bluuebunny/crossref_metadata_2025 huggingface dataset:
Ethylene augments root hypoxia tolerance through amelioration of reactive oxygen species and growth cessation
Authors: Liu Zeguang , Hartman Sjon , van Veen Hans , Zhang Hongtao , Leeggangers Hendrika A.C.F. , Martopawiro Shanice , Bosman Femke , de Deugd Florian , Su Peng , Hummel Maureen , Rankenberg Tom , Hassall Kirsty L. , Bailey-Serres Julia , Theodoulou Frederica L. , Voesenek Laurentius A.C.J. , Sasidharan Rashmi
Published: January 2022

Flooded plants experience impaired gas diffusion underwater, leading to oxygen deprivation (hypoxia). The volatile plant hormone ethylene is rapidly trapped in submerged plant cells and is instrumental for enhanced hypoxia acclimation. However, the precise mechanisms underpinning ethylene-enhanced hypoxia survival remain unclear. We studied the effect of ethylene pre-treatment on hypoxia survival of primaryArabidopsis thalianaroot tips. Both hypoxia itself and re-oxygenation following hypoxia are highly damaging to root tip cells and ethylene pre-treatments reduced this damage. Ethylene pre-treatment alone altered the abundance of transcripts and proteins involved in hypoxia responses, root growth, translation and reactive oxygen species (ROS) homeostasis. Through imaging and manipulating ROS abundancein planta, we demonstrate that ethylene limits excessive ROS formation during hypoxia and subsequent re-oxygenation and improves oxidative stress survival. In addition, we show that ethylene leads to rapid root growth cessation and this quiescence behaviour contributes to enhanced hypoxia tolerance. Collectively, our results show that the early flooding signal ethylene modulates a variety of processes that all contribute to hypoxia survival.
Functional gradients in the human lateral prefrontal cortex revealed by a comprehensive coordinate-based meta-analysis
Authors: Abdallah Majd , Zanitti Gaston , Iovene Valentin , Wassermann Demian
Published: January 2022

The human lateral prefrontal cortex (LPFC) enables flexible goal-directed behavior. Yet, its organizing principles remain actively debated despite decades of research. Meta-analysis efforts to map the LPFC have either been restricted in scope or suffered from limited expressivity in meta-analysis tools. The latter short-coming hinders the complexity of questions that can be expressed in a meta-analysis and hence limits the specificity of structure-function associations. Here, we adopt NeuroLang, a novel approach to meta-analysis based on first-order probabilistic logic programming, to infer the organizing principles of the LPFC with greater specificity from 14,371 neuroimaging publications. Our results reveal a rostrocaudal and a dorsoventral gradient, respectively explaining the most and second-most variance in whole-brain meta-analytic connectivity in the LPFC. Moreover, we find a cross-study agreement on a spectrum of increasing abstraction from caudal to rostral LPFC both in specific network connectivity and structure-function associations that supports a domain-general role for the mid-LPFC. Furthermore, meta-analyzing inter-hemispheric asymmetries along the rostrocaudal gradient reveals specific associations with topics of language, memory, response inhibition, and error processing. Overall, we provide a comprehensive mapping of the organizing principles of task-dependent activity in the LPFC, grounding future hypothesis generation on a quantitative overview of past findings.
SHARPIN serine 146 phosphorylation mediates ARP2/3 interaction, cancer cell invasion and metastasis
Authors: Butt Umar , Khan Meraj H , Pouwels Jeroen , Westermarck Jukka
Published: January 2022

The adaptor protein SHARPIN is involved in a number of cellular processes and promotes cancer progression and metastasis. However, how the choice between different functions of SHARPIN is post-translationally regulated is unclear. Here we have characterized SHARPIN phosphorylation by mass spectrometry and in vitro kinase assay. Focusing on two uncharacterized phosphorylation sites, serine 131 and 146, in the unstructured linker region of SHARPIN, we demonstrate their role in SHARPIN-ARP2/3 complex interaction, whereas they play no role in integrin inhibition or LUBAC activation. Consistent with its novel role in ARP2/3 regulation, serine 146 (S146) phosphorylation of SHARPIN promoted lamellopodia formation. Notably, CRISPR-Cas9 mediated knockout of SHARPIN abrogated three-dimensional (3D) invasion of several cancer cell lines. The 3D invasion of cancer cells was rescued by overexpression of the wild-type SHARPIN, but not by SHARPIN S146A mutant, identifying S146 as an invasion promoting phosphorylation switch. Finally, we demonstrate that inhibition of phosphorylation at S146 significantly reduces the in vivo metastasis in the zebrafish model. Collectively, these results demonstrate that SHARPIN S146 phosphorylation constitutes a single functional determinant of cancer cell invasion both in vitro and in vivo.
Amphibian mucus triggers a developmental transition in the frog-killing chytrid fungus
Authors: Robinson Kristyn A , Prostak Sarah M , Campbell Grant Evan H , Fritz-Laylin Lillian K
Published: January 2022

