bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incomplete recruitment of protective T cells facilitatesTrypanosoma cruzipersistence in the mouse colon
Authors: Ward Alexander I. , Lewis Michael D. , Taylor Martin C. , Kelly John M. 
Published: February 2021

AbstractTrypanosoma cruziis the etiological agent of Chagas disease. Following T cell mediated suppression of the acute phase infection, this intracellular eukaryotic pathogen persists in a limited sub-set of tissues at extremely low-levels. The reasons for this tissue-specific chronicity are not understood. Using a dual bioluminescent:fluorescent reporter strain, which allows experimental infections to be imaged at single-cell resolution, we have characterised the ‘hyper-local’ immunological microenvironment of rare parasitized cells in the mouse colon, a key site of persistence. We demonstrate that incomplete recruitment of T cells to infection foci permits the occurrence of repeated cycles of intracellular parasite replication and differentiation to motile trypomastigotes at a frequency sufficient to perpetuate chronic infections. The life-long persistence of parasites in this tissue site continues despite the presence, at a systemic level, of a highly effective T cell response. Overcoming this low-level dynamic host:parasite equilibrium represents a major challenge for vaccine development.
Marked differences in local bone remodeling in response to different marrow stimulation techniques in a large animal
Authors: Zlotnick H.M. , Locke R.C. , Stoeckl B.D. , Patel J.M. , Gupta S. , Browne K.D. , Koh J. , Carey J.L. , Mauck R.L. 
Published: February 2021

AbstractMarrow stimulation, including subchondral drilling and microfracture, is the most commonly performed cartilage repair strategy, whereby the subchondral bone plate is perforated to release marrow-derived cells into a cartilage defect to initiate repair. Novel scaffolds and therapeutics are being designed to enhance and extend the positive short-term outcomes of this marrow stimulation. However, the translation of these newer treatments is hindered by bony abnormalities, including bone resorption, intralesional osteophytes, and bone cysts, that can arise after marrow stimulation. In this study, three different marrow stimulation approaches — microfracture, subchondral drilling, and needle-puncture – were evaluated in a translationally relevant large animal model, the Yucatan minipig. The objective of this study was to determine which method of marrow access (malleted awl, drilled Kirschner wire, or spring-loaded needle) best preserved the underlying subchondral bone. Fluorochrome labels were injected at the time of surgery and 2 weeks post-surgery to capture bone remodeling over the first 4 weeks. Comprehensive outcome measures included cartilage indentation testing, histological grading, microcomputed tomography, and fluorochrome imaging. Our findings indicated that needle-puncture devices best preserved the underlying subchondral bone relative to other marrow access approaches. This may relate to the degree of bony compaction occurring with marrow access, as the Kirschner wire approach, which consolidated bone most, induced the most significant bone damage with marrow stimulation. This study provides basic science evidence in support of updated marrow stimulation techniques for preclinical and clinical practice.
Bortezomib inhibits lung fibrosis and fibroblast activation without proteasome inhibition
Authors: Penke Loka Raghu Kumar , Speth Jennifer , Wettlaufer Scott , Draijer Christina , Peters-Golden Marc 
Published: February 2021

AbstractThe FDA-approved proteasomal inhibitor bortezomib (BTZ) has attracted interest for its potential anti-fibrotic actions. However, neither itsin vivoefficacy in lung fibrosis nor its dependence on proteasome inhibition has been conclusively defined. Herein, we identify that therapeutic administration of BTZ in a mouse model of pulmonary fibrosis diminished the severity of fibrosis without reducing proteasome activity in the lung. Under conditions designed to mimic this lack of proteasome inhibitionin vitro, it reduced fibroblast proliferation, differentiation into myofibroblasts, and collagen synthesis. It promoted de-differentiation of myofibroblasts and overcame their characteristic resistance to apoptosis. Mechanistically, BTZ inhibited kinases important for fibroblast activation while inducing expression of dual-specificity phosphatase 1 or DUSP1, and knockdown of DUSP1 abolished its anti-fibrotic actions in fibroblasts. Our findings identify a novel proteasome-independent mechanism of anti-fibrotic actions for BTZ and support its therapeutic repurposing for pulmonary fibrosis.
Microglia become hypofunctional and release metalloproteases and tau seeds after phagocytosing live neurons with P301S tau aggregates
Authors: Brelstaff Jack H. , Mason Matthew , Katsinelos Taxiarchis , McEwan William A. , Ghetti Bernardino , Tolkovsky Aviva M. , Spillantini Maria Grazia 
Published: February 2021

