bluuebunny/crossref_metadata_2025 huggingface dataset:
The nuclear effector ArPEC25 from the necrotrophic fungusAscochyta rabieitargets the chickpea transcription factor CaβLIM1a and negatively modulates lignin biosynthesis for host susceptibility
Authors: Singh Shreenivas Kumar , Verma Sandhya , Singh Kunal , Shree Ankita , Singh Ritu , Srivastava Vikas , Kumar Kamal , Pandey Ashutosh , Verma Praveen Kumar
Published: September 2021

Fungal pathogens deploy a barrage of secreted effectors to subvert host immunity, often by evading, disrupting, or altering key components of transcription, defense signaling, and metabolic pathways. However, the underlying mechanisms of effectors and their host targets are largely unexplored in necrotrophic fungal pathogens. Here, we describe the effector protein ArPEC25, which is secreted by the necrotrophAscochyta rabiei, the causal agent of Ascochyta blight disease in chickpea (Cicer arietinum), and is indispensable for virulence. After entering host cells, ArPEC25 localizes to the nucleus and targets the host LIM transcription factor CaβLIM1a. CaβLIM1a is a transcriptional regulator ofCaPAL1, which encodes phenylalanine ammonia lyase, the regulatory, gatekeeping enzyme of the phenylpropanoid pathway. ArPEC25 inhibits the transactivation of CaβLIM1a by interfering with its DNA binding ability. This results in negative regulation of the phenylpropanoid pathway and decreased levels of intermediates of lignin biosynthesis, thereby suppressing lignin production. Our findings illustrate the role of fungal effectors in enhancing virulence by targeting a key defense pathway that leads to the biosynthesis of various secondary metabolites and antifungal compounds. This study provides a template for the study of less explored necrotrophic effectors and their host target functions.

One-sentence summary

TheAscochyta rabieieffector ArPEC25 enters the host nucleus and targets the transcription factor CaβLIM1a to manipulate phenylpropanoid pathway for negative modulation of chickpea lignin biosynthesis.
Males are more sensitive to their audience than females when scent-marking in the redfronted lemur
Authors: Peckre Louise R. , Michiels Alexandra , Socias-Martínez Lluís , Kappeler Peter M. , Fichtel Claudia
Published: September 2021

Audience effects, i.e. changes in behaviour caused by the presence of conspecifics, have rarely been studied in the context of olfactory communication, even though they may provide important insights into the functions of olfactory signals. Functional sex differences in scent-marking behaviours are common and influenced by the social system. To date, patterns of functional sex differences in scent-marking behaviours remain unknown in species without overt dominance relationships. We investigated sex differences in intra-group audience effects on anogenital scent-marking in a wild population of redfronted lemurs (Eulemur rufifrons) by performing focal scent-marking observations. With a combination of generalised linear mixed models and exponential random graph models, we found different audience effects in both sexes. Males were overall more sensitive than females to their audience. Only males seemed to be sensitive to the presence of both members of the opposite sex and same-sex conspecifics in the audience. Females were only moderately sensitive to the presence of other females in the audience. This study offers a potential behavioural pattern associated with anogenital scent-marking that seem to differ from those described for species exhibiting female dominance, supporting the notion that the social systems co-varies with scent-marking behaviours and scent-complexity in strepsirrhines.
The AmiC/NlpD pathway dominates peptidoglycan breakdown in Neisseria meningitidis and affects cell separation, NOD1 agonist production, and infection
Authors: Chan Jia Mun , Hackett Kathleen T. , Woodhams Katelynn L. , Schaub Ryan E. , Dillard Joseph P.
Published: September 2021

The human-restricted pathogen Neisseria meningitidis, which is best known for causing invasive meningococcal disease, has a nonpathogenic lifestyle as an asymptomatic colonizer of the human naso- and oropharyngeal space. N. meningitidis releases small peptidoglycan (PG) fragments during growth. It was demonstrated previously that N. meningitidis releases low levels of tripeptide PG monomer, which is an inflammatory molecule recognized by the human intracellular innate immune receptor NOD1. In this present study, we demonstrated that N. meningitidis released more PG-derived peptides compared to PG monomers. Using a reporter cell line overexpressing human NOD1, we showed that N. meningitidis activates NOD1 using PG-derived peptides. Generation of such peptides required the presence of the periplasmic N-acetylmuramyl-L-alanine amidase AmiC, and the outer membrane lipoprotein, NlpD. AmiC and NlpD were found to function in cell separation, and mutation of either amiC or nlpD resulted in large clumps of unseparated N. meningitidis cells instead of the characteristic diplococci. Using stochastic optical reconstruction microscopy, we demonstrated that FLAG epitope-tagged NlpD localized to the septum, while similarly-tagged AmiC was found at the septum in some diplococci but distributed around the cell in most cases. In a human whole blood infection assay, an nlpD mutant was severely attenuated and showed particular sensitivity to complement. Thus, in N. meningitidis the cell separation proteins AmiC and NlpD are necessary for NOD1 stimulation and for survival during infection of human blood.
Long COVID: Assessment of Neuropsychiatric Symptoms in Children and Adolescents - A Clinical Data Analysis
Authors: Frölich Jan , Banaschewski Tobias , Ulmer Annabelle
Published: September 2021

COVID-19 infections in adults often result in medical, neuropsychiatric, and unspecific symptoms, called Long COVID, and the premorbid functional status cannot be achieved. Regarding the course in children and adolescents, however, reliable data are not yet available.

