bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor cell-intrinsic HFE drives glioblastoma growth
Authors: Troike Katie M. , Silver Daniel J. , Ghosh Prabar K. , Mulkearns-Hubert Erin E. , Hubert Christopher G. , Connor James R. , Fox Paul L. , Kristensen Bjarne W. , Lathia Justin D.
Published: April 2022

Background

Glioblastoma (GBM) tumor cells modulate expression of iron-associated genes to enhance iron uptake from the surrounding microenvironment, driving proliferation and tumor growth. The homeostatic iron regulator (HFE) gene, encoding the iron sensing HFE protein, is upregulated in GBM and correlates with poor survival outcomes. However, the molecular mechanisms underlying these observations remain unclear. Identification of pathways for targeting iron dependence in GBM tumors is therefore a critical area of investigation.

Methods

We interrogated the impact of cell-intrinsic Hfe expression on proliferation and tumor growth through genetic loss and gain of function approaches in syngeneic mouse glioma models. We determined the expression of iron-associated genes and their relationship with survival in GBM using public datasets and identified differentially expressed pathways in Hfe knockdown cells through Nanostring transcriptional profiling.

Results

Loss of Hfe induced apoptotic cell death in vitro and inhibited tumor growth in vivo while overexpression of Hfe accelerated both proliferation and tumor growth. Analysis of iron gene signatures in Hfe knockdown cells revealed alterations in the expression of several iron-associated genes, suggesting global disruption of intracellular iron homeostasis. Analyzing differentially expressed pathways further identified oxidative stress as the top pathway upregulated with Hfe loss. Enhanced 55Fe uptake and generation of reactive oxygen species (ROS) were found with Hfe knockdown, implicating toxic iron overload resulting in apoptotic cell death.

Conclusions

Collectively, these findings identify a novel role for HFE in regulating iron homeostasis in GBM tumors and provide a potential avenue for future therapeutic development.

Key Points

HFE is an iron sensor that is upregulated in GBM and negatively impacts survival.

HFE overexpression drives proliferation and tumor growth in vivo.

Loss of HFE increases production of reactive oxygen species and induces apoptosis, extending survival in vivo.

Importance of Study

Dysregulation of iron metabolism is an important feature of GBM contributing to tumor growth and negatively impacting survival. The identification of key iron regulators controlling this process is therefore important for therapeutic targeting. We identify HFE as an important regulator of iron homeostasis in GBM and suggest a role for sexual dimorphism in HFE-mediated tumor iron regulation that ultimately results in differential survival outcomes. Our findings demonstrate that HFE drives tumor cell proliferation and survival in GBM and may be a viable target for modulating tumor iron flux and inducing apoptosis in tumor cells.
Predicting Dog Phenotypes from Genotypes
Authors: Bartusiak Emily R. , Barrabés Míriam , Rymbekova Aigerim , Gimbernat-Mayol Julia , López Cayetana , Barberis Lorenzo , Montserrat Daniel Mas , Giró-i-Nieto Xavier , Ioannidis Alexander G.
Published: April 2022

We analyze doggenotypes(i.e., positions of dog DNA sequences that often vary between different dogs) in order to predict the correspondingphenotypes(i.e., unique observed characteristics). More specifically, given chromosome data from a dog, we aim to predict the breed, height, and weight. We explore a variety of linear and non-linear classification and regression techniques to accomplish these three tasks. We also investigate the use of a neural network (both in linear and non-linear modes) for breed classification and compare the performance to traditional statistical methods. We show that linear methods generally outperform or match the performance of non-linear methods for breed classification. However, we show that the reverse is true for height and weight regression. Finally, we evaluate the results of all of these methods based on the number of input features used in the analysis. We conduct experiments using different fractions of the full genomic sequences, resulting in input sequences ranging from 20 SNPs to ∼200k SNPs. In doing so, we explore the impact of using a very limited number of SNPs for prediction. Our experiments demonstrate that these phenotypes in dogs can be predicted with as few as 0.5% of randomly selected SNPs (i.e., 992 SNPs) and that dog breeds can be classified with 50% balanced accuracy with as few as 0.02% SNPs (i.e., 40 SNPs).
Multiplex genome editing of human pluripotent stem cells using Cpf1
Authors: Ma Haiting , Jaenisch Rudolf
Published: April 2022

Targeted genome editing of human pluripotent stem cells (hPSC) is critical for basic and translational research, and can be achieved with site-specific endonucleases. Class 2 clustered regularly interspaced short palindromic repeats (CRISPR) Cpf1 represents a class of RNA programmable DNA endonucleases with features that could be complementary to the widely used Class 1 CRISPR-Cas9 system. Here we engineered a single vector system to deliver both Cpf1 and guide RNA, and achieved efficient knockin in transformed human cells. We then adopted the system to function in hPSCs by increasing expression levels of Cpf1, and showed that Cpf1 efficiently mediate homology directed repair in multiple loci (including knockin of a 6 kb cassette at theINS) in multiple hPSC lines, resulting in clones with transgenic cassettes integrated only at the targeted loci in the genome. Furthermore, with delivery of Cpf1 and a single U6 promoter-driven guide RNA array composed of anAAVS1-targeting guide and aMAFB-targeting guide, we demonstrated efficient multiplex genome editing in hPSCs at theAAVS1(knockin) andMAFB(knockout) loci. Targeted hPSCs expressed pluripotency markers, and could be directed to differentiate to pancreatic β-like cells, neural progenitor cells, and neuronsin vitro. GeneratedINSreporter cells differentiated into β-like cells that express tdTomato and luciferase specifically in insulin-expressing cells, allowing forin vivotracking of human β-like cells in humanized mice. By targeted screening of potential off-target sequences with most homology to guide RNA targeted sequences, we could not detect off-target mutations for all guide RNAs at the condition of efficient genome editing with Cpf1 in hPSCs. This work provides a system complementary to Cas9 for potentially precise genome editing in hPSCs.
Larger but younger fish when growth outpaces mortality in heated ecosystem
Authors: Lindmark Max , Karlsson Malin , Gårdmark Anna
Published: April 2022

