bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterizing Affective Variability in Bipolar Disorder and Borderline Personality Disorder, and the Effects of Lithium, Using a Generative Model of Affect
Authors: Pulcu Erdem , Saunders Kate E.A. , Harmer Catherine J. , Harrison Paul J. , Goodwin Guy M. , Geddes John R. , Browning Michael
Published: February 2022

The affective variability of Bipolar Disorder (BD) is thought to qualitatively differ from that of Borderline Personality Disorder (BPD), with changes in affect persisting for longer in BD. However, quantitative studies have not been able to confirm this distinction. It has therefore not been possible to accurately quantify how treatments like lithium influence affective variability in BD. We assessed the affective variability associated with BD and BPD as well as the effect of lithium using a novel computational model that defines two subtypes of variability: affective changes that persist (volatility) and changes that do not (noise). We hypothesized that affective volatility would be raised in the BD group, noise would be raised in the BPD group and that lithium would impact affective volatility. Daily affect ratings were prospectively collected for up to 3 years from patients with BD, BPD and non-clinical controls. In a separate experimental-medicine study, patients with BD were randomized to receive lithium or placebo, with affect ratings collected from week -2 to +4. We found a diagnostically specific pattern of affective variability. Affective volatility was raised in patients with BD whereas affective noise was raised in patients with BPD. Rather than suppressing affective variability, lithium increased the volatility of positive affect in both studies. These results provide a quantitative measure of the affective variability associated with BD and BPD. They suggest a novel mechanism of action for lithium, whereby periods of persistently low or high affect are avoided by increasing the volatility of affective responses.
Data-Driven Flow-Map Models for Data-Efficient Discovery of Dynamics and Fast Uncertainty Quantification of Biological and Biochemical Systems
Authors: Makrygiorgos Georgios , Berliner Aaron J. , Shi Fengzhe , Clark Douglas S. , Arkin Adam P. , Mesbah Ali
Published: February 2022

Computational models are increasingly used to investigate and predict the complex dynamics of biological and biochemical systems. Nevertheless, governing equations of a biochemical system may not be (fully) known, which would necessitate learning the system dynamics directly from, often limited and noisy, observed data. On the other hand, when expensive models are available, systematic and efficient quantification of the effects of model uncertainties on quantities of interest can be an arduous task. This paper leverages the notion of flow-map (de)compositions to present a framework that can address both of these challenges via learning data-driven models useful for capturing the dynamical behavior of biochemical systems. Data-driven flow-map models seek to directly learn the integration operators of the governing differential equations in a black-box manner, irrespective of structure of the underlying equations. As such, they can serve as a flexible approach for deriving fast-toevaluate surrogates for expensive computational models of system dynamics, or, alternatively, for reconstructing the long-term system dynamics via experimental observations. We present a data-efficient approach to data-driven flow-map modeling based on polynomial chaos Kriging. The approach is demonstrated for discovery of the dynamics of various benchmark systems and a co-culture bioreactor subject to external forcing, as well as for uncertainty quantification of a microbial electrosynthesis reactor. Such data-driven models and analyses of dynamical systems can be paramount in the design and optimization of bioprocesses and integrated biomanufacturing systems.
Estimating the distribution of livestock in space and time: a time-series contribution to livestock density mapping
Authors: Meisner Julianne , Kato Agapitus , Lemerani Marshall , Miaka Erick Mwamba , Taban Acaga Ismail , Wakefield Jonathan , Rowhani-Rahbar Ali , Pigott David , Mayer Jonathan , Rabinowitz Peter
Published: February 2022

More than one billion people rely on livestock for income, nutrition, and social cohesion, however livestock keeping can facilitate disease transmission and contribute to climate change. While data on the distribution of livestock thus have broad utility across a range of applications, efforts to map the distribution of livestock on a large scale are limited to the Gridded Livestock of the World (GLW) project. We present a complimentary effort to map the distribution of cattle and pigs in Malawi, Uganda, Democratic Republic of Congo (DRC), and South Sudan. In contrast to GLW, which uses dasymmetric modeling applied to census data to produce time-stratified estimates of livestock counts and spatial density, our work uses complex survey data and distinct modeling methods to generate a time-series of livestock distribution, defining livestock density as the ratio of animals to humans. In addition to favorable cross-validation results and general agreement with national density estimates derived from external data on national human and livestock populations, our results demonstrate extremely good agreement with GLW-3 estimates, supporting the validity of both efforts. Our results furthermore offer a high-resolution time series result and employ a definition of density which is particularly well-suited to the study of livestock-origin zoonoses.
A comprehensive comparison on cell type composition inference for spatial transcriptomics data
Authors: Chen Jiawen , Liu Weifang , Luo Tianyou , Yu Zhentao , Jiang Minzhi , Wen Jia , Gupta Gaorav P. , Giusti Paola , Zhu Hongtu , Yang Yuchen , Li Yun
Published: February 2022

Spatial transcriptomic (ST) technologies allow researchers to examine high-quality RNA-sequencing data along with maintained two-dimensional positional information as well as a co-registered histology image. A popular use of ST omics data is to provide insights about tissue structure and spatially unique features. However, due to the technical nature unique to most ST data, the resolution varies from a diameter of 2-10μm to 50-100μm instead of single-cell resolution, which brings uncertainty into cell number and cell mixture within each ST spot. Motivated by the important role for spatial arrangement of cell types within a tissue in physiology and disease pathogenesis, several ST deconvolution methods have been developed and are being used to explore gene expression variation and identification of spatial domains. The aim of this work is to review state-of-the-art methods for ST deconvolution, while comparing their strengths and weaknesses. Specifically, we use four real datasets to examine the performance of eight methods across different tissues and technological platforms.