The frog-killing fungusBatrachochytrium dendrobatidis(Bd) grows within the mucus-coated skin of amphibians. Each lifecycle,Bdtransitions from its motile, dispersal form to its sessile growth form in a complex process called encystation. Although encystation is critical toBdgrowth, whether and how this developmental transition is triggered by external signals was previously unknown. We discovered that exposure to amphibian mucus triggers rapid and reproducible encystation within minutes. This response can be recapitulated with purified mucin, the bulk component of mucus, but not by similarly-viscous methylcellulose or simple sugars. Mucin-induced encystation does not require gene expression, but does require surface adhesion, calcium signaling, and modulation of the actin cytoskeleton. Mucus-induced encystation may represent a key mechanism for synchronizingBddevelopment with arrival at the host.
Probabilistic Edge Weights fine-tune Boolean network dynamics
Authors: Deritei Dávid , Kunšič Nina , Csermely Péter
Published: January 2022

Biological systems are noisy by nature. This aspect is reflected in our experimental measurements and should be reflected in the models we build to better understand these systems. Noise can be especially consequential when trying to interpret specific regulatory interactions, i.e. regulatory network edges. In this paper, we propose a method to explicitly encode edge-noise in Boolean dynamical systems by probabilistic edge-weight (PEW) operators. PEW operators have two important features: first, they introduce a form of edge-weight into Boolean models through the noise, second, the noise is dependent on the dynamical state of the system, which enables more biologically meaningful modeling choices. Moreover, we offer a simple-to-use implementation in the already well-established BooleanNet framework. In two application cases, we show how the introduction of just a few PEW operators in Boolean models can fine-tune the emergent dynamics and increase the accuracy of qualitative predictions. This includes fine-tuning interactions which cause non-biological behaviors when switching between asynchronous and synchronous update schemes in dynamical simulations. Moreover, PEW operators also open the way to encode more exotic cellular dynamics, such as cellular learning, and to implementing edge-weights for regulatory networks inferred from omics data.
Out of sight: Surveillance strategies for emerging vectored plant pathogens
Authors: Mastin Alexander J. , van den Bosch Frank , Bourhis Yoann , Parnell Stephen
Published: January 2022

Emerging pests and pathogens of plants are a major threat to natural and managed ecosystems worldwide. Whilst it is well accepted that surveillance activities are key to both the early detection of new incursions and the ability to identify pest-free areas, the performance of these activities must be evaluated to ensure they are fit for purpose. This requires consideration of the number of potential hosts inspected or tested as well as the epidemiology of the pathogen and the detection method used. In the case of plant pathogens, one particular concern is whether the visual inspection of plant hosts for signs of disease is able to detect the presence of these pathogens at low prevalences, given that it takes time for these symptoms to develop. One such pathogen is the ST53 strain of the vector-borne bacterial pathogen Xylella fastidiosa in olive hosts, which was first identified in southern Italy in 2013. Additionally, X. fastidiosa ST53 in olive has a rapid rate of spread, which could also have important implications for surveillance. In the current study, we evaluate how well visual surveillance would be expected to perform for this pathogen and investigate whether molecular testing of either tree hosts or insect vectors offer feasible alternatives. Our results identify the main constraints to each of these strategies and can be used to inform and improve both current and future surveillance activities.
Widespread transposon co-option in the Caenorhabditis germline regulatory network
Authors: Carelli Francesco , Cerrato Chiara , Dong Yan , Appert Alex , Dernburg Abby , Ahringer Julie
Published: January 2022

The movement of selfish DNA elements can lead to widespread genomic alterations with potential to create novel functions. Here we show that transposon expansions in Caenorhabditis nematodes led to extensive rewiring of germline transcriptional regulation. We find that about one third of C. elegans germline-specific promoters have been co-opted from two related Miniature Inverted Repeat Transposable Elements (MITEs), CERP2 and CELE2. The promoters are regulated by HIM-17, a THAP domain-containing transcription factor related to a transposase. Expansion of CERP2 occurred prior to radiation of the Caenorhabditis genus, as did fixation of mutations in HIM-17 through positive selection, whereas CELE2 expanded only in C. elegans. Through comparative analyses in C. briggsae, we find evolutionary conservation of most CERP2 co-opted promoters, but a substantial fraction of events are species specific. Our work reveals the emergence of a novel transcriptional network driven by TE co-option with a major impact on regulatory evolution.
Macrophage activation of cGAS and TRIM5 distinguish pandemic and non-pandemic HIV
Authors: Zuliani Alvarez Lorena , Govasli Morten L. , Rasaiyaah Jane , Monit Chris , Perry Stephen O. , Sumner Rebecca P. , McAlpine-Scott Simon , Dickson Claire , Faysal K. M. Rifat , Hilditch Laura , Miles Richard J. , Bibollet-Ruche Frederic , Hahn Beatrice H. , Boecking Till , Pinotsis Nikos , James Leo C. , Jacques David A. , Towers Greg J.
Published: January 2022

