bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of the Human Pharmacokinetics of 30 Modern Antibiotics Using the ANDROMEDA Software
Authors: Fagerholm Urban , Hellberg Sven , Alvarsson Jonathan , Spjuth Ola
Published: March 2023

The ANDROMEDA software, based on machine learning, conformal prediction and a new physiologically-based pharmacokinetic model, was used to predict and characterize the human clinical pharmacokinetics of 30 selected modern small antibiotic compounds (investigational and marketed drugs). A majority of clinical pharmacokinetic data was missing. ANDROMEDA successfully filled this gap. Most antibiotics were predicted and measured to have limited permeability, good metabolic stability and multiple elimination pathways. According to predictions, most of the antibiotics are mainly eliminated renally and biliary and every other antibiotic is mainly eliminated via the renal route. Mean prediction errors for steady state volume of distribution, unbound fraction in plasma, renal and total clearance, oral clearance, fraction absorbed, fraction excreted renally, oral bioavailability and half-life were 1.3- to 2.3-fold. The overall median and maximum prediction errors were 1.5- and 4.8-fold, respectively, and 92 % of predictions had <3-fold error. Results are consistent with those obtained in previous validation studies and are better than with the best laboratory-based prediction methods, which validates ANDROMEDA for predictions of human clinical pharmacokinetics of modern antibiotic drugs, which to a great extent demonstrate pharmacokinetic characteristics challenging for laboratory methods (metabolic stability, limited permeability, efflux and multiple elimination pathways). Advantages with ANDROMEDA include that results are produced without the use of animals and cells and that predictions and decision-making can be done already at the design stage.
Potential of LocalBacillusspp. Isolates as Wilt Disease Biocontrol Agents forFusarium(Fusarium oxysporumf. sp.cepae) on Wakegi Onions (Allium×wakegiAraki)
Authors: Asrul Asrul
Published: March 2023

The use of biological agents as a biocontrol against plant pathogens was often ineffective because it worked slowly. The objective of this research was to examine the potential of local isolates of Bacillus spp. as a biocontrol agent in suppressing Fusarium wilt disease (Fusarium oxysporumf. sp.cepae) on wakegi onions. The research was designed using a completely randomized design with the treatment of rhizosphere bacterial isolates. The treatments consisted of control (without isolate application), isolates KP17, KP5, DB9, DB12, DB18, DG4, and DG11 so that the number of treatments was eight. Each treatment was repeated 5 times and each replication consisted of 10 wakegi onion plants. This research was divided into 2 stages, namely laboratory research which included isolation, characterization of colony morphology of rhizosphere bacterial isolates, and in vitro testing of the inhibitory power of biocontrol agents against pathogens. The test in the greenhouse was in the form of a disease case suppression test. The results obtained seven candidate isolates of biocontrol from 46 isolates obtained from the rhizosphere of the wakegi onion. These isolates had similarities with Bacillus spp. based on colony morphology, physiology, and biochemistry characteristics. Among the isolates found, the DB12 isolate had the potential to be developed as a biocontrol agent compared to other isolates.
Ancient origins of complex neuronal genes
Authors: McCoy Matthew J. , Fire Andrew Z.
Published: March 2023

How nervous systems evolved is a central question in biology. An increasing diversity of synaptic proteins is thought to play a central role in the formation of specific synapses leading to nervous system complexity. The largest animal genes, often spanning millions of base pairs, are known to be enriched for expression in neurons at synapses and are frequently mutated or misregulated in neurological disorders and diseases. While many of these genes have been studied independently in the context of nervous system evolution and disease, general principles underlying their parallel evolution remain unknown. To investigate this, we directly compared orthologous gene sizes across eukaryotes. By comparing relative gene sizes within organisms, we identified a distinct class of large genes with origins predating the diversification of animals and in many cases the emergence of dedicated neuronal cell types. We traced this class of ancient large genes through evolution and found orthologs of the large synaptic genes driving the immense complexity of metazoan nervous systems, including in humans and cephalopods. Moreover, we found that while these genes are evolving under strong purifying selection as demonstrated by low dN/dS scores, they have simultaneously grown larger and gained the most isoforms in animals. This work provides a new lens through which to view this distinctive class of large and multi-isoform genes and demonstrates how intrinsic genomic properties, such as gene length, can provide flexibility in molecular evolution and allow groups of genes and their host organisms to evolve toward complexity.
Automatic sleep staging by a hybrid model based on deep 1D-ResNet-SE and LSTM with single-channel raw EEG signals
Authors: Li Weiming , Gao Junhui
Published: March 2023

