bluuebunny/crossref_metadata_2025 huggingface dataset:
Orthogonal neural representations support perceptual judgements of natural stimuli
Authors: Srinath Ramanujan , Ni Amy M. , Marucci Claire , Cohen Marlene R. , Brainard David H.
Published: February 2024

In natural behavior, observers must separate relevant information from a barrage of irrelevant information. Many studies have investigated the neural underpinnings of this ability using artificial stimuli presented on simple backgrounds. Natural viewing, however, carries a set of challenges that are inaccessible using artificial stimuli, including neural responses to background objects that are task-irrelevant. An emerging body of evidence suggests that the visual abilities of humans and animals can be modeled through the linear decoding of task-relevant information from visual cortex. This idea suggests the hypothesis that irrelevant features of a natural scene should impair performance on a visual task only if their neural representations intrude on the linear readout of the task relevant feature, as would occur if the representations of task-relevant and irrelevant features are not orthogonal in the underlying neural population. We tested this hypothesis using human psychophysics and monkey neurophysiology, in response to parametrically variable naturalistic stimuli. We demonstrate that 1) the neural representation of one feature (the position of a central object) in visual area V4 is orthogonal to those of several background features, 2) the ability of human observers to precisely judge object position was largely unaffected by task-irrelevant variation in those background features, and 3) many features of the object and the background are orthogonally represented by V4 neural responses. Our observations are consistent with the hypothesis that orthogonal neural representations can support stable perception of objects and features despite the tremendous richness of natural visual scenes.

Significance Statement

We studied how the structure of the mid-level neural representation of multiple visual features supports robust perceptual decisions. We combined array recording with parametrically controlled naturalistic images to demonstrate that the representation of a central object’s position in monkey visual area V4 is orthogonal to that of several background features. In addition, we used human psychophysics with the same stimulus set to show that observers’ ability to judge a central object’s position is largely unaffected by variation in the same background features. This result supports the hypothesis that orthogonal neural representations can enable stable and robust perception in naturalistic visual environments and advances our understanding of how visual processing operates in the real world.
Fluorescence Shadow Imaging of Hypsibius exemplaris Reveals Morphological Differences Between Sucrose- and CaCl2-Induced Osmobiotes
Authors: Flinn Brendin B , O'Dell Hayden M , Joseph Kara M , Smythers Amanda L , Neff David P , Hicks Leslie M , Norton Michael L , Kolling Derrick RJ
Published: February 2024

Tardigrades are renowned for their ability to survive a wide array of environmental stressors. In particular, tardigrades can curl in on themselves while losing a significant proportion of their internal water content to form a structure referred to as a tun. In surviving varying conditions, tardigrades undergo distinct morphological transformations that could indicate different underlying mechanisms of stress sensing and tolerance specific to the stress condition. Presently, methods to effectively distinguish between morphological transformations, including between tuns induced by different stress conditions, are lacking. Herein, a new approach for discriminating between tardigrade morphological states is developed and utilized to compare sucrose- and CaCl2-induced tuns. A novel method of shadow imaging with confocal laser scanning microscopy enabled production of three-dimensional renderings of tardigrades in various physiological states resulting in tardigrade volume measurements. Combining these measurements with qualitative morphological analysis using scanning electron microscopy revealed that sucrose- and CaCl2-induced tuns have distinct morphologies, including differences in the amount of water expelled during tun formation. Further, varying the concentration of the applied stressor did not affect the amount of water lost, pointing towards water expulsion being a controlled process that is adapted to the specific stressors.
Next‐generation phenotyping in Nigerian children with Cornelia de Lange Syndrome
Authors: Arlt Annabelle , Knaus Alexej , Hsieh Tzung-Chien , Klinkhammer Hannah , Bhasin Meghna , Alexander Hustinx , Shahida Moosa , Krawitz Peter , Ekure Ekanem
Published: February 2024

Next-generation phenotyping (NGP) can be used to compute the similarity of dysmorphic patients to known syndromic diseases. So far, the technology has been evaluated in variant prioritization and classification, providing evidence for pathogenicity if the phenotype matched with other patients with a confirmed molecular diagnosis. In a Nigerian cohort of individuals with facial dysmorphism, we used the NGP tool GestaltMatcher to screen portraits prior to genetic testing and subjected individuals with high similarity scores to exome sequencing (ES). Here, we report on two individuals with global developmental delay, pulmonary artery stenosis, and genital and limb malformations for whom GestaltMatcher yielded Cornelia de Lange syndrome as the top hit. ES revealed a known pathogenic nonsense variant, NM_133433.4: c.598C>T; p.(Gln200*), as well as a novel frameshift variant c.7948dup; p.(Ile2650Asnfs*11) in NIPBL. Our results suggest that NGP can be used as a screening tool and thresholds could be defined for achieving high diagnostic yields in ES. Training the AI with additional cases of the same ethnicity might further increase the positive predictive value of GestaltMatcher.
Patient-derived functional immuno-oncology platform identifies responders to ATR inhibitor and immunotherapy combinations in ovarian cancer
Authors: Nagaraj Ashwini S , Salko Matilda , Sirsikar Aditi , Erkan Erdogan Pekcan , Pietilä Elina A , Niemiec Iga , Bao Jie , Marchi Giovanni , Szabó Angéla , Nowlan Kirsten , Pikkusaari Sanna , Kanerva Anna , Tapper Johanna , Koivisto-Korander Riitta , Kauppi Liisa , Hautaniemi Sampsa , Vähärautio Anna , Tang Jing , Haltia Ulla-Maija , Kekäläinen Eliisa , Virtanen Anni , Salo Tuula , Färkkilä Anniina
Published: February 2024