Pandemic viruses remain a global threat to health and economics but how they adapt to become pandemic remains poorly understood. Here we compare pandemic HIV-1(M) and non-pandemic HIV-(O) and HIV-2 strains finding that non-pandemic HIV replicate poorly in myeloid cell models due to activation of cGAS and TRIM5, and ensuing antiviral responses. We use phylogenetics and viral capsid structural biology to define specific differences between pandemic and non-pandemic HIV capsids and demonstrate that their genetic reversal in HIV-1(M) mutants causes TRIM5, cGAS and innate immune activation. We propose a model in which the parental lineage of pandemic HIV-1(M) has uniquely evolved a dynamic capsid that avoids activation of cGAS and TRIM5 to establish cloaked replication in myeloid cells. The unique adaptations of the pandemic virus lineage suggests a role in effective human-to-human transmissibility and highlight the importance of avoiding innate immune activation during pandemic human-to-human viral transmission.
The UBR box E3 ligases Poe and Hyd are required for efficient Pericentrin degradation
Authors: Varadarajan Ramya , Galletta Brian J. , Fagerstrom Carey J. , Haase Karen Plevock , Rusan Nasser M.
Published: January 2022

Centrosomes are the major microtubule organizing centers (MTOC) of many cells and are composed of centrioles and the pericentriolar material (PCM). Centrosomes are an essential part of diverse cellular processes and require precise regulation of their protein levels. One protein whose levels must be regulated is Pericentrin – PCNT in humans and PLP in Drosophila. Increased PCNT expression and its protein accumulation is linked to clinical conditions including cancer, mental disorders, and ciliopathies. However, the mechanisms by which PCNT levels are regulated remains underexplored. Our previous study (Galletta, 2020) demonstrated that PLP levels are sharply downregulated during early spermatogenesis and this regulation is essential to spatially position PLP on the proximal end of centrioles. We hypothesized that the sharp drop in PLP protein was a result of a rapid protein degradation during the male pre-meiotic G2 phase. In this study we show that the N-terminal region of PLP is required for regulating its levels, which when elevated, extends PLP’s position distally on centrioles. Consequently, PCM was also mispositioned leading to defects in spermatids. We then performed a targeted screen where we identified the E2 ligases, Rad6 and UbcD1, and the UBR box family E3 ligases, Poe (UBR4) and Hyd (UBR5) as factors that promote PLP degradation in spermatocytes. Collectively, our study suggests that Poe and Hyd directly bind the N-terminus of PLP and target it for degradation, ensuring proper centriole/basal body assembly and male fertility.
Brain temperature affects quantitative features of hippocampal sharp wave ripples
Authors: Petersen Peter C. , Vöröslakos Mihály , Buzsáki György
Published: January 2022

Biochemical mechanisms are temperature-dependent. Brain temperature shows wide variations across brain states, and such changes may explain quantitative changes in network oscillations. Here we report on the coupling of various hippocampal sharp wave ripple features to brain temperature. Ripple frequency, occurrence rate and duration correlated with temperature dynamics. By focal manipulation of the brain temperature in the hippocampal CA1 region, we show that ripple frequency can be increased and decreased by local heating and cooling, respectively. Changes of other parameters, such as the rate of SPW-R and ripple duration were not consistently affected. Our findings suggest that brain temperature in the CA1 region plays a leading role in affecting the ripple frequency, whereas other parameters of SPW-Rs may be determined by mechanisms upstream from the CA1 region. These findings illustrate that physiological variations of brain temperature exert important effects on hippocampal circuit operations.
Metatranscriptomics reveals a shift in microbial community composition and function during summer months in a coastal marine environment
Authors: Sutherland Ben J. G. , Finke Jan F. , Saunders Robert , Warne Snehal , Schulze Angela D. , Strohm Jeff H. T. , Chan Amy M. , Suttle Curtis A. , Miller Kristina M.
Published: January 2022

Temperate coastal marine waters are often thermally stratified from spring through fall but can be dynamic and disrupted by tidal currents and wind-driven upwelling. These mixing events introduce deeper, cooler water with a higher partial pressure of CO2 (pCO2), and its associated microbial communities to the surface. Anecdotally, these events impact shellfish hatcheries and farms, warranting improved understanding of changes in composition and activity of marine microbial communities in relation to environmental processes. To characterize both compositional and functional changes associated with abiotic factors, here we generate a reference metatranscriptome from the Strait of Georgia over representative seasons and analyze metatranscriptomic profiles of the microorganisms present within intake water containing different pCO2 levels at a shellfish hatchery in British Columbia from June through October. Abiotic factors studied include pH, temperature, alkalinity, aragonite, calcite and pCO2. Community composition changes were observed to occur at broad taxonomic levels, and most notably to vary with temperature and pCO2. Functional gene expression profiles indicated a strong difference between early (June-July) and late summer (August-October) associated with viral activity. The taxonomic data suggests this could be due to the termination of cyanobacteria and phytoplankton blooms by viral lysis in the late season. Functional analysis indicated fewer differentially expressed transcripts associated with abiotic variables (e.g., pCO2) than with the temporal effect. Microbial composition and activity in these waters varies with both short-term effects observed alongside abiotic variation as well as long-term effects observed across seasons. The analysis of both taxonomy and functional gene expression simultaneously in the same samples by environmental RNA (eRNA metatranscriptomics) provided a more comprehensive view for monitoring water bodies than either would in isolation.
Evaluation of the effects of vaccination regimes on the transmission dynamics of COVID-19 pandemic
Authors: Nakamoto Ichiro
Published: January 2022

