bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid GPR183-mediated recruitment of eosinophils to the lung after Mycobacterium tuberculosis infection
Authors: Bohrer Andrea C. , Castro Ehydel , Tocheny Claire E. , Assmann Maike , Schwarz Benjamin , Bohrnsen Eric , Makiya Michelle A. , Legrand Fanny , Hilligan Kerry L. , Baker Paul J. , Torres-Juarez Flor , Hu Zhidong , Ma Hui , Wang Lin , Niu Liangfei , Zilu Wen , Lee Sang H. , Kamenyeva Olena ,   Tuberculosis Imaging Program, Kauffman Keith D. , Donato Michele , Sher Alan , Barber Daniel L. , Via Laura E. , Scriba Thomas J. , Khatri Purvesh , Song Yanzheng , Wong Ka-Wing , Bosio Catharine M. , Klion Amy D. , Mayer-Barber Katrin D.
Published: February 2022

Influx of eosinophils into the lungs is typically associated with type-II responses during allergy, fungal and parasitic infections. However, we previously reported that eosinophils accumulate in lung lesions during type-I inflammatory responses to Mycobacterium tuberculosis (Mtb) in humans, macaques, and mice where they contribute to host resistance. Here we show eosinophils migrate into the lungs of macaques and mice as early as one week after Mtb-exposure. In mice this influx was CCR3 independent and instead required cell-intrinsic expression of the oxysterol-receptor GPR183, which is highly expressed on human and macaque eosinophils. Murine eosinophils interacted directly with bacilli-laden alveolar macrophages, which upregulated the oxysterol-synthesizing enzyme Ch25h, and eosinophil recruitment was impaired in Ch25h deficient mice. Our findings show that eosinophils are among the first cells from circulation to sense and respond to Mtb infection of alveolar macrophages and reveal a novel role for GPR183 in the migration of eosinophils into lung tissue.

HIGHLIGHTS

In mice and macaques eosinophils accumulate early in Mtb-infected lungs preceding neutrophils Eosinophils interact with Mtb-infected cells in the alveoli in mice

Early pulmonary eosinophil migration occurs independently of CCR3 in mice

Early lung migration in mice requires Ch25h and eosinophil-intrinsic GPR183 expression
Lifespan can be extended during a specific time window early in life
Authors: Aiello G. , Sabino C. , Pernici D. , Audano M. , Antonica F. , Gianesello M. , Quattrone A. , Mitro N. , Romanel A. , Soldano A. , Tiberi L.
Published: February 2022

Lifespan is determined by complex and tangled mechanisms that are largely unknown. The early postnatal stage has been proposed to play a role in lifespan, but its contribution is still controversial. Here, we found that a short rapamycin treatment during early life can prolong lifespan in Mus musculus and Drosophila melanogaster. Notably, the same treatment at later time points has no evident effect on lifespan, suggesting that we found a crucial time-window involved in lifespan modulation. We discovered that sulfotransferases are upregulated during early rapamycin treatment both in newborn mice and Drosophila larvae. Furthermore, overexpression of the sulfotransferase dST1 triggers an increment in the lifespan of Drosophila melanogaster. Our findings unveil a novel link between early-life treatments and long-term effects on lifespan.

One Sentence Summary

Early life events increase lifespan.
Mosaic receptor-binding domain nanoparticles induce protective immunity against SARS-CoV-2 challenges
Authors: Lee Dan Bi , Kim Hyojin , Jeong Ju Hwan , soon Jang Ui , Chang You Yeon , Roh Seokbeom , Jeon Hyunbum , Kim Eun Jeong , Han Su Yeon , Maeng Jin Young , Magez Stefan , Radwanska Magdalena , Mun Ji Young , Jun Hyun Sik , Lee Gyudo , Song Min-Suk , Lee Hye-Ra , Chung Mi Sook , Baek Yun Hee , Kim Kyung Hyun
Published: February 2022

Recurrent spillovers of α- and β-coronaviruses (CoV) such as acute respiratory syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, SARS-CoV-2, and possibly human CoV (NL63, 229E, OC43, and HKU1) have caused serious morbidity and mortality worldwide. Six receptor binding domains (RBDs) derived from α- and β-CoV that are considered to have originated from animals and cross-infected humans were linked to proliferating cell nuclear antigen (PCNA) heterotrimeric subunits, PCNA1, PCNA2, and PCNA3. These were used to form a scaffold-based mosaic multivalent antigen, 6RBD-np. Electron microscopic and atomic force microscopic images show a ring-shaped disk with six protruding RBDs, like jewels in a crown, with a size of 40 nm. Prime-boost immunizations with 6RBD-np in BALB/c mice elicited strong, dose-dependent antibody responses. In human angiotensin converting enzyme 2-transgenic mice, the same immunization induced full-protection against SARS-CoV-2 wild type and Delta challenges, resulting in a 100% survival rate. The mosaic 6RBD-np provides a potential platform for developing a pan-CoV vaccine against newly emerging SARS-CoV-2 variants and future CoV spillovers.