Responses to single agent immunotherapies have remained modest in high-grade serous ovarian cancer (HGSC), suggesting the need for combination treatments. Identifying clinically effective immunotherapy combinations (IC) requires pre-clinical testing using models representing the patient-specific immune microenvironment. Here, we established a functional immuno-oncology platform for high-throughput and functional testing of IC using HGSC patient-derived immunocompetent cultures (iPDCs) established on patient-derived omentum gel matrix. We employed genomic and single-cell analysis to assess the intricate and functional characteristics of the iPDCs combined with tumor and immune cell-specific cytotoxic responses. Corroborating the clinical response to Poly (ADP-ribose) polymerase inhibitors (PARPi), iPDCs showed homologous recombination deficiency (HRD) - specific response to PARPi. Importantly, drug responses from iPDCs of chemotherapy and PARPi refractory patients corresponded with patient outcomes and aligned with distinct pathway activities from single-cell RNA sequencing analysis. Furthermore, iPDCs from HRD tumors showed response to anti-PD1 antibody as measured by decrease in tumor cells combined with augmented T cell activation. High-throughput drug testing followed by single cell-imaging from iPDCs revealed patient-specific responses to combination of ataxia telangiectasia and Rad3-related inhibitor (ATRi) with DNA damaging agents or immunotherapies. Integration of cytotoxic responses with immune cell states uncovered patient-specific immune activation with the combination of ATRi and a novel immunotherapy targeting Autotaxin (ATX), and this response was significantly associated with a tumor-cell replication stress biomarker in single-cell analysis of tCycIF highly multiplexed imaging. In conclusion, iPDCs provide a platform for high-throughput screening and functional testing of immuno-oncology agents for precision oncology in HGSC.
Infusing structural assumptions into dimensionality reduction for single-cell RNA sequencing data to identify small gene sets
Authors: Hackenberg Maren , Brunn Niklas , Vogel Tanja , Binder Harald
Published: February 2024

Dimensionality reduction greatly facilitates the exploration of cellular heterogeneity in single-cell RNA sequencing data. While most of such approaches are data-driven, it can be useful to incorporate biologically plausible assumptions about the underlying structure or the experimental design. We propose the boosting autoencoder (BAE) approach, which combines the advantages of unsupervised deep learning for dimensionality reduction and boosting for formalizing assumptions. Specifically, our approach selects small sets of genes that explain latent dimensions. As illustrative applications, we explore the diversity of neural cell identities and temporal patterns of embryonic development.
Sympathetic Signals Promote Immunosuppressive Neutrophils in Lung Tumors
Authors: Liu Jiaqi , Qiu Mantang , Wang Wenxiang , Cao Ying , Yang Fan , Chen Kezhong , Chen Jian , Yang Jing
Published: February 2024

It has become recognized that the nervous system can significantly influence cancer prognosis. However, the pathophysiological mechanism underlying neural modulation of the tumor immune microenvironment remains incompletely understood. Here, we exploit the advanced 3D imaging technique to reveal the frequent presence of sympathetic inputs in human non-small-cell lung cancer. Also, this spatial engagement of sympathetic innervations similarly occurs in the mouse models of lung tumors. Of importance, the local ablation of sympathetic signals strongly suppresses cancer progression. We then identify a neutrophil subtype uniquely present within lung tumors, whose immunosuppressive features are directly promoted by the sympathetic neurotransmitter norepinephrine via the b2-adrenergic receptor (Adrb2). In addition, norepinephrine stimulates the specific type of tumor cells to recruit such immunosuppressive neutrophils. Accordingly, we show that the Adrb2 antagonist effectively potentiates the anti-PD-L1 immunotherapy. Together, these results have elucidated a critical aspect of sympathetic signals in designating the immune microenvironment of lung tumors.
Single nuclei and spatial transcriptomes suggest a stratification of papillary and anaplastic thyroid cancer cells
Authors: Tourneur Adrien , Rodrigues Vitória Joel , Saiselet Manuel , Craciun Ligia , Larsimont Denis , Lefort Anne , Libert Frederick , Maenhaut Carine , Costagliola Sabine , Tarabichi Maxime , Romitti Mirian , Detours Vincent
Published: February 2024

