bluuebunny/crossref_metadata_2025 huggingface dataset:
Division of labour within psyllids: Metagenomics reveals an ancient dual endosymbiosis with metabolic complementarity in the genusCacopsylla
Authors: Dittmer Jessica , Corretto Erika , Serbina Liliya Štarhová , Michalik Anna , Nováková Eva , Schuler Hannes
Published: April 2023

Hemipteran insects are well-known for their ancient associations with beneficial bacterial endosymbionts, particularly nutritional symbionts providing the host with essential nutrients such as amino acids or vitamins lacking from the host’s diet. Thereby, these primary endosymbionts enable the exploitation of nutrient-poor food sources such as plant sap or vertebrate blood. In turn, the strictly host-associated lifestyle strongly impacts the genome evolution of the endosymbionts, resulting in small and degraded genomes. Over time, even the essential nutritional functions can be compromised, leading to the complementation or replacement of an ancient endosymbiont by another, more functionally versatile, bacterium. Herein, we provide evidence for a dual primary endosymbiosis in several psyllid species. Using metagenome sequencing, we produced the complete genome sequences of both the primary endosymbiont ‘CandidatusCarsonella ruddii’ and an as yet uncharacterizedEnterobacteriaceaebacterium from four species of the genusCacopsylla. The latter represents a new psyllid-associated endosymbiont clade for which we propose the name ‘CandidatusPsyllophila symbiotica’. Fluorescentin situhybridisation confirmed the co-localization of both endosymbionts in the bacteriome. The metabolic repertoire ofPsyllophilais highly conserved across host species and complements the tryptophan biosynthesis pathway that is incomplete in the co-occurringCarsonella.Unlike co-primary endosymbionts in other insects, the genome ofPsyllophilais almost as small as the one ofCarsonella, indicating an ancient co-obligate endosymbiosis rather than a recent association to rescue a degrading primary endosymbiont.

IMPORTANCE

Heritable beneficial bacterial endosymbionts have been crucial for the evolutionary success of numerous insects, enabling the exploitation of nutritionally limited food sources such as vertebrate blood and plant sap. Herein, we describe a previously unknown dual endosymbiosis in the psyllid genusCacospylla, consisting in the primary endosymbiont ‘CandidatusCarsonella ruddii’ and a co-occurringEnterobacteriaceaebacterium for which we propose the name ‘CandidatusPsyllophila symbiotica’. Its localization within the bacteriome and its small genome size confirm thatPsyllophilais a co-primary endosymbiont widespread within the genusCacopsylla.Despite its highly eroded genome,Psyllophilacomplements the tryptophan biosynthesis pathway that is incomplete in the co-occurringCarsonella.Moreover, the genome ofPsyllophilais almost as small as the one ofCarsonella, indicating an ancient dual endosymbiosis rather than a recent acquisition of a new symbiont. Hence, our results shed light on the dynamic interactions of psyllids and their endosymbionts over evolutionary time.
An estimate of pediatric lives saved due to non-pharmacologic interventions during the early COVID-19 pandemic
Authors: Faust Jeremy Samuel , Renton Benjamin , Du Chengan , Chen Alexander Junxiang , Li Shu-Xia , Lin Zhenqiu , Krumholz Harlan
Published: April 2023

The net effect of the pandemic mitigation strategies on childhood mortality is not known. During the first year of the COVID-19 pandemic, mitigation policies and behaviors were widespread, and although vaccinations and effective treatments were not yet widely available, the risk of death from SARS-CoV-2 infection was low. In that first year, there was a 7% decrease in medical (“natural causes”) mortality among children ages 0-9 during the first pandemic year (5% among infants <1 year and 15% among children ages 1-9) in the United States, resulting in an estimated 1,488 deaths due to medical causes averted among children ages 0-9, and 1,938 deaths averted over 24 months. The usual expected surge in winter medical deaths, particularly among children ages >1 year was absent. However, smaller increases in external (“non-natural causes”) mortality were also observed during the study period, which decreased the overall number of pediatric deaths averted during both years and the pandemic period. In total, 1,468 fewer all-cause pediatric deaths than expected occurred in the United States during the first 24 months of the COVID-19 pandemic.
C-di-AMP levels modulateStaphylococcus aureuscell wall thickness as well as virulence and contribute to antibiotic resistance and tolerance
Authors: Haunreiter Vanina Dengler , Tarnutzer Andrea , Bär Julian , von Matt Manuela , Hertegonne Sanne , Andreoni Federica , Vulin Clément , Künzi Lisa , Menzi Carmen , Kiefer Patrick , Christen Philipp , Vorholt Julia A. , Zinkernagel Annelies S.
Published: April 2023

Beta-lactam antibiotics are widely used to treat infections caused by the important human pathogenStaphylococcus aureus. Resistance to beta-lactams, as found in methicillin-resistantS. aureus(MRSA), renders effective treatment difficult. The second messenger cyclic di-3′,5′- adenosine monophosphate (c-di-AMP) promotes beta-lactam resistance in clinicalS. aureusisolates. C-di-AMP plays a crucial role in the regulation of cellular processes such as virulence, cell wall homeostasis and resistance to beta-lactams in many bacterial species. InS. aureus,c-di-AMP synthesis is mediated by the diadenylate cyclase DacA, while its degradation is carried out by the phosphodiesterases GdpP and Pde2.