Sleep staging is crucial in assessing sleep quality and diagnosing sleep disorders. Recent advances in deep learning methods with electroencephalogram (EEG) signals have shown remarkable success in automatic sleep staging. However, the use of deeper neural networks may lead to the issues of gradient disappearance and explosion, while the non-stationary nature and low signal-to-noise ratio of EEG signals can negatively impact feature representation. To overcome these challenges, we proposed a novel lightweight sequence-to-sequence deep learning model, 1D-ResNet-SE-LSTM, to classify sleep stages into five classes using single-channel raw EEG signals. Our proposed model consists of two main components: a one-dimensional residual convolutional neural network with a squeeze-and-excitation module to extract and reweight features from EEG signals, and a long short-term memory network to capture the transition rules among sleep stages. In addition, we applied the weighted cross-entropy loss function to alleviate the class imbalance problem. We evaluated the performance of our model on two publicly available datasets, Sleep-EDF Expanded and ISRUC-Sleep, and obtained an overall accuracy rate of 86.39% and 81.97%, respectively, along with corresponding macro average F1-scores of 81.95% and 79.94%. Our model outperforms existing sleep staging models, particularly for the N1 stage, where it achieves F1-scores of 59.00% and 55.53%. The kappa coefficient is 0.812 and 0.766 for the Sleep-EDF Expanded and ISRUC-Sleep datasets, respectively, indicating strong agreement with certified sleep experts. We also investigated the effect of different weight coefficient combinations and sequence lengths of EEG epochs used as input to the model on its performance. Furthermore, the ablation study was conducted to evaluate the contribution of each component to the model’s performance.
Morphogen-driven human iPSCs differentiation in 3Din vitromodels of gastrulation is precluded by physical confinement
Authors: Alsehli Haneen S. , Roy Errin , Williams Thomas , Kuziola Alicja , Guo Yunzhe , Green Jeremy , Gentleman Eileen , Danovi Davide
Published: March 2023

In early human development, gastrulation is tightly associated with lineage specification. The interplay between mechanical forces and biochemical signals during these processes is poorly understood. Here, we dissect the effects of biochemical cues and physical confinement on a 3D in vitro model of gastrulation that uses spheroids formed from human induced pluripotent stem cells (hiPSCs). First, we compare self-renewing versus differentiating media conditions in free-floating cultures, and observe the emergence of organised tri-germ layers. In these unconfined cultures, BMP4 exposure induces polarised expression of SOX17 in conjunction with spheroid elongation. We then physically confine spheroids using PEG-peptide hydrogels and observe dramatically reduced SOX17 expression, albeit rescued if gels that soften over time are used instead. Our study combines high-content imaging, synthetic hydrogels and hiPSCs-derived models of early development to define the drivers causing changes in shape and emergence of germ layers.
Proving sequence aligners can guarantee accuracy in almostO(mlogn) time through an average-case analysis of the seed-chain-extend heuristic
Authors: Shaw Jim , Yu Yun William
Published: March 2023

Seed-chain-extend withk-mer seeds is a powerful heuristic technique for sequence alignment used by modern sequence aligners. Although effective in practice for both runtime and accuracy, theoretical guarantees on the resulting alignment do not exist for seed-chain-extend. In this work, we give the first rigorous bounds for the efficacy of seed-chain-extend withk-mersin expectation. Assume we are given a random nucleotide sequence of length ∼nthat is indexed (or seeded) and a mutated substring of length ∼m≤nwith mutation rate θ < 0.206. We prove that we can find ak= Θ(logn) for thek-mer size such that the expected runtime of seed-chain-extend under optimal linear-gap cost chaining and quadratic time gap extension isO(mnf(θ)logn), wheref(θ) < 2.43 · θ holds as a loose bound. The alignment also turns out to be good; we prove that more than1−O(1m)fraction of the homologous bases isrecoverableunder an optimal chain. We also show that our bounds work whenk-mers aresketched, that is, only a subset of allk-mers is selected, and that sketching reduces chaining time without increasing alignment time or decreasing accuracy too much, justifying the effectiveness of sketching as a practical speedup in sequence alignment. We verify our results in simulation and on real noisy long-read data and show that our theoretical runtimes can predict real runtimes accurately. We conjecture that our bounds can be improved further, and in particular,f(θ) can be further reduced.
Digital transformation in tourism: bibliometric literature review based on machine learning approach
Authors: Madzík Peter , Falát Lukáš , Copuš Lukáš , Valeri Marco
Published: March 2023

Purpose

This bibliometric study provides an overview of research related to digital transformation (DT) in the tourism industry from 2013 to 2022. The goals of the research are as follows: (1) to identify the development of academic papers related to DT in the tourism industry, (2) to analyze dominant research topics and the development of research interest and research impact over time and (3) to analyze the change in research topics during the pandemic.

Design/methodology/approach

In this study, the authors processed 3,683 papers retrieved from the Web of Science and Scopus. The authors performed different types of bibliometric analyses to identify the development of papers related to DT in the tourism industry. To reveal latent topics, the authors implemented topic modeling based on latent Dirichlet allocation with Gibbs sampling.

Findings

The authors identified eight topics related to DT in the tourism industry: City and urban planning, Social media, Data analytics, Sustainable and economic development, Technology-based experience and interaction, Cultural heritage, Digital destination marketing and Smart tourism management. The authors also identified seven topics related to DT in the tourism industry during the Covid-19 pandemic; the largest ones are smart analytics, marketing strategies and sustainability.

Originality/value

To identify research topics and their development over time, the authors applied a novel methodological approach – a smart literature review. This machine learning approach is able to analyze a huge amount of documents. At the same time, it can also identify topics that would remain unrevealed by a standard bibliometric analysis.
Day-of-the-week effect and volatility in stock returns: evidence from the Indian stock market
Authors: Aggarwal Khushboo , Jha Mithilesh Kumar
Published: March 2023

Purpose

The purpose of this paper is to examine the existence of the day-of-the-week effect in the Indian stock market.

