bluuebunny/crossref_metadata_2025_split huggingface dataset:
High levels of cyclic diguanylate interfere with beneficial bacterial colonization
Authors: Isenberg Ruth Y. , Christensen David G. , Visick Karen L. , Mandel Mark J. 
Published: April 2022

ABSTRACTDuring colonization of the Hawaiian bobtail squid (Euprymna scolopes),Vibrio fischeribacteria undergo a lifestyle transition from a planktonic motile state in the environment to a biofilm state in host mucus. Cyclic diguanylate (c-di-GMP) is a cytoplasmic signaling molecule that is important for regulating motility-biofilm transitions in many bacterial species.V. fischeriencodes 50 proteins predicted to synthesize and/or degrade c-di-GMP, but a role for c-di-GMP regulation during host colonization has not been investigated. We examined strains exhibiting either low or high levels of c-di-GMP during squid colonization and found that while a low c-di-GMP strain had no colonization defect, a high c-di-GMP strain was severely impaired. Expression of a heterologous c-di-GMP phosphodiesterase restored colonization, demonstrating that the effect is due to high c-di-GMP levels. In the constitutive high c-di-GMP state, colonizingV. fischeriexhibited reduced motility, altered biofilm aggregate morphology, and a regulatory interaction where transcription of one polysaccharide locus is inhibited by the presence of the other polysaccharide. Our results highlight the importance of proper c-di-GMP regulation during beneficial animal colonization, illustrate multiple pathways regulated by c-di-GMP in the host, and uncover an interplay of multiple exopolysaccharide systems in host-associated aggregates.IMPORTANCEThere is substantial interest in studying cyclic diguanylate (c-di-GMP) in pathogenic and environmental bacteria, which has led to an accepted paradigm in which high c-di-GMP levels promote biofilm formation and reduce motility. However, considerably less focus has been placed on understanding how this compound contributes to beneficial colonization. Using theVibrio fischeri-Hawaiian bobtail squid study system, we took advantage of recent genetic advances in the bacterium to modulate c-di-GMP levels and measure colonization and track c-di-GMP phenotypes in a symbiotic interaction. Studies in the animal host revealed a c-di-GMP-dependent genetic interaction between two distinct biofilm polysaccharides, Syp and cellulose, that was not evident in culture-based studies: elevated c-di-GMP altered the composition and abundance of thein vivobiofilm by decreasingsyptranscription due to increased cellulose synthesis. This study reveals important parallels between pathogenic and beneficial colonization and additionally identifies c-di-GMP-dependent regulation that occurs specifically in the squid host.
Target-agnostic drug prediction integrated with medical record analysis uncovers differential associations of statins with increased survival in COVID-19 patients
Authors: Sperry Megan M. , Oskotsky Tomiko , Marić Ivana , Kaushal Shruti , Takeda Takako , Horvath Viktor , Powers Rani K. , Rodas Melissa , Furlong Brooke , Soong Mercy , Prabhala Pranav , Goyal Girija , Carlson Kenneth E. , Wong Ronald J. , Kosti Idit , Le Brian L. , Logue James , Hammond Holly , Frieman Matthew , Stevenson David K. , Ingber Donald E. , Sirota Marina , Novak Richard 
Published: April 2022