In this work, we assessed the effect of altered c-di-AMP levels due to mutations incacA,gdpPorgdpP/pde2on virulence determinants. We report that a previously described growth defect in bacteria producing high c-di-AMP levels is mainly attributable to smaller cell size. High c-di-AMP levels also led to decreased survival upon oxidative stress, reduced production of the antioxidant staphyloxanthin, increased oxacillin and fosfomycin resistance and increased cell wall thickness. While resistance to ceftaroline was not affected, high c-di-AMP levels promoted tolerance to this antibiotic. In response to cell wall stress induced by antibiotics, the three-component regulatory system VraTSR mediates an increase in cell wall synthesis via the cell wall stress stimulon (CWSS). Increased c-di-AMP levels led to an activation of the CWSS. Upon deletion ofvraR, resistance to oxacillin and fosfomycin as well as cell wall thickness diminished in the ΔgdpPmutant, indicating a contribution of the VraTSR system to the cell wall related phenotypes.

Importance

Antibiotic resistance and tolerance are substantial health-care related problems, hampering effective treatment of bacterial infections. Mutations in the phosphodiesterase GdpP, which degrades cyclic di-3′, 5′-adenosine monophosphate (c-di-AMP), have recently been associated with resistance to beta-lactam antibiotics in clinicalStaphylococcus aureusisolates. In this study, we show that high c-di-AMP levels decreased the cell size and increased the cell wall thickness inS. aureusmutant strains. As a consequence, an increase in resistance to cell wall targeting antibiotics such as oxacillin and fosfomycin as well as in tolerance to ceftaroline, a cephalosporine used to treat MRSA infections, were observed. These findings underline the importance of investigating the role of c-di-AMP in the development of tolerance and resistance to antibiotics in order to optimize treatment in the clinical setting.
Self-reported effects of classic psychedelics on stuttering
Authors: Gold Noah D. , Goldway Noam , Gerlach-Houck Hope , Jackson Eric S.
Published: April 2023

Stuttering is a neurodevelopmental communication disorder that can lead to significant social, occupational, and educational challenges. Traditional behavioral interventions for stuttering can be helpful, but effects are often limited. Classic psychedelics hold promise as a complement to traditional interventions, but their impact on stuttering is unknown. We conducted a qualitative content analysis to explore potential benefits and negative effects of psychedelics on stuttering using publicly available Reddit posts. A combined inductive-deductive approach was used whereby meaningful units were extracted and codes were initially assigned inductively. We then deductively applied an established framework to organize the effects (i.e., codes) into five subthemes (Behavioral, Emotional, Cognitive, Belief, and Social Connection), each of which was grouped under an organizing theme (positive, negative, neutral). Results indicated that the effects of psychedelics spanned all subthemes. Nearly 75% of participants reported overall positive effects. Nearly 60% of participants indicated positive behavioral change (e.g., reduced stuttering, increased speech control), 40% reported positive emotional benefit, 15% reported positive cognitive changes, 12% reported positive effects on beliefs, and 7% indicated positive social effects. Approximately 10% of participants reported negative behavioral effects (e.g., increased stuttering, reduced speech control). Psychedelics may help many stutterers improve communication, cultivate a healthier outlook, and promote psychological well-being. These preliminary results indicate that future clinical trials investigating psychedelic-assisted speech therapy for stuttering are warranted.
Monocyte-derived Dll4 is a novel contributor to persistent systemic inflammation in HIV patients
Authors: Wang Shumin , Singh Meera , Yang Hongmei , Morrell Craig N. , Mohamad Laith Awad , Xu Jasmine Jiayuan , Nguyen Tiffany , Ture Sara , Tyrell Alicia , Maggirwar Sanjay B. , Schifitto Giovanni , Pang Jinjiang
Published: April 2023

Background

In people living with HIV (PLWH) on combination antiretroviral therapy (cART), persistent systemic inflammation is a driving force for the progression of comorbidities, such as cardiovascular and cerebrovascular diseases. In this context, monocyte- and macrophage-related inflammation rather than T cell activation is a major cause of chronic inflammation. However, the underlying mechanism of how monocytes cause persistent systemic inflammation in PLWH is elusive.

Methods and Results

In vitro, we demonstrated that lipopolysaccharides (LPS) or tumor necrosis factor alpha (TNFα), induced a robust increase of Delta-like ligand 4 (Dll4) mRNA and protein expression in human monocytes and Dll4 secretion (extracellular Dll4, exDll4) from monocytes. Enhanced membrane-bound Dll4 (mDll4) expression in monocytes triggered Notch1 activation to promote pro-inflammatory factors expression. Dll4 silencing and inhibition of Nocth1 activation diminished the LPS or TNFα -induced inflammation. exDll4 releases in response to cytokines occurred in monocytes but not endothelial cells or T cells. In clinical specimens, we found that PLWH, both male and female, on cART, showed a significant increase in mDll4 expression, activation of Dll4-Notch1 signaling, and inflammatory markers in monocytes. Although there was no sex effect on mDII4 in PLWH, plasma exDll4 was significantly elevated in males but not females compared to HIV uninfected individuals. Furthermore, exDll4 plasma levels paralleled with monocytes mDll4 in male PLWH. Circulating exDll4 was also positively associated with pro-inflammatory monocytes phenotype and negatively associated with classic monocytes phenotype in male PLWH.