Design/methodology/approach

Generalized Autoregressive Conditional Heteroskedasticity (GARCH) (1, 1), Exponential GARCH (EGARCH) (1, 1) and Threshold GARCH (TGARCH) (1, 1) models are employed to examine the day-of-the-week effect in the Indian stock market for the period of 28 years from 3rd July, 1990 to 31st March, 2022.

Findings

The empirical results derived from the GARCH models indicate the existence of day-of-the-week effects on stock returns and volatility of the Indian stock market. The study reveals that all the days of the week are positive and significant in National Stock Exchange (NSE)-Nifty market returns. The findings confirm the persistence of ARCH and GARCH effects in the daily return series. Moreover, the asymmetric GARCH models show that the daily stock returns exhibit significant asymmetric (leverage) effects.

Practical implications

The results of this study established that the Indian stock market is not efficient and there exists an opportunity to the traders for predicting the future prices and earning abnormal profits in the Indian stock market. The findings of the study are important for traders, investors and portfolio managers to earn abnormal returns by cross-border diversification.

Originality/value

First, to the best of the authors' knowledge, this paper is the first to study the day-of-the-week effect in Indian stock market considering the most recent and longer time period (1990–2022). Second, unlike previous research, this study used GARCH models (GARCH, EGARCH and TGARCH) to capture the volatility clustering in the data.
Brand equity chain and brand equity measurement approaches
Authors: Oliveira Marta Olivia Rovedder de , Heldt Rodrigo , Silveira Cleo Schmitt , Luce Fernando Bins
Published: March 2023

Purpose

Although brand equity (BE) is a widely accepted concept, its definition is still elusive, and researchers have not reached a consensus about which measures provide the best estimates of this complex and multi-faceted construct. Hence, the authors propose a BE chain that incorporates consumer-based BE (CBBE) and firm-based BE (FBBE) measurement approaches, advocating in favor of a holistic approach and encouraging theoretical and empirical studies that assess the BE chain.

Design/methodology/approach

The methodology entailed an extensive literature review on the subject. The authors included many different sources and the most accepted ones for measuring CBBE and FBBE.

Findings

The authors present 10 propositions to build the BE chain, encompassing the different approaches of BE and including its antecedents and consequences.

Originality/value

Conceptualizing BE is a complex problem given the different viewpoints describing several aspects of this intangible marketing asset. Thus, this study aims to foster discussions about such viewpoints and provide a framework to support the sedimentation of BE conceptualization.
Drivers of gated community developments in Ghana: perspective of developers
Authors: Otchere Gideon Kwame , Mintah Kwabena , Callanan Judith
Published: March 2023

Purpose

Gated communities continue to spread in popularity across cities around the world. Ghana has seen considerable growth in the development of gated communities over the last few years. This phenomenon manifests in the majority new residential developments and most forms of residential property advertisement in the capital city. The purpose of this paper is to explore the drivers of gated community developments in Ghana from the perspective of gated community developers.

Design/methodology/approach

This paper used a qualitative research approach. Through face-to-face semi-structured interviews, data was collected from purposively selected key stakeholders in the gated community development market, including developers, managers and consultants.

Findings

The drivers identified from the developers' perspective were the demand for gated community properties, the control over and ease of management of assets and interests, the high development/production cost of real estate and speculative development of gated community properties.

Originality/value

This paper is an initial study that explores the drivers of gated community developments in Ghana from the perspective of gated community developers. This paper extends the literature on gated communities beyond the residents perspective.
Study on the anti‐inflammatory effect of stachyose by inhibiting TLR4/NF‐κB signalling pathway in vitro and in vivo
Authors: Jiang Songsong , Li Qian , Han Shiwen , Wang Hengpeng , Tang Xinlei , Wang Tao , Meng Xiangren
Published: March 2023

This study aimed to explore the anti‐inflammatory effect of stachyose, a tetrasaccharide extracted from Stachys sieboldii Miq. A lipopolysaccharide (LPS)‐stimulated RAW264.7 macrophages model and a dextran sodium sulfate (DSS)‐induced ulcerative colitis BALB/C mice model was used to assess the anti‐inflammatory effect of stachyose both in vitro and in vivo. The levels of nitric oxide (NO) and cytokines (interleukin‐1β, interleukin‐6 and tumour necrosis factor‐α) were detected using enzyme‐linked immunosorbent assay methods; moreover, haematoxylin–eosin staining was used to observe changes in intestinal morphology of mice. In addition, the possible mechanisms were explored by reverse transcription‐polymerase chain reaction and western blot. Results showed that stachyose and four other oligosaccharides (galacto‐oligosaccharides, xylo‐oligosaccharides, inulin and resistant dextrin) inhibited NO secretion and the production of pro‐inflammatory cytokines in LPS‐stimulated RAW264.7 macrophages in a dose‐dependent manner, whereas stachyose was most effective in vitro. In mice, different doses of stachyose significantly alleviated the symptoms of DSS‐induced ulcerative colitis and stachyose also significantly inhibited the production of inflammatory cytokines and myeloperoxidase in vivo. In addition, our findings illustrated that stachyose inhibited expression of toll‐like receptor 4 (TLR4) and suppressed the phosphorylation of nuclear factor (NF)‐κB p65 both in vitro and in vivo. Taken together, results demonstrated that stachyose exerted anti‐inflammatory effect through inhibition of the TLR4/NF‐κB signalling pathway.
Eelgrass (Zostera spp.) associated phytomyxids are host‐specific congeneric parasites and predominant eukaryotes in the eelgrass rhizosphere on a global scale
Authors: Kolátková Viktorie , Mooney Megan , Kelly Kate , Hineva Elitsa , Gawryluk Ryan M. R. , Elliott Joel
Published: March 2023