Ectotherms are predicted to “shrink” with global warming, in line with general growth models and the temperature-size rule (TSR), both predicting smaller adult sizes with warming. However, they also predict faster juvenile growth rates and thus larger size-at-age of young organisms. Hence, the result of warming on the size-structure of a population depends on the interplay between how mortality rate, juvenile- and adult growth rates are affected by warming. Here, we use two-decade long time series of biological samples from a unique enclosed bay heated by cooling water from a nearby nuclear power plant to become 5–10 °C warmer than its reference area. We used growth-increment biochronologies (12658 reconstructed length-at-age estimates from 2426 individuals) to quantify how >20 years of warming has affected body growth and size-at-age and catch data to quantify mortality rates and population size- and age structure of Eurasian perch (Perca fluviatilis). In the heated area, growth rates were faster for all sizes, and hence size-at-age was larger for all ages, compared to the reference area. While mortality rates were also higher (lowering mean age by 0.4 years), the faster growth rates lead to a 2 cm larger mean size in the heated area. Differences in the size-spectrum exponent (describing the proportion of fish by size) were less clear statistically. Our analyses reveal that mortality, in addition to plastic growth and size-responses, is a key factor determining the size structure of populations exposed to warming. Understanding the mechanisms by which warming affects the size- and age structure of populations is critical for predicting the impacts of climate change on ecological functions, interactions, and dynamics.
Slow oscillations promote long range effective communication: the key for memory consolidation in a broken down network
Authors: Niknazar Hamid , Malerba Paola , Mednick Sara C.
Published: April 2022

One of the most prominent and robust findings in cognitive neuroscience is the strengthening of memories during non-rapid eye movement (NREM) sleep, with slow oscillations (SOs, < 1Hz) playing a critical role in systems-level consolidation. However, NREM is a sleep period generally showing a breakdown in connectivity and reduction of synaptic plasticity with increasing depth: a brain state seemingly unfavorable to memory consolidation. Here, we present a novel approach to address this apparent paradox that leverages an event-related causality measure to estimate directional information flow during NREM sleep in epochs with and without SOs. Our results confirm that NREM is generally a state of dampened neural communication, but reveals that SOs provide two windows of enhanced large-scale communication before and after the SO trough. These peaks in communication are significantly higher when SOs are coupled with sleep spindles, compared with uncoupled SOs. To probe the functional relevance of these SO-selective peaks of information flow, we tested the temporal and topographic conditions that predict overnight episodic memory improvement. Our results show that global, long-range communication during SOs promote sleep-dependent systems consolidation of episodic memories. A significant correlation between peaks of information flow and memory improvement lends a predictive validity to our measurements of effective connectivity. In other words, we were able to predict memory improvement on the basis of independent electrophysiological observations during sleep. This work introduces a non-invasive approach to understanding information processing during sleep, a behavioral stage whose function, until now, has been understood only after synaptic reorganization after waking from sleep. Our findings provide a mechanism for how systems-level brain communication can occur during an otherwise low connectivity sleep state, indicating that SOs are a gating mechanism for large-scale neural communication, which is the necessary substrate for systems consolidation and long-term memory formation.
Spatiotemporal Patterning enabled by Gene Regulatory Networks
Authors: Roy Ushasi , Singh Divyoj , Vincent Navin , Haritas Chinmay , Jolly Mohit Kumar
Published: April 2022

Spatiotemporal pattern formation plays a key role in various biological phenomena including embryogenesis and neural network formation. Though the reaction-diffusion systems enabling pattern formation have been studied phenomenonlogically, the biomolecular mechanisms behind these processes has not been modelled in detail. Here, we study the emergence of spatiotemporal patterns due to simple synthetic commonly observed two- and three-node gene regulatory network motifs coupled with their molecular diffusion in one- and two-dimensional space. We investigate the patterns formed due to the coupling of inherent multistable and oscillatory behavior of toggle switch (two mutually repressing nodes), toggle switch with double self-activation, toggle triad (three mutually repressing nodes) and repressilator (three nodes repressing the other sequentially in a cyclic manner) with the effect of spatial diffusion of these molecules. We probe various parameter regimes corresponding to different regions of stability (monostable, multistable, oscillatory) and assess the impact of varying diffusion coefficients too. This analysis offers valuable insights into the design principles of pattern formation facilitated by these network motifs, and suggest mechanistic underpinnings of biological pattern formation.
Low-efficiency conversion of proliferative glia into induced neurons by Ascl1 in the postnatal mouse cerebral cortex in vivo
Authors: Galante Chiara , Marichal Nicolás , Schuurmans Carol , Berninger Benedikt , Péron Sophie
Published: April 2022