The COVID-19 pandemic has yet to be eliminated globally despite the advancement of immunization programs. Evaluation of the effects of the vaccination regimes of COVID-19 is critical for understanding the potential capacity of countermeasures and informing subsequent prioritization strategies of responses. Research and observational data provide broad support regarding the importance of effective vaccines, in contrast, debates remain on the timing and priority of booster vaccination under the assumption of resource constraint. This study aims to evaluate the effect of vaccination regimes on the trajectory of the COVID-19 pandemic from the medium-term perspective. We employ a mathematical model to infer critical epidemiological characteristics associated with COVID-19, thereafter perform simulation on the transmission dynamics of the epidemic up to 3 years. The outcomes imply that in the absence of severe variants of the pathogen, administration of booster vaccination curtails the peak size of total cases and share of severe infections at later waves. Nevertheless, it can be better off by prioritizing the primary doses to unvaccinated individuals when vaccine shortage is challenged. The effects of priority categories are consistent across a broad range of profiles. Increasing the rollout capacity (i.e., administration rate) of doses can render the reproduction number lower than one and hence contain the transmission of pandemic ultimately controlling for other factors. The timing of rollout of primary doses is pivotal in reducing the magnitude of transmission saturation. It is of importance to prioritize the administration of primary vaccination series to vulnerable individuals efficiently and thereafter increment of administration capacity when the supply of vaccine increases over time to scale down the size of an epidemic.
Social isolation during the COVID-19 pandemic in Spain: a population study
Authors: Martinez-Garcia Marina , Sansano-Sansano Emilio , Castillo-Hornero Andrea , Femenia Ruben , Roomp Kristof , Oliver Nuria
Published: January 2022

Since March of 2020, billions of people worldwide have been asked to limit their social contacts in an effort to contain the spread of the SARS-CoV-2 virus. However, little research has been carried out to date on the impact of such social distancing measures on the social isolation levels of the population. In this paper, we study the impact of the pandemic on the social isolation of the Spanish population, by means of 32,359 answers to a citizen survey collected over a period of 7 months. We uncover (1) a significant increase in the prevalence of social isolation in the population, reaching almost 26%; (2) gender and age differences, with the largest prevalence of isolation among middle-aged individuals; (3) a strong relationship between economic impact and social isolation; and (4) differences in social isolation, depending on the number of COVID-19 protection measures and on the perception of coronavirus infection risk by our participants. Our research sheds quantitative light on the sociological impact of the pandemic, and enables us to identify key factors in the interplay between the deployment of non-pharmaceutical interventions to contain the spread of an infectious disease and a population’s levels of social isolation.
Targeted photothrombotic stroke leads to disruptions in neurovascular coupling
Authors: Sunil Smrithi , Jiang John , Shah Shashwat , Kura Sreekanth , Kilic Kivilcim , Erdener Sefik Evren , Ayata Cenk , Devor Anna , Boas David A.
Published: January 2022

Functional neuroimaging, which measures hemodynamic responses to brain activity, has great potential for monitoring stroke patients. However, the neurophysiological interpretations of these hemodynamic signals remain a challenge as the stroke is likely to alter both neural activity and neurovascular coupling. To address this challenge, we simultaneously captured neural activity, through fluorescence calcium imaging, and hemodynamics, through intrinsic optical signal imaging, during longitudinal stroke recovery. We found that photothrombotic stroke to somatosensory forelimb region altered neurovascular coupling in the acute phase (2 days and 1 week post-stroke) within the affected forelimb and peri-infarct regions. Neurovascular coupling was reestablished in the chronic phase (4 weeks post-stroke), and acute recovery of neurovascular coupling predicted sensorimotor function. Stroke also resulted in increases in the power of global brain oscillations, which showed distinct patterns between calcium and hemodynamics. Increased calcium excitability in the contralesional hemisphere was associated with increased intrahemispheric connectivity. Additionally, acute increases in hemodynamic oscillations were associated with improved sensorimotor outcomes.

Teaser

Acute ischemic stroke leads to neurovascular uncoupling and the extent of early recoupling predicts sensorimotor recovery.
Common synaptic inputs are not distributed homogeneously among the motor neurons that innervate synergistic muscles
Authors: Del Vecchio A. , Germer C. , Kinfe T. M. , Nuccio S. , Hug F. , Eskofier B. , Farina D. , Enoka R. M.
Published: January 2022

The force generated by the muscles involved in an action is produced by common synaptic inputs received by the engaged motor neurons. The purpose of our study was to identify the low-dimensional latent components, defined hereafter as neural modules, underlying the discharge rates of the motor units from two knee extensors (vastus medialis and lateralis) and two hand muscles (index and thumb muscles) during isometric contractions. The neural modules were extracted by factor analysis from the pooled motor units and no assumptions were made regarding the orthogonality of the modules or the association between the modules and each muscle. Factor analysis identified two independent neural modules that captured most of the covariance in the discharge rates of the motor units in the synergistic muscles. Although the neural modules were strongly correlated with the discharge rates of motor units in each of the synergistic pair of muscles, not all motor units in a muscle were correlated with the neural module for that muscle. The distribution of motor units across the pair of neural modules differed for each muscle: 80% of the motor units in first dorsal interosseous were more strongly correlated with the neural module for that muscle, whereas the proportion was 70%, 60%, and 45% for the thenar, vastus medialis, and vastus lateralis muscles. All other motor units either belonged to both modules or to the module for the other muscle (15% for vastus lateralis). Based on a simulation of 480 integrate-and-fire neurons receiving independent and common inputs, we demonstrate that factor analysis identifies the three neural modules with high levels of accuracy. Our results indicate that the correlated discharge rates of motor units arise from at least two sources of common synaptic input that are not distributed homogeneously among the motor neurons innervating synergistic muscles.
Genomic estimation of quantitative genetic parameters in wild admixed populations
Authors: Aase Kenneth , Jensen Henrik , Muff Stefanie
Published: January 2022