Objective

380 children and adolescents/young adults aged between 6 and 21 years, being treated for various psychiatric diseases in an outpatient clinical service, were examined for COVID-19 infections and Long COVID symptoms following a structured protocol.

Results

Three patients had COVID-19; one patient had symptoms of Long COVID in his medical history, but they could not be objectivized in an in-depth neuropsychiatric and neuropsychological assessment.

Conclusions

Long COVID seems to occur rarely in children and adolescents. Objectivizing the symptoms is a difficult task that requires various diagnostic considerations.
Two new compartmental epidemiological models and their equilibria
Authors: Balisacan Jonas , Chyba Monique , Shanbrom Corey
Published: September 2021

Abstract

Compartmental models have long served as important tools in mathematical epidemiology, with their usefulness highlighted by the recent COVID-19 pandemic. However, most of the classical models fail to account for certain features of this disease and others like it, such as the ability of exposed individuals to recover without becoming infectious, or the possibility that asymptomatic individuals can indeed transmit the disease but at a lesser rate than the symptomatic. Furthermore, the rise of new disease variants and the imperfection of vaccines suggest that concept of endemic equilibrium is perhaps more pertinent than that of herd immunity.

Here we propose a new compartmental epidemiological model and study its equilibria, characterizing the stability of both the endemic and disease-free equilibria in terms of the basic reproductive number. Moreover, we introduce a second compartmental model, generalizing our first, which accounts for vaccinated individuals, and begin an analysis of its equilibria.
CaV1.3 enhanced store operated calcium promotes resistance to androgen deprivation in prostate cancer
Authors: O’Reilly Debbie , Downing Tim , Kouba Sana , Potier-Cartereau Marie , McKenna Declan J , Vandier Christophe , Buchanan Paul
Published: September 2021

Androgen deprivation therapy (ADT) is the main treatment for advanced prostate cancer (PCa) but resistance results in progression to terminal castrate resistant PCa (CRPC), where there is an unmet therapeutic need. Aberrant intracellular calcium (Cai2+) is known to promote neoplastic transformation and treatment resistance. There is growing evidence that expression of voltage gated calcium channels (VGCC) is increased in cancer, particularly the CACNA1D/CaV1.3 in CRPC. The aim of this study was to investigate if increased CaV1.3 drives resistance to ADT and determine its associated impact on Cai2+ and cancer biology.

Bioinformatic analysis revealed that CACNA1D gene expression is increased in ADT treated PCa patients regardless of TMPRSS2:ERG status. Corroborated in both in vivo LNCaP xenograft mouse and in vitro PCa cell line models which demonstrated a significant increase in CaV1.3 protein expression following ADT with bicalutamide. The expression was found to be a shortened 170kDA CaV1.3 isoform associated which failed to mediate calcium influx following membrane depolarisation. Instead, under ADT CaV1.3 mediated a rise in basal cytosolic calcium and an increase in store operated calcium entry (SOCE). This in turn drove both proliferation and survival of long-term ADT CRPC cells.

Overall, this study demonstrates for the first time in PCa that increased SOCE through a novel CaV1.3 mechanism which represents a novel oncogenic switch that contributes to ADT resistance and promotes CRPC biology. Highlighting aberrant intracellular calcium in CRPC as a potential area for therapeutic development to improve patient outcomes.
Evolution and functional dynamics of dehydrins in model Brachypodium grasses
Authors: Decena M.A. , Galvez-Rojas S. , Agostini F. , Sancho R. , Contreras-Moreira B. , Des Marais D. L. , Hernández P. , Catalán P.
Published: September 2021

Dehydration proteins (dehydrins, DHNs) confer tolerance to water-stress deficit to plants, thus playing a fundamental role in plant response and adaptation to water-deprivation stressful environments. We have performed a comparative genomics and evolutionary study of DHN genes in four model Brachypodium grass species, and a drought-induced functional analysis in 32 ecotypes of the flagship species B. distachyon, to gain insight into the origins and dynamics of these proteins and the correlated drought-mediated phenotypic responses in ecotypes showing different hydric requirements. Genomic sequence analysis detected 10 types of dehydrin genes (Bdhn) across the Brachypodium species, totalling 47 genes. Domain and conserved motif contents of peptides encoded by Bdhn genes revealed eight protein architectures, YSɸK2 being the most common architecture. Bdhn genes were spread across several chromosomes and more frequent in syntenic chromosomes 3 and 4 of B. distachyon, 4 and 5 of B. stacei and 4 of B. sylvaticum. Tandem and segmental duplication events were detected for four Bdhn genes. Selection analysis indicated that all the Bdhn genes were constrained by purifying selection. Three upstream cis-regulatory motifs (BES1, MYB124, ZAT) were consistently detected in several Bdhn genes. Functional analysis in 32 natural accessions of B. distachyon demonstrated that only four Bdhn genes (Bdhn1, Bdhn2, Bdhn3, Bdhn7) were expressed in mature leaves and that all of them were significantly more highly expressed in plants under drought conditions. These genes corresponded to wheat orthologs that were also significantly more expressed under drought stress. Brachypodium dehydrin expression was significantly correlated with drought-response phenotypic traits (plant biomass, leaf carbon and proline contents and WUE increases, leaf water and nitrogen content changes) being more pronounced in drought-tolerant ecotypes. Bdhn expression, associated phenotypic trait changes and climate niche variation did not show significant phylogenetic signal when tested in the B. distachyon genealogical-species tree. By contrast, some of them showed low or marginal significant phylogenetic signal when tested in the B. distachyon Bdhn tree, suggesting that Bdhn gene evolution is partially related to adaptation to drought in this species. Our results demonstrate that dehydrin composition and regulation is a key factor determining the acquisition of water-stress tolerance in grasses.
Tbet expression by Tregs is needed to protect against Th1-mediated immunopathology duringToxoplasmainfection in mice
Authors: Warunek Jordan , Jin Richard M. , Blair Sarah J. , Garis Matthew , Marzullo Brandon , Wohlfert Elizabeth A.
Published: September 2021