The proneural transcription factor Achaete-scute complex-like 1 (Ascl1) is a major regulator of neural progenitor fate, implicated both in neurogenesis and oligodendrogliogenesis. Ascl1 has been widely used to reprogram non-neuronal cells into induced neurons. In vitro, Ascl1 induces efficient reprogramming of proliferative astroglia from the early postnatal cerebral cortex into interneuron-like cells. Here, we examined whether Ascl1 can similarly induce neuronal reprogramming of glia undergoing proliferation in the postnatal mouse cerebral cortex in vivo. Toward this, we targeted cortical glia at the peak of proliferative expansion (i.e., postnatal day 5) by injecting a retrovirus encoding for Ascl1 into the mouse cerebral cortex. In sharp contrast to the very efficient reprogramming in vitro, Ascl1-transduced glial cells were converted into doublecortin-immunoreactive neurons only with low efficiency in vivo. Interfering with the phosphorylation of Ascl1 by mutation of six conserved proline-directed serine/threonine phosphorylation sites (Ascl1SA6) has been previously shown to increase its neurogenic activity in the early embryonic cerebral cortex. We therefore tested whether transduction of proliferative glia with a retrovirus encoding Ascl1SA6 improved their conversion into neurons. While in vitro glia-to-neuron conversion was markedly enhanced, in vivo reprogramming efficiency remained low. However, both wild-type and mutant Ascl1 reduced the relative number of cells expressing the astrocytic marker glial fibrillary acidic protein (GFAP) and increased the relative number of cells expressing the oligodendroglial marker Sox10 in vivo. Together, our results indicate that the enhanced neurogenic response of proliferative postnatal glia to Ascl1SA6 versus Ascl1 observed in vitro is not recapitulated in vivo.
Integrated AlphaFold2 and DEER investigation of the conformational dynamics of a pH-dependent APC antiporter
Authors: Alamo Diego del , DeSousa Lillian , Nair Rahul M. , Rahman Suhaila , Meiler Jens , Mchaourab Hassane S.
Published: April 2022

The Amino Acid-Polyamine-Organocation transporter GadC contributes to the survival of pathogenic bacteria under extreme acid stress by exchanging extracellular glutamate for intracellular GABA. Its structure, determined exclusively in an inward-facing conformation at alkaline pH, consists of the canonical LeuT-fold of a conserved five-helix inverted repeat, thereby resembling functionally divergent transporters such as the serotonin reuptake transporter SERT and the glucose-sodium symporter transporter SGLT1. However, despite this structural similarity, it is unclear if the conformational dynamics of antiporters such as GadC follows the blueprint of these or other well-studied LeuT-fold transporters. Here, we used double electron-electron resonance (DEER) spectroscopy to monitor the conformational dynamics of GadC in lipid bilayers in response to acidification and substrate binding. To guide experimental design and facilitate the interpretation of the DEER data, we generated an ensemble of structural models in multiple conformations using a recently introduced AlphaFold2 methodology. Our experimental results reveal acid-induced conformational changes that dislodge the C-terminus from the permeation pathway coupled with rearrangement of helices that enable isomerization between both inward- and outward-facing states. The substrate glutamate, but not GABA, modulates the dynamics of an extracellular thin gate without shifting the equilibrium between inward- and outward-facing conformations. In addition to introducing an integrated methodology for probing transporter conformational dynamics, the congruence of the DEER data with patterns of structural rearrangements deduced from ensembles of AlphaFold2 models illuminate the conformational cycle of GadC underpinning transport and exposes yet another example of the divergence between the dynamics of different functional families in the LeuT-fold.

SIGNIFICANCE STATEMENT

The transporter GadC contributes to acid resistance in bacterial pathogens by exchanging two substrates, glutamate and GABA, using a mechanism termed alternating access. In this study, the conformational dynamics underlying alternating access was studied using a combination of spectroscopy and computational modeling. A conformationally diverse ensemble of models, generated using AlphaFold2, guided the design and interpretation of double electron-electron resonance spectroscopy experiments. We found that whereas GadC was inactive and conformationally homogeneous at neutral pH, low pH induced isomerization between two conformations. From our integrated computational/experimental investigation emerges a transport model that may be relevant to eukaryotic homologs that are involved in other cellular processes.
CellDrift: Inferring Perturbation Responses in Temporally-Sampled Single Cell Data
Authors: Jin Kang , Schnell Daniel , Li Guangyuan , Salomonis Nathan , Surya Prasath V. B. , Szczesniak Rhonda , Aronow Bruce J.
Published: April 2022