Conclusion

Pro-inflammatory stimuli increase Dll4 expression and Dll4-Notch1 signaling activation in monocytes and enhance monocyte proinflammatory phenotype, contributing to persistent systemic inflammation in male and female PLWH. Therefore, monocyte mDll4 could be a potential biomarker and therapeutic target of systemic inflammation. Plasma exDll4 may also play an additional role in systemic inflammation but primarily in men.
Protein language model-based end-to-end type II polyketide prediction without sequence alignment
Authors: Huang Jiaquan , Gao Qiandi , Tang Ying , Wu Yaxin , Zhang Heqian , Qin Zhiwei
Published: April 2023

Natural products are important sources for drug development, and the precise prediction of their structures assembled by modular proteins is an area of great interest. In this study, we introduce DeepT2, an end-to-end, cost-effective, and accurate machine learning platform to accelerate the identification of type II polyketides (T2PKs), which represent a significant portion of the natural product world. Our algorithm is based on advanced natural language processing models and utilizes the core biosynthetic enzyme, chain length factor (CLF or KSβ), as computing inputs. The process involves sequence embedding, data labeling, classifier development, and novelty detection, which enable precise classification and prediction directly from KSβwithout sequence alignments. Combined with metagenomics and metabolomics, we evaluated the ability of DeepT2 and found this model could easily detect and classify KSβeither as a single sequence or a mixture of bacterial genomes, and subsequently identify the corresponding T2PKs in a labeled categorized class or as novel. Our work highlights deep learning as a promising framework for genome mining and therefore provides a meaningful platform for discovering medically important natural products.
Cell state-dependent chromatin targeting in NUT carcinoma
Authors: Alekseyenko Artyom A. , Zee Barry M. , Dhoondia Zuzer , Kang Hyuckjoon , Makofske Jessica L. , Kuroda Mitzi I.
Published: April 2023

Aberrant transcriptional programming and chromatin dysregulation are common to most cancers. Whether by deranged cell signaling or environmental insult, the resulting oncogenic phenotype is typically manifested in transcriptional changes characteristic of undifferentiated cell growth. Here we analyze targeting of an oncogenic fusion protein, BRD4-NUT, composed of two normally independent chromatin regulators. The fusion causes the formation of large hyperacetylated genomic regions or megadomains, mis-regulation ofc-MYC, and an aggressive carcinoma of squamous cell origin. Our previous work revealed largely distinct megadomain locations in different NUT carcinoma patient cell lines. To assess whether this was due to variations in individual genome sequences or epigenetic cell state, we expressed BRD4-NUT in a human stem cell model and found that megadomains formed in dissimilar patterns when comparing cells in the pluripotent state with the same cell line following induction along a mesodermal lineage. Thus, our work implicates initial cell state as the critical factor in the locations of BRD4-NUT megadomains. These results, together with our analysis of c-MYC protein-protein interactions in a patient cell line, are consistent with a cascade of chromatin misregulation underlying NUT carcinoma.
Flux Sampling in Genome-scale Metabolic Modeling of Microbial Communities
Authors: Gelbach Patrick E. , Finley Stacey D.
Published: April 2023

1.

Microbial communities play a crucial role in ecosystem function through metabolic interactions. Genome-scale modeling is a promising method to understand these interactions. Flux balance analysis (FBA) is most often used to predict the flux through all reactions in a genome-scale model. However, the fluxes predicted by FBA depend on a user-defined cellular objective. Flux sampling is an alternative to FBA, as it provides the range of fluxes possible within a microbial community. Furthermore, flux sampling may capture additional heterogeneity across cells, especially when cells exhibit sub-maximal growth rates. In this study, we simulate the metabolism of microbial communities and compare the metabolic characteristics found with FBA and flux sampling. We find significant differences in the predicted metabolism with sampling, including increased cooperative interactions and pathway-specific changes in predicted flux. Our results suggest the importance of sampling-based and objective function-independent approaches to evaluate metabolic interactions and emphasize their utility in quantitatively studying interactions between cells and organisms.
Pharmacological chaperones restore proteostasis of epilepsy-associated GABAAreceptor variants
Authors: Wang Ya-Juan , Seibert Hailey , Ahn Lucie Y. , Schaffer Ashleigh E. , Mu Ting-Wei
Published: April 2023

Recent advances in genetic diagnosis identified variants in genes encoding GABAAreceptors as causative for genetic epilepsy. Here, we selected eight disease-associated variants in the α1 subunit of GABAAreceptors causing mild to severe clinical phenotypes and showed that they are loss of function, mainly by reducing the folding and surface trafficking of the α1 protein. Furthermore, we sought client protein-specific pharmacological chaperones to restore the function of pathogenic receptors. Applications of positive allosteric modulators, including Hispidulin and TP003, increase the functional surface expression of the α1 variants. Mechanism of action study demonstrated that they enhance the folding and assembly and reduce the degradation of GABAAvariants without activating the unfolded protein response in HEK293T cells and human iPSC-derived neurons. Since these compounds cross the blood-brain barrier, such a pharmacological chaperoning strategy holds great promise to treat genetic epilepsy in a GABAAreceptor-specific manner.
Chronic exposure of mosquito larvae to pesticide residues endangers a new generation of agrochemicals repurposed for malaria prevention
Authors: Ambadiang Marilene M. , Fouet Caroline , Ashu Fred A. , Penlap-Beng Véronique , Kamdem Colince
Published: April 2023