Key Points

Cell mixture inference is a critical step in the analysis of spatial transcriptomics (ST) data to prevent downstream analysis suffering from confounding factors at the spot level.

Existing ST deconvolution methods can be classified into three groups: probabilistic-based, non-negative matrix factorization and non-negative least squares based, and other deep learning framework-based methods.

We compared eight ST deconvolution methods by using two single cell level resolution datasets and two spot level resolution ST datasets. We provided practical guidelines for the choice of method under different scenarios as well as the optimal subsets of genes to use for each method.
Natural language signatures of psilocybin microdosing
Authors: Sanz Camila , Cavanna Federico , Muller Stephanie , de la Fuente Laura , Zamberlan Federico , Palmucci Matías , Janeckova Lucie , Kuchar Martin , Carrillo Facundo , García Adolfo M. , Pallavicini Carla , Tagliazucchi Enzo
Published: February 2022

Serotonergic psychedelics are being studied as novel treatments for mental health disorders and as facilitators of improved well-being, mental function and creativity. Recent studies have found mixed results concerning the effects of low doses of psychedelics (“microdosing”) on these domains. However, microdosing is generally investigated using instruments designed to assess larger doses of psychedelics, which might lack sensitivity and specificity for this purpose. Following a double-blind and placebo-controlled experimental design, we explored natural language as a resource to identify speech produced under the acute effects of psilocybin microdoses, focusing on variables known to be affected by higher doses: verbosity, semantic variability and sentiment scores. Except for semantic variability, these metrics presented significant differences between a typical active microdose of 0.5 g of psilocybin mushrooms and an inactive placebo condition. Moreover, machine learning classifiers trained using these metrics were capable of distinguishing between conditions with high accuracy (AUC≈0.8). Our results constitute first proof that low doses of serotonergic psychedelics can be identified from unconstrained natural speech, with potential for widely applicable, affordable, and ecologically valid monitoring of microdosing schedules.
Competition contributes to both warm and cool range edges
Authors: Lyu Shengman , Alexander Jake M.
Published: February 2022

Competition plays an important role in shaping species’ spatial distributions. However, it remains unclear where and how competition regulates species’ range limits. In a field experiment with plants originating from low and high elevations and conducted across an elevation gradient in the Swiss Alps, we find that both lowland and highland species can better persist in the presence of competition within than beyond their elevation ranges, suggesting that competition helps set both lower and upper elevation range limits of these species. Furthermore, the reduced ability of pairs of lowland or highland species to coexist beyond their range edges is mainly driven by diminishing niche differences; changes in both niche differences and relative fitness differences drive weakening competitive dominance of lowland over highland species with increasing elevation. These results highlight the need to account for competitive interactions and investigate underlying coexistence mechanisms to understand current and future species distributions.
Gut microbiome disturbances of altricial Blue and Great tit nestlings are countered by continuous microbial inoculations from parental microbiomes
Authors: Diez-Méndez David , Bodawatta Kasun H. , Freiberga Inga , Klečková Irena , Jønsson Knud A. , Poulsen Michael , Sam Katerina
Published: February 2022

Gut microbial communities are complex and heterogeneous and play critical roles for animal hosts. Early-life disruptions to microbiome establishment can negatively impact host fitness and development. However, the consequences of such early-life disruptions are unknown in wild birds. To help fill this gap, after validating the disruptive influence of antibiotic and probiotic treatments on the gut microbiome in adult Great tits (Parus major) (efficacy experiment), we investigated the effect of continuous early-life gut microbiome disruptions on the establishment and development of gut communities in wild Great and Blue tit (Cyanistes caeruleus) nestlings (field experiment). Despite negative impacts of treatments on microbial alpha and beta diversities in the efficacy experiment, treatment did not affect the composition of nestling microbiomes in the field experiment. Independent of treatment, nestling gut microbiomes of both species grouped by brood, sharing high numbers of bacterial taxa with both the nest environment and their mother. The distance between nests increased inter-brood microbiome dissimilarity, but only in Great tits, indicating species-specific influence of environment on microbiomes. The strong maternal effect, driven by continuous recolonization from the nest environment and vertical transfer of microbes during feeding thus appear to provide resilience towards early-life disruptions in nestling gut microbiomes.
From bacteria to plants: a repurposing strategy in the pursuit for novel herbicides
Authors: Mackie Emily R. R. , Barrow Andrew S. , Giel Marie-Claire , Hulett Mark D. , Gendall Anthony R. , Panjikar Santosh , Soares da Costa Tatiana P.
Published: February 2022