Sixty percent of papillary thyroid cancers (PTCs) are driven byBRAFV600E,a mutation associated with high inter- and intra-tumoral heterogeneity. PTCs may become highly aggressive anaplastic thyroid cancers (ATC). While single cell transcriptomics may resolve this heterogeneity, it is potentially confounded by batch effects whose correction may dampen inter-tumor variations. We profiled ATCs andBRAFV600EPTCs with single nuclei RNA-seq and spatial transcriptomics, and an experimental design disentangling biological and technical variations. It reveals that much transcriptional variation in cancer cells and several immune cell types is idiosyncratic, i.e. tumor-specific. It is associated in some cases with genomic aberrations and global tissue states like hypoxia. Beyond idiosyncrasies, differentiation markersSLC5A5 (N/S), TPO, TGandTSHRare lost in a sequence mirrored by their gain during human thyroid organoids maturation, suggesting a new classification of cancer cell states. PTC cells retainTSHRexpression and show features of partial EMT with a massive expression ofFN1,which promotes proliferation via an autocrine loop. In contrast, ATCs undergo full blown EMT, with expression of mesenchymal extracellular components and loss ofTSHR.Finally, we show that the microenvironment of cancer cells is driven by inflammation. These findings may help future stratifications ofBRAFV600EPTCs.
FLOWERING LOCUS C integrates carbon and nitrogen signaling for the proper timing of flowering in Arabidopsis
Authors: Gramma Vladislav , Olas Justyna Jadwiga , Zacharaki Vasiliki , Ponnu Jathish , Luzarowska Urszula , Musialak-Lange Magdalena , Wahl Vanessa
Published: February 2024

The timing of flowering in plants is modulated by both carbon (C) and nitrogen (N) signaling pathways. In a previous study, we established a pivotal role of the sucrose-signaling trehalose 6-phosphate pathway in regulating flowering under N-limited short-day conditions. In this work, we expand on our finding that wild-type plants grown under N-limited short days require an active trehalose 6-phosphate pathway to be able to flower. Both wild-type plants grown under N-limited conditions and knock-down plants of TREHALOSE PHOSPHATE SYNTHASE1 induce FLOWERING LOCUS C expression, a well-known floral repressor associated with the vernalization response. When exposed to an extended period of cold, a mutant of FLOWERING LOCUS C fails to respond to N availability, and flowers at the same time under N-limited and full-nutrition conditions. Our data suggest that SUCROSE NON-FERMENTING 1 RELATED KINASE 1-dependent trehalose 6-phosphate-mediated C signaling and a novel mechanism downstream of N signaling likely involving NIN-LIKE PROTEIN 7 impact the expression of FLOWERING LOCUS C. Collectively, our data underscore the existence of a multi-factor regulatory system in which both C and N signaling pathways jointly govern the regulation of flowering in plants.
Mapping Spatial Patterns to Energetic Benefits in Groups of Flow-coupled Swimmers
Authors: Heydari Sina , Hang Haotian , Kanso Eva
Published: February 2024

The coordinated motion of animal groups through fluids is thought to reduce the cost of locomotion to individuals in the group. However, the connection between the spatial patterns observed in collectively moving animals and the energetic benefits at each position within the group remains unclear. To address this knowledge gap, we study the spontaneous emergence of cohesive formations in groups of fish, modeled as flapping foils, all heading in the same direction. We show in pairwise formations and with increasing group size that (1) in side-by-side arrangements, the reciprocal nature of flow coupling results in an equal distribution of energy re-quirements among all members, with reduction in cost of locomotion for swimmers flapping inphase but an increase in cost for swimmers flapping antiphase, and (2) in inline arrangements, flow coupling is non-reciprocal for all flapping phase, with energetic savings in favor of trailing swimmers, but only up to a finite number of swimmers, beyond which school cohesion and energetic benefits are lost at once. We explain these findings mechanistically and we provide efficient diagnostic tools for identifying locations in the wake of single and multiple swimmers that offer op-portunities for hydrodynamic benefits to aspiring followers. Our results imply a connection between the resources generated by flow physics and social traits that influence greedy and cooperative group behavior.
Long-term evolution experiments fully reveal the potential for thermal adaptation
Authors: Antunes Marta A. , Grandela Afonso , Matos Margarida , Simões Pedro
Published: February 2024

Global warming is leading to worldwide biodiversity decline at a fast pace. Evolutionary responses may be crucial in allowing organisms to cope with prolonged effects of climate change. This urges the need for a better understanding of the dynamics of adaptation to warming environments. In particular, addressing how reproductive success evolves in deteriorating environments is extremely relevant, as this trait is more likely constrained at lower temperatures than upper physiological thermal limits. Experimental evolution under a warming environment can elucidate the potential of populations to respond to rapid environmental changes. The few studies following such framework lack analysis of long-term response. We here focus on the long-term thermal evolution of twoDrosophila subobscurapopulations, from different European latitudes, under warming temperatures. We estimated the reproductive success of these populations in two test environments: the ancestral (control) and the warming environment after 39 and 52 generations of thermal evolution. We found that a relevant long-term adaptive response to warming temperatures can occur, but the pace of such response is slow. In addition, we observed contrasting responses in the ancestral environmental and differences in the evolutionary dynamics between populations of distinct histories, with those originally from higher latitude only showing an adaptive response under the to the warming environment regime in at a later generation. This study reinforces the need for long-term evolution experiments to fully reveal the potential for thermal response. It also highlights that the scrutiny of several populations in this context is needed for a measure of variation within a species. Accounting for these sources of variation - both temporal and spatial - will allow for more robust assessments of climate change responses.
Integrating single-cell multimodal epigenomic data using 1D-convolutional neural networks
Authors: Gao Chao , Welch Joshua D
Published: February 2024