Cells and tissues respond to perturbations in multiple ways that can be sensitively reflected in alterations of gene expression. Current approaches to finding and quantifying the effects of perturbations on cell-level responses over time disregard the temporal consistency of identifiable gene programs. To leverage the occurrence of these patterns for perturbation analyses, we developed CellDrift (https://github.com/KANG-BIOINFO/CellDrift), a generalized linear model-based functional data analysis method capable of identifying covarying temporal patterns of various cell types in response to perturbations. As compared to several other approaches, CellDrift demonstrated superior performance in the identification of temporally varied perturbation patterns and the ability to impute missing time points. We applied CellDrift to multiple longitudinal datasets, including COVID-19 disease progression and gastrointestinal tract development, and demonstrated its ability to identify specific gene programs associated with sequential biological processes, trajectories, and outcomes.
Similarity-Based Multimodal Regression
Authors: Chen Andrew A. , Weinstein Sarah M. , Adebimpe Azeez , Gur Ruben C. , Gur Raquel E. , Merikangas Kathleen Ries , Satterthwaite Theodore D. , Shinohara Russell T. , Shou Haochang
Published: April 2022

To better understand complex human phenotypes, large-scale studies have increasingly collected multiple data modalities across domains such as imaging, mobile health, and physical activity. The properties of each data type often differ substantially and require either separate analyses or extensive processing to obtain comparable features for a combined analysis. Multimodal data fusion enables certain analyses on matrix-valued and vector-valued data, but it generally cannot integrate modalities of different dimensions and data structures. For a single data modality, multivariate distance matrix regression provides a distance-based framework for regression accommodating a wide range of data types. However, no distancebased method exists to handle multiple complementary types of data. We propose a novel distance-based regression model, which we refer to as Similarity-based Multimodal Regression (SiMMR), that enables simultaneous regression of multiple modalities through their distance profiles. We demonstrate through simulation, imaging studies, and longitudinal mobile health analyses that our proposed method can detect associations in multimodal data of differing properties and dimensionalities, even with modest sample sizes. We perform experiments to evaluate several different test statistics and provide recommendations for applying our method across a broad range of scenarios.
Lateral Orbitofrontal Cortex and Basolateral Amygdala Regulate Sensitivity to Delayed Punishment during Decision-making
Authors: Liley Anna E. , Gabriel Daniel B. K. , Simon Nicholas W.
Published: April 2022

In real-world decision-making scenarios, negative consequences do not always occur immediately after a choice. This delay between action and outcome drives the underestimation, or “delay discounting”, of punishment. While the neural substrates underlying sensitivity to immediate punishment have been well-studied, there has been minimal investigation of delayed consequences. Here, we assessed the role of lateral orbitofrontal cortex (LOFC) and basolateral amygdala (BLA), two regions implicated in cost/benefit decision-making, in sensitivity to delayed vs immediate punishment. The delayed punishment decision-making task (DPDT) was used to measure delay discounting of punishment in rodents. During DPDT, rats choose between a small, single pellet reward and a large, three pellet reward accompanied by a mild foot shock. As the task progresses, the shock is preceded by a delay that systematically increases or decreases throughout the session. We observed that rats avoid choices associated with immediate punishment, then shift preference toward these options when the punishment is delayed. LOFC inactivation did not influence choice of rewards with immediate punishment, but decreased choice of delayed punishment. We also found that BLA inactivation reduced choice of delayed punishment, but this was only evident when punishment was initially delivered immediately after a choice, then preceded by a delay as the task progressed. Therefore, both LOFC and BLA contribute to the delay discounting of punishment, and may serve as promising therapeutic targets to improve sensitivity to delayed punishment during decision-making.

Significance Statement

Negative consequences occurring after a delay are often underestimated, which can lead to maladaptive decision-making. While sensitivity to immediate punishment during reward-seeking has been well-studied, the neural substrates underlying sensitivity to delayed punishment remain unclear. Here, we used the Delayed Punishment Decision-making Task to determine that lateral orbitofrontal cortex and basolateral amygdala both regulate the discounting of delayed punishment, suggesting that these regions may be potential targets to improve decision-making in psychopathology.
Fast Kernel-based Association Testing of non-linear genetic effects for Biobank-scale data
Authors: Fu Boyang , Pazokitoroudi Ali , Sudarshan Mukund , Subramanian Lakshminarayanan , Sankararaman Sriram
Published: April 2022

Our knowledge of non-linear genetic effects on complex traits remains limited, in part, due to the modest power to detect such effects. While kernel-based tests offer a powerful approach to test for nonlinear relationships between sets of genetic variants and traits, current approaches cannot be applied to Biobank-scale datasets containing hundreds of thousands of individuals. We propose, FastKAST, a Kernel-based approach that can test for non-linear effects of a set of variants on a trait. FastKAST provides calibrated hypothesis tests while enabling analysis of Biobank-scale datasets with hundreds of thousands of individuals. We applied FastKAST to thirty quantitative traits measured across ≈ 300 K unrelated white British individuals in the UK Biobank to detect sets of variants with nonlinear effects at genome-wide significance.
Effect of Positive Allosteric Modulation and Orthosteric Agonism of Dopamine D2 Receptors on Respiration in Mouse Models of Rett Syndrome
Authors: Maletz Sebastian N. , Reid Brandon T. , Baekey David M. , Whitaker-Fornek Jessica R. , Bateman Jordan T. , Bissonnette John M. , Levitt Erica S.
Published: April 2022