T. gondiiinfection has proven to be an ideal model to understand the delicate balance between protective immunity and immune-mediated pathology during infection. Lethal infection causes a collapse of Tregs mediated by loss of IL-2, and conversion of Tregs to IFNγ producing cells. Importantly, these Tregs highly express the Th1 transcription factor Tbet. To determine the role of Tbet in Tregs, we infectedTbx21f/f-Foxp3YFPCreand control Foxp3YFPCremice with the type II strain ofT. gondii, ME49. The majority ofTbx21f/f-Foxp3YFPCremice succumb to a non-lethal acute infection. Notably, parasite burden is comparable betweenTbx21f/f-Foxp3YFPCreand Foxp3YFPCrecontrol mice. We found thatTbx21f/f-Foxp3YFPCremice have significantly higher serum levels of proinflammatory cytokines IFNγ and TNFα, suggestive of a heightened immune response. To test if CD4+T cells were driving immunopathology, we treatedTbx21f/f-Foxp3YFPCremice with anti-CD4 depleting antibody and partially rescued these mice. Broad spectrum antibiotic treatment also improved survival, demonstrating a role for commensal flora in immunopathology inTbx21f/f-Foxp3YFPCremice. RNA-seq analysis reinforced that Tbet regulates several key cellular pathways, including chromosome segregation, cytokine receptor activity and cell cycle progression, that help to maintain fitness in Tregs during Th1 responses. Taken together, our data shows an important role for Tbet in Tregs in preventing lethal immunopathology duringToxoplasma gondiiinfection, further highlighting the protective role of Treg plasticity to self and microbiota.
Tissue scale properties of the extracellular matrix regulates nuclear shape, organisation and fate in the embryonic midline sutures
Authors: Alves-Afonso Diana , Ryan Allyson Quinn , Lahola-Chomiak Adrian , Prakash Mangal , Jug Florian , Modes Carl D. , Tabler Jacqueline M.
Published: September 2021

Balancing self-renewal and differentiation is a key feature of every stem cell niche and one that is tuned by mechanical interactions of cells with their neighbors and surrounding extracellular matrix. The fibrous stem cell niches that develop as sutures between skull bones must balance the complex extracellular environment that emerges to define them with self-renewal and bone production. Here, we address the role for physical stimuli in suture development by probing the relationship between nuclear shape, organization and gene expression in response to a developing collagen network in embryonic midline sutures. This work complements genetic approaches used to study sutures and provides the first quantitative analyses of physical structure in these sutures. By combining multiple imaging modalities with novel shape description, in addition to network analysis methods, we find the early emergence of a complex extracellular collagen network to have an important role in regulating morphogenesis and cell fate. We show that disrupted collagen crosslinking can alter ECM organization of midline sutures as well as stimulate expression of bone differentiation markers. Further, our findings suggest that in vivo, skeletal tissues can uncouple the response of the nuclear lamina from collagen mediated tissue stiffening seen in vitro. Our findings highlight a crucial relationship between the cellular microenvironment, tissue stiffness and geometry with gene expression in normal development and maintenance of progenitor fate in embryonic sutures.
Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly
Authors: Conde-Dusman María J. , Dey Partha N. , Elía-Zudaire Oscar , Rabaneda Luis G. , García-Lira Carmen , Grand Teddy , Briz Victor , Velasco Eric R. , Andero Raúl , Niñerola Sergio , Barco Angel , Paoletti Pierre , Wesseling John F. , Gardoni Fabrizio , Tavalin Steven J. , Pérez-Otaño Isabel
Published: September 2021

De novo protein synthesis is required for synapse modifications underlying stable memory encoding. Yet neurons are highly compartmentalized cells and how protein synthesis can be regulated at the synapse level is unknown. Here we characterize neuronal signaling complexes formed by the postsynaptic scaffold GIT1, the mTOR kinase and Raptor that couple synaptic stimuli to mTOR-dependent protein synthesis; and identify NMDA receptors containing GluN3A subunits as key negative regulators of GIT1 binding to mTOR. Disruption of GIT1/mTOR complexes by enhancing GluN3A expression or silencing GIT1 inhibits synaptic mTOR activation and restricts the mTOR-dependent translation of specific activity-regulated mRNAs. Conversely, GluN3A removal enables complex formation, potentiates mTOR-dependent protein synthesis, and facilitates the consolidation of associative and spatial memories in mice. The memory enhancement becomes evident with light or spaced training, can be achieved by selectively deleting GluN3A from excitatory neurons during adulthood, and does not compromise other aspects of cognition such as memory flexibility or extinction. Our findings provide mechanistic insight into synaptic translational control and reveal a potentially selective target for cognitive enhancement.
Structural anatomy of C1 domain interactions with DAG and other agonists
Authors: Katti Sachin S. , Krieger Inna V. , Ann Jihyae , Lee Jeewoo , Sacchettini James C. , Igumenova Tatyana I.
Published: September 2021