Herbicide resistance represents one of the biggest threats to our natural environment and agricultural sector. Thus, new herbicides are urgently needed to tackle the rise in herbicideresistant weeds. Here, we employed a novel strategy to repurpose a ‘failed’ antibiotic into a new and target-specific herbicidal compound. Specifically, we identified an inhibitor of bacterial dihydrodipicolinate reductase (DHDPR), an enzyme involved in lysine biosynthesis in plants and bacteria, that exhibited no antibacterial activity but severely attenuated germination of the plant Arabidopsis thaliana. We confirmed that the inhibitor targets plant DHDPR orthologues in vitro, and exhibits no toxic effects against human cell lines. A series of analogues were then synthesised with improved efficacy in germination assays and against soil-grown A. thaliana plants. We also showed that our lead compound is the first lysine biosynthesis inhibitor with herbicidal activity against a weed species, providing proof-of-concept that DHDPR inhibition may represent a much-needed new herbicide mode of action. Furthermore, this study exemplifies the untapped potential of repurposing ‘failed’ antibiotic scaffolds to fast-track the development of herbicide candidates targeting the respective plant enzymes to combat the global rise in herbicide-resistant weeds.
Allosteric interactions prime androgen receptor dimerization and activation
Authors: Wasmuth Elizabeth V. , Broeck Arnaud Vanden , LaClair Justin R. , Hoover Elizabeth A. , Lawrence Kayla E. , Paknejad Navid , Pappas Kyrie , Matthies Doreen , Wang Biran , Feng Weiran , Watson Philip A. , Zinder John C. , Karthaus Wouter R. , de la Cruz M. Jason , Hite Richard K. , Manova-Todorova Katia , Yu Zhiheng , Weintraub Susan T. , Klinge Sebastian , Sawyers Charles L.
Published: February 2022

The androgen receptor (AR) is a steroid receptor and master transcription factor that governs gene expression programs required for luminal development of prostate epithelium, formation of muscle tissue and maintenance of the male phenotype. AR misregulation is a hallmark of multiple malignancies, including prostate cancer, where AR hyperactivation and expansion of its transcriptome occur in part through AR gene amplification and interaction with oncoprotein cofactors. Despite its biological importance, how AR’s individual domains and its protein cofactors cooperate to bind DNA have remained elusive. Using a combination of reconstitution biochemistry and single particle cryo-electron microscopy (EM), we have isolated three conformational states of AR bound to DNA. We observe that AR forms a non-obligate dimer, with the buried dimer interface utilized by related ancestral nuclear receptors repurposed to facilitate cooperative DNA binding. We identify surfaces bridging AR’s domains responsible for allosteric communication, that are compromised in partial androgen insensitivity syndrome (PAIS), and are reinforced by AR’s oncoprotein cofactor, ERG, and DNA binding site motifs. Finally, we present evidence that this plastic dimer interface for transcriptional activation may have been adopted by AR at the expense of DNA binding. Our work highlights how fine-tuning of AR’s cooperative interactions translate to consequences in development and disease.
Persisting pulmonary dysfunction in pediatric post-acute Covid-19
Authors: Heiss Rafael , Wagner Alexandra , Tan Lina , Schmidt Sandy , Regensburger Adrian P. , Ewert Franziska , Mammadova Dilbar , Buehler Adrian , Vogel-Claussen Jens , Voskrebenzev Andreas , Rauh Manfred , Rompel Oliver , Nagel Armin M. , Lévy Simon , Bickelhaupt Sebastian , May Matthias S. , Uder Michael , Metzler Markus , Trollmann Regina , Woelfle Joachim , Knieling Ferdinand
Published: February 2022

The frequency and extent of persistent sequelae in children and adolescents after infection with SARS-CoV-2 still needs to be comprehensively determined. In this cross-sectional clinical trial, we used non-invasive, label-free morphologic and free-breathing phase-resolved functional low-field magnetic resonance imaging (LF-MRI) to identify pulmonary changes in children and adolescents from 5 to <18 years after previously PCR-confirmed SARS-CoV-2 infection. While morphological pathologies were less frequent in children, functional LF-MRI visualized widespread ventilation, perfusion and combined ventilation/perfusion defects compared to healthy controls. The loss of functional lung parenchyma was more pronounced in long Covid than recovered patients. While pulmonary dysfunction was persistent even month after primary infection, LF-MRI demonstrated high capability to visualize and detect these changes in children and adolescents. (Clinicaltrials.org ID NCT04990531)
Discrimination of bacterial and viral infection using host-RNA signatures integrated in a lab-on-a-chip technology
Authors: Pennisi Ivana , Moniri Ahmad , Miscourides Nicholas , Miglietta Luca , Moser Nicolas , Habgood-Coote Dominic , Herberg Jethro A. , Levin Michael , Kaforou Myrsini , Rodriguez-Manzano Jesus , Georgiou Pantelis
Published: February 2022

