bluuebunny/crossref_metadata_2025 huggingface dataset:
Discovery of lipid binding sites in a ligand-gated ion channel by integrating simulations and cryo-EM
Authors: Bergh Cathrine , Rovšnik Urška , Howard Rebecca J. , Lindahl Erik
Published: January 2023

Ligand-gated ion channels transduce electrochemical signals in neurons and other excitable cells. Aside from canonical ligands, phospholipids are thought to bind specifically to the transmembrane domain of several ion channels. However, structural details of such lipid contacts remain elusive, partly due to limited resolution of these regions in experimental structures. Here, we discovered multiple lipid interactions in the channel GLIC by integrating cryo-electron microscopy and large-scale molecular simulations. We identified 25 bound lipids in the GLIC closed state, a conformation where none, to our knowledge, were previously known. Three lipids were associated with each subunit in the inner leaflet, including a buried interaction disrupted in mutant simulations. In the outer leaflet, two intrasubunit sites were evident in both closed and open states, while a putative intersubunit site was preferred in open-state simulations. This work offers molecular details of GLIC-lipid contacts particularly in the ill-characterized closed state, testable hypotheses for state-dependent binding, and a multidisciplinary strategy for modeling protein-lipid interactions.
A bioinformatics screen reveals Hox and chromatin remodeling factors at theDrosophilahistone locus
Authors: Hodkinson Lauren J. , Smith Connor , Comstra H. Skye , Albanese Eric H. , Ajani Bukola A. , Arsalan Kawsar , Daisson Alvero Perez , Forrest Katherine B. , Fox Elijah H. , Guerette Matthew R. , Khan Samia , Koenig Madeleine P. , Lam Shivani , Lewandowski Ava S. , Mahoney Lauren J. , Manai Nasserallah , Miglay JonCarlo , Miller Blake A. , Milloway Olivia , Ngo Vu D. , Oey Nicole F. , Punjani Tanya A. , SiMa HaoMin , Zeng Hollis , Schmidt Casey A. , Rieder Leila E.
Published: January 2023

Cells orchestrate histone biogenesis with strict temporal and quantitative control. To efficiently regulate histone biogenesis, the repetitiveDrosophila melanogasterreplication-dependent histone genes are arrayed and clustered at a single locus. Regulatory factors concentrate in a nuclear body known as the histone locus body (HLB), which forms around the locus. Historically, HLB factors are largely discovered by chance, and few are known to interact directly with DNA. It is therefore unclear how the histone genes are specifically targeted for unique and coordinated regulation. To expand the list of known HLB factors, we performed a candidate-based screen by mapping 30 publicly available ChIP datasets and 27 factors to theDrosophilahistone gene array. We identified novel transcription factor candidates, including theDrosophilaHox proteins Ultrabithorax, Abdominal-A and Abdominal-B, suggesting a new pathway for these factors in influencing body plan morphogenesis. Additionally, we identified six other transcription factors that target the histone gene array: JIL-1, Hr78, the long isoform of fs(1)h as well as the generalized transcription factors TAF-1, TFIIB, and TFIIF. Our foundational screen provides several candidates for future studies into factors that may influence histone biogenesis. Further, our study emphasizes the powerful reservoir of publicly available datasets, which can be mined as a primary screening technique.
Sterol derivative binding to the orthosteric site causes conformational changes in an invertebrate Cys-loop receptor
Authors: De Gieter Steven , Wijckmans Eveline , Pasini Diletta , Ulens Chris , Efremov Rouslan G.
Published: January 2023