Rett syndrome (RTT) is an autism spectrum disorder caused by loss-of-function mutations in the methyl-CPG-binding protein 2 (Mecp2) gene. Frequent apneas and irregular breathing are prevalent in RTT, and also occur in rodent models of the disorder, including Mecp2Bird and Mecp2R168X mice. Sarizotan, a serotonin 5-HT1a and dopamine D2-like receptor agonist, reduces the incidence of apneas and irregular breathing in mouse models of RTT (Abdala et al., 2014). Targeting the 5HT1a receptor alone also improves respiration in RTT mice (Levitt et al., 2013). However, the contribution of D2 receptors in correcting these respiratory disturbances remains untested. PAOPA, a dopamine D2 receptor positive allosteric modulator, and quinpirole, a dopamine D2 receptor orthosteric agonist, were used in conjunction with whole-body plethysmography to evaluate whether activation of D2 receptors is sufficient to improve breathing disturbances in female heterozygous Mecp2Bird/+ and Mecp2R168X/+ mice. PAOPA did not significantly change apnea incidence or irregularity score in RTT mice. PAOPA also had no effect on the ventilatory response to hypercapnia (7% CO2). In contrast, quinpirole reduced apnea incidence and irregularity scores and improved the hypercapnic ventilatory response in Mecp2R168X/+ and Mecp2Bird/+ mice, while also reducing respiratory rate. These results suggest that D2 receptors do contribute to the positive effects of sarizotan in the correction of respiratory abnormalities in Rett syndrome. However, positive allosteric modulation of the D2 receptor alone is not sufficient to evoke these effects.
Determinants of Spike Infectivity, Processing and Neutralization in SARS-CoV-2 Omicron subvariants BA.1 and BA.2
Authors: Pastorio Chiara , Zech Fabian , Noettger Sabrina , Jung Christoph , Jacob Timo , Sparrer Konstantin M.J. , Kirchhoff Frank
Published: April 2022

The SARS-CoV-2 Omicron variant rapidly outcompeted other variants and currently dominates the COVID-19 pandemic. Its enhanced transmission, immune evasion and pathogenicity is thought to be driven by numerous mutations in the Omicron Spike protein. Here, we examined the impact of amino acid changes that are characteristic for the BA.1 and/or BA.2 Omicron lineages on Spike function, processing and susceptibility to neutralization. Individual mutations of S371F/L, S375F and T376A in the ACE2 receptor-binding domain as well as Q954H and N969K in the hinge region 1 impaired infectivity, while changes of G339D, D614G, N764K and L981F moderately enhanced it. Most mutations in the N-terminal region and the receptor binding domain reduced sensitivity of the Spike protein to neutralization by sera from individuals vaccinated with the BNT162b2 vaccine or therapeutic antibodies. Our results represent a systematic functional analysis of Omicron Spike adaptations that allowed this SARS-CoV-2 variant to overtake the current pandemic.

HIGHLIGHTS

S371F/L, S373P and S375F impair Spike function and revert in some BA. 1 isolates

Changes of Q954H and N969K in HR1 reduce while L981F enhances S-mediated infection

Omicron-specific mutations in the NTD and RBD of Spike reduce neutralization

N440K, G446S, E484A and Q493K confer resistance to bamlanivimab or imdevimab
3’ RNA sequencing does not increase power or reduce costs for gene expression analysis
Authors: Crow Taylor M , Gill JA , Whitehead Andrew , Runcie Daniel E
Published: April 2022

Background

Sequencing RNA transcripts for gene expression profiling is a popular and important technique with broad utility in biological sciences. We set out to comprehensively compare the two most popular methods for generating sequencing libraries for differential gene expression analysis: 3-end sequencing, which generates libraries from the 3’ end of an RNA transcript; and traditional RNA sequencing, which generates libraries from whole RNA transcripts. We include three species in our experiment to test whether our findings replicate across genomes and genome assemblies.

Results

We found similar levels of precision and power to detect differentially expressed genes between the two methods. Notably, whole transcript RNA-seq performed better in the non-traditional model species included in our study.

Conclusion

Overall, we recommended whole transcript RNA sequencing for the added benefits of alternative splicing detection, and gene-body variant detection.
Schizophrenia-derived hiPSC brain microvascular endothelial cells show impairments in angiogenesis and blood-brain barrier function
Authors: Casas Bárbara S. , Vitória Gabriela , Prieto Catalina P. , Casas Mariana , Chacón Carlos , Uhrig Markus , Ezquer Fernando , Ezquer Marcelo , Rehen Stevens K. , Palma Verónica
Published: April 2022

Schizophrenia (SZ) is a complex neuropsychiatric disorder, affecting 1% of the world population. Long-standing clinical observations and molecular data have pointed out a possible vascular deficiency that could be acting synergistically with neuronal dysfunction in SZ.