Diacylglycerol (DAG) is a versatile lipid whose 1,2-sn-stereoisomer serves both as second messenger in signal transduction pathways that control vital cellular processes, and as metabolic precursor for downstream signaling lipids such as phosphatidic acid1,2. DAG effector proteins compete for available lipid using conserved homology 1 (C1) domains as DAG-sensing modules. Yet, how C1 domains recognize and capture DAG in the complex environment of a biological membrane has remained unresolved for the 40 years since the discovery of Protein Kinase C (PKC)3 as the first member of the DAG effector cohort. Herein, we report the first high-resolution crystal structures of a C1 domain (C1B from PKCδ) complexed to DAG and to each of four potent PKC agonists that produce different biological readouts and that command intense therapeutic interest. This structural information details the mechanisms of stereospecific recognition of DAG by the C1 domains, the functional properties of the lipid-binding site, and the identities of the key residues required for the recognition and capture of DAG and exogenous agonists. Moreover, the structures of the five C1 domain complexes provide the high-resolution guides for the design of agents that modulate the activities of DAG effector proteins.
In lupus nephritis, specificin situinflammatory states are associated with refractory disease and progression to renal failure
Authors: Abraham Rebecca , Durkee Madeleine , Ai Junting , Veselits Margaret , Casella Gabriel , Asano Yuta , Chang Anthony , Ko Kichul , Oshinsky Charles , Peninger Emily , Giger Maryellen , Clark Marcus R.
Published: September 2021

In human lupus nephritis (LN), tubulointerstitial inflammation (TII) on biopsy predicts progression to end stage renal disease (ESRD). However, while approximately half of patients with moderate or severe TII develop ESRD, half do not. Therefore, we hypothesized that TII is heterogeneous, with distinct inflammatory states associated with different renal outcomes. We interrogated renal biopsies from LN longitudinal and cross-sectional cohorts using both conventional and highly multiplexed confocal microscopy. To accurately segment cells across whole biopsies, and to understand their spatial relationships, we developed unique computational pipelines by training and implementing several deep learning models and other computer vision techniques. Surprisingly, across biopsies, high B cell densities were strongly associated with protection from ESRD. In contrast, elevated CD4-T cell population densities, which included CD8, γδ and double negative (CD4-CD8-δ-, DN) T cells, were associated with both acute refractory renal failure and gradual progression to ESRD. Interestingly, lymphocytes and dendritic cells were organized into discrete clusters or neighborhoods that could be characterized by the enrichment for specific cell populations. B cells were often organized into large neighborhoods with CD4+ T cells including T follicular helper-like cells. In contrast, the CD4-T cell populations formed small cellular neighborhoods whose frequency predicted subsequent progression to ESRD. These data reveal that in LN, specificin situinflammatory states are associated with refractory disease and progression to ESRD.

One sentence summary

Using deep machine learning to analyze confocal microscopy data, we demonstrate that in lupus nephritis, CD4-T cell populations, including CD8+ and γδ T cells, organize into specific spatial neighborhoods that predict progression to renal failure.
AbmR is a mycobacterial dual-function transcription factor and ribonucleoprotein with distinct DNA and RNA-binding determinants
Authors: Girardin Roxie C. , Pata Janice , Qin Xiaohong , Sui Haixin , McDonough Kathleen A.
Published: September 2021

The bacteriumMycobacterium tuberculosis(Mtb) must adapt to myriad host-associated stressors. A recently identified transcription factor, AbmR (ATP-bindingmcr11-regulator), regulates expression of an essential stress-responsive small RNA (Mcr11) and inhibits the growth of Mtb. Previously, AbmR was found to make 39S complexes of unknown function. Here we report that AbmR 39S complexes are comprised of AbmR and co-purifying RNAs and that RNA-binding inhibits AbmR’s DNA-binding function. While AbmR binds DNA and regulates gene expression in a sequence specific manner, RNA-binding is not sequence specific. Amino acid R146 is important for DNA-binding but completely dispensable for RNA-binding and 39S complex formation, establishing that the RNA- and DNA-binding functions of AbmR are distinct. RNA bound by AbmR was protected from RNase digestion, supporting an RNA modulatory function for the 39S complex. We also found thatabmRis required for optimal survival during treatment with the ATP-depleting antibiotic bedaquiline, which is associated with extended RNA stability. These data establish a paradigm wherein a transcription factor assembles into large complexes to transition between mutually exclusive DNA-binding gene regulatory and RNA-binding RNA modulatory functions. Our findings indicate that AbmR is a dual-function protein that may have novel RNA regulatory roles in stress adapted Mtb.
IL-10 receptor blockade delivered simultaneous with BCG vaccination sustains long term protection against Mycobacterium tuberculosis infection in mice
Authors: Dwivedi Varun , Gautam Shalini , Headley Colwyn A. , Piergallini Tucker , Torrelles Jordi B , Turner Joanne
Published: September 2021