Significance

Despite the arsenal of COVID-19 vaccines, hospitalization and mortality associated with SARS-CoV-2 (acute respiratory syndrome coronavirus 2) variants remain high. There is an urgent need to develop next-generation COVID vaccines that provide broad protection against diseases by current and newly emerging SARS-CoV-2 variants. In this study, six receptor binding domains (RBDs) derived from α- and β-CoV were linked to proliferating cell nuclear antigen (PCNA) heterotrimeric scaffolds. They assemble to create a stable mosaic multivalent nanoparticle, 6RBD-np, displaying a ring-shaped disk with six protruding antigens. The prime-boost immunization in BALB/c and human angiotensin converting enzyme 2-transgenic mice with the 6RBD-np elicited strong, dose-dependent antibody responses and induced full-protection against both the SARS-CoV-2 wild type (WT) and Delta challenges. This study provides proof-of-concept that the mosaic 6RBD-np induces 100% protection against SARS-CoV-2 WT and Delta. It provides the potential of co-displaying heterologous antigens for novel vaccine designs, which can be deployed countering future pandemics.
Dilated cardiomyopathy mutation E525K in human beta-cardiac myosin stabilizes the interacting heads motif and super-relaxed state of myosin
Authors: Rasicci D.V. , Tiwari P. , Desetty R. , Sadler F.W. , Sivaramakrishnan S. , Craig R. , Yengo C.M.
Published: February 2022

The auto-inhibited, super-relaxed (SRX) state of cardiac myosin is thought to be crucial for regulating contraction, relaxation, and energy conservation in the heart. We used single ATP turnover experiments to demonstrate that a dilated cardiomyopathy (DCM) mutation (E525K) in human beta-cardiac myosin increases the fraction of myosin heads in the SRX state (with slow ATP turnover), especially in physiological ionic strength conditions. We also utilized FRET between a C-terminal GFP tag on the myosin tail and Cy3ATP bound to the active site of the motor domain to estimate the fraction of heads in the closed, interacting-heads motif (IHM); we found a strong correlation between the IHM and SRX state. Negative stain EM and 2D class averaging of the construct demonstrated that the E525K mutation increased the fraction of molecules adopting the IHM. Overall, our results demonstrate that the E525K DCM mutation may reduce muscle force and power by stabilizing the auto-inhibited SRX state. Our studies also provide direct evidence for a correlation between the SRX biochemical state and the IHM structural state in cardiac muscle myosin. Furthermore, the E525 residue may be implicated in crucial electrostatic interactions that modulate this conserved, auto-inhibited conformation of myosin.

Significance Statement

Dilated cardiomyopathy can be caused by single point mutations in cardiac muscle myosin, the motor protein that powers contraction of the myocardium. We found that the E525K DCM mutation in the cardiac myosin heavy chain stabilizes the auto-inhibited, super-relaxed state, suggesting a mechanism by which this mutation reduces muscle force and power. The E525K mutation also highlights critical electrostatic interactions important for forming the conserved, auto-inhibited conformational state of striated muscle myosins.
Tracer particles sense local stresses in an evolving multicellular spheroid without affecting the anomalous dynamics of the cancer cells
Authors: Samanta Himadri S. , Sinha Sumit , Thirumalai D.
Published: February 2022

Measurements of local stresses on the cancer cells (CCs), inferred by embedding inert compressible tracer particles (TPs) in a growing multicellular spheroid (MCS), show that pressure decreases monotonically as the distance from the core of the MCS increases. How faithfully do the TPs report the local stresses in the CCs is an important question because pressure buildup in the MCS is dynamically generated due to CC division, which implies that the CC dynamics should be minimally altered by the TPs. Here using theory and simulations, we show that although the TP dynamics is unusual, exhibiting sub-diffusive behavior on times less than the CC division times and hyper-diffusive dynamics on in the long-time limit, they do not affect the long-time CC dynamics or the local CC stress distributions. The CC pressure profile within the MCS, which decays from a high value at the core to the periphery, is almost identical with and without the TPs. That the TPs have insignificant effect on the local stresses in the MCS implies that they are reliable reporters of the CC microenvironment.
The Influence of Leaf Anatomical Traits on Photosynthetic in Coffee Leaves
Authors: Xiao Ziwei , Ma Guanrun , Bai Xuehui , Li Jinhong , Zhao Mingzhu , Su Linlin , Zhou Hua
Published: February 2022

Leaf photosynthesis is largely determined by anatomical features. This study aimed to reveal the quantitative effects of the anatomical structure ofCoffea arabicaleaves on photosynthesis. Pearson’s correlation and path analysis were used to explore the correlation between leaf structure and photosynthesis. To calculate the comprehensive evaluation value of the correlation between leaf anatomical traits and photosynthetic parameters, the Criteria Importance Through Intercriteria Correlation (CRITIC) method was used to obtain the objective weight of each photosynthetic parameter. Most of the anatomical traits of the leaf significantly (P<0.05) to highly significantly (P<0.01) correlated with photosynthetic parameters, suggesting that anatomical traits greatly affected the photosynthetic capacity inCoffea arabicaleaf. Likewise, path coefficient analysis revealed that the photosynthetic capacity of Arabic coffee leaves is strongly correlated, both directly and indirectly, with the stomatal characteristics of the leaves. The results of the comprehensive evaluation also indicated that leaf thickness (LT) and stomatal density (d) were the anatomical characteristics most closely related to photosynthesis. In these results, understanding the effects of the anatomical structure of coffee leaves on photosynthesis, may provide useful information for coffee breeding programs and the management of coffee plantations to increase photosynthesis.
Partial illustration of human sperm DNA via microscopy and quantitative analysis of nucleotides
Authors: Barzideh Jaleh
Published: February 2022

Background

general structure of human sperm has not been profiled yet. Human sperm DNA characterization should progress the medical diagnostic and therapeutic methods rather than developing biological sciences. The aim of the present study was to provide biological insights into the common structure of human sperm. The value of this investigation is establishing an initial basic map of sperm head structure that leads to further advanced standardization of normality in this creature. For this purpose, analytical and microscopic methods were applied.