Together with increasing environmental and anthropogenic pressures, pathogenic diseases are one of the important factors contributing to the ongoing decline of seagrass meadows worldwide; yet the diversity and ecology of the microorganisms acknowledged as seagrass parasites remain critically understudied. Here, we investigate phytomyxid parasites (Rhizaria: Endomyxa: Phytomyxea) of three different eelgrass (Zostera spp.) species found in the Northern hemisphere. We present molecular evidence that Plasmodiophora bicaudata, a long‐recognized parasite of dwarf eelgrass taxa, is closely related to the novel phytomyxid recently discovered in root hairs of Zostera marina, and together they form a distinct clade within the order Phagomyxida, proposed here as Feldmanniella gen. nov. A full life cycle is systematically described in a phagomyxid representative for the first time, proving its conformity with the generalized phytomyxid life history, despite previous uncertainties. The presence of primary infection stages in nearly all collected eelgrass specimens, and subsequent analysis of amplicon sequences from a global Z. marina dataset, reveal phytomyxids to be ubiquitous and one of the predominant microeukaryotes associated with eelgrass roots on a global scale. Our discoveries challenge the current view of Phytomyxea as rare entities in seagrass meadows and suggest their generally low pathogenicity in natural ecosystems.
Saying Yes without Yes: The Positive Response System in Latin
Authors: Potočnik Tomaž
Published: March 2023

The article studies a set of three positive response strategies in Latin: the echo response and the positive response particles ita and sic. It aims to determine their functions and division of labour and to establish what kind of agreement strategy existed in Latin, based on the typology of positive response systems by Sadock and Zwicky (1985). The main data for the study are drawn from the comedies of Plautus and Terence. Based on their position in an utterance, an attempt is made to determine whether the occurrences of ita and sic can be considered positive response particles, comparable to modern positive response particles, such as yes. By comparing the antecedents which trigger the response strategies studied here, it is shown that they are not interchangeable and that the echo response is the default positive response strategy, while ita and sic have a limited use, at least in the Latin of Plautus and Terence. The dynamic‐diachronic section shows that both the echo and non‐echo responses originate in the so‐called sentence answer.
A new Coffee Brewing Control Chart relating sensory properties and consumer liking to brew strength, extraction yield, and brew ratio
Authors: Guinard Jean‐Xavier , Frost Scott , Batali Mackenzie , Cotter Andrew , Lim Lik X. , Ristenpart William D.
Published: March 2023

The classic Coffee Brewing Control Chart (BCC) was originally developed in the 1950s. It relates coffee quality to brew strength and extraction yield, and it is still widely used today by coffee industry professionals around the world to provide guidance on the brewing of coffee. Despite its popularity, recent experimental studies have revealed that sensory attributes and consumer preferences actually follow much more complicated trends than those indicated by the classic BCC. Here, we present a methodology to synthesize the results of these recent studies on drip‐brewed coffee to generate new versions of the BCC: a new Sensory BCC that displays a broad array of statistically significant sensory attributes across typical total dissolved solids and percent extraction ranges, a new Consumer BCC that highlights the existence of two preference clusters with different likes and dislikes across those ranges, a new Sensory and Consumer BCC that combines both sensory descriptive and consumer preferences on the same chart, and a more streamlined BCC that omits consumer preferences and focuses on the overarching sensory descriptive trends. The new BCCs provide more accurate insight on how best to brew coffee to achieve desired sensory profiles.

Practical Application

Through the manipulation of yield and extraction parameters, the new Sensory and Consumer Coffee Brewing Control Chart presented here can be used by brewers of drip coffee to design coffees with specific sensory profiles and match the preferences of different consumer types.
Long‐term endoscopic surveillance in HBV compensated cirrhotic patients treated with Tenofovir or Entecavir for 11 years
Authors: Farina Elisa , Loglio Alessandro , Tosetti Giulia , Degasperi Elisabetta , Viganò Mauro , Gentile Carmine , Monico Sara , Perbellini Riccardo , Borghi Marta , Facchetti Floriana , Uceda Renteria Sara Colonia , Ceriotti Ferruccio , Cerini Federica , Primignani Massimo , Lampertico Pietro
Published: March 2023

Background

Long‐term administration of TDF/ETV in patients with HBV‐related compensated cirrhosis reduces HCC and decompensation events but the effect of this regimen on development/regression of oesophageal varices (EV) is currently unknown.

Aim

To assess the risk of EV development/progression in this population.

Methods

A total of 186 Caucasian HBV‐monoinfected compensated cirrhotics were enrolled in a long‐term cohort study from TDF/ETV introduction. Upper GI endoscopies were performed according to Baveno recommendations. Primary endpoint was development/progression of oesophageal/gastric varices over time.