Mycobacterium bovis bacillus Calmette-Guérin (BCG) immunization still remains the best vaccination strategy available to control the development of active tuberculosis (TB). Protection afforded by BCG vaccination gradually wanes over time and while booster strategies have promise, they remain under development. An alternative approach is to improve BCG efficacy through host-directed therapy. Building upon prior knowledge that blockade of interleukin-10 receptor 1 (IL-10R1) during early Mycobacterium tuberculosis (M.tb) infection improves and extends control of M.tb infection in mice, we employed a combined anti-IL-10R1/BCG vaccine strategy. A subcutaneous, single vaccination of BCG/αIL10-R1 increased the numbers of CD4+ and CD8+ central memory T cells, and reduced TH1 and TH17 cytokine levels in the lung for up to 7 weeks post vaccination. Subsequent M.tb challenge in mice showed both an early (4 week) and sustained long-term (47 week) control of infection, which was associated with increased survival. In contrast, protection of BCG/saline vaccinated mice waned 8 weeks post M.tb infection. Our findings demonstrate that a single and simultaneous vaccination with BCG/αIL10-R1 sustains long-term protection, identifying a promising approach to enhance and extend the current BCG mediated protection against TB.
Therapeutic activation of virus-specific resident memory T cells within the glioblastoma microenvironment
Authors: Ning Jianfang , Gavil Noah , Wu Shaoping , Wijeyesinghe Sathi , Weyu Eyob , Ma Jun , Li Ming , Grigore Florina-Nicoleta , Dhawan Sanjay , Skorput Alexander G.J. , Musial Shawn C , Chen Clark C , Masopust David , Rosato Pamela C
Published: September 2021

Glioblastoma multiforme (GBM) is among the most aggressive, treatment resistant cancers, and despite standard of care surgery, radiation and chemotherapy, is invariably fatal. GBM is marked by local and systemic immunosuppression, contributing to resistance to existing immunotherapies that have had success in other tumor types. Memory T cells specific for previous infections reside in tissues throughout the host and these tissue resident memory T cells (TRM) are capable of rapid and potent immune activation. Here, we show that virus-specific memory CD8+ T cells expressing tissue resident markers populate mouse and human glioblastoma microenvironment. Reactivating virus-specific TRM through intra-tumoral delivery of adjuvant-free virus-derived peptide triggered local immune activation. This delivery translated to anti-neoplastic effects, which improved survival in a murine glioblastoma model. Our results indicate that virus-specific TRM are a significant part of the glioblastoma immune microenvironment and can be leveraged to promote anti-tumoral immunity.
Machine learning enables accurate and rapid prediction of active molecules against breast cancer cells
Authors: He Shuyun , Zhao Duancheng , Ling Yanle , Cai Hanxuan , Cai Yike , Zhang Jiquan , Wang Ling
Published: September 2021

Breast cancer (BC) has surpassed lung cancer as the most frequently occurring cancer, and it is the leading cause of cancer-related death in women. Therefore, there is an urgent need to discover or design new drug candidates for BC treatment. In this study, we first collected a series of structurally diverse datasets consisting of 33,757 active and 21,152 inactive compounds for 13 breast cancer cell lines and one normal breast cell line commonly used in in vitro antiproliferative assays. Predictive models were then developed using five conventional machine learning algorithms, including naïve Bayesian, support vector machine, k-Nearest Neighbors, random forest, and extreme gradient boosting, as well as five deep learning algorithms, including deep neural networks, graph convolutional networks, graph attention network, message passing neural networks, and Attentive FP. A total of 476 single models and 112 fusion models were constructed based on three types of molecular representations including molecular descriptors, fingerprints, and graphs. The evaluation results demonstrate that the best model for each BC cell subtype can achieve high predictive accuracy for the test sets with AUC values of 0.689–0.993. Moreover, important structural fragments related to BC cell inhibition were identified and interpreted. To facilitate the use of the model, an online webserver called ChemBC and its local version software were developed to predict potential anti-BC agents.

Availability

ChemBC webserver is available at http://chembc.idruglab.cn/ and its local version Python software is maintained at a GitHub repository (https://github.com/idruglab/ChemBC).

Contact

zjqgmc@163.com or lingwang@scut.edu.cn

Supplementary information

Supplementary data are available at Bioinformatics online.
Chromatin accessibility combined with enhancer clusters activation mediates heterogeneous response to dexamethasone in myeloma cells
Authors: Gaborit Victor , Cruard Jonathan , Guerin-Charbonnel Catherine , Derrien Jennifer , Alberge Jean-Baptiste , Douillard Elise , Roi Nathalie , Devic Magali , Campion Loïc , Westermann Frank , Moreau Phillipe , Herrmann Carl , Bourdon Jérémie , Magrangeas Florence , Minvielle Stéphane
Published: September 2021

Glucocorticoids (GC) effects occur through binding to the GC receptor (GR) which, once translocated to the nucleus, binds to GC response elements (GREs) to activate or repress target genes. Among GCs, dexamethasone (Dex) is widely used in treatment of multiple myeloma (MM), mainly in combination regimens. However, despite a definite benefit, all patients relapse. Moreover, while GC efficacy can be largely attributed to lymphocyte-specific apoptosis, its molecular basis remains elusive.