The unmet clinical need for accurate point-of-care (POC) diagnostic tests able to discriminate bacterial from viral infection demands a solution that can be used both within healthcare settings and in the field and that can also stem the tide of antimicrobial resistance. Our approach to solve this problem is to combine the use of Host-gene signatures with our Lab-on-a-chip (LoC) technology enabling low-cost LoC expression analysis to detect Infectious Disease.Host-gene expression signatures have been extensively study as a potential tool to be implemented in the diagnosis of infectious disease. On the other hand LoC technologies using Ion-sensitive field-effect transistor (ISFET) arrays, in conjunction with isothermal chemistries, are offering a promising alternative to conventional lab-based nucleic acid amplification instruments, owing to their portable and affordable nature. Currently, the data analysis of ISFET arrays are restricted to established methods by averaging the output of every sensor to give a single time-series. This simple approach makes unrealistic assumptions, leading to insufficient performance for applications that require accurate quantification such as RNA host transcriptomics. In order to reliably quantify host-gene expression on our LoC platform enabling the classification of bacterial and viral infection on chip, we propose a novel data-driven algorithm for extracting time-to-positive values from ISFET arrays. The algorithm proposed is based on modelling sensor drift with adaptive signal processing and clustering sensors based on their behaviour with unsupervised learning methods. Results show that the approach correctly outputs a time-to-positive for all the reactions, with a high correlation to RT-qLAMP (0.85, R2 = 0.98, p < 0.01), resulting in a classification accuracy of 100 % (CI, 95 - 100). By leveraging more advanced data processing methods for ISFET arrays, this work aims to bridge the gap between translating assays from microarray analysis (expensive lab-based discovery method) to ISFET arrays (cheap point-of-care diagnostics) providing benefits on tackling infectious disease outbreak and diagnostic testing in hard-to-reach areas of the world.
A prefrontal to lateral entorhinal pathway disrupts memory
Authors: Hisey Erin , Soderling Scott H.
Published: February 2022

While the neural circuits underlying memory encoding, storage, and retrieval are well characterized, the circuits that act to disrupt memory are enigmatic. Here we find that silencing a projection from the prefrontal cortex to the lateral entorhinal cortex surprisingly improves spatial working memory and contextual memory. We then found that the same cell type shows increased activity during errors in a spatial working memory test. Finally we found that optogenetic activation of the same activity patterns can disrupt working memory performance. By using a combination of intersectional genetic and in vivo imaging techniques we advance evidence that a novel prefrontal-entorhinal pathway critically participates in memory disruption.
Consistent measurement of LAG-3 expression across multiple staining platforms with the 17B4 antibody clone
Authors: Wojcik John B. , Desai Keyur , Avraam Konstantinos , Vandebroek Arno , Dillon Lloye M. , Giacomazzi Giorgia , Rypens Charlotte , Benci Joseph L.
Published: February 2022

Context

An immunohistochemistry (IHC) assay developed to detect lymphocyte-activation gene 3 (LAG-3), a novel immune checkpoint inhibitor target, has demonstrated high analytical precision and interlaboratory reproducibility using a Leica staining platform, but has not been investigated on other IHC staining platforms.

Objective

To evaluate the performance of LAG-3 IHC assays using the 17B4 antibody clone across widely used IHC staining platforms: Agilent/Dako Autostainer Link 48 (ASL-48) and VENTANA BenchMark ULTRA (VBU) compared with Leica BOND-RX (BOND-RX).

Design

Eighty formalin-fixed paraffin-embedded melanoma tissue blocks were cut into consecutive sections and evaluated using staining platform–specific IHC assays with the 17B4 antibody clone. Duplicate testing was performed on the BOND-RX platform to assess intraplatform agreement. LAG-3 expression using a numerical score was evaluated by a pathologist and with a digital scoring algorithm. LAG-3 positivity was determined from manual scores using a ≥ 1% cutoff.

Results

LAG-3 IHC staining patterns and intensities were visually similar across all 3 staining platforms. Pearson correlation was ≥ 0.88 for interplatform and BOND-RX intraplatform concordance when LAG-3 expression was evaluated with a numerical score determined by a pathologist. Correlation increased with a numerical score determined with a digital scoring algorithm (Pearson correlation ≥ 0.93 for all comparisons). Overall percentage agreement was ≥ 77.5% for interplatform and BOND-RX intraplatform comparisons when a ≥ 1% cutoff was used to determine LAG-3 positivity.

Conclusions

Data from this study demonstrate that LAG-3 expression can be robustly and reproducibly assessed across 3 major commercial IHC staining platforms using the 17B4 antibody clone.
Exploring the phycosphere of Emiliania huxleyi: from bloom dynamics to microbiome assembly experiments
Authors: Câmara dos Reis Mariana , Romac Sarah , Le Gall Florence , Marie Dominique , Frada Miguel J. , Koplovitz Gil , Cariou Thierry , Henry Nicolas , de Vargas Colomban , Jeanthon Christian
Published: February 2022