Agrochemicals have been successfully repurposed to control mosquitoes worldwide, but pesticides used in agriculture challenge their effectiveness by contaminating surface waters and helping larval populations develop resistance. Thus, knowledge of the lethal and sublethal effects of residual pesticide exposure on mosquitoes is critical for selecting effective insecticides. Here we implemented a new experimental approach to predict the efficacy of agricultural pesticides newly repurposed for malaria vector control. We mimicked insecticide resistance selection as it occurs in contaminated aquatic habitats by rearing field-collected mosquito larvae in water containing a dose of insecticide capable of killing individuals from a susceptible strain within 24 h. We then simultaneously monitored short-term lethal toxicity within 24 h and sublethal effects for 7 days. We found that due to chronic exposure to agricultural pesticides, some mosquito populations are currently pre-adapt to resist neonicotinoids if those were used in vector control. Larvae collected from rural and agricultural areas where neonicotinoid formulations are intensively used for insect pest management were able to survive, grow, pupate and emerge in water containing a lethal dose of acetamiprid, imidacloprid or clothianidin. These results emphasize the importance of addressing exposure of larval populations to formulations applied in agriculture prior to using agrochemicals against malaria vectors.
Systematic review of precision subclassification of type 2 diabetes
Authors: Misra Shivani , Wagner Robert , Ozkan Bige , Schön Martin , Sevilla-Gonzalez Magdalena , Prystupa Katsiaryna , Wang Caroline C. , Kreienkamp Raymond J. , Cromer Sara J. , Rooney Mary R. , Duan Daisy , Thuesen Anne Cathrine Baun , Wallace Amelia S. , Leong Aaron , Deutsch Aaron J. , Andersen Mette K. , Billings Liana K. , Eckel Robert H , Sheu Wayne Huey-Herng , Hansen Torben , Stefan Norbert , Goodarzi Mark O. , Ray Debashree , Selvin Elizabeth , Florez Jose C. ,   ADA/EASD PMDI, Meigs James B. , Udler Miriam S.
Published: April 2023

Heterogeneity in type 2 diabetes presentation, progression and treatment has the potential for precision medicine interventions that can enhance care and outcomes for affected individuals. We undertook a systematic review to ascertain whether strategies to subclassify type 2 diabetes are associated with improved clinical outcomes, show reproducibility and have high quality evidence. We reviewed publications that deployed ‘simple subclassification’ using clinical features, biomarkers, imaging or other routinely available parameters or ‘complex subclassification’ approaches that used machine learning and/or genomic data. We found that simple stratification approaches, for example, stratification based on age, body mass index or lipid profiles, had been widely used, but no strategy had been replicated and many lacked association with meaningful outcomes. Complex stratification using clustering of simple clinical data with and without genetic data did show reproducible subtypes of diabetes that had been associated with outcomes such as cardiovascular disease and/or mortality. Both approaches require a higher grade of evidence but support the premise that type 2 diabetes can be subclassified into meaningful groups. More studies are needed to test these subclassifications in more diverse ancestries and prove that they are amenable to interventions.
Suicide prevention curriculum development for health and social care students: Protocol for a scoping review
Authors: Gallagher Kerrie , O’ Brien Clíodhna , Dhalaigh Doireann Ní , Corcoran Paul , Griffin Eve
Published: April 2023

Background

Suicide has become a serious public health concern and international research has shown that the majority of individuals who died by suicide had received healthcare in the year prior to their death. This presents an opportunity for suicide prevention by strategically training healthcare students in suicide prevention knowledge and skills.

Objective

The objective of this scoping review is to identify the literature on the development and implementation of suicide prevention curricula for undergraduate and postgraduate students of health and social care degree programmes.

Inclusion criteria

Studies will only be considered eligible for inclusion if they describe the development and/or implementation of suicide prevention curricula being taught to health and social care degree students in higher education/university settings. Quantitative, qualitative and mixed method studies published between 2011 and 2023 (inclusive) and in the English language will be considered eligible.

Methods

This scoping review will be conducted according to the PRISMA guidelines for scoping reviews (PRISMA-ScR). The developed search strategy will be implemented across seven databases: Australian Educational Index, British Educational Index, ERIC (Education Resources Information Center), PsycINFO, Embase, Scopus and Web of Science. Several grey literature databases will also be consulted. Further potential results will be located by hand-searching the reference lists of included articles. The search strategy will include variations of the terms ‘university students’, ‘suicide prevention’ and ‘education’. The search terms will be limited to titles, abstracts, and keywords in databases that allow it. Two reviewers will complete the screening using the predefined inclusion criteria. A third reviewer will resolve any conflicts during the screening and eligibility appraisal processes. Results will be presented in the form of tabulated results and an accompanying narrative summary, describing key findings and context related to learning outcomes, methodologies employed and implementation of the identified programmes.
The Epidemiological and Economic Burden of Diabetes in Ghana: A Scoping Review to Inform Health Technology Assessment
Authors: Gad Mohamed , Kazibwe Joseph , Abassah-Konadu Emmanuella , Amankwah Ivy , Owusu Richmond , Gulbi Godwin , Torres-Rueda Sergio , Asare Brian , Vassall Anna , Ruiz Francis
Published: April 2023