Methods

High-performance Liquid Chromatography (HPLC) and flow cytometry were hired to quantify the DNA compositions. As well fluorescent, confocal and advanced light microscopy was applied to identify the stained sperm DNA by chromomycinA3 (CMA3) and 5-methylcytosine antibody (5-mc)

Results

HPLC demonstrated the mean values of nucleotide bases’ percentage in the structure of the sperm DNA regardless of the fraction that sperm was collected from gradient wash, sequenced from 27.6%, 8.92%, 27.05% and 35.36%. Also, quantitative flow cytometry of global 5-methylcytosine showed not a regular fluctuation in individuals with normal sperm while, there is a permanent increase in 50% fraction collected from percoll gradients.

CMA3-positivity levels as well, were negatively correlated with sperm quality harvest by percoll gradients (p<0.0001), and positively correlated (P<0.05) with global methylation as determined by flow cytometry. Interestingly, in this text microscopy of immunocytochemistry of sperm cells stained by CMA3, demonstrated a different view from cells’ heads.

Conclusions

obviously these explorations suggest some new possibilities in assessment of rough chemical level of nucleotides and cytochemistry of sperm head structure. The chromatin brightness presented with CMA3 by microscopy shows a direct relation with more extensive DNA methylation in sperms collected from low gradients of percoll wash. While, fluctuated 5-methylcytosine levels show personal presentation and even exclusive to individual sperm expression. This study induces further research on new assumptions in nuclear equilibrium in the axiom of DNA ladder in related to 5-mcytosine level in human sperm.
Prolonged β-Adrenergic Stimulation Disperses Ryanodine Receptor Clusters in Cardiomyocytes: Implications for Heart Failure
Authors: Shen Xin , van den Brink Jonas , Bergan-Dahl Anna , Kolstad Terje R. , Norden Einar S. , Hou Yufeng , Laasmaa Martin , Quick Ann P. , Espe Emil K.S. , Sjaastad Ivar , Wehrens Xander H.T. , Edwards Andrew G. , Soeller Christian , Louch William E.
Published: February 2022

Ryanodine Receptors (RyRs) exhibit dynamic arrangements in cardiomyocytes, and we previously showed that “dispersion” of RyR clusters disrupts Ca2+ homeostasis during heart failure (HF) (Kolstad et al., eLife, 2018). Here, we investigated whether prolonged β-adrenergic stimulation, a hallmark of HF, promotes RyR cluster dispersion, and examined the underlying mechanisms. We observed that treatment of healthy rat cardiomyocytes with isoproterenol for 1 hour triggered progressive fragmentation of RyR clusters. Pharmacological inhibition of CaMKII reversed these effects, while cluster dispersion was reproduced by specific activation of CaMKII, and in mice with constitutively active Ser2814-RyR. A similar role of protein kinase A (PKA) in promoting RyR cluster fragmentation was established by employing PKA activation or inhibition. Progressive cluster dispersion was linked to declining Ca2+ spark fidelity and magnitude, and slowed release kinetics from Ca2+ propagation between more numerous RyR clusters. In healthy cells, this served to dampen the stimulatory actions of β-adrenergic stimulation over the longer term, and protect against pro-arrhythmic Ca2+ waves. However, during HF, RyR dispersion was linked to impaired Ca2+ release. Thus, RyR localization and function are intimately linked via channel phosphorylation by both CaMKII and PKA which, while finely tuned in healthy cardiomyocytes, underlies impaired cardiac function during pathology.

Significance statement

The heartbeat is triggered by the release of Ca2+ from Ryanodine Receptors (RyRs) within cardiomyocytes. Recent data indicate RyR arrangement is highly malleable. However, mechanisms controlling RyR reorganisation and the subsequent impact on Ca2+ homeostasis remain unclear. Here, we show that prolonged β-adrenergic stimulation causes RyR clusters to disperse, drastically altering the frequency and kinetics of Ca2+ release events called “Ca2+ sparks” in a process that is dependent on CaMKII and PKA. In healthy cells, these compensatory effects protect against arrhythmogenic Ca2+ over-activity. However, during heart failure, RyR hyper-phosphorylation and dispersion impairs Ca2+ release and cardiac performance. Thus, RyR localization and function are intimately linked via channel phosphorylation which, while finely tuned in health, underlies impaired cardiac function during pathology.
Silencing KCC2 in mouse dorsal hippocampus compromises spatial and contextual memory
Authors: Simonnet Clémence , Sinha Manisha , Goutierre Marie , Moutkine Imane , Daumas Stéphanie , Poncer Jean Christophe
Published: February 2022