Coccolithophores have global ecological and biogeochemical significance as the most important calcifying marine phytoplankton group. The structure and selection of prokaryotic communities associated with the most abundant coccolithophore and bloom-forming species, Emiliania huxleyi, are still poorly known. In this study, we assessed the diversity of bacterial communities associated with an E. huxleyi bloom in the Celtic Sea, exposed axenic E. huxleyi cultures to prokaryotic communities derived from bloom and non-bloom conditions and followed the dynamics of their microbiome composition over one year. Bloom-associated prokaryotic communities were dominated by SAR11, Marine group II Euryarchaeota, Rhodobacterales and contained substantial proportions of known indicators of phytoplankton bloom demises such as Flavobacteriaceae and Pseudoalteromonadaceae. Taxonomic richness of replicated co-cultures resulting from natural communities with axenic E. huxleyi rapidly shifted and then stabilized over time, presumably by ecological selection favoring more beneficial populations. Recruited microbiomes from the environment were consistently dependent on the composition of the initial bacterioplankton community. Phycosphere-associated communities derived from the E. huxleyi bloom depth were highly similar to one another, suggesting deterministic processes, whereas cultures from non-bloom conditions show an effect of both deterministic processes and stochasticity. Overall, this work sheds new light on the importance of the initial inoculum composition in microbiome recruitment and elucidates the temporal dynamics of its composition and long-term stability.
A phospholipase assay screen identifies synergistic inhibitors of the P. aeruginosa toxin ExoU
Authors: Foulkes Daniel M. , McLean Keri , Hermann Anne , Johnson James , Winstanley Craig , Berry Neil , Fernig David G. , Kaye Stephen B.
Published: February 2022

The opportunistic pathogen Pseudomonas aeruginosa is a leading cause of disability and mortality worldwide and the World Health Organisation has listed it with the highest priority for the need of new therapies. P. aeruginosa strains that express ExoU are implicated in the worst clinical outcomes. ExoU is phospholipase that is secreted by P. aeruginosa directly into the cytoplasm of target host cells, where its catalytic activity, directed towards plasma membranes, causes rapid cell lysis. Inhibition of ExoU may be a novel strategy to combat acutely cytotoxic ExoU expressing P. aeruginosa infections. Using an in vitro phospholipase assay, we performed a high throughput screen to identify compounds that might be repurposed as therapeutic ExoU inhibitors. We discovered a panel of compounds that appeared to inhibit ExoU through distinct mechanisms. Compound C prevented ExoU membrane localisation in HEK293T cells and caused colocalization with lysosomes, whereas compound D prevented PIP2 dependent oligomerisation of ExoU in vitro suggestive of synergistic action. Indeed, the concentrations required by compounds C and D to inhibit in vitro ExoU catalytic activity, when used in combination, was in the nanomolar region. In corneal scratch and infection assays, these compounds reduced ExoU mediated cytotoxicity, as assessed by fluorescence microscopy and lactate dehydrogenase release assays.
Visual and auditory cortices represent acoustic speech-related information during silent lip reading
Authors: Bröhl Felix , Keitel Anne , Kayser Christoph
Published: February 2022

Speech is an intrinsically multisensory signal and seeing the speaker’s lips forms a cornerstone of communication in acoustically impoverished environments. Still, it remains unclear how the brain exploits visual speech for comprehension and previous work debated whether lip signals are mainly processed along the auditory pathways or whether the visual system directly implements speech-related processes. To probe this question, we systematically characterized dynamic representations of multiple acoustic and visual speech-derived features in source localized MEG recordings that were obtained while participants listened to speech or viewed silent speech. Using a mutual-information framework we provide a comprehensive assessment of how well temporal and occipital cortices reflect the physically presented signals and speech-related features that were physically absent but may still be critical for comprehension. Our results demonstrate that both cortices are capable of a functionally specific form of multisensory restoration: during lip reading both reflect unheard acoustic features, with occipital regions emphasizing spectral information and temporal regions emphasizing the speech envelope. Importantly, the degree of envelope restoration was predictive of lip reading performance. These findings suggest that when seeing the speaker’s lips the brain engages both visual and auditory pathways to support comprehension by exploiting multisensory correspondences between lip movements and spectro-temporal acoustic cues.

Highlights

Visual and auditory cortex represent unheard acoustic information during lip reading

Auditory cortex emphasizes the acoustic envelope

Visual cortex emphasizes a pitch signature

Tracking of unheard features in auditory cortex is associated with behavior
Proteasomal downregulation of the pro-apoptotic MST2 pathway contributes to BRAF inhibitor resistance in melanoma
Authors: Romano David , García-Gutiérrez Lucia , Duffy David J. , Flaherty Keith T. , Frederick Dennie T. , Kolch Walter , Matallanas David
Published: February 2022

The RAS-RAF-MEK-ERK pathway is hyperactivated in almost all malignant melanomas, and mutations in BRAF or NRAS account for most of these cases. BRAF inhibitors are highly efficient for treating patients with BRAFV600E mutations, but tumours frequently acquire resistance within a few months. Multiple resistance mechanisms have been identified, due to mutations or network adaptations that revive ERK signalling. We have previously shown that RAF proteins inhibit the MST2 proapoptotic pathway in a kinase independent fashion. Here, we have investigated the role of the MST2 pathway in mediating resistance to BRAF inhibitors. We show that the BRAFV600E mutant protein, but not the wildtype BRAF protein, strongly binds to MST2 and inhibits MST2 pro-apoptotic signalling. Downregulation of MST2 reduces BRAF inhibitor induced apoptosis. In BRAF inhibitor resistant cell lines MST2 pathway proteins are downregulated by ubiquitination and subsequent proteasomal degradation rendering cells refractory to MST2 pathway induced apoptosis. Restoration of apoptosis can be achieved by increasing MST2 pathway protein expression using proteasome inhibitors. In summary, we show that the MST2 pathway plays a role in the acquisition of BRAF inhibitor resistance in melanoma.
Reactive astrocytes transduce blood-brain barrier dysfunction through a TNFα-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin
Authors: Kim Hyosung , Leng Kun , Park Jinhee , Sorets Alexander G. , Kim Suil , Shostak Alena , Sturgeon Sarah M. , Neal Emma H. , McMahon Douglas G. , Schrag Matthew S. , Kampmann Martin , Lippmann Ethan S.
Published: February 2022