AbstractThe microtubule-associated protein tau aggregates in multiple neurodegenerative diseases, causing inflammation and changing the inflammatory signature of microglia by unknown mechanisms. We have shown that microglia phagocytose live neurons containing tau aggregates cultured from P301S tau transgenic mice due to neuronal tau aggregate-induced exposure of the ‘eat me’ signal phosphatidylserine. Here we show that after phagocytosis, microglia become hypophagocytic while releasing seed-competent insoluble tau aggregates. These microglia activate acidic β-galactosidase, and release senescence-associated cytokines and matrix remodeling enzymes alongside tau, indicating a senescent phenotype. In particular, the marked NFκB-induced activation of matrix metalloprotease 3 (MMP3/stromelysinl) was replicated in the brains of P301S mutant tau transgenic mice, and in human brains from tauopathy patients. These data show that microglia that have been activated to ingest live neurons with tau aggregates behave hormetically, becoming hypofunctional while acting as vectors of tau aggregate spreading.
Asymmetric Contraction of Adherens Junctions arises through RhoA and E-cadherin feedback
Authors: Cavanaugh Kate E. , Staddon Michael , Chmiel Theresa A. , Harmon Robert , Budnar Srikanth , Yap Alpha S. , Banerjee Shiladitya , Gardel Margaret L. 
Published: February 2021

AbstractTissue morphogenesis often arises from the culmination of discrete changes in cell-cell junction behaviors, namely ratcheted junction contractions that lead to collective cellular rearrangements. Mechanochemical signaling in the form of RhoA underlies these ratcheted contractions, which occur asymmetrically as one highly motile vertex contracts toward a relatively less motile tricellular vertex. The underlying mechanisms driving asymmetric vertex movement remains unknown. Here, we use optogenetically controlled RhoA in model epithelia together with biophysical modeling to uncover the mechanism lending to asymmetric vertex motion. We find that both local and global RhoA activation leads to increases in junctional tension, thereby facilitating vertex motion. RhoA activation occurs in discrete regions along the junction and is skewed towards the less-motile vertex. At these less-motile vertices, E-cadherin acts as an opposing factor to limit vertex motion through increased frictional drag. Surprisingly, we uncover a feedback loop between RhoA and E-cadherin, as regional optogenetic activation of specified junctional zones pools E-cadherin to the location of RhoA activation. Incorporating this circuit into a mathematical model, we find that a positive feedback between RhoA-mediated tension and E-cadherin-induced frictional drag on tricellular vertices recapitulates experimental data. As such, the location of RhoA determines which vertex is under high tension, pooling E-cadherin and increasing the frictional load at the tricellular vertex to limit its motion. This feedback drives a tension-dependent intercellular “clutch” at tricellular vertices which stabilizes vertex motion upon tensional load.
Towards a two-stage model of action-stopping: Attentional capture explains motor inhibition during early stop-signal processing
Authors: Tatz Joshua R. , Soh Cheol , Wessel Jan R. 
Published: February 2021