Introduction

Diabetes remains one of the four major causes of morbidity and mortality globally among non-communicable diseases (NCDs. It is predicted to increase in sub–Saharan Africa by over 50% by 2045. The aim of this study is to identify, map and estimate the burden of diabetes in Ghana, which is essential for optimising NCD country policy and understanding existing knowledge gaps to guide future research in this area.

Methods

We followed the Arksey and O’Malley framework for scoping reviews. We searched electronic databases including Medline, Embase, Web of Science, Scopus, Cochrane and African Index Medicus following a systematic search strategy. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews was followed when reporting the results.

Results

A total of 36 studies were found to fulfil the inclusion criteria. The reported prevalence of diabetes at national level in Ghana ranged between 2.80% – 3.95%. At the regional level, the Western region reported the highest prevalence of diabetes: 39.80%, followed by Ashanti region (25.20%) and Central region at 24.60%. The prevalence of diabetes was generally higher in women in comparison to men. Urban areas were found to have a higher prevalence of diabetes than rural areas. The mean annual financial cost of managing one diabetic case at the outpatient clinic was estimated at GHS 540.35 (2021 US $194.09). There was a paucity of evidence on the overall economic burden and the regional prevalence burden.

Conclusion

Ghana is faced with a considerable burden of diabetes which varies by region and setting (urban/rural). There is an urgent need for effective and efficient interventions to prevent the anticipated elevation in burden of disease through the utilisation of existing evidence and proven priority-setting tools like Health Technology Assessment (HTA).
Assessing awareness of blood cancer symptoms and barriers to symptomatic presentation: Measure development and results from a population survey in the UK
Authors: Boswell Laura , Harris Jenny , Ip Athena , Russell Jessica , Black Georgia , Whitaker Katriina L
Published: April 2023

Background

Low levels of cancer awareness may contribute to delays in seeking medical help and subsequent delays in diagnosis. For blood cancer this may be a particularly prominent problem due to the high prevalence of undifferentiated symptoms such as bodily pain, weakness, nausea and weight loss, resulting in low symptom awareness. The delay is exacerbated by the dismissal of similar symptoms which are often interpreted as mild disease, resulting in multiple consultations prior to diagnosis. This study describes the development of a Cancer Awareness Measure for Blood Cancer (Blood CAM) and presents results from a population-representative survey using the measure.

Methods

A rapid systematic review identified constructs relevant to blood cancer. Items were taken from previous awareness measures and other literature and reviewed by expert groups including health care professionals and patients. Cognitive interviews were conducted with ten members of the public to check comprehension and clarity. A total sample of 434 participants completed the survey at Time 1 and n=302 at Time 2 (two weeks later).

Results

Internal reliability was high across the different constructs included in the questionnaire (>0.70) and test-retest reliability was moderate to good (0.49-0.79). The most commonly recognised blood cancer symptoms were unexplained weight loss (68.9%) and unexplained bleeding (64.9%) and the least commonly recognised symptoms were night sweats (31.3%) breathlessness and rash/itchy skin (both 44%). In terms of symptom experience, fatigue was the most commonly reported symptom (26.7%) followed by night sweats (25.4%).

Exploratory factor analysis of barriers to presenting at primary care revealed three distinct categories of barriers; emotional, external/practical and service/healthcare professional related. Service and emotional barriers were most common.

Conclusions

We developed a valid and reliable tool to assess blood cancer awareness and showed variable awareness of blood cancer symptoms which can help target public health campaigns. We also incorporated additional measures (e.g. confidence to re-consult, ability to understand symptoms) that could be used to tailor public messaging for blood cancer and for other harder to suspect and diagnose cancers.
Subchronic alteration of vestibular hair cells in mice: implications for multisensory gaze stabilization
Authors: Schenberg Louise , Palou Aïda , Simon François , Bonnard Tess , Barton Charles-Elliot , Fricker Desdemona , Tagliabue Michele , Llorens Jordi , Beraneck Mathieu
Published: April 2023

The functional complementarity of the vestibulo-ocular reflex (VOR) and optokinetic reflex (OKR) allows for optimal combined gaze stabilization responses (CGR) in light. While sensory substitution has been reported following complete vestibular loss, the capacity of the central vestibular system to compensate for partial peripheral vestibular loss remains to be determined. Here, we first demonstrate the efficacy of a 6-week subchronic ototoxic protocol in inducing transient and partial vestibular loss which equally affects the canal- and otolith-dependent VORs. Immunostaining of hair cells in the vestibular sensory epithelia revealed that organ-specific alteration of type I, but not type II, hair cells correlates with functional impairments. The decrease in VOR performance is paralleled with an increase in the gain of the OKR occurring in a specific range of frequencies where VOR normally dominates gaze stabilization, compatible with a sensory substitution process. Comparison of unimodal OKR or VOR versus bimodal CGR revealed that visuo-vestibular interactions remain reduced despite a significant recovery in the VOR. Modeling and sweep-based analysis revealed that the differential capacity to optimally combine OKR and VOR correlates with the reproducibility of the VOR responses. Overall, these results shed light on the multisensory reweighting occurring in pathologies with fluctuating peripheral vestibular malfunction.
COVID-19 and silent hypoxemia in a minimal closed-loop model of the respiratory rhythm generator
Authors: Diekman Casey O. , Thomas Peter J. , Wilson Christopher G.
Published: April 2023