Astrocytes are critical components of the neurovascular unit that support blood-brain barrier (BBB) function in brain microvascular endothelial cells (BMECs). Transformation of astrocytes to a reactive state in response to injury and disease can be protective or harmful to BBB function, but the underlying mechanisms for these effects remain mostly unclear. Using a human induced pluripotent stem cell (iPSC)-derived coculture model of BMEC-like cells and astrocytes, we found that tumor necrosis factor alpha (TNFα) transitions astrocytes to an inflammatory reactive state through activated STAT3 signaling, whereby the resultant astrocytes disrupt passive BBB function and induce vascular cell adhesion molecule 1 (VCAM-1) expression in the BMEC-like cells. These associations between inflammatory reactive astrocytes, STAT3 activation, and vascular VCAM-1 expression were corroborated in human postmortem tissue. Bioinformatic analyses coupled with CRISPR interference techniques in the iPSC model revealed that inflammatory reactive astrocytes transduce BBB disruption in part through SERPINA3, which encodes alpha 1-antichymotrypsin (α1ACT), a secreted serine protease inhibitor associated with aging, neuroinflammation, and Alzheimer’s disease. In murine ex vivo cortical explant cultures, shRNA-mediated silencing of Serpina3n in astrocytes reduced vascular VCAM-1 expression after TNFα challenge. Further, direct treatment with recombinant Serpina3n in both ex vivo explant cultures and the brain in vivo (via intracerebroventricular injection into wild-type mice) was sufficient to induce vascular VCAM-1 expression and reduce tight junction integrity. Overall, our results define the TNFα-STAT3 signaling axis as a driver of an inflammatory reactive astrocyte subtype responsible for BBB dysfunction. Our results also identify α1ACT as an explicit mediator of BBB damage and suggest that inhibition of α1ACT expression or activity could represent a therapeutic avenue for reversing BBB deficits in aging and neurodegenerative disease.
Epstein-Barr virus latency programs dynamically sensitize B-cells to ferroptosis
Authors: Burton Eric M. , Voyer Jewel , Gewurz Benjamin E.
Published: February 2022

Epstein-Barr virus (EBV) causes 200,000 cancers annually. Upon B-cell infection, EBV induces lipid metabolism to support B-cell proliferation. Yet, little is known about how latent EBV infection, or human B-cell stimulation more generally, alter sensitivity to ferroptosis, a non-apoptotic form of programmed cell death driven by iron-dependent lipid peroxidation and membrane damage. To gain insights, we analyzed lipid reactive oxygen species (ROS) levels and ferroptosis vulnerability in primary human CD19+ B-cells infected by EBV or stimulated by key B-cell receptors. Prior to the first mitosis, EBV-infected cells were exquisitely sensitive to blockade of glutathione biosynthesis, a phenomenon not observed with B-cell receptor stimulation. Subsequently, EBV-mediated Burkitt-like hyper-proliferation generated elevated levels of lipid ROS, which necessitated SLC7A11-mediated cystine import and glutathione peroxidase 4 (GPX4) activity to prevent ferroptosis. By comparison, B-cells were sensitized to ferroptosis induction by combinatorial CD40-ligand and interleukin-4 stimulation or anti-B-cell receptor and Toll-like receptor 9 stimulation upon GPX4 inhibition, but not with SLC7A11 blockade. EBV transforming B-cells became progressively resistant to ferroptosis induction upon switching to the latency III program and lymphoblastoid physiology. Similarly, latency I Burkitt cells were particularly vulnerable to blockade of SLC7A11 or GPX4 or cystine withdrawal, while latency III Burkitt and lymphoblastoid cells were comparatively resistant. The selenocysteine biosynthesis kinase PSTK was newly implicated as a cellular target for ferroptosis induction including in Burkitt cells, likely due to roles in GPX4 biosynthesis. These results highlight ferroptosis as an intriguing therapeutic target for the prevention or treatment of particular EBV-driven B-cell malignancies.