SummaryThe ability to stop an already initiated action is paramount to adaptive behavior. Most scientific debate in the field of human action-stopping currently focuses on two interrelated questions. First: Which mental and neural processes underpin the implementation of inhibitory control, and which reflect the attentional detection of salient stop-signals instead? Second: Why do physiological signatures of inhibition occur at two different latencies after stop-signals (for visual signals, either before or after ∼150ms)? Here, we address both questions via two pre-registered experiments that combined transcranial magnetic stimulation, electromyography, and multi-variate pattern analysis of whole-scalp electroencephalography. Using a stop-signal task that also contained a second type of salient signal that did not require stopping, we found that both signals induced equal amounts of early-latency inhibitory activity, whereas only later signatures (after 175ms) distinguished the two. These findings resolve ongoing debates in the literature and strongly suggest a two-step model of action-stopping.
Podophyllotoxin and Quercetinin SilicoDerivatives Docking Analysis with Cyclooxygenase-2 and Aminopeptidase-N
Authors: Manukyan A.E. , Hovhannisyan A.A. 
Published: February 2021

ABSTRACTThe cyclooxygenase (COX) enzymesaretumor markers, the inhibition of which can be used in the prevention and therapy of carcinogenesis. It was found that COX-2 IS considered as targets for tumor inhibition. Aminopeptidase N (APN) is a type II membrane-bound metalloprotease associated with cancer, being identified as a cell marker on the surface of malignant myeloid cells and reached a high level of expression in progressive tumors. In anticancer therapy, plant compounds are considered that can inhibit their activity. Modeling of the COX-2 and APN enzymes was carried out on the basis of molecular models of three-dimensional structures from the PDB database [PDB ID: 5f19, 4fyq] RCSB. For docking analysis, 3D ligand models were created using MarvinSketch based on the PubChem database [CID: 5280343, 5281654].In silicoexperiments, for the first time, revealed the possible interaction and inhibition of COX-2 and APN by quercetin and quercetin derivatives. Aspirin and Marimastat were taken to compare the results. Possible biological activities and possible side effects of the ligands have been identified.
On bridging paired-end RNA-seq data
Authors: Li Xiang , Shi Qian , Shao Mingfu 
Published: February 2021

AbstractMotivationThe widely-used high-throughput RNA-sequencing technologies (RNA-seq) usually produce paired-end reads. We explore if full fragments can be computationally reconstructed from the sequenced two ends—a problem here we refer to asbridging. Solving this problem provides longer, more informative RNA-seq reads, and hence benefits downstream RNA-seq analysis such as transcriptome assembly and expression quantification. However, bridging is a challenging and complicated task owing to alternative splicing, transcript noises, and sequencing errors. It remains unclear if the data itself provides sufficient information for accurate bridging, let alone proper models and efficient algorithms that characterize and determine the true bridges.Algorithmic ResultsWe studied this problem in two settings: reference-based bridging, which assumes reads alignments are available and reconstructs the alignments of full fragments, andde novobridging, which reconstructs sequences of entire fragments from sequences of the two ends. We proposed a novel mathematical formulation that works for both settings—to seek a path in an underlying graph data structure (i.e., splice graph for reference-based bridging, and compacted de Bruijn graph for de novo bridging) such that its bottleneck weight is maximized. This formulation characterizes true bridges and is efficient in filtering out false bridges. This formulation admits optimal substructure property, and hence efficient dynamic programming algorithms can be designed. For reference-based bridging, we designed such an algorithm to calculate the topNbridging paths, followed by a voting approach to select one using the distribution of fragment length. Forde novobridging, we designed a new truncated Dijkstra’s algorithm. To further speed up, we proposed a novel algorithm that reuses the shortest path tree to avoid running the truncated Dijkstra’s algorithm from scratch for all vertices. These innovations result in scalable algorithms that can bridge all paired-end reads in a compacted de Bruijn graph with millions of vertices.Experimental ResultsWe showed that paired-end RNA-seq reads can be accurately bridged to a large extend. Our reference-based bridging tool could correctly bridge more than 79.6% of reads. Forde novobridging, high precision was observed with varied sensitivity. We also showed that bridging can improve reference-based transcript assembly: the improvement was significant (up to 14.4% measured with adjusted precision), and universal in all combinations with different aligners and assemblers.AvailabilityImplementations of the algorithms for reference-based andde novobridging are available athttps://github.com/Shao-Group/rnabridge-alignandhttps://github.com/Shao-Group/rnabridge-denovo, respectively. Scripts, datasets, and documentations that can reproduce the experimental results in this manuscript are available athttps://github.com/Shao-Group/rnabridge-test.
Considerations on activity determinants of fungal polyphenol oxidases based on mutational and structural studies
Authors: Nikolaivits Efstratios , Valmas Alexandros , Dedes Grigorios , Topakas Evangelos , Dimarogona Maria 
Published: February 2021