As SZ is a neurodevelopmental disease, the use of human induced pluripotent stem cells (hiPSC) allows disease biology modeling retaining the patient’s unique genetic signature. Previously, we reported a VEGF-A signaling impairment in SZ-hiPSC derived neural lineages leading to a decreased angiogenesis. Here, we present a functional characterization of SZ-derived brain microvascular endothelial-like cells (BEC), the counterpart of the neurovascular crosstalk, revealing an intrinsically defective Blood-Brain Barrier (BBB) phenotype. Transcriptomic assessment of genes related to endothelial function among three control (Ctrl BEC) and five schizophrenia patients derived BEC (SZP BEC), revealed that SZP BEC have a distinctive expression pattern of angiogenic and BBB-associated genes. Functionally, SZP BEC showed a decreased angiogenic response in vitro and higher transpermeability than Ctrl BEC. Immunofluorescence staining revealed less expression and altered distribution of tight junction proteins in SZP BEC. Moreover, SZP BEC’s secretome reduced barrier capacities in the brain microvascular endothelial cell line HCMEC/D3 and in an in vivo permeability assay in mice. Overall, our results describe an intrinsic failure of SZP BEC for proper barrier function. These findings are consistent with the hypothesis that traces schizophrenia origins to brain development and BBB dysfunction.
The impact of gamification on the patient's engagement in the online health community
Authors: Ouyang Peng , Wang Jian-Jun , Ali Usman
Published: April 2022

Purpose

Gamification has been widely implemented to improve user engagement in the online health community (OHC). While its effect on the physicians' engagement has recently been documented, whether and how gamification influences the patients' engagement in the OHC remains an untapped research area. The purpose of this study is to fill this dearth by encompassing the gamification strategy of Haodf.com, which awards the “Annual Physician” badges to the physicians, to analyze how this gamification approach motivates patients’ engagement in the OHC.

Design/methodology/approach

Real-world data are leveraged from the OHC. The Tobit model is employed for modeling the gamification-patient's engagement nexus in an OHC. Robust findings are obtained by incorporating different measures of a dependent variable, a set of control variables about the physician's characteristics and hospital's features, and alternative estimation techniques.

Findings

The results reveal that a patient's engagement in the OHC in the form of appointments and review-posting behavior is enhanced by the gamification strategy. Besides, the positive influence of gamification on the patient's engagement is further strengthened by the physician's professional capital. It is basically obtained that the gamification is an efficacious tool to accelerate not only the physicians' engagement but also of the patients in the OHC platform.

Originality/value

The study provides both theoretical and empirical discussion to enrich the understanding on how OHCs enhance patients' engagement by developing gamification techniques. The findings guide the practitioners of OHC to better understand the implications of their gamification design to optimize user engagement.
Robust stability analysis of switched grey neural network models with distributed delays over C
Authors: Zhang Lei , Xue Huanbin , Li Zeying , Wei Yong
Published: April 2022

Purpose

The purpose of this paper is to study the dynamic behavior of complex-valued switched grey neural network models (SGNMs) with distributed delays when the system parameters and external input are grey numbers.

Design/methodology/approach

Firstly, by using the properties of grey matrix, M-matrix theory and Homeomorphic mapping, the existence and uniqueness of equilibrium point of the SGNMs were discussed. Secondly, by constructing a proper Lyapunov functional and using the average dwell time approach and inequality technique, the robust exponential stability of the SGNMs under restricted switching was studied. Finally, a numerical example is given to verify the effectiveness of the proposed results.

Findings

Sufficient conditions for the existence and uniqueness of equilibrium point of the SGNMs have been established; sufficient conditions for guaranteeing the robust stability of the SGNMs under restricted switching have been obtained.

Originality/value

(1) Different from asymptotic stability, the exponential stability of SGNMs which include grey parameters and distributed time delays will be investigated in this paper, and the exponential convergence rate of the SGNMs can also be obtained; (2) the activation functions, self-feedback coefficients and interconnected matrices are with different forms in different subnetworks; and (3) the results obtained by LMIs approach are complicated, while the proposed sufficient conditions are straightforward, which are conducive to practical applications.
How health consciousness and social consciousness affect young consumers purchase intention towards organic foods
Authors: Su Yuandong , Khaskheli Asadullah , Raza Syed Ali , Yousufi Sara Qamar
Published: April 2022

Purpose

This current research investigates antecedents affecting young consumers' purchasing intention of organic foods in a developing nation’s (Pakistan) context utilizing Theory of Planned Behavior. For this purpose, theoretical framework comprising characteristics of a product, concerns of consumers and consciousness were proposed.

Design/methodology/approach

Responses were collected from a sample comprising 418 young consumers through the convenience sampling technique. The data has been evaluated through Structural Equation Modeling.

Findings

Findings demonstrate that characteristics of products and concerns of consumers significantly affect young consumer's health and social consciousness. However, such health and social consciousness were found to have an insignificant effect on young consumers' attitudes. Moreover, findings also show that attitude is positively linked with young consumers' purchase frequency towards organic foods. Outcomes also approve moderation of environmental awareness between attitude and organic food purchasing intention.

Practical implications

The present study offers numerous implications for marketers, policymakers and socio-ecological organizations regarding development of intervention strategies to promote the purchase of organic foods. The study provides implications regarding making organic foods more accessible to all consumers in order to increase organic food consumption in developing countries.