Significance

EBV contributes to B-cell Burkitt and post-transplant lymphoproliferative disease (PTLD). EBV transforming programs activate lipid metabolism to convert B-cells into immortalized lymphoblastoid cell lines (LCL), a PTLD model. We found that stages of EBV transformation generate lipid reactive oxygen species (ROS) byproducts to varying degrees, and that a Burkitt-like phase of B-cell outgrowth is dependent on lipid ROS detoxification by glutathione peroxidase 4 and its cofactor glutathione. Perturbation of this redox defense in early stages of B-cell transformation or in Burkitt cells triggered ferroptosis, a programmed cell death pathway. LCLs were less dependent on this defense, a distinction tied to EBV latency programs. This highlights ferroptosis induction as a novel therapeutic approach for prevention or treatment of EBV+ lymphomas.
Zebrafish fin regeneration requires generic and regeneration-specific responses of osteoblasts to trauma
Authors: Sehring Ivonne , Haffner-Luntzer Melanie , Ignatius Anita , Huber-Lang Markus , Weidinger Gilbert
Published: February 2022

Successful regeneration requires the coordinated execution of multiple cellular responses to injury. In amputated zebrafish fins, mature osteoblasts dedifferentiate, migrate towards the injury and form proliferative osteogenic blastema cells. We show that osteoblast migration is preceded by cell elongation and alignment along the proximodistal axis, which require actomyosin, but not microtubule turnover. Surprisingly, osteoblast dedifferentiation and migration can be uncoupled. Using pharmacological and genetic interventions, we found that NF-κB and retinoic acid signalling regulate dedifferentiation without affecting migration, while the complement system and actomyosin dynamics are required for migration but not dedifferentiation. Furthermore, by removing bone at two locations within a fin ray, we established a trauma model containing two injury sites. We found that osteoblasts dedifferentiate at and migrate towards both sites, while accumulation of osteogenic progenitor cells and regenerative bone formation only occur at the distal-facing injury. Together, these data indicate that osteoblast dedifferentiation and migration represent generic injury responses that are differentially regulated and can occur independently of each other and of regenerative growth. Successful bone regeneration appears to require the coordinated execution of generic and regeneration-specific responses of osteoblast to trauma.

Abstract Figure
Enablers for facilitating life cycle assessment: key stakeholder perspectives of Sri Lankan construction industry
Authors: Amarasinghe Isuri Anuradha , Hadiwattege Chandanie
Published: February 2022

Purpose

Despite the desire to improve the sustainability of the construction industry, Sri Lanka is still plagued by the low-level adoption of essential methods such as Life Cycle Assessment (LCA) in building and infrastructure delivery. It is indispensable to investigate enablers for facilitating LCA because identification of enablers is a crucial step in the implementation of LCA. This study aims to analyze internal and external enablers for facilitating LCA for the Sri Lankan construction industry from the perspective of five stakeholder categories (academia, government, construction industry, society and environmentalists) and also aims to develop strategies to strengthen the enablers.

Design/methodology/approach

An explanatory research design was used. The five stakeholder categories identified above, whose contribution is essential for implementing LCA in Sri Lanka, were selected for data collection. A total of 20 semi-structured interviews were held representing each stakeholder category. The Repertory Grid Interview (RGI) technique was utilized and data analysis was performed using content analysis.

Findings

The results revealed that “ability to identify opportunities for environmental improvements as an extremely important internal enabler for all stakeholder categories” and “the positive growth in the country to achieve environmental sustainability”, “the availability of standardized LCA guides and handbooks” as extremely important external enablers for all stakeholder categories for facilitating LCA in the Sri Lankan construction industry. Further, strategies including making people aware of the LCA concept and development of the LCA database, etc. were proposed to strengthen the enablers.

Practical implications

Knowledge generated through this study would enable the abovementioned stakeholders to make informed decisions to promote the implementation of LCA in the Sri Lankan construction industry. Further, the results of this study have raised awareness of the issues that Sri Lanka will need to solve to expand the LCA applications.

Originality/value

So far, research on LCA has not looked into enablers that can facilitate the implementation of LCA in the Sri Lankan construction industry. This research provides a comprehensive view of the internal and external enablers for facilitating LCA from the perspective of five stakeholder categories and identifies enablers that led the abovementioned stakeholders to pursue the implementation of LCA in the Sri Lankan construction industry. The study also proposes strategies for strengthening the enablers.
Openness strategies and the success of international entrepreneurship
Authors: Gimenez-Fernandez Elena M. , Ferraris Alberto , Troise Ciro , Sandulli Francesco Domenico
Published: February 2022

Purpose

External knowledge is a key resource for the success and the survival of born global firms; however, existing models provide minimal evidence on how these firms should source this knowledge resource. Thus, the purpose of this research is to increase understanding on the impact of diverse knowledge search and knowledge formal protection in international new ventures (INVs).

Design/methodology/approach

The study uses a quantitative methodology based on a sample of start-ups from the Spanish Community Innovation Survey data. Using ordinary least squares regressions on a 10-year period panel data, this research tests the moderator role of a heterogeneous base of international partners and formal knowledge appropriation strategy on the relationship between start-ups and their export performance.

Findings

The results show that compared to non-born global start-ups, born global firms benefit more from establishing relationships with a set of heterogeneous international partners. By contrast, all start-ups benefit from an extensive appropriation strategy if they establish such alliances with diverse international partners.

Originality/value

The study extends current theory on international entrepreneurship by providing a new theoretical framework for INVs of both the extensive use of formal mechanisms of knowledge protection and the access to heterogeneous and distant knowledge. This study has also several implications for knowledge management domain.
Do global factors drive the interconnectedness among green, Islamic and conventional financial markets?
Authors: Karim Sitara , Naeem Muhammad Abubakr
Published: February 2022

Purpose

This study aims to examine the connectedness among green, Islamic and conventional financial markets from December 2008 to May 2021. Moreover, the impact of global factors on the connectedness of given financial markets is also observed.