ABSTRACTPolyphenol oxidases (PPOs) are an industrially relevant family of enzymes, being involved in the post-harvest browning of fruits and vegetables, as well as in human melanogenesis. Their involvement lies in their ability to oxidize phenolic or polyphenolic compounds, that subsequently form pigments. PPO family includes tyrosinases and catechol oxidases, which in spite of their high structural similarity, exhibit different catalytic activities. Long-standing research efforts have not yet managed to decipher the structural determinants responsible for this differentiation, as every new theory is disproved by a more recent study. In the present work, we combined biochemical along with structural data, in order to rationalize the function of a previously characterized PPO fromThermothelomyces thermophila(TtPPO). The crystal structure of aTtPPO variant, determined at 1.55 Å resolution, represents the second known structure of an ascomycete PPO. Kinetic data of structure-guided mutants prove the implication of “gate” residue L306, residue HB1+1 (G292) and HB2+1 (Y296) inTtPPO function against various substrates. Our findings demonstrate the role of L306 in the accommodation of bulky substrates and that residue HB1+1 is unlikely to determine monophenolase activity as suggested from previous studies.IMPORTANCEPPOs are enzymes of biotechnological interest. They have been extensively studied both biochemically and structurally, with a special focus on the plant-derived counterparts. Even so, explicit description of the molecular determinants of their substrate specificity is still pending. Especially for ascomycete PPOs, only one crystal structure has been determined so far, thus limiting our knowledge on this tree branch of the family. In the present study, we report the second crystal structure of an ascomycete PPO. Combined with site-directed mutagenesis and biochemical studies, we depict the amino acids in the vicinity of the active site that affect enzyme activity, and perform a detailed analysis on a variety of substrates. Our findings improve current understanding of structure-function relations of microbial PPOs, which is a prerequisite for the engineering of biocatalysts of desired properties.
Bioptim, a Python framework for Musculoskeletal Optimal Control in Biomechanics
Authors: Michaud Benjamin , Bailly François , Charbonneau Eve , Ceglia Amedeo , Sanchez Léa , Begon Mickael 
Published: February 2021

AbstractMusculoskeletal simulations are useful in biomechanics to investigate the causes of movement disorder, to estimate non-measurable physiological quantities or to study the optimality of human movement. We introduceBioptim, an easy-to-use Python framework for biomechanical optimal control, handling musculoskeletal models. Relying on algorithmic differentiation and the multiple shooting formulation,Bioptiminterfaces nonlinear solvers to quickly provide dynamically consistent optimal solutions. The software is both computationally efficient (C++ core) and easily customizable, thanks to its Python interface. It allows to quickly define a variety of biomechanical problems such as motion tracking/prediction, muscle-driven simulations, parameters optimization, multiphase problems, etc. It is also intended for real-time applications such as moving horizon estimation and model predictive control. Six contrasting examples are presented, comprising various models, dynamics, objective functions and constraints. They include data-driven simulations (i.e., a multiphase muscle driven gait cycle and an upper-limb real-time moving horizon estimation of muscle forces) and predictive simulations (i.e., a muscle-driven pointing task, a twisting somersault with a quaternion-based model, a position controller using external forces, and a multiphase torque-driven maximum-height jump motion).
Bioorthogonal labeling of transmembrane proteins with non-canonical amino acids allows access to masked epitopes in live neurons
Authors: Bessa-Neto Diogo , Kuhlemann Alexander , Beliu Gerti , Pecoraro Valeria , Doose Sören , Retailleau Natacha , Chevrier Nicolas , Perrais David , Sauer Markus , Choquet Daniel 
Published: February 2021