Recent experimental developments enable single-cell multimodal epigenomic profiling, which measures multiple histone modifications and chromatin accessibility within the same cell. Such parallel measurements provide exciting new opportunities to investigate how epigenomic modalities vary together across cell types and states. A pivotal step in using this type of data is integrating the epigenomic modalities to learn a unified representation of each cell, but existing approaches are not designed to model the unique nature of this data type. Our key insight is to model single-cell multimodal epigenome data as a multi-channel sequential signal. Based on this insight, we developed ConvNet-VAEs, a novel framework that uses 1D-convolutional variational autoencoders (VAEs) for single-cell multimodal epigenomic data integration. We evaluated ConvNet-VAEs on nano-CT and scNTT-seq data generated from juvenile mouse brain and human bone marrow. We found that ConvNet-VAEs can perform dimension reduction and batch correction better than previous architectures while using significantly fewer parameters. Furthermore, the performance gap between convolutional and fully-connected architectures increases with the number of modalities, and deeper convolutional architectures can increase performance while performance degrades for deeper fully-connected architectures. Our results indicate that convolutional autoencoders are a promising method for integrating current and future single-cell multimodal epigenomic datasets.
Molecular response to multiple trace element contamination of the European sardine
Authors: Beauvieux Anaïs , Fromentin Jean-Marc , Saraux Claire , Romero Diego , Couffin Nathan , Brown Adrien , Metral Luisa , Bertile Fabrice , Schull Quentin
Published: February 2024

In marine ecosystems, the presence of trace elements resulting from anthropogenic activities has raised concerns regarding their potential effects on marine organisms. This study delves into the intricate relationship between trace element contamination and the physiological responses of a key marine species in the Mediterranean Sea: the European sardine. Since 2008, this species has been experiencing a significant crisis in the region, prompting numerous studies to investigate the potential factors behind the dramatic decline in sardines’ size, age, and body condition. However, thorough information on chemical contamination by trace elements and its physiological impact on this species was lacking. We found evidence for the accumulation of multiple elements in sardines, with a light East-West contamination gradient within the Gulf of Lions. While macro-physiological parameters (i.e. body condition) were not affected by contamination, pathways involved in cellular organization and response to stress were clearly upregulated, particularly in the liver, but also in muscle. In addition, a global upregulation in processes linked to the immune system, lipid homeostasis and oxidative stress was recorded in the liver. The associated energetic cost may add a substantial burden to sardines that already face multi-factorial constraints. This study also allows to pinpoint biomarkers of exposure and effects that may be important for monitoring Mediterranean sardine’s health. The results of this study and particularly the complex changes in protein expression demonstrate the need for future studies to test the concomitant effects of multiple stressors acting simultaneously, including large scale contamination.
Balance Between EGF/STAT1 and IFNγ/NRF2 Signaling Controls ECM1 Expression and Determines Hepatic Homeostasis versus Chronic Liver Disease
Authors: Li Yujia , Huang Chenjun , Fan Weiguo , Hammad Seddik , Berger Lea , Géraud Cyrill , Yao Ye , Link Frederik , Tong Chenhao , Nwosu Zeribe C. , Erdösi Pia , Piorońska Weronika , Gould Kerry , Meyer Christoph , Feng Rilu , Liu Hui , Shao Chen , Sun Bing , Ding Huiguo , Liebe Roman , Ebert Matthias P. A. , Weng Honglei , Gao Chunfang , ten Dijke Peter , Dooley Steven , Wang Sai
Published: February 2024

In healthy livers, extracellular matrix protein 1 (ECM1) is essential for liver homeostasis by keeping latent transforming growth factor-β (LTGF-β) quiescent. Upon hepatocyte damage, ECM1 is downregulated, facilitating LTGF-β activation and fibrogenesis. However, little is known about how hepatic ECM1 is regulated. Here we found in healthy hepatocytes, EGF/EGFR signaling sustains ECM1 expression through phosphorylating STAT1 at S727, enhancing its binding to theECM1promoter and boosting gene transcription. During liver inflammation, accumulating IFNγ disrupts this process by downregulating EGFR and inhibiting EGF/EGFR/STAT1-mediatedECM1promoter binding. Mechanistically, IFNγ-induced STAT1 phosphorylation at Y701 impairs the binding of p-STAT1 S727 to the ECM1 promoter. Additionally, IFNγ induces NRF2 nuclear translocation, which repressively binds to theECM1promoter, further reducing its expression. These findings were confirmed in several chronic liver disease (CLD) mouse models. Moreover, AAV8-ECM1 significantly attenuates liver fibrosis and injuries in Western diet (WD)-fed mice. Notably, in patients with CLD, ECM1 levels align with EGFR expression, while NRF2 and LTGF-β activation show a negative correlation with both.
Inhibition of Soluble Epoxide Hydrolase Reduces Inflammation and Myocardial Injury in Arrhythmogenic Cardiomyopathy
Authors: Panigrahy Dipak , Kelly Abigail , Wang Weicang , Yang Jun , Hwang Sung Hee , Gillespie Michael , Howard Isabella , Bueno-Beti Carlos , Asimaki Angeliki , Penna Vinay , Lavine Kory , Edin Matthew , Zeldin Darryl , Hammock Bruce , Saffitz Jeffrey
Published: February 2024