Heritable genetic variation among free‐living animals or plants is essential for populations to respond to selection and adapt. It is therefore important to be able to estimate additive genetic variance VA, which can be obtained using a GLMM known as the animal model. An underlying assumption of the standard animal model is that the study population is genetically unstructured, which is often unrealistic. In fact, admixture might be the norm rather than the exception in the wild, like in geographically structured populations, in the presence of (im)migration or in reintroduction and conservation contexts. Unfortunately, animal model estimators may be biased in such cases. The so‐called genetic group animal models that account for genetically differentiated subpopulations have recently become popular, but methodology is currently only available for cases where relatedness among individuals can be estimated from pedigrees.

To ensure that genetic group animal models with heterogeneous VA remain applicable to populations with genomic data but no pedigrees, there is a clear need to generalize these models to the case when exclusively genomic data are available. We therefore introduce such methodology for wild admixed systems by extending methods that were recently suggested in the context of plant breeding. Our extension relaxes the limiting assumptions that currently restrict their use to artificial breeding set‐ups.

We illustrate the usefulness of the extended genomic genetic group animal model on a wild admixed population of house sparrows resident in an island system in Northern Norway, where genome‐wide data on more than 180,000 single nucleotide polymorphisms (SNPs) are available to derive genomic relatedness. We compare our estimates of quantitative genetic parameters to those derived from a corresponding pedigree‐based genetic group animal model. The satisfactory agreement indicates that the new method works as expected.

Our extension of the very popular animal model ensures that the upcoming challenges with increasing availability of genomic data for quantitative genetic studies of wild admixed populations can be handled. To make the method widely available to the scientific community, we offer guidance in the form of a tutorial including step‐by‐step instructions to facilitate implementation.
Selective attention to lesson‐relevant contextual information promotes 3‐ to 5‐year‐old children's learning
Authors: King Jill , Markant Julie
Published: January 2022

Attending to distracting or competing information is typically considered detrimental to learning, but the presence of competing information can also facilitate learning when it is relevant to ongoing task goals. Educational settings often contain contextual elements such as classroom decorations or visual aids to enhance student learning. Despite this, most research examining effects of contextual information on children's learning has only utilized lesson‐irrelevant stimuli. While this research has shown that increased looking to task‐irrelevant information hinders learning, the extent to which looking to lesson‐relevant information can benefit children's learning is unknown. We addressed this question by examining 3‐ to 5‐year‐old children's attention to and learning from lesson‐relevant contextual information. We recorded children's eye movements as they viewed video science lessons while lesson‐relevant and ‐irrelevant images appeared in the periphery. We assessed learning based on improvements in content knowledge following the video lessons and separately measured selective attention skills using the Track‐It task. Children overall spent more time looking at lesson‐relevant versus ‐irrelevant images, and those with more initial knowledge of the lesson topics or more advanced selective attention skills showed increased preferential looking to the relevant images. This increased preferential looking to lesson‐relevant images related to more effective learning during trials in which both relevant and irrelevant images were present. These results suggest that the effects of competing contextual information on early learning depend on the relationship between information content and task goals, as well as children's ability to actively select task‐relevant information from their environment.
Paradoxical changes of coronary computed tomography derived fractional flow reserve
Authors: Tsugu Toshimitsu , Tanaka Kaoru , Nagatomo Yuji , Belsack Dries , De Maeseneer Michel , De Mey Johan
Published: January 2022

A total of 1335 outpatients with suspected coronary artery disease and who underwent computed tomography derived fractional flow reserve (FFRCT) analysis were examined. Only four patients showed reverse increase of FFRCT from the proximal to the distal vessel and all of them had a large ramus artery (RAM). Of all parameters (vessel length, lumen volume, plaque volume, and left ventricular mass), only the bifurcation angle was significantly higher in reverse increase of FFRCT with RAM group (106.0 ± 15.8°) than normal FFRCT with RAM group (82.6 ± 21.7°) and normal FFRCT without RAM group (66.9 ± 21.1°).
A cytosolic disulfide bridge‐supported dimerization is crucial for stability and cellular distribution of Coxsackievirus B3 protein 3A
Authors: Voss Martin , Kleinau Gunnar , Gimber Niclas , Janek Katharina , Bredow Clara , Thery Fabien , Impens Francis , Schmoranzer Jan , Scheerer Patrick , Kloetzel Peter‐Michael , Beling Antje
Published: January 2022