Delayed upregulation of the neuronal chloride extruder KCC2 underlies the progressive shift in GABA signaling polarity during development. Conversely, KCC2 downregulation is observed in a variety of neurological and psychiatric disorders often associated with cognitive impairment. Reduced KCC2 expression and function in mature networks may disrupt GABA signaling and promote anomalous network activities underlying these disorders. However, the causal link between KCC2 downregulation, altered brain rhythmogenesis and cognitive function remains elusive. Here, by combining behavioral exploration with in vivo electrophysiology we assessed the impact of chronic KCC2 silencing in mouse dorsal hippocampus and showed it compromises both spatial and contextual memory. This was associated with altered hippocampal rhythmogenesis and neuronal hyperexcitability, with increased CA1 pyramidal cell burst firing during non-REM sleep. Reducing neuronal excitability with terbinafine, a specific Task-3 leak potassium channel activator, occluded the impairment of contextual memory upon KCC2 silencing. Our results establish a causal relationship between KCC2 expression and cognitive performance and suggest that impaired rhythmopathies and neuronal hyperexcitability are central to the deficits caused by KCC2 silencing in the adult mouse brain.
Multi-eGO: anin-silicolens to look into protein aggregation kinetics at atomic resolution
Authors: Scalone Emanuele , Broggini Luca , Visentin Cristina , Erba Davide , Toplek Fran Bačić , Peqini Kaliroi , Pellegrino Sara , Ricagno Stefano , Paissoni Cristina , Camilloni Carlo
Published: February 2022

Protein aggregation into amyloid fibrils is the archetype of aberrant biomolecular self-assembly processes, with more than 50 diseases associated that are mostly uncurable. Understanding aggregation mechanisms is thus of fundamental importance and goes in parallel with the characterization of the structures of the transient oligomers formed in the process. Oligomers have been proven elusive to high-resolution structural techniques, while the large sizes and long-time scales typical of aggregation processes have limited, so far, the use of computational methods. To surmount these limitations, we introduce here multi-eGO, an atomistic, hybrid structure-based model, which leveraging on the knowledge of monomers conformational dynamics and of fibril structures, can efficiently capture the essential structural and kinetics aspects of protein aggregation. Multi-eGO molecular dynamics simulations can describe the aggregation kinetics of thousands of monomers. The concentration dependence of the simulated kinetics, as well as the structural features of the resulting fibrils, are in qualitative agreement within vitroexperiments on an amyloidogenic peptide of Transthyretin, a protein responsible for one of the most common cardiac amyloidosis. Multi-eGO simulations allow to observe in time and at atomic resolution the formation of primary nuclei in a sea of transient lower order oligomers, to follow their growth and the subsequent secondary nucleation events, till the maturation of multiple fibrils. Multi-eGO, combined with the many experimental techniques deployed to study protein aggregation, can provide the structural basis needed to advance the design of molecules targeting amyloidogenic diseases.

Significance Statement

Alzheimer’s and Parkinson’s diseases are uncurable pathologies associated to the aberrant aggregation of specific proteins into amyloid fibrils. Understanding the mechanism leading to protein aggregation, by characterizing the structures of the oligomeric species populated in the process, would have a tremendous impact on the design of therapeutic molecules. We propose that a structure-based approach to molecular dynamics simulations can allow following at high resolution the aggregation kinetics of thousands of monomers. Having shown that simulations can describe the aggregation of a Transthyretin amyloidogenic peptide, we demonstrate how their efficiency allows acquiring a wealth of structural information. We foresee that integrating the latter with the many techniques developed to study protein aggregation will support the design of molecules to modulate amyloidogenesis.
Dyslexia linked to profound impairment in the magnocellular medial geniculate nucleus
Authors: Meng Qianli , Schneider Keith
Published: February 2022

The neurological basis of dyslexia, a common reading disorder, remains unclear but is hypothesized to be caused by either dysfunction of the magnocellular system in the brain, abnormal temporal processing, and/or deficient phonological skills. Using functional magnetic resonance imaging, we measured activity in the magnocellular portion of the medial geniculate nucleus, the auditory relay in the thalamus, and observed profoundly attenuated responses to non-linguistic transient but not sustained sounds in every subject with dyslexia we tested, compared to normal readers. Our finding unifies these three hypotheses and identifies a core deficit causing dyslexia.
D2 dopamine receptor expression, sensitivity to rewards, and reinforcement learning in a complex value-based decision-making task
Authors: Banuelos Cristina , Creswell Kasey , Walsh Catherine , Manuck Stephen B. , Gianaros Peter J. , Verstynen Timothy
Published: February 2022