Results

At TDF/ETV start, median age was 61 years, 80% males, 60% HBV‐DNA undetectable, 63% NUCs previously exposed, 73% normal ALT, 40% platelets <150,000/mmc and 25 (13%) with low‐risk varices (LRV). During 11 years of antiviral therapy and 666 endoscopies performed, 9 patients either developed or had a progression of oesophageal or gastric varices with an 11‐year cumulative probability of 5.1% (95% CI 3–10%); no patient bled. Out of 161 patients without EV at baseline, the 11‐year probably was 4.5% with all varices developing within the first six years of treatment. In 25 patients with LRV at baseline, the 11‐year probability of progression or regression was 9.3% and 58%, respectively. Only baseline platelet count (HR 0.96, p = 0.028) was associated with LRV development at multivariate analysis: platelet ≤90,000/mmc (AUROC 0.70) had 98.1% specificity, 42.9% sensitivity, 50% PPV for LRV onset.

Conclusions

In compensated cirrhotic patients under long‐term effective TDF/ETV treatment, the 11‐year risk of developing/progressing EV is negligible, thus challenging the current endoscopic surveillance recommendations in patients without EV at baseline.
Estimation of Time-Specific Intervention Effects on Continuously Distributed Time-to-Event Outcomes by Targeted Maximum Likelihood Estimation
Authors: Rytgaard Helene C. W. , Eriksson Frank , van der Laan Mark J.
Published: March 2023

This work considers targeted maximum likelihood estimation (TMLE) of treatment effects on absolute risk and survival probabilities in classical time-to-event settings characterized by right-censoring and competing risks. TMLE is a general methodology combining flexible ensemble learning and semiparametric efficiency theory in a two-step procedure for substitution estimation of causal parameters. We specialize and extend the continuous-time TMLE methods for competing risks settings, proposing a targeting algorithm that iteratively updates cause-specific hazards to solve the efficient influence curve equation for the target parameter. As part of the work, we further detail and implement the recently proposed highly adaptive lasso estimator for continuous-time conditional hazards with L1-penalized Poisson regression. The resulting estimation procedure benefits from relying solely on very mild nonparametric restrictions on the statistical model, thus providing a novel tool for machine-learning-based semiparametric causal inference for continuous-time time-to-event data. We apply the methods to a publicly available dataset on follicular cell lymphoma where subjects are followed over time until disease relapse or death without relapse. The data display important time-varying effects that can be captured by the highly adaptive lasso. In our simulations that are designed to imitate the data, we compare our methods to a similar approach based on random survival forests and to the discrete-time TMLE.
Goal attainment of children with cerebral palsy participating in multi‐modal intervention
Authors: Bain Kathryn , Bombria Suzanne Davis , Chapparo Christine Janet , Donelly Michelle , Heard Robert , Treacy Sue
Published: March 2023

Aim

We aimed to determine if there was a significant difference in the functional performance of family requested daily tasks by a heterogeneous group of children with cerebral palsy following a programme of neuro‐developmental treatment and in comparison to a randomly control group.

Background

There are considerable challenges in conducting research into the functional performance of children with cerebral palsy. These include the highly heterogeneous nature of the population group, poor ecological and treatment fidelity, floor and ceiling effects in assessments, and insensitivity to the diverse functional needs and goals of children and families. Therapists and families identified functional goals and specified all aspects of performance details for each goal on five point goal attainment scales. Children with cerebral palsy were assigned randomly to treatment and alternate treatment groups. Children were video recorded attempting to perform targeted functional skills at pre‐test, post‐pest and follow‐up. Videos were recorded and rated by expert clinicians blind to experimental condition.

Results

After the first round of target intervention and alternate treatment had been completed, a significant difference in the goal attainment was noted between the control group and the treatment group at the post test, indicating that intervention was associated with a higher level of goal attainment than that attained by the control group (p = 0.0321) with a large effect size.

Conclusions

The study provided evidence of an effective way to investigate and to enhance the available motor capacity of children with moderate to severe cerebral palsy during participation in requested daily task performance, as reflected in goal attainment. Goal attainment scales were a reliable measure that was able to be used to detect changes in functional goals among a highly heterogeneous population group with individualized goals that were meaningful to each child and family.
Akebia saponin D acts via the PPAR‐gamma pathway to reprogramme a pro‐neurogenic microglia that can restore hippocampal neurogenesis in mice exposed to chronic mild stress
Authors: Zhang Jinqiang , Liu Qin , Su Dapeng , Li Liangyuan , Xiao Chenghong , He Hui , You Zili , Zhou Tao
Published: March 2023

Background

Using drugs to modulate microglial function may be an effective way to treat disorders, such as depression, that involve impaired neurogenesis. Akebia saponin D (ASD) can cross the blood–brain barrier and exert anti‐inflammatory and neuroprotective effects, so we wondered whether it might influence adult hippocampal neurogenesis to treat depression.

Methods

We exposed C57BL/6 mice to chronic mild stress (CMS) as a model of depression and then gave them ASD intraperitoneally once daily for 3 weeks. We investigated the effects of ASD on microglial phenotype, hippocampal neurogenesis, and animal behavior. The potential role of the peroxisome proliferator‐activated receptor‐gamma (PPAR‐γ) or BDNF–TrkB pathway in the pro‐neurogenesis and anti‐depressant of ASD was identified using there inhibitors GW9662 and K252a, respectively. The neurogenic effects of ASD‐treated microglia were evaluated using conditioned culture methods.