Silent hypoxemia, or ‘happy hypoxia’, is a puzzling phenomenon in which patients who have contracted COVID-19 exhibit very low oxygen saturation (SaO2< 80%) but do not experience discomfort in breathing. The mechanism by which this blunted response to hypoxia occurs is unknown. We have previously shown that a computational model (Diekman et al., 2017, J. Neurophysiol) of the respiratory neural network can be used to test hypotheses focused on changes in chemosensory inputs to the central pattern generator (CPG). We hypothesize that altered chemosensory function at the level of the carotid bodies and/or thenucleus tractus solitariiare responsible for the blunted response to hypoxia. Here, we use our model to explore this hypothesis by altering the properties of the gain function representing oxygen sensing inputs to the CPG. We then vary other parameters in the model and show that oxygen carrying capacity is the most salient factor for producing silent hypoxemia. We call for clinicians to measure hematocrit as a clinical index of altered physiology in response to COVID-19 infection.
Fast Viral Dynamics Revealed by Microsecond Time-Resolved Cryo-EM
Authors: Harder Oliver F. , Barrass Sarah V. , Drabbels Marcel , Lorenz Ulrich J.
Published: April 2023

Observing proteins as they perform their tasks has largely remained elusive, which has left our understanding of protein function fundamentally incomplete. To enable such observations, we have recently proposed a novel technique that improves the time resolution of cryo-electron microscopy (cryo EM) to microseconds. Here, we demonstrate that microsecond time-resolved cryo-EM enables observations of fast protein dynamics. We use our approach to elucidate the mechanics of the capsid of cowpea chlorotic mottle virus (CCMV), whose large-amplitude motions play a crucial role in the viral life cycle. We observe that a pH jump causes the extended configuration of the capsid to contract on the microsecond timescale. While this is a concerted process, the motions of the capsid proteins involve different timescales, leading to a curved reaction path.
Epistasis facilitates functional evolution in an ancient transcription factor
Authors: Metzger Brian P.H. , Park Yeonwoo , Starr Tyler N. , Thornton Joseph W.
Published: April 2023

A protein’s genetic architecture – the set of causal rules by which its sequence produces its functions – also determines its possible evolutionary trajectories. Prior research has proposed that genetic architecture of proteins is very complex, with pervasive epistatic interactions that constrain evolution and make function difficult to predict from sequence. Most of this work has analyzed only the direct paths between two proteins of interest – excluding the vast majority of possible genotypes and evolutionary trajectories – and has considered only a single protein function, leaving unaddressed the genetic architecture of functional specificity and its impact on the evolution of new functions. Here we develop a new method based on ordinal logistic regression to directly characterize the global genetic determinants of multiple protein functions from 20-state combinatorial deep mutational scanning (DMS) experiments. We use it to dissect the genetic architecture and evolution of a transcription factor’s specificity for DNA, using data from a combinatorial DMS of an ancient steroid hormone receptor’s capacity to activate transcription from two biologically relevant DNA elements. We show that the genetic architecture of DNA recognition consists of a dense set of main and pairwise effects that involve virtually every possible amino acid state in the protein-DNA interface, but higher-order epistasis plays only a tiny role. Pairwise interactions enlarge the set of functional sequences and are the primary determinants of specificity for different DNA elements. They also massively expand the number of opportunities for single-residue mutations to switch specificity from one DNA target to another. By bringing variants with different functions close together in sequence space, pairwise epistasis therefore facilitates rather than constrains the evolution of new functions.
Spiking neural networks provide accurate, efficient and robust models for whisker stimulus classification and allow for inter-individual generalization
Authors: Albrecht Steffen , Vandevelde Jens R. , Vecchi Edoardo , Berra Gabriele , Bassetti Davide , Stüttgen Maik C. , Luhmann Heiko J. , Horenko Illia
Published: April 2023

With the help of high-performance computing, we benchmarked a selection of machine learning classification algorithms on the tasks of whisker stimulus detection, stimulus classification and behavior prediction based on electrophysiological recordings of layer-resolved local field potentials from the barrel cortex of awake mice. Machine learning models capable of accurately analyzing and interpreting the neuronal activity of awake animals during a behavioral experiment are promising for neural prostheses aimed at restoring a certain functionality of the brain for patients suffering from a severe brain injury. The liquid state machine, a highly efficient spiking neural network classifier that was designed for implementation on neuromorphic hardware, achieved the same level of accuracy compared to the other classifiers included in our benchmark study. Based on application scenarios related to the barrel cortex and relevant for neuroprosthetics, we show that the liquid state machine is able to find patterns in the recordings that are not only highly predictive but, more importantly, generalizable to data from individuals not used in the model training process. The generalizability of such models makes it possible to train a model on data obtained from one or more individuals without any brain lesion and transfer this model to a prosthesis required by the patient.