ABSTRACTProgress in biological imaging is intrinsically linked to advances in labeling methods. The explosion in the development of high-resolution and super-resolution imaging calls for new approaches to label targets with small probes. These should allow to faithfully report the localization of the target within the imaging resolution – typically nowadays a few nanometers - and allow access to any epitope of the target, in the native cellular and tissue environment. We report here the development of a complete labeling and imaging pipeline using genetic code expansion and non-canonical amino acids in primary neurons that allows to fluorescently label masked epitopes in target transmembrane proteins in live neurons, both in dissociated culture and organotypic brain slices. This allowed us to image the differential localization of two glutamate receptor auxiliary proteins in complex with their partner with a variety of methods including widefield, confocal, anddSTORM super-resolution microscopy.
Ethnography of the socio-sanitary reception in Rome. How are HIV/AIDS and hepatitis b involved in creating the construction of legal categories assigned to migrants?
Authors: Santilli Cecilia 
Published: February 2021

Purpose
This paper aims to investigate the role that Italian third sector organizations have in the process of social and administrative categorization of newly arrived migrants living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/Aids) or hepatitis b. In Italy, free access to health is provided to all migrants and residence permits for medical treatment is granted for migrants living with a “serious illness” since the 1990s. The case of HIV/Aids and hepatitis b shows how this political openness, however, clashes with the tightening of migration policies.

Design/methodology/approach
The study is based on ethnographic research conducted between 2014 and 2016 within an associative centre that deals with the socio-health care of newly arrived migrants in Rome. In addition to the participant observations, the study is based in semi-structured interviews conducted with 10 health-care providers (nurses, health-care assistants and socio-cultural mediators) and doctors and with 22 migrants coming from Sub-Saharan Africa and living with HIV/AIDS (10) and hepatitis b (12).

Findings
In Italy, the two infections have been identified as top diseases among migrant populations in the country but if HIV/Aids is always considered as a “serious illness”, hepatitis b is considered as a public health priority only in the case of a treatment prescription. These aspects have an important impact on the interactions between medical and social professionals and migrants affected by HIV/AIDS and hepatitis b, contributing differently to the creation of legal categories assigned to migrants.

Originality/value
The case of HIV/Aids and hepatitis b shows how the political openness of the public health system, clashes with the tightening of migration policies and analyse the role of the third sector has in this issue.
A bibliometric analysis of the International Journal of Islamic and Middle Eastern Finance and Management
Authors: Özdemir Mücahit , Selçuk Mervan 
Published: February 2021

Purpose
The purpose of this paper is to indicate the current state of studies on Islamic finance and management through a bibliometric analysis of the only social science citation index (SSCI)-indexed journal in this field.

Design/methodology/approach
The paper uses a bibliometric analysis, collecting data from the 319 papers published in the International Journal of Islamic and Middle Eastern Finance and Management (IMEFM) from 2008 to 2019. Moreover, VOSviewer software has been used to illustrate the citation analysis (including most cited papers, most cited authors and authors’ affiliated institutions and countries) and the keyword map.

Findings
The number of papers published in each issue of the IMEFM is found to have significantly increased owing to its unique situation being the only SSCI-indexed journal in this domain. The share of the empirical researches in total papers published annually has steadily risen, reaching 95% in 2019. In terms of case countries, although Malaysia is the most examined country in the papers, other countries such as Indonesia and Turkey are found to have been used as a case country by researchers recently. Islamic banking-related papers are the most prevalent studies, as expected, with mainly their performance being examined. Meanwhile, the number of papers about Islamic social financial institutions has notably grown in recent years. Finally, technology-based initiatives such as crowdfunding and cryptocurrencies are noted to have not yet been the subject of any paper.

Originality/value
The main contribution of this study is its analysis of the only SSCI-indexed journal on Islamic finance and management using bibliometrics. Also, all the papers published in the journal have been reviewed in terms of methodology, case country/country groups and topics/subtopics to lead the way for future research.