Results

We found that CMS upregulated pro‐inflammatory factors and inhibited hippocampal neurogenesis in dentate gyrus of mice, while inducing depressive‐like behaviors. Dramatically, ASD (40 mg/kg) treatment reprogrammed an arginase (Arg)‐1+ microglial phenotype in dentate gyrus, which increased brain‐derived neurotrophic factor (BDNF) expression and restored the hippocampal neurogenesis, and partially ameliorated the depressive‐like behaviors of the CMS‐exposed mice. K252a or neurogenesis inhibitor blocked the pro‐neurogenic, anti‐depressant effects of ASD. Furthermore, ASD activated PPAR‐γ in dentate gyrus of CMS mice as well as in primary microglial cultures treated with lipopolysaccharide. Blocking the PPAR‐γ using GW9962 suppressed the ASD‐reprogrammed Arg‐1+ microglia and BDNF expression in dentate gyrus of CMS mice. Such blockade abolished the promoted effects of ASD‐treated microglia on NSPC proliferation, survival, and neurogenesis. The pro‐neurogenic and anti‐depressant effects of ASD were blocked by GW9962.

Conclusion

These results suggested that ASD acts via the PPAR‐γ pathway to induce a pro‐neurogenic microglia in dentate gyrus of CMS mice that can increase BDNF expression and promote NSPC proliferation, survival, and neurogenesis.
Do Australian adolescents with permission to drink at home engage in different alcohol use behaviours and experience more harms than those without such permission?
Authors: Quinn Brendan , Evans‐Whipp Tracy , Prattley Jennifer , Rioseco Pilar , Rowland Bosco
Published: March 2023

Introduction

Around half of Australian students aged 16–17 are estimated to have drunk alcohol in the past month, with 11% drinking at ‘risky’ levels. This study investigated: (i) how many Australian adolescents aged 16–17 had parental permission to drink at home in 2016/17 and whether prevalence differed by adolescent sex; (ii) whether adolescents allowed to drink at home had drunk more recently and were drinking greater quantities; (iii) if adolescents allowed to drink at home experienced more alcohol‐related harms; and (iv) if parental drinking patterns were associated with permitting adolescents to drink at home.

Methods

Data from Wave 7 of the Longitudinal Study of Australian Children were used. Descriptive and bivariate analyses addressed Aims i–iii. Nested multivariable logistic regression models addressed aim iv.

Results

In 2016/17, 28% of Australian adolescents aged 16–17 were allowed to drink alcohol at home. More adolescents with permission had drunk alcohol in the past month (77% vs. 63% of those without permission). There was no difference in quantity of alcohol consumed in the past week between groups. More adolescents allowed to drink at home had experienced alcohol‐related harm compared to those without permission (23% vs. 17%). In multivariable analyses, alcohol consumption by primary parents was associated with an increased likelihood of allowing adolescents to drink at home.

Discussions and Conclusions

In order to reduce adolescent alcohol use and associated harms, parents should avoid permitting alcohol use among adolescents at home. Frequent (twice or more/week) primary parental alcohol consumption was especially associated with greater odds of allowing adolescents to drink at home.
Contrasting long‐term trends in juvenile abundance of a widespread cold‐water salmonid along a latitudinal gradient: effects of climate, stream size and migration strategy
Authors: Donadi Serena , Näslund Joacim , Sandin Leonard , Sers Berit , Vasemägi Anti , Degerman Erik
Published: March 2023

A changing climate reshapes the range distribution of many organisms, and species with relatively low thermal optima, like many salmonids, are increasingly expected to face local population extinctions at lower latitudes. Understanding where and how fast these changes are happening is of pivotal importance for successful mitigation and conservation efforts.

We used an extensive electrofishing database to explore temporal trends of juveniles of brown troutSalmo truttain 218 locations from 174 Swedish streams, over the last 30 years (1991–2020). We hypothesized that 1) declines in abundance have occurred predominately in the warmer, southern regions, while increases have occurred in the colder, northern regions, 2) larger stream sizes may partly offset negative effects of climate, and 3) migrating and resident populations are affected differently by a warming climate.

We found that abundance of brown trout juveniles generally declined in warmer regions especially in smaller streams (≤ 6 m wide), while the abundance increased in colder regions. In larger streams, negative effects of higher temperatures were seemingly buffered, as we found lower rates of decline or even positive trends. The rate of change (i.e. the slopes of the trends in abundance) was more pronounced towards the climate extremes, and was on average zero in regions with a normal annual air temperature (average temperature over 30 year period) around 5–6 °C. Warmer climate had stronger effects on migrating compared to resident populations, suggesting that climate‐induced loss of stream connectivity could be an additional factor that hinders recruitment in anadromous populations in a changing climate.