Author Summary

A neural prosthesis is a computationally driven device that restores the functionality of a damaged brain region for locked-in patients suffering from the aftereffects of a brain injury or severe stroke. As such devices are chronically implanted, they rely on small, low-powered microchips with limited computational resources. Based on recordings describing the neural activity of awake mice, we show that spiking neural networks, which are especially designed for microchips, are able to provide accurate classification models in application scenarios relevant in neuroprosthetics. Furthermore, models were generalizable across mice, corroborating that it will be possible to train a model on recordings from healthy individuals and transfer it to the patient’s prosthesis.
Mobilisation and analyses of publicly available SARS-CoV-2 data for pandemic responses
Authors: Rahman Nadim , O’Cathail Colman , Zyoud Ahmad , Sokolov Alexey , Munnink Bas Oude , Grüning Björn , Cummins Carla , Amid Clara , Nieuwenhuijse David , Visontai Dávid , Yuan David Yu , Gupta Dipayan , Prasad Divyae , Gulyás Gábor Máté , Rinck Gabriele , McKinnon Jasmine , Rajan Jeena , Knaggs Jeff , Skiby Jeffrey Edward , Stéger József , Szarvas Judit , Gueye Khadim , Papp Krisztián , Hoek Maarten , Kumar Manish , Ventouratou Marianna , Bouquieaux Marie-Catherine , Koliba Martin , Mansurova Milena , Haseeb Muhammad , Worp Nathalie , Harrison Peter W. , Leinonen Rasko , Thorne Ross , Selvakumar Sandeep , Hunt Sarah , Venkataraman Sundar , Jayathilaka Suran , Cezard Timothée , Maier Wolfgang , Waheed Zahra , Iqbal Zamin , Aarestrup Frank Møller , Csabai Istvan , Koopmans Marion , Burdett Tony , Cochrane Guy
Published: April 2023

The COVID-19 pandemic has seen large-scale pathogen genomic sequencing efforts, becoming part of the toolbox for surveillance and epidemic research. This resulted in an unprecedented level of data sharing to open repositories, which has actively supported the identification of SARS-CoV-2 structure, molecular interactions, mutations and variants, and facilitated vaccine development and drug reuse studies and design. The European COVID-19 Data Platform was launched to support this data sharing, and has resulted in the deposition of several million SARS-CoV-2 raw reads. In this paper we describe (1) open data sharing, (2) tools for submission, analysis, visualisation and data claiming (e.g. ORCiD), (3) the systematic analysis of these datasets, at scale via the SARS-CoV-2 Data Hubs as well as (4) lessons learned. As a component of the Platform, the SARS-CoV-2 Data Hubs enabled the extension and set up of infrastructure that we intend to use more widely in the future for pathogen surveillance and pandemic preparedness.
Ena/VASP proteins mediate endothelial cell repulsion from ephrin ligands
Authors: Zink Joana , Frömel Timo , Wittig Ilka , Fleming Ingrid , Benz Peter M.
Published: April 2023

The interaction of Eph receptor tyrosine kinases with their transmembrane ligands; the ephrins, is important for the regulation of cell-cell communication. Ephrin-Eph signaling is probably best known for the discrimination of arterial and venous territories by repulsion of venous endothelial cells away from those with an arterial fate. Ultimately, cell repulsion is mediated by initiating the collapse of the actin cytoskeleton in membrane protrusions. Here, we investigated the role of the Ena/VASP family of actin binding proteins in endothelial cell repulsion initiated by ephrin ligands. Human endothelial cells dynamically extended sheet-like lamellipodia over ephrin-B2 coated surfaces. While lamellipodia of control siRNA transfected cells rapidly collapsed, resulting in a pronounced cell repulsion from the ephrin-B2 surfaces, the knockdown of Ena/VASP proteins impaired the cytoskeletal collapse of membrane protrusions and the cells no longer avoided the repulsive surfaces. Mechanistically, ephrin-B2 stimulation elicited the EphB-mediated tyrosine phosphorylation of VASP, which abrogated its interaction with the focal adhesion protein Zyxin. Nck2 was identified as a novel VASP binding protein, which only interacted with the tyrosine phosphorylated VASP protein. Nck links Eph-receptors to the actin cytoskeleton. Therefore, we hypothesize that Nck-Ena/VASP complex formation is required for actin reorganization and/or Eph receptor internalization downstream of ephrin-Eph interaction in endothelial cells, with implications for endothelial navigation and pathfinding.
Knowledge sharing barriers and knowledge sharing facilitators in innovation
Authors: Salehi Mahdi , Sadeq Alanbari Sami Abdulridha
Published: April 2023

Purpose

The present study aims to assess the effect of barriers and knowledge sharing facilitators on organisational innovation in Iraq. Fundamentally, this paper seeks to answer “whether knowledge sharing can improve organisational innovation in firms listed on the Iraq Stock Exchange”.