Previous studies have implicated persistent innate immune signaling in the pathogenesis of arrhythmogenic cardiomyopathy (ACM), a familial non-ischemic heart muscle disease characterized by life-threatening arrhythmias and progressive myocardial injury. Here, we provide new evidence implicating inflammatory lipid autocoids in ACM. We show that specialized pro-resolving lipid mediators are reduced in hearts of Dsg2mut/mut mice, a well characterized mouse model of ACM. We also found that ACM disease features can be reversed in rat ventricular myocytes expressing mutant JUP by the pro-resolving epoxy fatty acid (EpFA) 14,15-eicosatrienoic acid (14-15-EET), whereas 14,15-EE-5(Z)E which antagonizes actions of the putative 14,15-EET receptor, intensified nuclear accumulation of the desmosomal protein plakoglobin. Soluble epoxide hydrolase (sEH), an enzyme that rapidly converts pro-resolving EpFAs into polar, far less active or even pro-inflammatory diols, is highly expressed in cardiac myocytes in Dsg2mut/mut mice. Inhibition of sEH prevented progression of myocardial injury in Dsg2mut/mut mice and led to recovery of contractile function. This was associated with reduced myocardial expression of genes involved in the innate immune response and fewer pro-inflammatory macrophages expressing CCR2, which mediate myocardial injury in Dsg2mut/mut mice. These results suggest that pro-inflammatory eicosanoids contribute to the pathogenesis of ACM and, further, that inhibition of sEH may be an effective, mechanism-based therapy for ACM patients.
Workflow enhancement of TurboID-mediated proximity labeling for SPY signaling network mapping
Authors: Grismer Tarabryn S , Karundasa Sumudu S , Shrestha Ruben , Byun Danbi , Ni Weimin , Reyes Andres V , xu shouling
Published: February 2024

TurboID-based proximity labeling coupled to mass spectrometry (PL-MS) has emerged as a powerful tool for mapping protein-protein interactions in both plant and animal systems. Despite advances in sensitivity, PL-MS studies can still suffer from false negatives, especially when dealing with low abundance bait proteins and their transient interactors. Protein-level enrichment for biotinylated proteins is well developed and popular, but direct detection of biotinylated proteins by peptide-level enrichment and the difference in results between direct and indirect detection remain underexplored. To address this gap, we compared and improved enrichment and data analysis methods using TurboID fused to SPY, a low-abundance O-fucose transferase, using an AAL-enriched SPY target library for cross-referencing. Our results showed that MyOne and M280 streptavidin beads significantly outperformed antibody beads for peptide-level enrichment, with M280 performing best. In addition, while a biotin concentration less than 50 uM is recommended for protein-level enrichment in plants, higher biotin concentrations can be used for peptide-level enrichment, allowing us to improve detection and data quality. MSFragger protein identification and quantification software outperformed Maxquant and Protein Prospector for SPY interactome enrichment due to its superior detection of biotinylated peptides. Our improved washing protocols for protein-level enrichment mitigated bead collapse issues, improving data quality, and reducing experimental time. We found that the two enrichment methods provided complementary results and identified a total of 160 SPY-TurboID-enriched interactors, including 60 previously identified in the AAL-enriched SPY target list and 100 additional novel interactors. SILIA quantitative proteomics comparing WT and spy-4 mutants showed that SPY affects the protein levels of some of the identified interactors, such as nucleoporin proteins. We expect that our improvement will extend beyond TurboID to benefit other PL systems and hold promise for broader applications in biological research.
Mice lackingAstn2have ASD-like behaviors and altered cerebellar circuit properties
Authors: Hanzel Michalina , Fernando Kayla , Maloney Susan E , Gong Shioaching , Mätlik Kärt , Zhao Jiajia , Pasolli H Amalia , Heissel Søren , Dougherty Joseph D , Hull Court , Hatten Mary E
Published: February 2024

Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. We recently reported a family with a paternally inherited intragenicASTN2duplication with a range of neurodevelopmental disorders, including autism spectrum disorder (ASD), learning difficulties, and speech and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study the role of ASTN2 in cerebellar circuit function, we generated global and PC-specific conditionalAstn2knockout (KO and cKO, respectively) mouse lines.Astn2KO mice exhibit strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization calls, hyperactivity and repetitive behaviors, altered social behaviors, and impaired cerebellar-dependent eyeblink conditioning. Hyperactivity and repetitive behaviors were also prominent inAstn2cKO animals. By Golgi staining,Astn2KO PCs have region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis ofAstn2KO cerebellum reveals a marked upregulation of ASTN2 family member, ASTN1, a neuron-glial adhesion protein. Immunohistochemistry and electron microscopy demonstrate a large increase in Bergmann glia volume in the molecular layer ofAstn2KO animals. Electrophysiological experiments indicate a reduced frequency of spontaneous excitatory postsynaptic currents (EPSCs), as well as increased amplitudes of both spontaneous EPSCs and inhibitory postsynaptic currents (IPSCs) in theAstn2KO animals, suggesting that pre- and postsynaptic components of synaptic transmission are altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties.
Molecular basis of inhibition of the amino acid transporter B0AT1 (SLC6A19)
Authors: Xu Junyang , Hu Ziwei , Dai Lu , Yadav Aditya , Jiang Yashan , Broer Angelika , Gardiner Michael , McLeod Malcolm , Yan Renhong , Broer Stefan
Published: February 2024