RNA viruses in the Picornaviridae family express a large 250 kDa viral polyprotein that is processed by virus‐encoded proteinases into mature functional proteins with specific functions for virus replication. One of these proteins is the highly conserved enteroviral transmembrane protein 3A that assists in reorganizing cellular membranes associated with the Golgi apparatus. Here, we studied the molecular properties of the Coxsackievirus B3 (CVB3) protein 3A with regard to its dimerization and its functional stability. By applying mutational analysis and biochemical characterization, we demonstrate that protein 3A forms DTT‐sensitive disulfide‐linked dimers via a conserved cytosolic cysteine residue at position 38 (Cys38). Homodimerization of CVB3 protein 3A via Cys38 leads to profound stabilization of the protein, whereas a C38A mutation promotes a rapid proteasome‐dependent elimination of its monomeric form. The lysosomotropic agent chloroquine (CQ) exerted only minor stabilizing effects on the 3A monomer but resulted in enrichment of the homodimer. Our experimental data demonstrate that disulfide linkages via a highly conserved Cys‐residue in enteroviral protein 3A have an important role in the dimerization of this viral protein, thereby preserving its stability and functional integrity.
Frailty and mortality associations in patients with COVID‐19: a systematic review and meta‐analysis
Authors: Subramaniam Ashwin , Shekar Kiran , Afroz Afsana , Ashwin Sushma , Billah Baki , Brown Hamish , Kundi Harun , Lim Zheng Jie , Ponnapa Reddy Mallikarjuna , Curtis J. Randall
Published: January 2022

Background

Observational data during the pandemic have demonstrated mixed associations between frailty and mortality.

Aim

To examine associations between frailty and short‐term mortality in patients hospitalised with coronavirus disease 2019 (COVID‐19).

Methods

In this systematic review and meta‐analysis, we searched PubMed, Embase and the COVID‐19 living systematic review from 1 December 2019 to 15 July 2021. Studies reporting mortality and frailty scores in hospitalised patients with COVID‐19 (age ≥18 years) were included. Data on patient demographics, short‐term mortality (in hospital or within 30 days), intensive care unit (ICU) admission and need for invasive mechanical ventilation (IMV) were extracted. The quality of studies was assessed using the Newcastle−Ottawa Scale.

Results

Twenty‐five studies reporting 34 628 patients were included. Overall, 26.2% (n = 9061) died. Patients who died were older (76.7 ± 9.6 vs 69.2 ± 13.4), more likely male (risk ratio (RR) = 1.08; 95% confidence interval (CI): 1.06–1.11) and had more comorbidities. Fifty‐eight percent of patients were frail. Adjusting for age, there was no difference in short‐term mortality between frail and non‐frail patients (RR = 1.04; 95% CI: 0.84–1.28). The non‐frail patients were commonly admitted to ICU (27.2% (4256/15639) vs 29.1% (3567/12274); P = 0.011) and had a higher mortality risk (RR = 1.63; 95% CI: 1.30–2.03) than frail patients. Among patients receiving IMV, there was no difference in mortality between frail and non‐frail (RR = 1.62; 95% CI 0.93–2.77).

Conclusion

This systematic review did not demonstrate an independent association between frailty status and short‐term mortality in patients with COVID‐19. Patients with frailty were less commonly admitted to ICU and non‐frail patients were more likely to receive IMV and had higher mortality risk. This finding may be related to allocation decisions for patients with frailty amidst the pandemic.
COVID‐19 pandemic 2020: a tertiary Melbourne hospital's experience
Authors: Farrow Brodie , Bonney Asha , Singh Kasha P. , Tong Steven , Irving Louis , Lim Wen Kwang , Lim Seok , Johnson Douglas , Marshall Caroline , Buising Kirsty , Liu Belinda , Cowie Benjamin , Rees Megan , Miller Alistair
Published: January 2022

Background

The COVID‐19 pandemic has affected different parts of Australia in distinct ways across 2020 and 2021. In 2020, Melbourne was the epicentre of COVID‐19. As one of the key tertiary centres caring for the patients affected by the outbreaks, the Royal Melbourne Hospital (RMH) managed the majority of the Victorian inpatient caseload.

Aims

To review the demographics, management and outcomes of patients with COVID‐19 cared for by the RMH services in 2020.

Methods

A single health service retrospective cohort analysis of demographics, interventions and outcomes was conducted to characterise the RMH experience in 2020.

Results

From January to December 2020, 433 patients required admission more than 24 h. The demographics of affected patients and outcomes changed over the course of the study. Overall, 47% (203/433) required oxygen, most frequently (36%; 154/433) with low‐flow devices (nasal prongs or hudson mask), and 11% (47/433) of patients required admission to intensive care. We recorded a 30‐day mortality of 24% (104/433) mortality overall, rising to over 50% in patients aged over 80 years.

Conclusions

The experience of this health service in 2020 demonstrated changing demographics over time, with associated differences in outcomes; notably marked mortality in older populations, frequent complications and limited inter‐site transfer possible with mobilised resources.
Steroid Use for Recovery of advanced atrioVentricular block Immediately after VALvular surgery (SURVIVAL): A preliminary randomized clinical trial
Authors: Ghodsi Saeed , Masoudkabir Farzad , Hosseini Zahra , Davarpasand Tahereh , Yavari Negin , Mohebi Mehrnaz , Talasaz Azita H. , Jalali Arash , Ahmadi‐Tafti Seyed H. , Bagheri Jamshid , Hasanzadeh Hakimeh
Published: January 2022

Background

Atrioventricular block (AVB) is an important complication following valvular surgery. Several factors including inflammation‐mediated injury might trigger AVB.