Design/methodology/approach

For the study, the research method is practical, in the form of an objective and descriptive survey. The study sample includes all financial managers of manufacturing companies listed on the Iraq Stock Exchange. The sampling method of the present study is based on Cochran comprising of 467 participants; a total number of 211 questionnaires were completed as the study's sample. This paper uses PLS tests to assess the effect of independent variables on dependent variables.

Findings

Results show that knowledge sharing barriers have no impact on the organisational innovation of firms listed on the Iraq Stock Exchange, but that knowledge sharing facilitators can enhance the organisational innovation of these firms.

Originality/value

This paper is the first study on the effect of barriers and knowledge sharing facilitators on organisational innovation of firms listed on the Iraq Stock Exchange, which is an emergent country with specific conditions (lack of specialised workforce and modern systematic infrastructure), therefore the results will provide helpful information that will contribute to the development of science and knowledge.
How shopping habits change with artificial intelligence: smart speakers' usage intention
Authors: Aiolfi Simone
Published: April 2023

Purpose

The research aims to understand how smart speakers are perceived by their actual and potential users, their attitude towards smart speakers and consequently their intention to use them.

Design/methodology/approach

The authors apply a structural equation modelling (SEM) approach to test the research hypotheses through data coming from a structured questionnaire.

Findings

The results show that the higher the importance attributed to usefulness and ease of use, the higher the positive attitude that in turn positively affects the intention to use smart speakers. A significant relationship also emerged between task technology fit and attitude towards smart speakers, as well as between perceived enjoyment and attitude towards smart speakers. Perceived privacy risk, innovativeness and social attraction have been found to not significantly impact attitudes towards smart speakers.

Originality/value

Although several academic studies have focused on various aspects of smart technologies, only a few studies discuss the factors that push consumers to use smart speakers for activities related to commercial transactions. Therefore, looking at the rapid rise of smart speakers for daily tasks and the gradual acceptance of voice interaction with digital tools, the authors proposed a study about Italian users' intention to use smart speakers. Specifically, to fill the gap in the existing literature, the authors applied a SEM approach to identify utilitarian and hedonic benefits that motivate the use of these devices.
Assessing the kid's behaviour with factors of social media advertising: DEMATEL application
Authors: Bandil Deepika , Agrawal Vivek , Mohanty R.P.
Published: April 2023

Purpose

Kids get exposed to advertising on social media platforms when they visit them to perform various goals. The purpose of this study is to find out the factors which affect kids' behaviour when the kids encounter advertising on social media and also to establish causal relationships amongst the factors of social media advertising (SMA).

Design/methodology/approach

A total of 11 factors of SMA have been identified with the help of experts and the causal relationships amongst the SMA factors have been constructed by the implementation of decision-making trail and laboratory evaluation (DEMATEL). Based on the established relationships, a causal diagram has been also developed to understand the structural nature of interdependence amongst the factors.

Findings

DEMATEL technique is based on logical steps, which have assisted in categorising the identified factors into two groups: cause group and effect group. Cause group factors are the reasons for the effect group factors to occur. Customisation, entertainment, information and interactivity have been observed as cause factors whereas, relevance, engagement with SMA, purchase intention, product involvement, advertising value, attitude towards SMA and irritation have been observed as effect factors. Product involvement is found to have the highest level of interaction with all other factors. Information and interactivity are observed to influence all other factors.

Research limitations/implications

Kids possess a limited understanding of the selling intent of advertisers which makes kids vulnerable to advertising. This study supports that the content of the advertisement should be kept in accordance with the need of kids and also suggests that marketers should emphasise cause group factors which derive subsequent consequences on effect group factors. The foremost limitation of this study lies in the process of identifying the factors through expert opinions. The sets of contextual relationships may vary when different experts are considered.

Originality/value

This study strives to identify the factors which affect kids' understanding of SMA and also establishes causal relationships amongst them. This kind of study is unique in state of the art and to the authors' knowledge no significant research has been conducted in India which involves establishment of inter-relationships amongst SMA factors that affect kids' behaviour.
Ruin heritage and its reuse: the case of ruin bars in Budapest
Authors: Mérai Dóra , Kulikov Volodymyr
Published: April 2023

Purpose

The paper discusses ethical issues related to the adaptive reuse of ruin heritage on the example of the so-called ruin bars in Budapest's District VII. It explores how heritage discourse can contribute to the sustainable development of urban neighborhoods. The authors address the question by focusing on how a processual approach can be instrumental in identifying responsible and socially sustainable ways to reuse dilapidated heritage in a residential area.

Design/methodology/approach

The problem is analyzed through a case study based on field observation, participant observation, stakeholder interviews, policy analysis and media and social media content analysis.

Findings

The authors argue that ethical reuse of ruin heritage must take into consideration the values and interests of multiple stakeholders and the broadest range of consequences at the level of neighborhood and city. An integrated heritage and planning policy should consider and involve as active participants all the heritage communities concerned. Importantly, these groups, comprising both new and longtime residents, must include the vulnerable and marginalized.

Practical implications

The findings can be used by heritage managers for identifying and addressing ethical issues in their adaptive heritage reuse practices and by policymakers for integrating heritage management in urban development and making cities more inclusive (SDG #11).

Originality/value

The paper explores how ethical it is for business enterprises to build on the ruin esthetics in a residential district and what the ethical implications of this reuse process are for various stakeholders.