Cys-loop receptors or pentameric ligand-gated ion channels are mediators of electrochemical signaling throughout the animal kingdom. Because of their critical function in neurotransmission and high potential as drug targets, Cys-loop receptors from humans and closely related organisms have been thoroughly investigated, whereas molecular mechanisms of neurotransmission in invertebrates are less understood. When compared with vertebrates, the invertebrate genomes underwent a drastic expansion in the number of the nACh-like genes associated with receptors of unknown function. Understanding this diversity contributes to better insight into the evolution and possible functional divergence of these receptors. In this work, we studied orphan receptor Alpo4 from an extreme thermophile wormAlvinella pompejana. Sequence analysis points towards its remote relation to characterized nACh receptors. We solved the first cryo-EM structure of a lophotrochozoan nACh-like receptor in which a CHAPS molecule is tightly bound to the orthosteric site. We show that the binding of CHAPS leads to extending of the loop C at the orthosteric site and a clockwise quaternary twist between extracellular and transmembrane domains. Both the ligand binding site and the channel pore reveal unique features. These include a conserved Trp residue in loop B of the ligand binding site which is flipped into an apparent self-liganded state in the apo structure. The ion pore of Alpo4 is tightly constricted by a ring of methionines near the extracellular entryway of the channel pore. Our data provide a structural basis for a functional understanding of Alpo4 and hints towards new strategies for designing specific channel modulators.
Distinctive and complementary roles of E2F transcription factors during plant replication stress responses
Authors: Nisa Maherun , Eekhout Thomas , Bergis Clara , Pedroza-Garcia Jose-Antonio , He Xiaoning , Mazubert Christelle , Vercauteren Ilse , Brik-Chaouche Rim , Drouin-Wahbi Jeannine , Latrasse David , Bergounioux Catherine , Vandepoele Klaas , Benhamed Moussa , De Veylder Lieven , Raynaud Cécile
Published: January 2023

Survival of living organisms is fully dependent on their maintenance of genome integrity, being permanently threatened by replication stress in proliferating cells. Although the plant DNA damage response (DDR) regulator SOG1 has been demonstrated to cope with replicative defects, accumulating evidence points to other pathways functioning independently of SOG1. Here, we have studied the role of the Arabidopsis E2FA and EF2B transcription factors, two well-characterized regulators of DNA replication, in the response to replication stress. Through a combination of reverse genetics and chromatin-immunoprecipitation approaches, we show that E2FA and E2FB share many target genes with SOG1, providing evidence for their involvement in the DDR. Analysis of double and triple mutant combinations revealed that E2FB, rather than E2FA, plays the most prominent role in sustaining growth in the presence of replicative defects, either operating antagonistically or synergistically with SOG1. Reversely, SOG1 aids in overcoming the replication defects of E2FA/E2FB-deficient plants. Our data reveal a complex transcriptional network controlling the replication stress response, in which both E2Fs and SOG1 act as key regulatory factors.

ONE-SENTENCE SUMMARY

The Arabidopsis E2FA and EF2B transcription factors differently contribute to the plant’s response to DNA replication defects in a cooperative way with the DNA damage response regulator SOG1.
D-type K+ current controls the function of electrically coupled neurons in a species-specific fashion
Authors: Dapino Antonella , Davoine Federico , Curti Sebastian
Published: January 2023

Electrical synapses supported by gap junctions, are known to form networks of electrically coupled neurons in many regions of the mammalian brain, where they play relevant functional roles. Yet, how electrical coupling support sophisticated network operations, and the contribution of the intrinsic electrophysiological properties of neurons to these operations, remains incompletely understood. Here, comparative analysis of electrically coupled mesencephalic trigeminal (MesV) neurons, uncovered remarkable difference in the operation of these networks in highly related species. While spiking of MesV neurons might support the recruitment of coupled cells in rats, this rarely occurs in mice. Using whole-cell recordings, we determined that the higher efficacy in postsynaptic recruitment in rat’s MesV neurons does not result from coupling strength of larger magnitude, but instead from the higher excitability of coupled neurons. Consistently, MesV neurons from rats present a lower threshold current for activation, more hyperpolarized firing level as well as a higher ability to generate repetitive discharges, in comparison to their counterparts from mice. This difference in neuronal excitability results from a significantly higher magnitude of the D-type K+ current (ID) in MesV neurons from mice, indicating that the expression level of this current gates the recruitment of postsynaptic coupled neurons. Since MesV neurons are primary afferents critically involved in the organization of orofacial behaviors, such mechanism might support lateral excitation, by which activation of single neurons at the periphery can spread to coupled partners. Thus, by amplifying sensory inputs, lateral excitation may significantly contribute to information processing and organization of motor outputs.
Long timescale anti-directional rotation inDrosophilaoptomotor behavior
Authors: Mano Omer , Choi Minseung , Tanaka Ryosuke , Creamer Matthew S. , Matos Natalia C.B. , Shomar Joseph , Badwan Bara A. , Clandinin Thomas R. , Clark Damon A.
Published: January 2023