Methods

Patients with advanced postoperative AVB were randomly assigned to receive either dexamethasone (0.4 mg/kg, maximum 30 mg/day) intravenously for 3 days or conservative care only. Primary endpoint was recovery rate in Day 5 since randomization. Secondary endpoints were recovery rate in Day 7 and Day 10, cumulative AVB time, permanent pacemaker (PPM) implantation rate, length of stay in critical care units, and postoperative major adverse events (MAE).

Results

We enrolled 139 subjects (48.9% male) with mean age of 59.9 years randomly allocated to intervention group (n = 69) and control group (n = 70). Dexamethasone led to higher recovery rates at Day 5 (82.6% vs. 62.9%, p = .009) and Day 7 (88.4% vs. 61.4%, p < .0001) respectively. This benefit ceased at Day 10 (83.05% vs. 78.6%, p = .547). Median cumulative AVB time was shorter in dexamethasone group compared with control group (41 h vs. 64 h, p = .044). PPM implantation rates were similar between the dexamethasone and control groups (15.9% vs. 17.1%, respectively, p = .849). Median length of stay in intensive care unit (ICU) (10 days vs. 12 days, p = .03) and MAE (17.4% vs. 25.7%, p = .133) tended to be lower with dexamethasone.

Conclusion

Dexamethasone may serve as a safe and effective medication to help hasten recovery of advanced AVB after valvular surgery.
Device‐related infection associated with increased mortality risk in de novo transvenous implantable cardioverter‐defibrillator medicare patients
Authors: El‐Chami Mikhael F. , Liu Yiyan , Griffiths Robert I. , Knight Bradley P. , Weiss Raul , Mark George E. , Biffi Mauro , Probst Vincent , Lambiase Pier D. , Miller Marc A. , Jacobsen Caroline M. , Baddour Larry M.
Published: January 2022

Introduction

Transvenous implantable cardioverter‐defibrillators (TV‐ICD) infection is a serious complication that frequently requires complete device removal for attempted cure, which can be associated with patient morbidity and mortality. The objective of this study is to assess mortality risk associated with TV‐ICD infection in a large Medicare population with de novo TV‐ICD implants.

Methods

A survival analysis was conducted using 100% fee‐for‐service Medicare facility‐level claims data to identify patients who underwent de novo TV‐ICD implantation between 7/2016 and 1/2018. TV‐ICD infection within 2 years of implantation was identified using International Classification of Disease, 10th Edition and current procedural terminology codes. Baseline patient risk factors associated with mortality were identified using the Charlson Comorbidity Index categories. Infection was treated as a time‐dependent variable in a multivariate Cox proportional hazards model to account for immortal time bias.

Results

Among 26,742 Medicare patients with de novo TV‐ICD, 518 (1.9%) had a device‐related infection. The overall number of decedents was 4721 (17.7%) over 2 years, with 4555 (17%) in the noninfection group and 166 (32%) in the infection group. After adjusting for baseline patient demographic characteristics and various comorbidities, the presence of TV‐ICD infection was associated with an increase of 2.4 (95% CI: 2.08–2.85) times in the mortality hazard ratio.

Conclusion

The rate of TV‐ICD infection and associated mortality in a large, real‐world Medicare population is noteworthy. The positive association between device‐related infection and risk of mortality further highlights the need to reduce infections
Destigmatizing perceptions about Black adolescent depression: randomized controlled trial of brief social contact–based video interventions
Authors: Martin Andrés , Calhoun Amanda , Páez José , Amsalem Doron
Published: January 2022

Objective

To test the utility of brief social contact–based video interventions of a Black adolescent girl to reduce stigmatized attitudes and increase help‐seeking intentions around adolescent depression.

Methods

We conducted a randomized controlled trial (RCT) with 14‐ to18‐year‐old healthy volunteers drawn from the general US population. We enrolled participants through a crowdsourcing platform (n = 1,093) and randomly assigned participants to one of three video conditions (117 s each): depressed (DEP); depressed, adjusted to aspects unique to being a Black adolescent girl (including experienced or internalized racism; ADJ); and control (CONT). The primary outcome was the Depression Stigma Scale (DSS); secondary outcomes were the General Health‐Seeking Questionnaire (GHSQ), and thermometers for Black and white race perception “warmth”.

Results

Following the intervention, the DSS changed from baseline across the three conditions (p < .001). ADJ outperformed both DEP (p = .031) and CONT (p < .001). A race‐by‐intervention interaction (p < .001) revealed different response profiles between Black (ADJ = DEP = CONT; p = .726) and non‐Black participants (ADJ > DEP > CONT; p < .001). DEP and ADJ both resulted in higher treatment‐seeking intentions for both the emotional problems and the suicidal thought subscales of the GHSQ. We found a race‐by‐intervention interaction (p = .01) for the Black thermometer, which revealed a significant 2° increase in warmth among white (p < .001), but not Black, viewers (p = .06).