The epithelial neutral amino acid transporter B0AT1 (SLC6A19) is the major transporter for the absorption of neutral amino acids in the intestine and their reabsorption in the kidney. Mouse models have demonstrated that lack of B0AT1 can normalize elevated plasma amino acids in rare disorders of amino acid metabolism such as phenylketonuria and urea-cycle disorders. This discovery has resulted in a quest to identify high-affinity selective inhibitors of B0AT1 for the treatment of disorders of amino acid metabolism. Here we employed a medicinal chemistry approach to improve lead compounds that were identified in a previous high-throughput screen. This effort yielded a group of compounds that inhibited B0AT1 with IC50-values of 31-90 nM. High-resolution cryo-EM structures of B0AT1 in the presence of two compounds from this series identified an allosteric binding site in the vestibule of the transporter. Mechanistically, binding of these inhibitors prevents a substantial movement of TM1 and TM6 that is required for the transporter to make a conformational change from an outward open state to the occluded state.
When the goose stops laying golden eggs: supervening loss of trust in long-term contracts under the PICC
Authors: Mohamed Hassan
Published: February 2024

Purpose

The purpose of this paper is to examine the supervening loss of inter-organisational trust in long-term commercial contracts. The underlying research question is whether contract law – the legal institution regulating economic exchanges – should intervene and enable a party to a long-term commercial contract to extricate itself from a situation where a relationship of trust has broken down irretrievably.

Design/methodology/approach

This paper uses doctrinal methodology and theoretical conceptualisation to answer the underlying research question. The legal instrument chosen for analysis purposes is the UNIDROIT Principles of International Commercial Contracts. This paper also draws on extant literature on inter-organisational trust (including conceptual and empirical studies) to support the arguments and propositions. Furthermore, this study proceeds to assess the substantive justifiability of the proposed remedial measure using four normative values: legal certainty and predictability, protection of the performance interest, economic efficiency and the preservation of the relation.

Findings

The central argument put forward in this paper is the reformulation of draft Article 6.3.1 proposed by the UNIDROIT Working Group on Long-Term Contracts, which confers a novel right to terminate for a compelling reason. This paper presents a multidimensional model of inter-organisational trust that would serve as the conceptual framework for the proposed reformulation of the provision and establishes a coherent juridical basis for the legal solution that would accord with the Principles of International Commercial Contracts’ general remedial scheme. As for the normative assessment, this paper demonstrates that the proposed remedial measure would significantly promote efficient outcomes and positively serve the norms of legal certainty, protection of the performance interest and the preservation of the relation.

Originality/value

This paper addresses the lacuna in current legal scholarship in relation to the adverse socio-economic effects following trust violation and deterioration in inter-organisational relationships. Additionally, the propositions and findings should contribute to the workings of the UNIDROIT in adopting new rules and principles that would serve the special requirements of cross-border trade.
Leader’s paradox mindset, organisational change capability, and performance: a multi-level analysis
Authors: Supriharyanti Elisabeth , Sukoco Badri Munir , Widianto Sunu , Soparnot Richard
Published: February 2024

Purpose

This study aims to propose a multi-level (bottom-up) analysis to build an organizational change capability (OCC) development model by integrating paradox and social cognitive theories. Using these theories, OCC (Level 2) is influenced by the leader’s paradox mindset (Level 1) and collective PsyCap (Level 2). The study also examined the moderating effect of magnitude to change on the effect of leader’s paradox mindset on OCC.

Design/methodology/approach

The proposed hypotheses were tested empirically using data from 327 respondents and 48 work teams from 21 leading private higher education institutions in Indonesia. To analyze the data, a multi-level analysis was conducted with Mplus software.

Findings

The results showed that, in a cross-level relationship, leader’s paradox mindset had a positive effect on OCC, whereas OCC mediated the effect of leader’s paradox mindset on organizational change performance. On an organizational level, collective PsyCap affected OCC, and OCC significantly mediated the relationship between collective PsyCap and organizational change performance. Moreover, the authors found a moderating effect of magnitude on change of leader’s paradox mindset to OCC.