In the basal ganglia, different dopamine subtypes have opposing dynamics at post-synaptic receptors, with the ratio of D1 to D2 receptors determining the relative sensitivity to gains and losses, respectively, during value-based learning. This effective sensitivity to reward feedback interacts with phasic dopamine levels to determine the effectiveness of learning, particularly in dynamic feedback situations where frequency and magnitude of rewards need to be integrated over time to make optimal decisions. Using both simulations and behavioral data in humans, we evaluated how reduced sensitivity to losses, relative to gains, leads to suboptimal learning in the Iowa Gambling Task (IGT), a complex value-learning task. In the behavioral data, we tested individuals with a variant of the human dopamine receptor D2 (DRD2; -141C Ins/Del and Del/Del) gene that associates with lower levels of D2 receptor expression (N=119) and compared their performance to non-carrier controls (N=319). The magnitude of the reward response was measured by looking at ventral striatal (VS) reactivity to rewards in the Cards task using fMRI. DRD2 variant carriers had generally lower performance in the IGT than non-carriers, consistent with reduced sensitivity to losses. There was also a positive association between VS reactivity and performance in the IGT, however, we found no statistically significant difference in this effect between DRD2 carriers and non-carriers. Thus, while reduced D2 receptor expression was associated with less efficient learning in the IGT, we did not find evidence for the moderation of this effect by the magnitude of the reward response.
Generating an in vitro gut model with physiologically relevant biophysical mucus properties
Authors: McCright Jacob , Sinha Arnav , Maisel Katharina
Published: February 2022

Introduction

Gastrointestinal (GI) in vitro models have received lasting attention as an effective tool to model drug and nutrient absorption, study GI diseases, and design new drug delivery vehicles. A complete model of the GI epithelium should at a minimum include the two key functional components of the GI tract: mucus and the underlying epithelium. Mucus plays a key role in protecting and lubricating the GI tract, poses a barrier to orally administered therapies and pathogens, and serves as the microenvironment for the GI microbiome. These functions are reliant on the biophysical material properties of the mucus produced, including viscosity and pore size.

Methods

In this study, we generated in vitro models containing Caco-2 enterocyte-like cells and HT29-MTX goblet-like cells and determined the effects of coculture and mucus layer on epithelial permeability and biophysical properties of mucus using multiple particle tracking (MPT).

Results

We found that mucus height increased as the amount of HT29-MTX goblet-like cells increased. Additionally, we found that increasing the amount of HT29-MTX goblet-like cells within culture corresponded to an increase in mucus pore size and mucus microviscosity, measured using MPT. When compared to ex vivo mucus samples from mice and pigs, we found that a 90:10 ratio of Caco-2:HT29-MTX coculture displayed similar mucus pore size to porcine jejunum and that the mucus produced from 90:10 and 80:20 ratios of cells shared mechanical properties to porcine jejunum and ileum mucus.

Conclusions

GI coculture models are valuable tools in simulating the mucus barrier and can be utilized for a variety of applications including the study of GI diseases, food absorption, or therapeutic development.

Biography

Dr. Maisel joined the University of Maryland in January 2019 having done interdisciplinary training in nanotechnology, mucosal immunology, lymphatic immunology, and immunoengineering. She completed her PhD in Biomedical Engineering at the Johns Hopkins University in 2014 after which she was an NIH postdoctoral fellow at the University of Chicago in Molecular Engineering and Immunology. The Maisel Lab uses in vitro modeling, nanotechnology, and immunoengineering approaches to study and develop treatments for diseases at mucosal surfaces. They are interested in designing nanoparticles to take advantage of and study the interface between biological barriers, particularly the lymphatics, interstitial tissue, and mucosal surfaces, and nanoparticles. Dr. Maisel has won a number of awards, including NSF GRFP and NIH F32 fellowships as a trainee, the American Lung Association Dalsemer Award, LAM Foundation Career Development Award, an NSF CAREER Award, and an NIH NIGMS Maximizing Investigator Research Award. Her work has led to numerous high-impact publications, particularly in the field of drug delivery and mucosal immunoengineering, and several patents.
Using Mathematical Modeling to Distinguish Intrinsic and Acquired Targeted Therapeutic Resistance in Head and Neck Cancer
Authors: Cardenas Santiago D. , Reznik Constance J. , Ranaweera Ruchira , Song Feifei , Chung Christine H. , Fertig Elana J. , Gevertz Jana L.
Published: February 2022

The promise of precision medicine has been limited by the pervasive therapeutic resistance to many targeted therapies for cancer. Inferring the timing (i.e., pre-existing or acquired) and mechanism (i.e., drug-induced) of such resistance is crucial for designing effective new therapeutics. This paper studies the mechanism and timing of cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) using tumor volume data obtained from patient-derived tumor xenografts. We propose a family of mathematical models, with each member of the family assuming a different timing and mechanism of resistance. We present a method for fitting these models to individual volumetric data, and utilize model selection and parameter sensitivity analyses to ask: which member of the family of models best describes HNSCC response to cetuximab, and what does that tell us about the timing and mechanisms driving resistance? We find that along with time-course volumetric data to a single dose of cetuximab, the initial resistance fraction and, in some instances, dose escalation volumetric data are required to distinguish among the family of models and thereby infer the mechanisms of resistance. These findings can inform future experimental design so that we can best leverage the synergy of wet laboratory experimentation and mathematical modeling in the study of novel targeted cancer therapeutics.
Reduced variability of bursting activity during working memory
Authors: Lundqvist Mikael , Rose Jonas , Warden Melissa , Buschman Tim , Herman Pawel , Miller Earl
Published: February 2022