To determine the functional role of GR binding in myeloma cells, we generated bulk and single cell multi-omic data and high-resolution contact maps of active enhancers and target genes. We show that a minority (6%) of GR binding sites are associated with enhancer activity gains and increased interaction loops. We find that enhancers contribute to regulate gene activity through combinatorial assembly of large stretches of enhancers and/or enhancer cliques. Furthermore, one enhancer, proximal to GR-responsive genes, is predominantly associated with increased chromatin accessibility and higher H3K27ac occupancy. Finally, we show that Dex exposure leads to co-accessibility changes between predominant enhancer and other regulatory regions of the interaction network. Notably, these epigenomic changes are associated with cell-to-cell transcriptional heterogeneity. As consequences, BIM critical for GR-induced apoptosis and CXCR4 protective from chemotherapy-induced apoptosis are rather upregulated in different cells.

In summary, our work provides new insights into the molecular mechanisms involved in Dex escape.
The Import of Skin Tissue Dynamics in Tactile Sensing
Authors: Rongala Udaya B. , Seyfarth Andre , Hayward Vincent , Jörntell Henrik
Published: September 2021

The mammalian skin is a densely innervated soft tissue where embedded neural mechanoreceptors report to the brain the mechanical events arising at its surface. Up to now, models of the transformations of these events into neural signals relied on quasistatic or viscoelastic mechanical models of the skin. Here, we employed a model which, in addition to elasticity and viscosity, accounted for mass to accurately reproduce the propagation of mechanical waves observed in vivo. Skin dynamics converted sensory inputs into rapidly evolving spatiotemporal patterns that magnified the information made available to a population of mechanoreceptors. Accounting for dynamics greatly enhanced the separability of tactile inputs and was efficient for a large range of mechanical parameter values. This advantage vanished when these parameters were set to approximate the quasistatic or viscoelastic cases.
Molecular organization and mechanics of single vimentin filaments revealed by super-resolution imaging
Authors: Vicente Filipe Nunes , Lelek Mickael , Tinevez Jean-Yves , Tran Quang D. , Pehau-Arnaudet Gerard , Zimmer Christophe , Etienne-Manneville Sandrine , Giannone Gregory , Leduc Cécile
Published: September 2021

Intermediate filaments (IF) are involved in key cellular functions including polarization, migration, and protection against large deformations. These functions are related to their remarkable ability to extend without breaking, a capacity that should be determined by the molecular organization of subunits within filaments. However, this structure-mechanics relationship remains poorly understood at the molecular level. Here, using super-resolution microscopy (SRM), we show that vimentin filaments exhibit a ~49 nm axial repeat both in cells and in vitro. As unit-length-filaments (ULFs) were measured at ~59 nm, this demonstrates a partial overlap of ULFs during filament assembly. Using an SRM-compatible stretching device, we also provide evidence that the extensibility of vimentin is due to the unfolding of its subunits and not to their sliding, thus establishing a direct link between the structural organization and its mechanical properties. Overall, our results pave the way for future studies of IF assembly, mechanical and structural properties in cells.
Accurate grasp detection learning using oriented regression loss
Authors: Zhao Xuan , Yu Hancheng , Feng Mingkui , Sun Gang
Published: September 2021

Purpose

Robot automatic grasping has important application value in industrial applications. Recent works have explored on the performance of deep learning for robotic grasp detection. They usually use oriented anchor boxes (OABs) as detection prior and achieve better performance than previous works. However, the parameters of their loss belong to different coordinates, this may affect the regression accuracy. This paper aims to propose an oriented regression loss to solve the problem of inconsistency among the loss parameters.

Design/methodology/approach

In the oriented loss, the center coordinates errors between the ground truth grasp rectangle and the predicted grasp rectangle rotate to the vertical and horizontal of the OAB. And then the direction error is used as an orientation factor, combining with the errors of the rotated center coordinates, width and height of the predicted grasp rectangle.

Findings

The proposed oriented regression loss is evaluated on the YOLO-v3 framework to the grasp detection task. It yields state-of-the-art performance with an accuracy of 98.8% and a speed of 71 frames per second with GTX 1080Ti on Cornell datasets.

Originality/value

This paper proposes an oriented loss to improve the regression accuracy of deep learning for grasp detection. The authors apply the proposed deep grasp network to the visual servo intelligent crane. The experimental result indicates that the approach is accurate and robust enough for real-time grasping applications.
Obstacle avoidance and path planning of humanoid robot using fuzzy logic controller aided owl search algorithm in complicated workspaces
Authors: Kashyap Abhishek Kumar , Parhi Dayal R.
Published: September 2021

Purpose

This paper aims to outline and implement a novel hybrid controller in humanoid robots to map an optimal path. The hybrid controller is designed using the Owl search algorithm (OSA) and Fuzzy logic.

Design/methodology/approach

The optimum steering angle (OS) is used to deal with the obstacle located in the workspace, which is the output of the hybrid OSA Fuzzy controller. It is obtained by feeding OSA's output, i.e. intermediate steering angle (IS), in fuzzy logic. It is obtained by supplying the distance of obstacles from all directions and target distance from the robot's present location.

Findings

The present research is based on the navigation of humanoid NAO in complicated workspaces. Therefore, various simulations are performed in a 3D simulator in different complicated workspaces. The validation of their outcomes is done using the various experiments in similar workspaces using the proposed controller. The comparison between their outcomes demonstrates an acceptable correlation. Ultimately, evaluating the proposed controller with another existing navigation approach indicates a significant improvement in performance.