Originality/value

Although young consumers are aware of organic food products, their knowledge about the concept is limited. Therefore, this study provides an understanding of consumer's perspective regarding their purchase intention of organic foods, which will help marketers, researchers and food producers to achieve marketing strategies for the development of these products.
Authentic leadership: boosting organisational learning capability and innovation success
Authors: Domínguez-Escrig Emilio , Mallén Broch Francisco Fermín , Chiva Ricardo , Lapiedra Alcamí Rafael
Published: April 2022

Purpose

Despite the growing interest in the study of authentic leadership, there is little empirical evidence of the consequences of this type of leadership for companies. On the other hand, the mediating variables that may explain these results have not been explored in depth either. Although the academic literature suggests, from a theoretical point of view, that these leaders could favour innovation, little has been studied from an empirical perspective. This study aims to try to cover these gaps.

Design/methodology/approach

The main goal of this study is to analyse the mediating effect of organisational learning capability in the relationship between authentic leadership and innovation success. Considering a sample frame of 263 Spanish companies, this study tested the proposed hypotheses through structural equations.

Findings

The results provide empirical evidence of the positive effect of authentic leaders to promote organisational learning capability. In addition, this study confirms the positive effect of organisational learning capability on innovation success. Finally, organisational learning capability mediates the relationship between authentic leadership and innovation success.

Originality/value

To the best of the authors’ knowledge, this is the first attempt to empirically study the effects of authentic leadership on organisational learning capability and innovation success.
Integrin β2 and β3: Two plasmatocyte markers deepen our understanding of the development of plasmatocytes in the silkworm Bombyx mori
Authors: Zhang Kui , Su Jingjing , Hu Xin , Yan Xiaomin , Chen Siyuan , Li Chongyang , Pan Guangzhao , Chang Hongbo , Tian Wenli , Abbas Muhammad Nadeem , Cui Hongjuan
Published: April 2022

Insect hemocytes play important biological roles at developmental stages, metamorphosis, and innate immunity. As one of the most abundant cell types, plasmatocytes can participate in various innate immune responses, especially in encapsulation and node formation. Here, 2 molecular markers of plasmatocytes, consisting of integrin β2 and β3, were identified and used to understand the development of plasmatocytes. Plasmatocytes are widely distributed in the hematopoietic system, including circulating hemolymph and hematopoietic organs (HPOs). HPOs constantly release plasmatocytes with high proliferative activity in vitro; removal of HPOs leads to a dramatic reduction in the circulating plasmatocytes, and the remaining plasmatocytes gradually lose their ability to proliferate in vivo. Our results demonstrated that the release of plasmatocytes from HPOs is regulated by insulin‐mediated signals and their downstream pathways, including PI3K/Akt and MAPK/Erk signals. The insulin/PI3K/Akt signaling pathway can significantly irritate the hematopoiesis, and its inhibitor LY294002 could inhibit the hemocytes discharged from HPOs. While the insulin/MAPK/Erk signaling pathway plays a negative regulatory role, inhibiting its activity with U0126 can markedly promote the discharge of plasmatocytes from HPOs. Our results indicate that the circulating plasmatocytes are mainly generated and discharged by HPOs. This process is co‐regulated by the PI3K/Akt and MAPK/Erk signals in an antagonistic manner to adjust the dynamic balance of the hemocytes. These findings can enhance our understanding of insect hematopoiesis.
Cardiopulmonary exercise testing to observe subclinical abnormalities in cardiopulmonary function in patients undergoing peritoneal dialysis
Authors: Wu Xin , Zhang Ying , Wang FengLi , Xiang Jie
Published: April 2022

Background

Decreased cardiorespiratory fitness (CRF) related to cardiopulmonary function increases the risk of cardiovascular disease in patients with end‐stage kidney disease. Thus, early detection of the cause of impaired cardiopulmonary function in patients undergoing peritoneal dialysis (PD) is of important clinical significance.

Methods

In this cross‐sectional study, symptom‐restricted cardiopulmonary exercise testing (CPET) was performed in 30 patients undergoing PD and in 23 age‐ and sex‐matched healthy control subjects. A fixed workload was added every minute until fatigue, and breath‐by‐breath respiratory gas was analysed with an automated gas analyzer at 10‐s intervals.

Results

The peak oxygen uptake (16.39 ± 0.83 vs. 25.77 ± 1.33 ml/kg/min p < 0.001) and the oxygen uptake at the anerobic threshold of patients undergoing PD (9.61 ± 0.34 vs. 14.55 ± 0.64 ml/kg/min; p < 0.001) were lower than in healthy control subjects, and both of these parameters correlated with body mass index and left atrial dimension. A steeper minute ventilation/carbon dioxide production slope (27.20 ± 0.68 vs. 24.29 ± 0.69；p < 0.01) and a lower end‐tidal carbon dioxide partial pressure (37.93 ± 0.54 vs. 41.27 ± 0.83 mmHg；p < 0.05) were observed in patients undergoing PD. The oxygen pulse and oxygen uptake efficiency slope was smaller in patients undergoing PD. The Maximum heart rate (126.07 ± 4.01 vs. 149.96 ± 5.29 bpm；p < 0.01) and 1‐min heart rate recovery (13.93 ± 1.52 vs. 24.39 ± 1.61 bpm；p < 0.01) were also lower in patients undergoing PD.