Locomotor movements cause visual images to be displaced across the eye, a retinal slip that is counteracted by stabilizing reflexes in many animals. In insects, optomotor turning causes the animal to turn in the direction of rotating visual stimuli, thereby reducing retinal slip and stabilizing trajectories through the world. This behavior has formed the basis for extensive dissections of motion vision. Here, we report that under certain stimulus conditions, twoDrosophilaspecies, including the widely studiedD. melanogaster, can suppress and even reverse the optomotor turning response over several seconds. Such ‘anti-directional turning’ is most strongly evoked by long-lasting, high-contrast, slow-moving visual stimuli that are distinct from those that promote syn-directional optomotor turning. Anti-directional turning, like the syn-directional optomotor response, requires the local motion detecting neurons T4 and T5. A subset of lobula plate tangential cells, CH cells, show involvement in these responses. Imaging from a variety of direction-selective cells in the lobula plate shows no evidence of dynamics that match the behavior, suggesting that the observed inversion in turning direction emerges downstream of the lobula plate. Further, anti-directional turning declines with age and exposure to light. These results show thatDrosophilaoptomotor turning behaviors contain rich, stimulus-dependent dynamics that are inconsistent with simple reflexive stabilization responses.
Solving the spike sorting problem with Kilosort
Authors: Pachitariu Marius , Sridhar Shashwat , Stringer Carsen
Published: January 2023

Spike sorting is the computational process of extracting the firing times of single neurons from recordings of local electrical fields. This is an important but hard problem in neuroscience, complicated by the non-stationarity of the recordings and the dense overlap in electrical fields between nearby neurons. To solve the spike sorting problem, we have continuously developed over the past eight years a framework known as Kilosort. This paper describes the various algorithmic steps introduced in different versions of Kilosort. We also report the development of Kilosort4, a new version with substantially improved performance due to new clustering algorithms inspired by graph-based approaches. To test the performance of Kilosort, we developed a realistic simulation framework which uses densely sampled electrical fields from real experiments to generate non-stationary spike waveforms and realistic noise. We find that nearly all versions of Kilosort outperform other algorithms on a variety of simulated conditions, and Kilosort4 performs best in all cases, correctly identifying even neurons with low amplitudes and small spatial extents in high drift conditions.
When do we share knowledge? A mixed-methods study of helping behaviors and HR management practices
Authors: Gonçalves Tiago , Curado Carla , Martsenyuk Natalia
Published: January 2023

Purpose

The purpose of this work is to investigate the relationship between human resources management practices (HRMP) and altruistic helping behaviors (HB) with knowledge sharing behavior (KSB) following a theoretical rationale supported by the Theory of Planned Behavior and the Social Exchange Theory.

Design/methodology/approach

The study explores linear and non-linear relationships between the variables to further understand knowledge sharing in the context of prosocial behaviors. The study sample gathers data from 130 employees coming from service sector companies operating in Portugal. The authors analyze the linear relationship following a structural equation model (SEM) approach using a partial least squares (PLS) analysis. Then, the authors conduct a fuzzy-set qualitative comparative analysis (fsQCA) to analyze non-linear relationships and provide insight over circumstances where the presence and absence of knowledge sharing behavior is achieved.

Findings

Quantitative findings show that HRMP positively impacts KSB outcomes. Similarly, HB also positively impacts KSB. Qualitative findings show a single configuration leading to the presence of KSB, corroborating the quantitative results. On the other hand, findings offer multiple alternative configurations leading to the absence of KSB.

Originality/value

Few studies explore the complex combination between HRMP and individual HB impacting knowledge sharing, with lesser studies discussing circumstances leading to the absence of KSB. We explore a) the linear influence of HB and HRMP and, b) their asymmetric combined influence along with employee demographics to better understand KSB complexity – ensuring a conceptual and managerial contribution driving future work and practices.
A real effect across time: disclosure quality, cost of capital and profitability
Authors: Cai Cynthia Weiyi
Published: January 2023

Purpose

In the presence of “real effects” of disclosure in a production economy, this research aims to investigate the link between disclosure and cost of capital relating to different time periods: namely the post-disclosure cost of capital (the cost of capital subsequent to disclosure), the pre-disclosure cost of capital (the cost of capital for the period leading up to disclosure) and the overall cost of capital (the cost of capital across both periods). The author also extends the analysis to whether and how in the presence of a real effect of disclosure, investors' ex ante welfare might be affected.

Design/methodology/approach

This research is conducted via stylized models.