Originality/value

A new framework is developed to guide humanoid NAO in complicated workspaces, which is hardly seen in the available literature. Inspection in simulation and experimental workspaces verifies the robustness of the designed navigational controller. Considering minimum error ranges and near collaboration, the findings from both frameworks are evaluated against each other in respect of specified navigational variables. Finally, concerning other present approaches, the designed controller is also examined, and major modifications in efficiency have been reported.
New Zealand’s ANZAC nurses: marketizing the great war for a 21st-century fit
Authors: Krisjanous Jayne , Hallett Christine
Published: September 2021

Purpose

The aim of this paper is to demonstrate how a historical event packaged as an iconic heritage cultural brand can be marketized and modified over time to ensure brand longevity and continued emotional commitment and loyalty through the leverage of stories and associations more closely aligned with modern-day audiences. The authors do this through examining the marketization of the New Zealand World War 1 (WWI) nurse to today’s audiences. The periods of study are WWI (1914–1918) and then the modern day. The New Zealand Army Nursing Service (NZANS) during WWI has previously had little attention as a key actor in the Australia and New Zealand Army Corp (ANZAC), Today ANZAC is held as pivotal in the birth of New Zealand’s perception of nationhood and as an iconic heritage cultural brand. The history and legend of the ANZAC plays an important role in New Zealand culture and is fundamental to the “Anzac Spirit”, a signifier of what it means to be a New Zealander.

Design/methodology/approach

A historical case study method is used. The primary source of data is 1914–1918, and includes contemporaneous articles, and personal writings: diaries, letters and published memoirs. More contemporary works form the basis for discussion of marketization as it relates to the NZANS. The article first presents conceptual framing, then the development of the Anzac brand and the history of the NZANS and its role in WWI before turning to discussion on the marketization of this nursing service to today’s audiences and as part of the ANZAC/Anzac brand.

Findings

Today the story of the WWI NZANS nurse, previously seldom heard, has been co-opted and is becoming increasingly merged as an integral part of the Anzac story. The history of the NZANS during WWI has a great deal of agency today as part of that story, serving many functions within it and providing a valuable lever for marketization.

Originality/value

To date, there is a scarcity of marketing analysis that examines the marketization of history. By focusing on New Zealand WWI nursing as a contributor to the Anzac story, the authors contribute to the understanding of how marketers package and contemporize history for appeal to audiences through both sustaining and reworking cultural branding.
An empirical examination of Green Star certification uptake and its relationship with BIM adoption in New Zealand
Authors: Doan Dat Tien , GhaffarianHoseini Ali , Naismith Nicola , Ghaffarianhoseini Amirhosein , Zhang Tongrui , Tookey John
Published: September 2021

Purpose

Green building information modelling (BIM) has been highlighted as an essential topic owing to its potential benefits. However, both Green Star and BIM are still in their earlier stages in New Zealand. This paper aims to examine and evaluate the benefits, barriers/challenges and solutions for the integration of Green Star and BIM in New Zealand.

Design/methodology/approach

In this paper, a total of 77 responses collected from construction professionals in New Zealand using questionnaires were analysed through descriptive and statistical tests.

Findings

Building performance modelling used for Green Star assessment can be implemented using BIM; this was highlighted as the most significant benefit of the integration. Whereas, the most significant barrier preventing the integration of Green Star and BIM was the fact they are two completely separate processes. Regarding the solutions for the integration, showcasing BIM-Green Star benchmark projects was considered as the most effective solution amongst a range of eight provided.

Originality/value

The research provided insights into Green Star–BIM integration in New Zealand. By evaluating the significance of the benefits, barriers/challenges and solutions for the integration, this research could be used as a guideline for Green Star and BIM development by New Zealand Green Building Council (NZGBC), the Government and construction practitioners in New Zealand. Specifically, the results here could be valuable inputs for Green Star manuals and the New Zealand BIM handbook.
Mediat(iz)ing Catholicism: saint, spectacle, and theopolitics in Lima, Peru
Authors: Norget Kristin
Published: September 2021

This article examines the annual public procession in Lima, Peru, of the Señor de los Milagros (Lord of Miracles) in relation to issues at the intersection of Catholic Christianity, media, and political authority. Through a theopolitical lens alert to the intermeshing of political sovereignty and authority with theological (Catholic) worldviews, I inquire into media and the Señor de los Milagros procession along three key intersecting themes that link scales of local and global Catholicism: performance, identity/belonging, and control. Key to my argument is the idea of the miraculous (lo milagroso), a culturally resonant register of embodied affective experience with compelling power, which points to how senses of belonging, authority, and ‘proper’ Catholic subjecthoods are intensified by Catholicism's diffusion through new mediatic forms, especially in church‐generated productions. A consideration of media technologies, mediation, and Catholicism nuances theoretical assumptions within the anthropology of Christianity, and also suggests that the anthropology of religion should attend more closely to mediation and mediatization as newer media infrastructures – channelling flows of information, images, and affects – extend ‘the religious’ into other social spheres.
A 10‐year retrospective review of management and outcomes of pseudoaneurysms at a tertiary referral centre
Authors: Schlegel Richard N , Clements Warren , Koukounaras Jim , Goh Gerard S , Joseph Tim , Phan Tuan , Moriarty Heather K
Published: September 2021

Introduction

Pseudoaneurysms are uncommon but potentially life‐threatening. Treatment may involve a variety of interventions including observation, manual compression, ultrasound‐guided thrombin injection and a variety of endovascular and surgical techniques. Current treatments are largely based on observational data and there is no consensus on management. This study aimed to provide evidence for guiding clinical decisions regarding visceral artery pseudoaneurysm and peripheral artery pseudoaneurysm management.