Conclusions

On a short‐term basis, brief social contact–based videos proved effective among adolescents in reducing depression‐related stigma, increasing help‐seeking intentions, and providing an “empathic foothold” in the lives of racially stigmatized groups. Even as the enduring effects of these interventions remain to be determined, the deployment on social media of short videos opens new opportunities to reach a large number of at‐risk youth.”
The burden of NAFLD in type 2 diabetic subjects from the general population: A Nationwide population‐based follow‐up study (NASHCO)
Authors: Nabi Oumarou , Boursier Jerome , Lapidus Nathanaël , Mathurin Philippe , de Ledinghen Victor , Petit Jean‐Michel , Goldberg Marcel , Zins Marie , Lacombe Karine , Serfaty Lawrence
Published: January 2022

Background

The epidemiology and natural history of non‐alcoholic fatty liver disease (NAFLD) in diabetes have been mainly investigated in the hospital setting. The goal of this study was to evaluate the characteristics of NAFLD and its impact on morbidity and mortality in type 2 diabetic subjects in a community setting.

Method

This study included 199 341 participants in the nationwide Constances cohort. After patients with excessive alcohol consumption, viral hepatitis or other causes of liver disease were excluded, 164 285 were analysed and 8386 (5.3%) were considered to have type 2 diabetes. The non‐invasive diagnosis of NAFLD and advanced fibrosis was made using a combination of the fatty liver index and Forns index. Median follow‐up was 2.5 years.

Results

Diabetes increased the risk of NAFLD by sixfold (adjusted OR 6.05, 95% CI 5.68‐6.45) and the risk of advanced fibrosis by 3.76‐fold (aOR 3.76, 95% CI 2.87‐4.91) in NAFLD subjects. After controlling for confounders, the presence of NAFLD in diabetic subjects was associated with an increased risk of severe liver‐related events (aHR 2.53, 95% CI 1.36‐4.69), cardiovascular disease (CVD, aHR 2.71, 95% CI 1.72‐4.26) and overall mortality (aHR 2.91, 95% CI 1.53‐5.53). The risk of hepatic and extrahepatic complications in diabetic subjects with NAFLD significantly increased with the severity of fibrosis (P < .05).

Conclusion

This prospective, longitudinal study in a large community‐based cohort provides real‐world evidence of the risk for NAFLD and advanced fibrosis in diabetes, and its impact on liver disease progression, diabetes‐related complications such as CVD, and overall mortality. These data could be used to estimate real clinical and economic burden of NAFLD in diabetic subjects.
The Inhibitory Effect of Blue Light on Phagocytic Activity by ARPE‐19 Cells
Authors: Olchawa Magdalena M. , Herrnreiter Anja M. , Skumatz Christine M.B. , Krzysztynska‐Kuleta Olga I. , Mokrzynski Krystian T. , Burke Janice M. , Sarna Tadeusz J.
Published: January 2022

Chronic exposure of the retina to short wavelength visible light is a risk factor in pathogenesis of age‐related macular degeneration. The proper functioning and survival of photoreceptors depends on efficient phagocytosis of photoreceptor outer segments (POS) by retinal pigment epithelium. The purpose of this study was to analyze the phagocytic activity of blue light–treated ARPE‐19 cells, and to examine whether the observed effects could be related to altered levels of POS phagocytosis receptor proteins and/or to oxidation of cellular proteins and lipids. POS phagocytosis was measured by flow cytometry. Phagocytosis receptor proteins αv and β5 integrin subunits and Mer tyrosine kinase (MerTK) were quantified by western blotting. The intact functional heterodimer αvβ5 was quantified by immunoprecipitation followed by immunoblotting. Cellular protein and lipid hydroperoxides were analyzed by coumarin boronic acid probe and iodometric assay, respectively. Cell irradiation induced reversible inhibition of specific phagocytosis and transient reductions in phagocytosis receptor proteins. Full recovery of functional heterodimer was apparent. Significant photooxidation of cellular proteins and lipids was observed. The results indicate that transient inhibition of specific phagocytosis by blue light could be related to the reduction in phagocytosis receptor proteins. Such changes may arise from oxidative modifications of cell phagocytic machinery components.
Seed quality and the true price of native seed for mine site restoration
Authors: Pedrini Simone , D'Agui Haylee M. , Arya Tiana , Turner Shane , Dixon Kingsley W.
Published: January 2022

Native seed underpins the success of most terrestrial restoration efforts globally; however, the fragility of the native seed supply chain presents a key challenge to achieving global restoration goals. With the current heightened global focus on ecological restoration, seed supply chains are under unprecedented pressure worldwide. New and practical solutions are required to help the native seed industry move toward more sustainable and reliable supply, and in turn, facilitate more cost‐effective, successful, seed‐based restoration. Here we focus on species used in biodiverse mine site restoration in two regions of Western Australia as a test case for evaluating two key elements of the seed supply chain: seed quality and price. The study assessed seed quality in 185 species, then combined these results with seed price to determine the actual cost of pure live seeds (PLS) used in restoration. Average seed quality, expressed as a weight percentage of PLS, is 55%. The average price for a native seed batch across 129 species is $1,093 Australian dollars (AUD)/kg, and when adjusted for viability and purity is $2,600 (AUD)/ kg of PLS. We suggest replacing the traditional approach of pricing seed per unit weight ($/kg) with a new method that would reflect seed quality and unit number; price per thousand pure live seeds ($ TPLS). We posit that this new way of pricing native seeds would increase transparency and information flow in the marketing of native seeds, which will, in turn, enable seed users to more reliably plan for, and evaluate the cost‐effectiveness of seed‐based restoration projects.