SummaryImportanceDrug repurposing requires distinguishing established drug class targets from novel molecule-specific mechanisms and rapidly derisking their therapeutic potential in a time-critical manner, particularly in a pandemic scenario. In response to the challenge to rapidly identify treatment options for COVID-19, several studies reported that statins, as a drug class, reduce mortality in these patients. However, it is unknown if different statins exhibit consistent function or may have varying therapeutic benefit.ObjectivesTo test if different statins differ in their ability to exert protective effects based on molecular computational predictions and electronic medical record analysis.Main Outcomes and MeasuresA Bayesian network tool was used to predict drugs that shift the host transcriptomic response to SARS-CoV-2 infection towards a healthy state. Drugs were predicted using 14 RNA-sequencing datasets from 72 autopsy tissues and 465 COVID-19 patient samples or from cultured human cells and organoids infected with SARS-CoV-2, with a total of 2,436 drugs investigated. Top drug predictions included statins, which were then assessed using electronic medical records containing over 4,000 COVID-19 patients on statins to determine mortality risk in patients prescribed specific statins versus untreated matched controls. The same drugs were tested in Vero E6 cells infected with SARS-CoV-2 and human endothelial cells infected with a related OC43 coronavirus.ResultsSimvastatin was among the most highly predicted compounds (14/14 datasets) and five other statins, including atorvastatin, were predicted to be active in > 50% of analyses. Analysis of the clinical database revealed that reduced mortality risk was only observed in COVID-19 patients prescribed a subset of statins, including simvastatin and atorvastatin.In vitrotesting of SARS-CoV-2 infected cells revealed simvastatin to be a potent direct inhibitor whereas most other statins were less effective. Simvastatin also inhibited OC43 infection and reduced cytokine production in endothelial cells.Conclusions and RelevanceDifferent statins may differ in their ability to sustain the lives of COVID-19 patients despite having a shared drug target and lipid-modifying mechanism of action. These findings highlight the value of target-agnostic drug prediction coupled with patient databases to identify and clinically evaluate non-obvious mechanisms and derisk and accelerate drug repurposing opportunities.
Astrocyte-mediated transduction of muscle fiber contractions synchronizes hippocampal neuronal network development
Authors: Lee Ki Yun , Rhodes Justin S. , Saif M. Taher A. 
Published: April 2022

AbstractExercise supports brain health in part through enhancing hippocampal function. The leading hypothesis is that muscles release factors when they contract (e.g., lactate, myokines, growth factors) that enter circulation and reach the brain where they enhance plasticity (e.g., increase neurogenesis and synaptogenesis). However, it remains unknown how the muscle signals are transduced by the hippocampal cells to modulate network activity and synaptic development. Thus, we established an in vitro model in which the media from contracting primary muscle cells (CM) is applied to developing primary hippocampal cell cultures on a microelectrode array. We found that the hippocampal neuronal network matures more rapidly (as indicated by synapse development and synchronous neuronal activity) when exposed to CM than regular media (RM). This was accompanied by a 1.4-fold and 4.4-fold increase in the proliferation of neurons and astrocytes, respectively. Further, experiments established that the astrocytes release factors that inhibit neuronal excitability and facilitate network development. Results provide new insight into how exercise may support hippocampal function through regulating astrocyte proliferation and subsequent taming of neuronal activity into an integrated network.HighlightsContracting muscle conditioned media enhances neuronal activity.Contracting muscle conditioned media expedites neuronal maturation and accumulation of filamentous actin at presynaptic terminals.Contracting muscle conditioned media induces significant neuron and astrocyte proliferation.Astrocytes release factors that inhibit muscle media-induced neuronal activity.
Gestational Ethanol Exposure Induces Sex-specific Striatal Acetylcholine and Dopamine Deficits
Authors: Bariselli Sebastiano , Mateo Yolanda , Reuveni Noa , Lovinger David M 
Published: April 2022

ABSTRACTFetal alcohol exposure has deleterious consequences on the cognitive abilities and motor skills of patients affected by Fetal Alcohol Spectrum Disorder (FASD) and in pre-clinical models of gestational ethanol exposure (GEE). Deficits in striatal cholinergic and dopamine function impair action learning and execution, yet the effects of GEE on striatal acetylcholine and dopamine release remain unexplored. Here, we report that ethanol (EtOH) exposure during the first ten postnatal days (GEEP0-P10), which mimics EtOH consumption during the last gestational trimester in humans, induces enduring sex-specific anatomical and motor learning deficits in female mice. These behavioral impairments were accompanied by increased evoked-dopamine levels in the dorsolateral striatum (DLS) of GEEP0-P10 female, but not male, mice. Further experiments revealed impaired striatal β2-containing nicotinic acetylcholine receptor (nAChRs)-modulation of electrically evoked dopamine release. Using a genetically encoded acetylcholine sensor (GACh3.0), we found a reduced decay of acetylcholine transients in DLS of GEEP0-P10 females in the presence of an acetylcholinesterase inhibitor galantamine. Finally, we showed that this effect is associated with decreased excitability of striatal cholinergic interneurons (CINs), pointing to activity-dependent defects in acetylcholine release. Altogether, these data shed a new light on striatal deficits that might underlie cognitive and motor learning symptoms of patients affected by FASD.
Deciphering the mRNA-lncRNA-miRNA interaction landscape in human pluripotency
Authors: Ghosh Arindam , Som Anup 
Published: April 2022