Conclusion

Subclinical cardiopulmonary dysfunction may exist in patients with PD, and a reduction in CRF in patients undergoing PD is affected by both central and peripheral functions. CPET has potential value in revealing the mechanism of impaired CRF and in discovering subclinical abnormalities in cardiopulmonary function.
The contribution of canopy samples to assessments of forestry effects on native bees
Authors: Milam Joan , Cunningham‐Minnick Michael , Roberts Henry Patrick , Buelow Christopher , King David I.
Published: April 2022

Forest management is often practiced to enhance conditions for wildlife, including native bees. Evaluations of the effects of forest management on bees have shown that abundance and diversity are higher in newly created early‐successional conditions. To date, studies have restricted sampling to the forest understory; however, recent research finds that bee abundance is as high or higher in forest canopies than in understories, suggesting that previous observations of substantially greater bee abundance and diversity in recently managed areas could be an artifact of incomplete sampling of the vertical gradient within forests. To examine the potential implications of sampling biases associated with the failure of previous studies to include canopy samples in comparisons of managed and unmanaged forests, we sampled bees within a recently harvested forest as well as the understory and canopy of adjacent unmanaged forest. Bee abundance and diversity were an order of magnitude higher in managed areas compared to the unmanaged forest, even when understory and canopy samples were combined. These results suggest that not sampling the canopy is inconsequential with respect to the broadly reported conclusion that managed areas support more abundant and diverse bee communities than surrounding forest cover.
Conservation potentials and limitations of large carnivores in protected areas: A case study in Northeast China
Authors: Wen Dusu , Qi Jinzhe , Long Zexu , Gu Jiayin , Tian Yumiao , Roberts Nathan James , Yang Eryan , Kong Weiyao , Zhao Yan , Sun Quan , Jiang Guangshun
Published: April 2022

Protected areas are considered the cornerstone of endangered wildlife conservation. However, quantified conservation potentials and limitations of large carnivores in protected areas are lacking. In the Northeast Tiger and Leopard National Park (NTLNP) in China, our camera trap survey in 2019 found 26–27 adult Amur tigers and 49–59 adult Amur leopards occurring in the park. Based on spatial area, current prey populations, and environmental carrying capacity of prey, we estimated the supportable number of tigers to be 55, 90, and 101 individuals, respectively. For leopard, these values were 95, 356, and 572, respectively. Further simulations indicated that human land use change scenarios did not contribute much to increasing the potential prey‐supportable populations of Amur tiger and leopard. Our results showed that the number of tigers and leopards in NTLNP is currently low and has a high recovery potential. However, even the highest supportable population is not enough to support the sustainable existence of an Amur tiger population. Therefore, we suggest that, in addition to further restoration and improvement of the prey population and habitat quality in NTLNP, managers should strengthen the connectivity between NTLNP and other habitat patches to form a well‐connected network of protected areas. Promoting the spread of tigers and leopards outwards from this source population in NTLNP through ecological corridor construction would enlarge the area of habitat and is a crucial measure for realizing the sustainable survival of an Amur tiger population in Northeast China.
Physiologically‐based pharmacokinetic model‐based translation of OATP1B‐mediated drug–drug interactions from coproporphyrin I to probe drugs
Authors: Mochizuki Tatsuki , Aoki Yasunori , Yoshikado Takashi , Yoshida Kenta , Lai Yurong , Hirabayashi Hideki , Yamaura Yoshiyuki , Rockich Kevin , Taskar Kunal , Takashima Tadayuki , Chu Xiaoyan , Zamek‐Gliszczynski Maciej J. , Mao Jialin , Maeda Kazuya , Furihata Kenichi , Sugiyama Yuichi , Kusuhara Hiroyuki
Published: April 2022

The accurate prediction of OATP1B‐mediated drug–drug interactions (DDIs) is challenging for drug development. Here, we report a physiologically‐based pharmacokinetic (PBPK) model analysis for clinical DDI data generated in heathy subjects who received oral doses of cyclosporin A (CysA; 20 and 75 mg) as an OATP1B inhibitor, and the probe drugs (pitavastatin, rosuvastatin, and valsartan). PBPK models of CysA and probe compounds were combined assuming inhibition of hepatic uptake of endogenous coproporphyrin I (CP‐I) by CysA. In vivo Ki of unbound CysA for OATP1B (Ki,OATP1B), and the overall intrinsic hepatic clearance per body weight of CP‐I (CLint,all,unit) were optimized to account for the CP‐I data (Ki,OATP1B, 0.536 ± 0.041 nM; CLint,all,unit, 41.9 ± 4.3 L/h/kg). DDI simulation using Ki,OATP1B reproduced the dose‐dependent effect of CysA (20 and 75 mg) and the dosing interval (1 and 3 h) on the time profiles of blood concentrations of pitavastatin and rosuvastatin, but DDI simulation using in vitro Ki,OATP1B failed. The Cluster Gauss–Newton method was used to conduct parameter optimization using 1000 initial parameter sets for the seven pharmacokinetic parameters of CP‐I (β, CLint, all, FaFg, Rdif, fbile, fsyn, and vsyn), and Ki,OATP1B and Ki,MRP2 of CysA. Based on the accepted 546 parameter sets, the range of CLint, all and Ki,OATP1B was narrowed, with coefficients of variation of 12.4% and 11.5%, respectively, indicating that these parameters were practically identifiable. These results suggest that PBPK model analysis of CP‐I is a promising translational approach to predict OATP1B‐mediated DDIs in drug development.