first research studies which used FTA for identifying risks and hybridization of IT2FSs and risk score formulation for evaluating the risks.
Demand for green building in Ghana: a conceptual modeling and empirical study of the impediments
Authors: Guribie Francis Lanme , Akubah Joyce Twumwaa , Tengan Callistus , Blay Jnr Andrew Victor Kabenlah 
Published: September 2021

Purpose
The key to green building (GB) success is to have GB expansion driven by consumer demand rather than enforced rules and regulations. Yet, only a few studies have focused on the market impediments to GB development. This study systematically identified and evaluated the critical impediments to the demand for green and sustainable architecture by construction clients in Ghana.

Design/methodology/approach
The study adopted a two-stage data gathering approach. Qualitative data was collected first through an interview administered to 18 construction clients in Ghana. Based on the early findings, a survey instrument was subsequently developed to seek the views of 120 GB experts and professionals with 96 valid responses-returned.

Findings
The study discovered that – ineffective advertisement of GB, the perceived cost of implementation, lack of expertise, lack of financial incentives, illiterate construction market and risk and uncertainties were the top six reasons for the low demand for GB by construction clients in Ghana

Practical implications
Findings from this research would guide industry practitioners and stakeholders to make informed decisions regarding how to stimulate demand for GBs among construction clients.

Originality/value
The paper models and presents contextual realities on barriers to GB demand in Ghana. The study has added to previous studies by unearthing what constitutes the lack of demand for sustainable architecture. The findings of this study are expected to provide valuable information and insight to policymakers to catalyze green construction by actively involving construction clients.