ABSTRACTHuman embryonic stem cells offer a huge potential for the study of early human development and for application in biomedical sciences. Growing evidence has shown that besides the protein coding genes, the non-coding elements of the human genome play a crucial role in maintaining its property of self renewal and in cell fate determination. However, a clear understanding of this regulatory mechanism and the landscape of interactions between the coding and non-coding elements was still lacking. To fill in this void, we use transcriptomic data from RNA-seq and small RNA-seq experiments to reconstruct the core pluripotency circuitry involving mRNAs, lncRNAs and miRNAs. The overall interaction landscape revealed an alternate circuit for the maintenance of pluripotency devoid of the classic pluripotency transcription factors NANOG, SOX2 and POU5F1. We also identified networks specific to the naive and primed states of human pluripotency revealing a new set of transcriptomic markers that could not only be used to differentiate pluripotent state from non-pluripotent state but also to identify the intra-pluripotency state. The lncRNA DANT1 was found to be crucial in determination to the two pluripotency states as it formed a bridge between the naive and primed state specific pluripotency networks. Further, we also identified and computationally validated putative ceRNA mechanism involving DANT1, the miRNAs hsa-miR-30c-2-3p, hsa-miR-210-3p and hsa-let-7b-5p, and several key pluripotency related genes including PTPRZ1, SALL2, TOX3, ZNF695, and ZYG11A which warrants further experimental validation.HIGHLIGHTSReconstructed the key MLMi circuitry underlying human pluripotency by combining RNA-Seq data and known interaction information.Identified an alternate pluripotency circuit devoid of classic pluripotency transcription factors NANOG, SOX2 and POU5F1.Predicted a new set of markers that can not only distinguish between pluripotent and non-pluripotent states but also identify the intra-pluripotency state.Identified novel putative function of lncRNA DANT1 as ceRNA in formation of naive and primed state pluripotency.DANT1 harbours binding sites for miRNAs hsa-miR-30c-2-3p, hsa-miR-210-3p and hsa-let-7b-5p.
Two stages of bandwidth scaling drives efficient neural coding of natural sounds
Authors: He Fengrong , Stevenson Ian H. , Escabi Monty A. 
Published: April 2022

ABSTRACTTheories of efficient coding propose that the auditory system is optimized for the statistical structure of natural sounds, yet the transformations underlying optimal acoustic representations are not well understood. Using a database of natural sounds including human speech and a physiologically-inspired auditory model, we explore the consequences of peripheral (cochlear) and mid-level (auditory midbrain) filter tuning transformations on the representation of natural sound spectra and modulation statistics. Whereas Fourier-based spectrographic decompositions with equal resolution filters can preserve spectral details, cochlear filters with bandwidth scaling, sacrifice spectral information while producing a more robust temporal representation. Cochlear bandwidth scaling produces a frequency-dependent gain that counteracts the tendency of natural sound power to decrease with frequency, resulting in a whitened output representation. Mid-level auditory filter scaling further enhance the representation of natural sounds by producing a whitened modulation power spectrum (MPS) with higher modulation entropy than both the cochlear outputs and the conventional Fourier MPS. These findings suggest that the tuning characteristics of the peripheral and mid-level auditory system together produce a whitened output representation in three dimensions (frequency, temporal and spectral modulation) that reduces redundancies and allows for a more efficient use of neural resources. This hierarchical multi-stage tuning strategy is thus likely optimized to extract available information and may underlies perceptual sensitivity to natural sounds.
Effectiveness of COVID-19 vaccines against hospitalization and death in Canada: A multiprovincial test-negative design study
Authors: Nasreen Sharifa , Febriani Yossi , Velásquez García Héctor Alexander , Zhang Geng , Tadrous Mina , Buchan Sarah A. , Righolt Christiaan H. , Mahmud Salaheddin M. , Janjua Naveed Zafar , Krajden Mel , De Serres Gaston , Kwong Jeffrey C. 
Published: April 2022