Working memories have long been thought to be maintained by persistent spiking. However, mounting evidence from multiple-electrode recording (and single-trial analyses) shows that the underlying spiking is better characterized by intermittent bursts of activity. A counterargument suggested this intermittent activity is at odds with observations that spike-time variability reduces during task performance. However, this counterargument rests on assumptions, such as randomness in the timing of the bursts, that may not be correct. Thus, we analyzed spiking and LFPs from the prefrontal cortex (PFC) of monkeys to determine if task-related reductions in variability can co-exist with intermittent spiking. We found that it does because both spiking and associated gamma bursts were task-modulated, not random. In fact, the task-related reduction in spike variability could be explained by a related reduction in gamma burst variability. Our results provide further support for the intermittent activity models of working memory as well as novel mechanistic insights into how spike variability is reduced during cognitive tasks.
Rapamycin treatment during development extends lifespan and healthspan
Authors: Shindyapina Anastasia V. , Cho Yongmin , Kaya Alaattin , Tyshkovskiy Alexander , Castro José P. , Gordevicius Juozas , Poganik Jesse R. , Horvath Steve , Peshkin Leonid , Gladyshev Vadim N.
Published: February 2022

The possibility that pace of development is tightly connected to aging is supported by the fact that the onset of reproduction is associated with lifespan and that many longevity interventions target growth and development. However, it has been unknown whether targeting development with pharmacological intervention can lead to a longer lifespan. To test this possibility, we subjected genetically diverse UMHET3 mice to the mTOR inhibitor rapamycin for the first 45 days of life and followed them up until death. Treated mice grew slower, with most of the deceleration occurring in the first week, and remained smaller for their entire lives. Their reproductive age was delayed but without affecting offspring numbers. The treatment was sufficient to extend the median lifespan by 10%, with the most effect in males, and to preserve better health as measured by frailty index, gait speed, and glucose and insulin tolerance tests. Mechanistically, the liver transcriptome of treated mice was younger at the completion of treatment and stayed younger into the old ages in males. Rapamycin initially reduced DNA methylation age of livers, however, that effect was lost with aging. Analogous to mice, rapamycin exposure only during development robustly extended the lifespan of Daphnia magna as well as reduced their body size, suggesting evolutionary conserved mechanisms of this early life effect. Overall, the results demonstrate that short-term rapamycin treatment during early life is a novel longevity intervention that establishes causality between pace of development and longevity in evolutionary distant organisms.
Rookognise: Acoustic detection and identification of individual rooks in field recordings using multi-task neural networks
Authors: Martin Killian , Adam Olivier , Obin Nicolas , Dufour Valérie
Published: February 2022

Individual-level monitoring is essential in many behavioural and bioacoustics studies. Collecting and annotating those data is costly in terms of human effort, but necessary prior to conducting analysis. In particular, many studies on bird vocalisations also involve manipulating the animals or human presence during observations, which may bias vocal production. Autonomous recording units can be used to collect large amounts of data without human supervision, largely removing those sources of bias. Deep learning can further facilitate the annotation of large amounts of data, for instance to detect vocalisations, identify the species, or recognise the vocalisation types in recordings. Acoustic individual identification, however, has so far largely remained limited to a single vocalisation type for a given species. This has limited the use of those techniques for automated data collection on raw recordings, where many individuals can produce vocalisations of varying complexity, potentially overlapping one another, with the additional presence of unknown and varying background noise. This paper aims at bridging this gap by developing a system to identify individual animals in those difficult conditions. Our system leverages a combination of multi-scale information integration, multi-channel audio and multi-task learning. The multi-task learning paradigm is based the overall task into four sub-tasks, three of which are auxiliary tasks: the detection and segmentation of vocalisations against other noises, the classification of individuals vocalising at any point during a sample, and the sexing of detected vocalisations. The fourth task is the overall identification of individuals. To test our approach, we recorded a captive group of rooks, a Eurasian social corvid with a diverse vocal repertoire. We used a multi-microphone array and collected a large scale dataset of time-stamped and identified vocalisations recorded, and found the system to work reliably for the defined tasks. To our knowledge, the system is the first to acoustically identify individuals regardless of the vocalisation produced. Our system can readily assist data collection and individual monitoring of groups of animals in both outdoor and indoor settings, even across long periods of time, and regardless of a species’ vocal complexity. All data and code used in this article is available online.
The gender differences in innovative mentality, leadership styles and organizational innovative behavior: the case the “40 Under 40” and their impact on organizational success
Authors: Berdecia-Cruz Zaida , Flecha Jose A. , Ortiz Maribel
Published: February 2022

Purpose

The innovative mentality, it has been found that it is poorly addressed, which in turn does not provide clear delineations in academic literature. The innovative mentality is an opposition to the traditional innovative culture and that this is observed indirectly through the new forms of action of the younger generations. The purpose of this study aims to seek to provide answers by analyzing how the innovative mentality of leaders 40 years of age and under impacts the transformational or transactional leadership styles. Second, this research analyzes whether the leadership style used in the “40 Under 40” impacts an innovative organizational behavior that positively drives toward organizational success.

Design/methodology/approach

The partial least squares structural equations method (PLS-SEM) is used to analyze a set of hypotheses to 103 professionals awarded the 40 under 40 of Caribbean Business Magazine in Puerto Rico between 2012 and 2016. The unit of analysis were young professionals recognized as the “40 Under 40” by theCaribbean Business Magazinein Puerto Rico between 2012 and 2016.