Considering predictions of increasing temperatures and frequency of summer droughts, management of cold‐water salmonid populations should focus on conserving and restoring riparian vegetation, wetlands, climate and thermal refugia, and habitat integrity overall. Such measures may, however, not suffice for small streams at lower latitudes, unless hydrological connectivity is maintained.
Stakeholder engagement in European brain research: Experiences of the Lifebrain consortium
Authors: Budin‐Ljøsne Isabelle , Friedman Barbara B. , Baaré William F. C. , Bartrés‐Faz David , Carver Rebecca B. , Drevon Christian A. , Ebmeier Klaus P. , Fjell Anders M. , Ghisletta Paolo , Henson Richard N. , Kievit Rogier , Madsen Kathrine S. , Nawijn Laura , Suri Sana , Solé‐Padullés Cristina , Walhovd Kristine B. , Zsoldos Enikő
Published: March 2023

Introduction

Stakeholder engagement remains scarce in basic brain research. However, it can greatly improve the relevance of investigations and accelerate the translation of study findings to policy. The Lifebrain consortium investigated risk and protective factors influencing brain health using cognition, lifestyle and imaging data from European cohorts. Stakeholder activities of Lifebrain—organized in a separate work package—included organizing stakeholder events, investigating public perceptions of brain health and dissemination. Here, we describe the experiences of researchers and stakeholders regarding stakeholder engagement in the Lifebrain project.

Methods

Stakeholder engagement in Lifebrain was evaluated through surveys among researchers and stakeholders and stakeholders' feedback at stakeholder events through evaluation forms. Survey data were analysed using a simple content analysis approach, and results from evaluation forms were summarized after reviewing the frequency of responses.

Results

Consortium researchers and stakeholders experienced the engagement activities as meaningful and relevant. Researchers highlighted that it made the research and research processes more visible and contributed to new networks, optimized data collection on brain health perceptions and the production of papers and provided insights into stakeholder views. Stakeholders found research activities conducted in the stakeholder engagement work package to be within their field of interest and research results relevant to their work. Researchers identified barriers to stakeholder engagement, including lack of time, difficulties in identifying relevant stakeholders, and challenges in communicating complex scientific issues in lay language and maintaining relationships with stakeholders over time. Stakeholders identified barriers such as lack of budget, limited resources in their organization, time constraints and insufficient communication between researchers and stakeholders.

Conclusion

Stakeholder engagement in basic brain research can greatly benefit researchers and stakeholders alike. Its success is conditional on dedicated human and financial resources, clear communication, transparent mutual expectations and clear roles and responsibilities.

Public Contribution

Patient organizations, research networks, policymakers and members of the general public were involved in engagement and research activities throughout the project duration.
Automatic identification of storytelling responses to past‐behavior interview questions via machine learning
Authors: Bangerter Adrian , Mayor Eric , Muralidhar Skanda , Kleinlogel Emmanuelle P. , Gatica‐Perez Daniel , Schmid Mast Marianne
Published: March 2023

Structured interviews often feature past‐behavior questions, where applicants are asked to tell a story about past work experience. Applicants often experience difficulties producing such stories. Automatic analyses of applicant behavior in responding to past‐behavior questions may constitute a basis for delivering feedback and thus helping them improve their performance. We used machine learning algorithms to predict storytelling in transcribed speech of participants responding to past‐behavior questions in a simulated selection interview. Responses were coded as to whether they featured a story or not. For each story, utterances were also manually coded as to whether they described the situation, the task/action performed, or results obtained. The algorithms predicted whether a response features a story or not (best accuracy: 78%), as well as the count of situation, task/action, and response utterances. These findings contribute to better automatic identification of verbal responses to past‐behavior questions and may support automatic provision of feedback to applicants about their interview performance.
IL‐1β promotes IL‐17A production of ILC3s to aggravate neutrophilic airway inflammation in mice
Authors: Yang Dan , Li Yi'na , Liu Ting , Yang Ling , He Lixiu , Huang Tingxuan , Zhang Lanlan , Luo Jian , Liu Chuntao
Published: March 2023