ABSTRACTBackgroundA major goal of COVID-19 vaccination is to prevent severe outcomes (hospitalizations and deaths). We estimated the effectiveness of mRNA and ChAdOx1 COVID-19 vaccines against severe outcomes in four Canadian provinces between December 2020 and September 2021.MethodsWe conducted this multiprovincial retrospective test-negative study among community-dwelling adults aged ≥18 years in Ontario, Quebec, British Columbia, and Manitoba using linked provincial databases and a common study protocol. Multivariable logistic regression was used to estimate province-specific vaccine effectiveness against COVID-19 hospitalization and/or death. Estimates were pooled using random effects models.ResultsWe included 2,508,296 tested subjects, with 31,776 COVID-19 hospitalizations and 5,842 deaths. Vaccine effectiveness was 83% after a first dose, and 98% after a second dose, against both hospitalization and death (separately). Against severe outcomes (hospitalization or death), effectiveness was 87% (95%CI: 71%–94%) ≥84 days after a first dose of mRNA vaccine, increasing to 98% (95%CI: 96%–99%) ≥112 days after a second dose. Vaccine effectiveness against severe outcomes for ChAdOx1 was 88% (95%CI: 75%–94%) ≥56 days after a first dose, increasing to 97% (95%CI: 91%–99%) ≥56 days after a second dose. Lower one-dose effectiveness was observed for adults aged ≥80 years and those with comorbidities, but effectiveness became comparable after a second dose. Two doses of vaccines provided very high protection for both homologous and heterologous schedules, and against Alpha, Gamma, and Delta variants.ConclusionsTwo doses of mRNA or ChAdOx1 vaccines provide excellent protection against severe outcomes of hospitalization and death.
Mechanical aspects of mothership with sensing drones system
Authors: Pakuła Aleksandra , Muchla Grzegorz , Załęcki Bartosz , Modzelewski Michał Jakub , Goetzendorf-Grabowski Tomasz 
Published: April 2022

Purpose
This paper aims to describe the mechanical aspects of unmanned Mothership Plane and Sensing Drones. The presented conceptual system shows the idea and possible way of designing different sizes and objective systems based on experience gained during the SAE Aero Design Competition.

Design/methodology/approach
The UAS is based on a SAE Aero Design Competition designed and manufactured Mothership Plane converted to a high endurance platform modified to launch up to six small copters. The process of designing and converting the Mothership is described. The methodology of selecting and planning either the structure or hardware of the drones is presented.

Findings
A key finding is that the presented conception of mothership plane deploying in flight a group of small sensing multirotors is achievable. Moreover, the modular build of the system provides the possibility to adapt currently existing unmanned aircrafts to be converted to the described mothership plane.

Practical implications
To conduct flight tests and to study encountered problems. Presentation of the unmanned aerial system (UAS) concept that can be used to scan an area and create 3D maps for Search and Rescue missions as well as agriculture applications.

Originality/value
The paper describes the conceptual approach to design a UAS consisting of the mothership plane and the sensing drones. The paper highlights the potential solutions gained by using such a UAS. The focus is to present a technology and system that can perform real time observations in widespread and difficult to reach areas.
Triple-speed coaxial magnetic gear for wind turbine applications: introduction and comprehensive analysis
Authors: Moghimi Ali , Hosseini Aliabadi Mahmood , Feshki Farahani Hassan 
Published: April 2022

Purpose
This paper aims to introduce a new structure for coaxial magnetic gears.