Findings

The study results contribute a novel theory about a new style of leadership, based on innovative mentality as a central axis, when combining different leadership styles. The second study examined whether there are significant differences between male and female gender through the proposed research model. The results reflect when the organizational innovative behavior is analyzed, the transactional leadership role used by women is highlighted.

Originality/value

This study distinguishes the “40 Under 40” from other leaders and has allowed their enterprises to be successful is their innovative leadership style, which is executed through their innovative mentality.
Foresights for big data across industries
Authors: Almeida Fernando
Published: February 2022

Purpose

The purpose of this study is to explore the potential and growth of big data across several industries between 2016 and 2020. This study aims to analyze the behavior of interest in big data within the community and to identify areas with the greatest potential for future big data adoption.

Design/methodology/approach

This research uses Google Trends to characterize the community’s interest in big data. Community interest is measured on a scale of 0–100 from weekly observations over the past five years. A total of 16 industries were considered to explore the relative interest in big data for each industry.

Findings

The findings revealed that big data has been of high interest to the community over the past five years, particularly in the manufacturing, computers and electronics industries. However, over the 2020s the interest in the theme decreased by more than 15%, especially in the areas where big data typically had the greatest potential interest. In contrast, areas with less potential interest in big data such as real estate, sport and travel have registered an average growth of less than 10%.

Originality/value

To the best of the author’s knowledge, this study is original in complementing the traditional survey approaches launched among the business communities to discover the potential of big data in specific industries. The knowledge of big data growth potential is relevant for players in the field to identify saturation and emerging opportunities for big data adoption.
In the digital age, the combination of technology and radical management practices drive competitive advantage
Authors: Denning Stephen
Published: February 2022

Purpose

The author asserts that Gary Hamel’s decade-old prediction of an oncoming avalanche of ‘radical management innovations’ has come true. They are already staring us in the face, not in a couple of tiny obscure foreign firms, but in the success of the most valuable firms in the world.

Design/methodology/approach

Whether traditional management thinkers want to recognize it or not, we are already living in a new economic age–with radically different management practices that are driving the growth of the economy.

Findings

The current new age has been triggered by combining extraordinary new technologies and new management principles.

Practical/implications

New technologies, without the change in management principles, are not enough to achieve transformative advantage.

Originality/value

Innovative firms with a total value of more than half the economy are being run with a radically different management mindset, principles and skills that ambitious managers need to adopt.
Analytical modelling of ultra-thin white topping cement concrete overlay on bituminous concrete pavement using ANSYS
Authors: Krishna U. Siva Rama , Ch Naga Satish Kumar
Published: February 2022

Purpose

The ultra-thin white topping (UTW) is a cement concrete overlay of the thickness of 50–100 mm on bituminous concrete pavements with surface failures. This is a long-lasting solution without having short-term failures. This paper aims to design an ultra-thin cement concrete overlay using a developed critical stress model with sustainable concrete materials for low-volume roads.

Design/methodology/approach

In this research paper, a parametric study was conducted using the ultra-thin concrete overlay finite element model developed with ANSYS software, considering the significant parameters affecting the performance and development. The non-linear regression equation was formed using a damped least-squares method to predict critical stress due to the corner load of 51 kN.

Findings

The parametric study results indicate that with a greater elastic modulus of bituminous concrete, granular layer along with 100 mm thickness of concrete layer reduces the critical corner stress, interface shear stress in a significant way responsible for debonding of concrete overlay, elastic strains in the pavement further the concrete overlay can bear infinite load repetitions. From validation, it is understood that the non-linear regression equation developed is acceptable with similar research work done.

Originality/value

From the semi-scale experimental study, it is observed that the quaternary blended sustainable concrete overlay having a high modulus of rupture of 6.34 MPa is competent with conventional cement concrete overlay in terms of failure load. So, concrete overlay with sustainable materials of 100 mm thickness and higher elastic modulus of the layers can perform in a sustainable way meeting the environmental and long-term performance requirements.
Synergistic effect of roflumilast with dexamethasone in a neutrophilic asthma mouse model
Authors: Park Chan Kwon , An Tai Joon , Kim Ji Hye , Rhee Chin Kook , Yoon Hyoung Kyu
Published: February 2022