Findings

The author demonstrates that, first, in contrast to findings in a pure-exchange economy, in a production-based economy where disclosure affects firms' investment decisions, both the overall cost of capital and the investors' ex ante welfare can be affected by disclosure quality. As disclosure quality improves, the post-disclosure cost of capital may either increase or decrease, as may the pre-disclosure cost of capital. The change in the post-disclosure cost of capital is not fully offset by the change in the pre-disclosure cost of capital, and therefore the overall cost of capital can either increase or decrease. Second, a firm's profitability of existing and new production are critical factors in determining whether cost of capital increases or decreases with disclosure quality. The author characterizes conditions under which higher disclosure quality increases or decreases the disclosing firm's cost of capital over different time periods. Third, when disclosure affects interrelated firms' production decisions, the disclosing firm's overall cost of capital changes with disclosure quality, even when the marginal (unconditional) distribution of the disclosing firm's cash flow is not affected by the disclosure.

Originality/value

This research contributes to a largely unexplored but important area: the real effect of disclosure on the cost of capital.
The role of supply chain alignment in coping with resource dependency in blockchain adoption: empirical evidence from China
Authors: Guan Wei , Ding Wenhong , Zhang Bobo , Verny Jerome
Published: January 2023

Purpose

The deployment of blockchain technology (BT) throughout the supply chain is usually led by large firms that dominate the supply chain. Leading firms can encourage other resource-constrained partners to get on board by providing technical and financial support. However, due to the uncertain consequences of relying on leading firms, these partners may still be reluctant to adopt BT. Drawing on resource dependence theory, this study aims to investigate whether and when supply chain alignment can be used as a dependency coping strategy to increase the willingness of resource-constrained partners to adopt BT. Moreover, it aims to examine the motivators for supply chain alignment.

Design/methodology/approach

This study adopted a survey research design and collected data from 364 small and medium-sized enterprises in China.

Findings

Supply chain alignment positively affects BT adoption. The effect of supply chain alignment on BT adoption is contingent on guanxi (a Chinese cultural tradition of interpersonal connections that facilitate a mutual exchange of favors). Relative advantage, technology complexity, organizational readiness and cost are motivators for supply chain alignment. Supply chain alignment mediates the effect of cost, technology complexity and relative advantage on BT adoption.

Originality/value

This research addresses the problem of resource dependency in the context of BT adoption which has been overlooked by previous research. Moreover, this paper enriches the BT literature by identifying supply chain alignment as an important channel for technology–organization–environment factors to influence BT adoption.
Shared leadership in integrated care networks: the case of “hub and spoke” networks in oral and maxillofacial surgery (OMFS) in the English NHS
Authors: Willcocks Steve , Willcocks Edward Joshua
Published: January 2023

Purpose

The purpose of this paper is to explore leadership in the context of the hub and spoke network in oral and maxillofacial surgery (OMFS) in the English National Health Service (NHS).

Design/methodology/approach

This paper is a conceptual paper using literature relating to the antecedents of shared leadership and relevant policy documents pertaining to both NHS policy and the development of OMFS. The paper is informed, theoretically by the conceptual lens of shared leadership.

Findings

The paper identifies the challenges that may be faced by policymakers and those involved in the hub and spoke network in developing shared leadership. It also reveals the implications for policymakers in developing shared leadership.

Research limitations/implications

The paper is conceptual. It is acknowledged that this is a preliminary study and further work will be required to test the conceptual framework empirically. The paper discusses the policy implications of developing leadership in the hub and spoke network. As networks are of interest internationally this has wider relevance to other countries.

Originality/value

There is limited research on the antecedents of shared leadership. In addition, the conceptual framework is applied to a new policy context.
Thermodynamical interactions in a rotating functionally graded semiconductor material with gravity
Authors: Sheoran Devender , Yadav Komal , Punia Baljit Singh , Kalkal Kapil Kumar
Published: January 2023

Purpose

The purpose of this paper is to analyse the transient effects in a functionally graded photo-thermoelastic (TE) medium with gravity and rotation by considering two generalised TE theories: Lord–Shulman (LS) and Green–Lindsay (GL). The governing equations are derived in rectangular Cartesian coordinates for a two dimensional problem.

Design/methodology/approach

All the physical properties of the semiconductor are supposed to vary exponentially with distance. The analytical solution is procured by employing normal mode technique on the resulting non-dimensional coupled field equations with appropriate boundary conditions.