Design/methodology/approach

This study first employed the time-varying parameter vector autoregressions (TVP-VAR) technique to explore the connectedness of markets. Second, This study utilized the wavelet coherence analysis to test the time-frequency impact of global factors in terms of implied volatilities of stock, oil, gold, currency and bond on the connectedness across financial markets.

Findings

This study finds Islamic stocks, sustainability index and S&P500 composite index are the net transmitters, whereas Sukuk, commodity index, bond market, clean energy and green bonds are the net recipient of spillovers. Time-varying features of green, Islamic and conventional financial markets are evident in system-wide connectedness. This study further evidenced that global factors drive the connectedness of financial markets, particularly during stressful times.

Practical implications

The findings of this study furnish significant implications for policymakers, regulatory authorities, investors, financial market participants and portfolio managers in terms of carefully assessing the unique characteristics offered by each financial market in terms of risk mitigation and diversifying the portfolios.

Originality/value

Using a portfolio of green, Islamic and conventional financial markets, the uniqueness of this study lies in the examination of the connectedness of these markets by deploying the TVP-VAR technique. In addition, wavelet analysis offers a significant contribution in terms of global factors driving the connectedness of green, Islamic and conventional markets.
Impact of coupling of technological innovation and standardisation on industrial development
Authors: Yang Jing , Shao Lushen , Jin Xiang , Zhou Lijun
Published: February 2022

Purpose

Using the industrial data between 2000 and 2016, this study analysed the process of coupling and coordinated development of technological innovation and standardisation. Accordingly, the study considered the high-tech industry (five sub-sectors) in China as the research object.

Design/methodology/approach

Based on the summary of innovation and standardisation literature review, this study constructed a theoretical model of the influence of technological innovation and standardisation on industrial development from the perspective of the coupling system. Furthermore, the study employed multivariate linear regression analysis to explore coupling coordination relationships.

Findings

The study results revealed that high coupling coordination between technological innovation and standardisation is highly conducive to industrial development. Moreover, requirements for standardisation levels differ owing to different stages and characteristics in each segmented industry.

Originality/value

This study primarily contributes to the literature by using a bibliometrics tool to summarise related literature on innovation and standardisation and provides a new perspective of reviewing, and it also offers new evidence on the coupling coordination relationship between innovation and standardisation in the high-tech industry.
Communication and leadership in times of crisis: analyzing the cultural competency of US state governors during the vaccine administration phase of the COVID-19 pandemic
Authors: Lofaro Ryan J. , Sapat Alka
Published: February 2022

Purpose

The purpose of this article is to analyze the common vaccine equity practices expressed by United States (US) governors in their COVID-19 press conferences—with a specific focus on equitable vaccine distribution and overcoming vaccine hesitancy—in order to provide an understanding of gubernatorial cultural competency during the vaccine administration phase of the pandemic.

Design/methodology/approach

This article employs a qualitative content analysis of the COVID-19 press conferences held by US governors from November 1, 2020, to August 14, 2021, to inductively identify themes in socially equitable and culturally competent vaccine administration strategies and rhetoric.

Findings

The article finds that common strategies aimed at providing equitable access to vaccines and combating vaccine hesitancy in communities of color include utilizing data to target communities where vaccines are needed, meeting people where they are at by working with community leaders and organizations, addressing language concerns, educating skeptics and appealing to communitarian and familial values. The findings also show that US governors tended to embrace a general prioritization lens rather than focusing on the unique needs of communities of color, with scant attention paid to the historical instances of public health discrimination that have influenced vaccine hesitancy within such communities.

Originality/value

This article provides an understanding of the equitable and culturally competent messages and strategies conveyed by sub-national leaders during the vaccination phase of the COVID-19 pandemic.
The relationship between retailer app use, perceived shopping value and loyalty: the moderating role of deal proneness
Authors: Flacandji Michaël , Vlad Mariana
Published: February 2022

Purpose

This paper studies the effects of retailer app use on perceived shopping value and loyalty toward the retailer. It also investigates whether deal proneness moderates the relationship between app use and perceived shopping value.

Design/methodology/approach

A sample of 427 French consumers took part in an online survey inquiring about a recent shopping experience. The authors compared customers who used a retailer app during their shopping experience with those who did not. Mediation and moderated mediation using PROCESS were performed to identify whether retailer app use improves loyalty intentions through perceived shopping value, with deal proneness used as a moderator.

Findings

The results show a positive and direct effect of retailer app use on loyalty. The effect is also mediated by utilitarian and hedonic shopping values. The authors also highlight the fact that deal proneness moderates the mediation effect of both utilitarian and hedonic shopping values between retailer app use and loyalty. More specifically, retail app use significantly increases shopping value for deal-prone customers.

Originality/value

In the age of omnichannel retailing, this study offers potential contributions to improve the theoretical knowledge of the impact of retailer apps on retailer–customer relations, helping businesses to develop and implement appropriate app-related strategies.