Originality/value

This study used a multi-level analysis to evaluate the mechanisms of influence of leader’s paradox mindset (bottom-up) on OCC and the moderation effect of magnitude to change in an Indonesian context.
Looking at the relationship between growth and profitability: the role of cost stickiness as a strategic liability
Authors: Lefebvre Vivien
Published: February 2024

Purpose

This paper aims to revisit the relationship between sales growth and profitability by exploring the direct and indirect effects of cost stickiness in the growth process. Cost stickiness refers to asymmetric variations of costs associated with increases and decreases in sales. Cost stickiness is analyzed as a strategic liability that negatively affects profitability because it contributes to organizational rigidity that causes opportunity costs.

Design/methodology/approach

The empirical design is based on a large sample of 65,599 French firms drawn from the Amadeus database and it covers the period 2010 to 2019. The authors take advantage of the presentation of expenses made by nature in Amadeus to calculate cost stickiness in a more direct way than what is commonly done in the literature. The authors use various regression models to test the hypotheses.

Findings

For firms that experience rapid growth in sales, cost stickiness has a positive moderating effect on the relation between sales growth and profitability because of a higher asset turnover efficiency. However, for firms that experience slow growth, no growth or a decrease in sales, cost stickiness plays a negative moderating effect on the relation between sales and profitability.

Originality/value

This work contributes to the discussion about the conditions under which high growth is associated with greater profitability and conceptualizes cost stickiness as a strategic liability. The empirical context, privately held firms, has been overlooked by previous research.
A bibliometric and scientometric analysis-based review of environmental health and safety research in the construction industry
Authors: Owusu-Boadi Juliet , Kissi Ernest , Abu Ivy Maame , Owusu Cecilia Dapaah , Baiden Bernard , Debrah Caleb
Published: February 2024

Purpose

The construction business is widely recognised for its inherent complexity and dynamic nature, which stems from the nature of the job involved. The industry is often regarded as one of the most challenging industries globally in terms of implementing environmental, health and safety (EHS) practices. However, in the absence of EHS, the construction industry cannot be considered sustainable. Therefore, this study aims to identify the trends, knowledge gaps and implications of EHS research to enhance construction activities and knowledge.

Design/methodology/approach

The study adopted a science mapping approach involving bibliometric and scientometric analysis of 407 construction EHS publications from the Scopus database with the VOSviewer software. The study is based on journal articles from the Scopus database without restriction to any time range.

Findings

The main focus of construction EHS research identified in the study includes sustainability-related studies, risk-related, environmental issues, EHS management, integrated management systems studies, health and safety related and EHS in the construction process. Some emerging areas also identified include productivity, design, culture, social sustainability and machine learning. The most influential and productive publication sources, countries/regions and EHS publications with the highest impact were also determined.

Research limitations/implications

Documents published in the Scopus database were considered for analysis because of the wider coverage of the database. Journal articles written in English language represent the inclusion criteria, whereas other documents were excluded from the analysis. The study also limited the search to articles with the engineering subject area.

Practical implications

The research findings will enlighten stakeholders and practitioners on the focal knowledge areas in the EHS research domain, which are vital for enhancing EHS in the industry.

Originality/value

To the best of the authors’ knowledge, this review-based study is the first attempt to internationally conduct a science mapping on extant literature in the EHS research domain through bibliometric and scientometric assessments.
Time–frequency correlation and risk spillovers between Euramerican mature and Asian emerging crude oil futures markets
Authors: Hong Shuifeng , Luo Yimin , Li Mengya , Yang Duoping
Published: February 2024

Purpose

This paper aims to empirically investigate time–frequency linkages between Euramerican mature and Asian emerging crude oil futures markets in terms of correlation and risk spillovers.

Design/methodology/approach

With daily data, the authors first undertake the MODWT method to decompose yield series into four different timescales, and then use the R-Vine Copula-CoVaR to analyze correlation and risk spillovers between Euramerican mature and Asian emerging crude oil futures markets.

Findings

The empirical results are as follows: (a) short-term trading is the primary driver of price volatility in crude oil futures markets. (b) The crude oil futures markets exhibit certain regional aggregation characteristics, with the Indian crude oil futures market playing an important role in connecting Euramerican mature and Asian emerging crude oil futures markets. What’s more, Oman crude oil serves as a bridge to link Asian emerging crude oil futures markets. (c) There are significant tail correlations among different futures markets, making them susceptible to “same fall but different rise” scenarios. The volatility behavior of the Indian and Euramerican markets is highly correlated in extreme incidents. (d) Those markets exhibit asymmetric bidirectional risk spillovers. Specifically, the Euramerican mature crude oil futures markets demonstrate significant risk spillovers in the extreme short term, with a relatively larger spillover effect observed on the Indian crude oil futures market. Compared with India and Japan in Asian emerging crude oil futures markets, China's crude oil futures market places more emphasis on changes in market fundamentals and prefers to hold long-term positions rather than short-term technical factors.

Originality/value

The MODWT model is utilized to capture the multiscale coordinated motion characteristics of the data in the time–frequency perspective. What’s more, compared to traditional methods, the R-Vine Copula model exhibits greater flexibility and higher measurement accuracy, enabling it to more accurately capture correlation structures among multiple markets. The proposed methodology can provide evidence for whether crude oil futures markets exhibit integration characteristics and can deepen our understanding of connections among crude oil futures prices.
Dualities of digital services: everyday digital services as positive and negative contributors to customer well-being
Authors: Kemppainen Tiina , Paananen Tiina Elina
Published: February 2024

Purpose

This study examines the dualities of digital services – that is, how customers’ favorite everyday digital services can positively and negatively contribute to their well-being. Thus, the study describes the meanings of favorite digital services as part of customers’ everyday lives and the types of well-being to which such services can contribute.