Findings

For the mechanically loaded thermally insulated surface, normal displacement, stress components, temperature distribution and carrier density are calculated numerically with the help of MATLAB software for a silicon semiconductor and displayed graphically. Some particular cases of interest have also been deduced from the present results.

Originality/value

The effects of rotation and non-homogeneity on the different physical fields are investigated on the basis of analytical and numerical results. Comparisons are made with the results predicted by GL theory in the presence and absence of gravity for different values of time. Comparisons are also made between the three theories in the presence of rotation, gravity and in-homogeneity. Such problems are very important in many dynamical systems.
Green human resource management and employee innovative behaviour: does inclusive leadership play a role?
Authors: Shafaei Azadeh , Nejati Mehran
Published: January 2023

Purpose

This study examines the relationship between green human resource management (green HRM) and employee innovative behaviour. It also investigates the mediating role of job satisfaction to explore the mechanism through which green HRM is related to employee innovative behaviour. Additionally, it examines the moderating role of inclusive leadership to determine the boundary condition of the relationship between green HRM and employee innovative behaviour.

Design/methodology/approach

The study used a quantitative research approach using survey and collected 508 responses from full-time employees in Australia.

Findings

The authors have found support for all the hypothesised relationships in the study. Specifically, green HRM is positively related to employee innovative behaviour. This relationship is mediated by job satisfaction and accentuated by inclusive leadership.

Originality/value

Green HRM promotes a green atmosphere in which employees can contribute to a safer and healthier environment. Despite the increasing attention to green HRM in the management literature, little is known about the mechanisms and boundary conditions explaining employees' responses to green HRM.
Carabid beetles have hump‐shaped responses to disturbance and resource gradients within agricultural landscapes
Authors: Muneret Lucile , Ricci Benoit , Vialatte Aude , Aviron Stéphanie , Ducourtieux Chantal , Biju‐Duval Luc , Petit Sandrine
Published: January 2023

Understanding the effects of the huge diversity of cropping systems on local biodiversity is challenging but necessary to implement agroecological systems. Through a functional approach, the translation of cropping systems into resource and disturbance gradients is a promising way to decipher the relationship between cropping systems and biodiversity but has never been implemented for arthropods.

To investigate the contributions of resource and disturbance gradients arising from cropping systems vs environmental context (regional effect, meteorological conditions and landscape characteristics) on beneficial arthropod communities, we used a dataset collected in 60 crop fields from three French areas over a 5‐year period. It includes all farmer interventions, crop sequences, meteorological data, landscape composition and carabid samplings.

We found that environmental context contributed to about 75% of explained carabid variations on average, while resource and disturbance gradients contributed to about 25% of explained carabid variations. The resource and disturbance gradients were particularly important in winter and in the spring preceding the spring–summer period to determine carabid variations.

Moreover, we identified thresholds above which resource and disturbance gradients start being beneficial or detrimental for carabids. For example, increased treatment index in spring decreased the total activity density of carabids during the spring–summer period.

Synthesis and applications. While implementing for the first time a functional approach to understand the effects of different facets of cropping systems on arthropods, our study also allows us to identify periods and thresholds above which specific practices affect carabids. Finally, avoiding bare soils all along the year, keeping pesticide use intensity below the identified thresholds and adopting a wide diversity of tillage strategies at the landscape scale should all contribute to enhance in‐field carabid occurrences and richness.
To be or not to be: The identity work of pharmacists as clinicians
Authors: McDermott Imelda , Astbury Jayne , Jacobs Sally , Willis Sarah , Hindi Ali , Seston Elizabeth , Schafheutle Ellen
Published: January 2023

This study explores how pharmacists legitimise the expansion of their clinical work and considers its impact on pharmacists’ professional identity work. In the context of pharmacy in the English NHS, there has been an ongoing policy shift towards pharmacists moving away from ‘medicines supply’ to patient‐facing, clinical work since the 1950s. Pharmacists are continuously engaging in ‘identity work’ and ‘boundary work’ to reflect the expansion of their work, which has led to the argument that pharmacists lack a clear professional identity. Drawing insights from linguistics and specifically Van Leeuwen's ‘grammar of legitimation’, this study explains how the Pharmacy Integration Fund, a nationally funded learning programme, provides the discursive strategies for pharmacists to legitimise their identity work as clinicians.
Debating the fate of the homemaker: The ERA and the death of the family wage
Authors: Swinth Kirsten
Published: January 2023