Design/methodology/approach
The study discusses the design and electromagnetic modeling of a triple-speed coaxial magnetic gear (TSCMG) for three different levels of torques in special applications such as wind energy conversion and electrical vehicles. The proposed TSCMG consists of inner, middle and outer rotor, which has one rotor more than its conventional counterpart. The suggested TSCMG’s related equations such as transform ratio and torque are calculated, then TSCMG is simulated in a finite element environment. A comprehensive study has been done on TSCMG, and results are compared with two other magnetic gears with the same volume but two speeds.

Findings
The obtained results show that the proposed structure for TSCMGs is significantly practical and applicable in higher ranges of torques. Finally, an experimental TSCMG is prototyped to verify the results.

Originality/value
The achievements are excellent and confirm that TSCMG can be used as powerful equipment in a wide range of application like permanent wind turbines to generate electricity in 24 h per every single day.
Inside the black box: How can gender diversity make a difference in the boardroom?
Authors: Khemakhem Hanen , Maalej Manel , Fontaine Richard 
Published: April 2022

PurposePrior research shows that a board of directors' gender diversity positively influences organizations. However, little is known about how and why gender diversity influences the board of directors' functioning and decisions. The objective of this paper is to investigate the differences between women and men when fulfilling their role as directors.Design/methodology/approachThis research uses a qualitative approach based on 29 in-depth semi-structured interviews with female and male board members.FindingsThe authors’ findings reveal that women are as involved as men in the board tasks and responsibilities. Also, women have the same understanding as men of their role and of the skills needed to be board members. However, women fulfil their role differently than men. Women come to board meetings more prepared, take more notes and do more follow-up, and they also dare to ask tough questions to top management. Women directors bring a different point of view — representing different interests — to board discussions, have a different communication style, are not a part of the boys' club and have a social upbringing that might explain gender differences in the boardroom.Research limitations/implicationsThis study could help boards and policymakers introduce diversity measures and provide ways to better integrate women into top decision-making groups such as board of directors.Practical implicationsThis study's findings can help organizations include females in key decision-making groups such as board of directors.Social implicationsThis study reveals that in the same social setting, with the same role and expectations, and the same understanding of their role, both genders continue to perform differently.Originality/valueBased on direct evidence from board members, this study highlights how and why women do their role in the boardroom differently.
Examining toxic supervision in higher education in India
Authors: Shahnawaz Mohammad Ghazi , Siddiqi Nasrina 
Published: April 2022

PurposeWith issues like increasing student dropout rates, low productivity and compromised quality, research in higher education is faced with a number of paralyzing challenges in India. This study aims to locate the role of toxic academic supervision in relation to decreased quality of research.Design/methodology/approachFollowing a sequential mixed method design, the research begins with a quantitative analysis, which is then followed by an in-depth qualitative exploration.FindingsThe results of mediation analysis in this study reveal that students who experience toxic research supervision have a weak sense of identification and are also poor at self-disclosure, which results in increased distress and reduced engagement and productivity. Moreover, identification and self-disclosure have also been found to partially mediate the relationship between toxic supervision and distress. Furthermore, a thematic analysis of this study provides a detailed behavioral profile of toxic academic supervisors and highlights the consequences of such supervision with regard to students' well-being and productivity.Research limitations/implicationsIn terms of theoretical contributions, the study provides evidence that the concept of toxic leadership has applicability outside of the organizational context; in the educational sphere as well and that the toxic leadership scale can be successfully used to assess the severity of toxic supervision within the academic domain, and corrective actions can be taken to mitigate the effect of such supervisory style on students.Practical implicationsThe study not only highlights the repercussions of toxicity in academia and higher education but also provides a detailed and in-depth description of the personality traits and behavioral idiosyncrasies of toxic supervisors, which can help in the early identification of toxic tendencies and can enable us to mitigate and prevent toxicity from the academic space and to ensure a conducive environment for students in higher education. Overall, the present research has important implications for researchers, academicians as well as policymakers.Originality/valueThe study is the first of its kind in terms of both, objective and methodology.