Asthma is a chronic airway inflammatory disease with heterogeneous features. Most cases of asthma are steroid sensitive, but 5%‐10% are unresponsive to steroids, leading to challenges in treatment. Neutrophilic asthma is steroid‐resistant and characterized by the absence or suppression of the T‐helper type II (TH2) process and an increase in the TH1 and/or TH17 process. Roflumilast (ROF) has anti‐inflammatory effects and has been used to treat chronic inflammatory airway diseases, such as chronic pulmonary obstructive disease. It is unclear whether ROF may have a therapeutic role in neutrophilic asthma. In this study, we investigated the synergistic effect of ROF with dexamethasone (DEX) in a neutrophilic asthma mouse model. C57BL/6 female mice sensitized to ovalbumin (OVA) were exposed to five intranasal OVA treatments and three intranasal lipopolysaccharide (LPS) treatments for an additional 10 days. During the intranasal OVA challenge, ROF was administrated orally, and DEX was injected intraperitoneally. Protein, pro‐inflammatory cytokines, inflammatory cytokines and other suspected markers were identified by enzyme‐linked immunosorbent assay, real‐time polymerase chain reaction, and western blot. Following exposure to LPS in OVA‐induced asthmatic mice, neutrophil predominant airway inflammation rather than eosinophil predominant inflammation was observed, with increases in airway hyperresponsiveness (AHR). The lungs of animals treated with ROF exhibited less airway inflammation and hyperresponsiveness. To investigate the mechanism underlying this effect, we examined the expression of proinflammatory cytokines suspected to be involved in inflammatory cytokines and proteins. Roflumilast reduced total protein in bronchioalveolar lavage fluid; levels of interleukin (IL)‐17A, IL‐1β messenger RNA, interferon γ and tumour necrosis factor α; and recovered histone deacetylase‐2 (HDAC2) activity. Combination therapy with ROF and DEX further reduced the levels of IL‐17, IL‐22 and IL‐1β mRNA and proinflammatory cytokines. The combination of ROF and DEX reduced lung inflammation and AHR much more than one of them alone. Roflumilast reduces AHR and lung inflammation in the neutrophilic asthma mouse model. Furthermore, additive effects were observed when DEX was added to ROF treatment, possibly because of recovery of HDAC2/β‐actin activity. This study demonstrates the anti‐inflammatory properties of ROF in a neutrophilic asthma mouse model.
Nocturnal emission and post‐pollination change of floral scent in the leafflower tree, Glochidion rubrum, exclusively pollinated by seed‐parasitic leafflower moths
Authors: Okamoto Tomoko , Svensson Glenn P. , Goto Ryutaro , Kawakita Atsushi , Kato Makoto
Published: February 2022

Many insect‐pollinated plants use floral scent signals to attract and guide the effective pollinators, and temporal patterns of their floral scent emission may be tuned to respond to the pollinator's activity and pollination status. In the intimate nursery pollination mutualism between monoecious Glochidion trees (Phyllanthaceae) and Epicephala moths (Gracillariidae), floral scent signals mediate species‐specific interactions and influence the moth's efficient pollen‐collecting and pollen‐depositing behaviors on male and female flowers, respectively. We tested the hypotheses that both sexes of flowers of Epicephala‐pollinated Glochidion rubrum exhibit a diel pattern of scent emission matching the activity period of the nocturnally active pollinator, and that female flowers change the chemical signal after pollination to reduce further visits and oviposition by the pollinator. We investigated the diel change of floral scent emissions during two consecutive days and the influence of pollination on the floral scent by conducting hand‐pollinations in the field. The total scent emission of male and female flowers was higher at night than in the day, which would be expected from the nocturnal visitations of Epicephala moths. Some compounds exhibited a clear nocturnal emission rhythm. Hand‐pollination experiments revealed that emission of two compounds, nerolidol and eugenol, drastically decreased in pollinated flowers, suggesting that these compounds may function as key attractants for the pollinator; however, the total scent emission of the female flower was not influenced by hand‐pollination. The pattern of the floral scent emission of G. rubrum may be optimized to attract nocturnal pollinators and reduce oviposition.
Duty calls but not for all: The policy involvement of cabinet ministers during crisis
Authors: SHPAIZMAN ILANA
Published: February 2022

During a crisis, the public expects the government to handle the situation. In parliamentary democracies, these expectations are directed to the cabinet and its ministers. Cabinet ministers are expected to be highly involved in policy making under their jurisdiction and in general. During periods of politics as usual, ministers differ in their policy involvement. This paper asks whether that changes during a crisis. Based on an analysis of cabinet ministers in Israel during the first wave of the COVID19 crisis, this paper finds that ministers’ policy involvement during a crisis is relatively low. Most ministers are little involved in issues outside their jurisdiction. Ministers less central to the crisis management are also little involved in issues under their jurisdiction. Ministers central to the crisis management are highly involved in introducing decisions on issues under their jurisdiction, but not necessarily in other aspects of policy making. These findings have implications for issues of accountability and trust.
Real Effects of a Widespread CSR Reporting Mandate: Evidence from the European Union's CSR Directive
Authors: FIECHTER PETER , HITZ JÖRG‐MARKUS , LEHMANN NICO
Published: February 2022

We investigate real effects of a widespread corporate social responsibility (CSR) reporting mandate. In 2014, the European Union (EU) passed Directive 2014/95 (hereafter, “CSR Directive”), mandating large listed EU firms to prepare annual nonfinancial reports beginning from fiscal year 2017 onward. We document that firms within the scope of the directive respond by increasing their CSR activities and that they start doing so before the entry‐into‐force of the directive. These real effects are concentrated in firms that are plausibly more strongly affected by the directive, that is, those with previously low levels of both CSR reporting and CSR activities. Using various alternative outcome variables (e.g., new CSR initiatives, improvements in CSR infrastructure, or firm performance), we show that these real effects reflect meaningful increases in CSR beyond firms’ potential attempts to “greenwash” CSR performance. Finally, we conduct tests that increase our confidence that the documented real effects are attributable to the CSR Directive and not general EU trends in CSR.