IL‐17A‐producing group 3 innate lymphoid cells (ILC3s) have been found to participate in the development of various phenotypes of asthma, however, little is known about how ILC3s mediate neutrophilic airway inflammation. Elevated IL‐1β has been reported in neutrophilic asthma (NA) and IL‐1β receptor is highly expressed on lung ILC3s. Therefore, we hypothesize that IL‐1β aggravates neutrophilic airway inflammation via provoking IL‐17A‐producing ILC3s. We sought to determine the pathological roles of the IL‐1β‐ILC3‐IL‐17A axis in neutrophilic airway inflammation. Lung ILC subsets were measured in eosinophilic asthma (ovalbumin [OVA]/Alum) and NA (OVA/lipopolysaccharides [LPS]) murine models. Rag2−/− (lacking adaptive immunity), RORc−/− (lacking transcription factor RORγt), Rag2−/−RORc−/− (lacking adaptive immunity and ILC3s), and ILCs depletion mice were used to verify the roles of ILC3s in neutrophilic airway inflammation by measurement of CXCL‐1, IL‐17A, IL‐22 and neutrophil counts in bronchoalveolar lavage fluid (BALF), detection of Muc5ac in lung tissues, and quantification of IL‐17A‐producing ILC3s after treatment of anti‐IL‐17A or recombinant IL‐1β (rIL‐1β) and its monoclonal antibody. NLRP3, Caspase 1 and their induction of IL‐1β were detected in lung tissues of OVA/LPS‐induced mice. The OVA/LPS model was characterized by an enrichment of airway neutrophilia, lung RORγt+ ILC3s and Th17 cytokines (IL‐17A and IL‐22) and neutrophilic chemokine C‐X‐C motif (chemokine) ligand 1 (CXCL‐1), compared to the phenotypic features of airway eosinophilia, GATA3+ ILC2s and type‐2 cytokines in OVA/Alum model. The concentration of CXCL‐1 and neutrophil counts in BALF were decreased by anti‐IL‐17A. RORγt deficiency led to a decrease in IL‐17A and CXCL‐1 levels and neutrophil counts in BALF. ILC depletion in Rag2−/− mice ameliorated OVA/LPS‐induced IL‐17A, IL‐22, CXCL‐1 and airway neutrophil counts. IL‐17A‐producing ILCs and BALF neutrophil counts were significantly lower in Rag2−/−RORc−/− mice than those in Rag2−/− mice. IL‐1β was highly expressed in BALF and bronchial epithelial cells (BECs) in OVA/LPS model, and administration of rIL‐1β substantially aggravated airway inflammation and promoted upregulation of RORγt+ and IL‐17A‐producing lung ILC3s, which were reversed by anti‐IL‐1β. NLRP3 and Caspase 1 expressions were enhanced by OVA/LPS, and their inhibitors abolished the OVA/LPS‐induced IL‐1β in BECs. ILC3s play a pathogenic role in the pathogenesis of NA, which is triggered by IL‐1β via promoting IL‐17A production of lung ILC3s.
On subsistence‐type rural independent retailers and crowdfunded microfinance—Prosocial lending, nudges, and unintended consequences
Authors: Yamalakonda Siddhartha , Nilakantan Rahul , Iyengar Deepak , Rao Shashank
Published: March 2023

Much of the extant scholarship in supply chain management (SCM) has had a developed world focus, although most of the global population resides outside this area. SCM scholars are now recognizing this limitation in the coverage of our communities' research. They have recognized that the logistical challenges of getting products to these underserved markets at the bottom of the economic pyramid (BOP) may be fundamentally different from the “big box” mindset that prevails in the west. There is growing recognition that supply chain entrepreneurship is critical to the logistics and physical distribution systems that can get products to such markets in a cost‐effective manner. Yet, such entrepreneurs, who are often small, and weakly integrated into the global economy, face several challenges in their daily business. Many of them rely on microfinance to fund their business. Yet, the microfinance model itself is changing into a web‐supported crowdfunded model. The current study investigates how an entrepreneur's circumstances with regard to their borrowing status as a first‐time borrower, and their intent with regard to business expansion influence their success in fundraising on a crowdfunding platform. Results reveal that BOP entrepreneurs who are “repeat borrowers” have difficulty in obtaining funding for their business plans.
Trajectories of cortical structures associated with stress across adolescence: a bivariate latent change score approach
Authors: Nweze Tochukwu , Banaschewski Tobias , Ajaelu Cyracius , Okoye Chukwuemeka , Ezenwa Michael , Whelan Robert , Papadopoulos Orfanos Dimitri , Bokde Arun L.W. , Desrivières Sylvane , Grigis Antoine , Garavan Hugh , Gowland Penny , Heinz Andreas , Brühl Rüdiger , Martinot Jean‐Luc , Martinot Marie‐Laure Paillère , Artiges Eric , Nees Frauke , Paus Tomáš , Poustka Luise , Hohmann Sarah , Millenet Sabina , Fröhner Juliane H. , Smolka Michael N. , Walter Henrik , Schumann Gunter , Hanson Jamie L. ,   IMAGEN Consortium
Published: March 2023

Background

Stress exposure in childhood and adolescence has been linked to reductions in cortical structures and cognitive functioning. However, to date, most of these studies have been cross‐sectional, limiting the ability to make long‐term inferences, given that most cortical structures continue to develop through adolescence.

Methods

Here, we used a subset of the IMAGEN population cohort sample (N = 502; assessment ages: 14, 19, and 22 years; mean age: 21.945 years; SD = 0.610) to understand longitudinally the long‐term interrelations between stress, cortical development, and cognitive functioning. To these ends, we first used a latent change score model to examine four bivariate relations – assessing individual differences in change in the relations between adolescent stress exposure and volume, surface area, and cortical thickness of cortical structures, as well as cognitive outcomes. Second, we probed for indirect neurocognitive effects linking stress to cortical brain structures and cognitive functions using rich longitudinal mediation modeling.

Results

Latent change score modeling showed that greater baseline adolescence stress at age 14 predicted a small reduction in the right anterior cingulate volume (Std. β = −.327, p = .042, 95% CI [−0.643, −0.012]) and right anterior cingulate surface area (Std. β = −.274, p = .038, 95% CI [−0.533, −0.015]) across ages 14–22. These effects were very modest in nature and became nonsignificant after correcting for multiple comparisons. Our longitudinal analyses found no evidence of indirect effects in the two neurocognitive pathways linking adolescent stress to brain and cognitive outcomes.

Conclusion

Findings shed light on the impact of stress on brain reductions, particularly in the prefrontal cortex that have consistently been implicated in the previous cross‐sectional studies. However, the magnitude of effects observed in our study is smaller than that has been reported in past cross‐sectional work. This suggests that the potential impact of stress during adolescence on brain structures may likely be more modest than previously noted.