Design/methodology/approach

We used a qualitative research approach through semi-structured interviews conducted in 2021 to collect data from 14 young adults (22–31 years old) who actively used digital services in their daily lives.

Findings

Our findings revealed that customers’ favorite everyday digital services can contribute to their mental well-being, social well-being, and intellectual well-being. Within these three dimensions of well-being, we identified nine dualities of digital services that describe their positive and negative contributions: (1) digital escapism versus digital disruption, (2) digital relaxation versus digital stress, (3) digital empowerment versus digital subjugation, (4) digital augmentation versus digital emptiness, (5) digital socialization versus digital isolation, (6) digital togetherness versus digital exclusion, (7) digital self-expression versus digital pressure, (8) digital learning versus digital dependence, and (9) digital inspiration versus digital stagnation.

Practical implications

These findings suggest that everyday digital services have the potential to contribute to customer well-being in various aspects – both positively and negatively – accentuating the need for service providers to decipher the impacts of their offerings on well-being. Indeed, understanding the relationship between digital services and customer well-being can help companies tailor their services to customers’ needs. Companies that prioritize customer well-being not only benefit their customers but also create sustainable growth opportunities in the long run. Further, companies can use the derived information in service design to develop marketing strategies that emphasize the positive impacts of their digital services on customer well-being.

Originality/value

Although prior transformative service studies have investigated the well-being of multiple stakeholders, such studies have focused on services related to the physical and healthcare domains. Consequently, the role of everyday digital services as contributors to customer well-being is an under-researched topic. In addition, the concept of well-being and its various dimensions has received limited attention in previous service research. By investigating everyday digital services and their multidimensional contribution to customer well-being, this study broadens the perspective on well-being within TSR and aids in refining a more precise conceptualization.
Smart choice with smart device: the use of apps in accelerated online education for nontraditional students
Authors: Wen Lei , Mi Danya
Published: February 2024

Purpose

Based on student responses to a set of customized questionnaires, this study aims to present evidence that while student evaluations of instructors and courses remain consistent, a designated mobile app enhances perceived online learning experience.

Design/methodology/approach

This study addresses quality assurance issues in accelerated online graduate-level education by identifying factors that influence nontraditional adult student preferences for using mobile applications (apps).

Findings

It is evident that affordability and functionality are the two most important determinants of nontraditional student preferences for app-based learning, followed by mobility and ease of purchase.

Originality/value

These findings underscore the potential of app learning to bolster positive perceptions of online education. Findings of this study imply that integrating additional app learning tools can be used as a quality assurance mechanism and enhance nontraditional students’ satisfaction through improving their perceived online learning experience.
Rapid positive response of young trees growth to warming reverses nitrogen loss from subtropical soil
Authors: Lyu Maokui , Chen Shidong , Zhang Qiufang , Yang Zhijie , Xie Jinsheng , Wang Chao , Wang Xiaohong , Liu Xiaofei , Xiong Decheng , Xu Chao , Lin Weisheng , Chen Guangshui , Chen Yuehmin , Yang Yusheng
Published: February 2024

Global warming is widely expected to alter nitrogen (N) cycling in terrestrial ecosystems by accelerating N transformations in soils. However, it is unclear how warming will affect plant–soil N cycling in subtropical ecosystems.

Here, we measured the N transformations including net ammoniation, nitrification, nitrous oxide emissions and nitrate in soil solution throughout the plant–soil continuum with 2 years of experimental soil warming (+5°C) in a young subtropical Chinese fir mesocosm. Seasonal variations of soil and plant (foliage and root) N concentrations and isotopes (δ15N), foliar water use efficiency and arbuscular mycorrhizal colonization rate were measured.

Soil warming significantly increased net ammonization and nitrification of the soil, together with the transient positive response observed in inorganic N of the soil. Warming increased nitrate N fluxes in soil solution and nitrous oxide emissions in the first year but not in the second year, suggesting N losses through leaching and gaseous in the initial period of warming. Warming primarily induced enrichment of 15N in foliage relative to the soil, which was attributed to the trade‐offs of persistent increases in plant N uptake caused by enhanced tree growth and a decrease in N losses with continuous warming. Furthermore, young trees' growth and N uptake capacity can rapidly acclimate to climate warming as a result of warming‐induced increases in arbuscular mycorrhizal colonization and foliar water use efficiency.

Our findings highlight that warming accelerates the plant–soil N cycle and promotes young trees' growth and N uptake, which in turn reduces soil N lost from this subtropical ecosystem. Therefore, our study suggests that the competition for N between plants and microbes governs whether subtropical forests are opened or closed N cycle systems under climate warming. We predict that subtropical young forests can still maintain their high productivity because young trees can maintain their N uptake capacity and adequate soil N supply in facing future climate warming.

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