Methods

Retrospective single‐centre review of patients diagnosed with visceral and peripheral artery pseudoaneurysms at a tertiary hospital (2010–2020).

Results

There were 285 patients included in this study. A total of 86 patients were diagnosed with a visceral artery pseudoaneurysm, and 49 of these (57%) were caused by trauma. A total of 199 patients were identified with a peripheral pseudoaneurysm; 76 of these (38%) were caused by trauma and 69 (35%) were due to access site complication during an endovascular procedure. Initial technical success was achieved in 266 patients (93.3%) with 19 requiring an additional treatment to achieve success. Conservative treatment (100% success), endovascular treatment (98.1%) and surgery (100%) were more successful than ultrasound‐guided compression (63.6%) and thrombin injection (83.8%). The median time from diagnosis to intervention was <9 h for visceral artery pseudoaneurysms and 24 h for peripheral artery pseudoaneurysms. There was no change in survival outcomes with respect to time from diagnosis and intervention.

Conclusion

In this study, pseudoaneurysms were treated with a high degree of success by observation or by using an endovascular approach, and those requiring endovascular intervention did not need to be treated immediately in an emergent setting.
Comprehensive analysis of treatment modes and clinical outcomes of small cell lung cancer transformed from epidermal growth factor receptor mutant lung adenocarcinoma
Authors: Wang Shouzheng , Xie Tongji , Hao Xuezhi , Wang Yan , Hu Xingsheng , Wang Lin , Li Yan , Li Junling , Xing Puyuan
Published: September 2021

Background

Transformation to small cell lung cancer (SCLC) is a resistance mechanism of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (LADC) patients treated with EGFR tyrosine kinase inhibitors (TKIs). Here, we describe the clinical characteristics and prognosis of these patients and explore the treatment modes after transformation.

Methods

EGFR‐mutant LADC patients with SCLC transformation were retrospectively included in the study. Demographic and clinical data were collected. Survival outcomes and corresponding influential factors were analyzed.

Results

Twenty‐nine patients were included in the study. The median progression‐free survival (PFS) of patients who received first‐line EGFR‐TKIs was 13.1 months. The median time to SCLC transformation was 27.5 months. After transformation, the objective response rates of patients who received first‐line chemotherapy with or without EGFR‐TKIs were 43.8% and 37.5%, respectively. The median PFS of patients reveiving chemotherapy with EGFR‐TKIs was significantly longer than that of patients receiving chemotherapy without EGFR‐TKIs (5.2 vs. 3.0 months; HR, 0.19; 95% CI: 0.05–0.72; p = 0.014). However, there was no significant difference in median overall survival (OS) between patients who received chemotherapy with or without EGFR‐TKIs (14.8 vs. 13.0 months; p = 0.474). In the multivariate Cox proportional hazards regression analysis, both anti‐angiogenic treatment (HR, 0.04; 95% CI: 0.01–0.29; p = 0.001) and local radiotherapy (HR, 0.28; 95% CI: 0.08–0.97; p = 0.044) were significantly associated with better patient OS after transformation.

Conclusions

Compared with chemotherapy alone, the combination of chemotherapy and EGFR‐TKIs as first‐line treatment after SCLC transformation can benefit patients in PFS but not in OS. However, anti‐angiogenic therapies and local radiotherapy can significantly prolong OS after transformation.
Commentary: Technology, power and inequalities – achieving a humane approach to the digital divide – a commentary on Aboujaoude and Gega (2021)
Authors: Holt Kim
Published: September 2021

This paper provides a critical reflection on how a myopic focus by researchers on internet addiction as a possible explanation for children’s behaviour has led to a missed opportunity to probe the impact of digital exclusion for children with a range of complex vulnerabilities. Holt reflects upon the work of Aboujaoude and Gega (2021), Missing the forest for the trees: How the focus on digital addiction diverted attention away from wider adverse effects. Screen time is far more complex; it’s use in child protection as a form of surveillance is linked to poverty, inequality and risk. Importantly, the focus of international research must explore both digital exclusion and how this can be managed, and the increased use of digital surveillance, to provide an important lens in respect of power and inequalities in society.
Commentary: Worshipping the internet – the perils of serving an unpredictable master – a commentary on Aboujaoude and Gega (2021)
Authors: Starcevic Vladan
Published: September 2021

Numerous links have been established between cybertechnology and mental health problems. Although the direction of causality in the relationship between internet misuse and mental disturbance remains unclear, the cyberworld may contribute to the shaping of psychopathology in various ways. These include internet‐enhanced impulsivity, disinhibition and aggression, attentional problems, difficulties in coping with online information and selective and constraining online interactions with likeminded individuals. One of the imperatives of public health is to help internet users, especially those who are vulnerable such as children and adolescents, to be aware of the risks involved in interactions with the digital technologies and educate them about circumventing the dangers and seeking help.