This article revisits the campaign to ratify the Equal Rights Amendment (ERA) to the United States Constitution to argue that amendment adversaries fought over the future of women's economic security. Post‐war US economic growth stalled in the 1970s, bringing the family‐wage ideal of male breadwinning and female homemaking down with it. In these unsettled years, how female economic dependence would be addressed was an open question: would it be by propping up male breadwinning, as ERA opponents wanted, or by combining good jobs with fairly compensated domestic labour and government assistance, as supporters believed the ERA promised? A revisionist interpretation of the ERA battle, this article shifts attention from conflict over gender identity and cultural values to economics and capitalist transformation. It examines arguments presented in pamphlets, the media and to Congress about how homemaking women could achieve security in the face of changing economic reality. The ERA's defeat was a Pyrrhic victory for conservatives. The threat to government‐sanctioned male breadwinning appeared to have been vanquished. But the family‐wage system was truly on the rocks, and supporters’ vision of a working‐family norm, with roles based on function, not gender, won out. Without the ERA, however, working mothers shouldered the consequences.
The age of insecuritisation: Insecure young workers in insecure jobs facing an insecure future
Authors: Rydzik Agnieszka , Bal P. Matthijs
Published: January 2023

Rapid political‐economic changes in recent decades have led to increasingly insecure youth labour markets and the weakening of state protections, resulting in growing precarisation for young people. This article examines how student‐workers from post‐1992 UK universities on zero‐hour contracts in hospitality experience insecuritisation and societal turbulence as a result of continual neoliberal flexibilization of labour markets. It shows how existing personal insecurity—reinforced by limited state protection, inexperience and socio‐economic background—is intensified by the addition of job insecurity, underpinned by transactional employment relations and workplace power asymmetries. It argues that these experiences can further precarisation of already insecure individuals and shape perceptions of future labour market insecurity. Drawing on 35 semi‐structured interviews, the article posits that insecurity is structurally entrenched in the lives of many student‐workers and zero‐hour contract work can further exacerbate it by sustaining existing inequalities, dialling down aspirations and hindering prospects of social mobility.
Reproduction strategy of nocturnal marine molluscs: running for love
Authors: GAO Xiaolong , ZHANG Mo , LIN Shihui , LYU Mingxin , LUO Xuan , YOU Weiwei , KE Caihuan
Published: January 2023

The cost of reproduction is the core driver of life history evolution in animals. This paper demonstrates that the cumulative distance moved and the duration of movement of sexually immature abalones, Haliotis discus hannai, kept in various male and female groups, were significantly higher than those of sexually mature individuals, except when kept in mixed cultures of mature males and females. After mixed‐culture, sexually mature males moved significantly further and for a longer duration than mature female abalones, and even more so than mature male abalones of any other group. Examination of the LC‐MS metabolomics of mature males cultured with sexually mature females (AM) and those cultured with sexually immature females (JM) showed that cyclic adenosine monophosphate (cAMP) acted as a differential metabolic biomarker. After 24‐h uninterrupted sampling, the concentration of 5‐HT and the expression levels of the 5‐HT2 and 5‐HT6 receptors in AM were significantly higher than those in JM. After further injection of 5‐HT2 and 5‐HT6 receptor antagonists, the concentrations of cAMP and PKA rose again, but the cumulative movement duration and distance of male abalones decreased significantly, showing that 5‐HT was involved in the regulation of movement behavior of male abalones through the 5‐HT2 and 5‐HT6 receptor‐activated cAMP‐PKA pathways. The results demonstrated a significant increase in the movement endurance of mature male abalones cultured with mature females, providing a theoretical basis for understanding the adaptive life history strategies of abalones and suggesting ways to protect diverse benthic resources for abalones during the reproductive stage.
Populism à la Carte: The paradoxical political communication of Narendra Modi on Twitter
Authors: Martelli Jean‐Thomas , Jumle Vihang
Published: January 2023

How and where is democracy ‘hacked’? Studies examining the variability of the populist discourse rely on the—often tacit—assumption that global digital platforms are used similarly from one country to the other. By examining political rhetoric on Twitter, we show that populist communication is tailored to a particular audience profile rather than a particular social media (SM). More specifically, we compare Indian Prime Minister Narendra Modi's tweets with his addresses on multiple mediums. We describe how Modi uses wide‐reaching media such as radio to unfold a populist narrative based on institutional disintermediation, layman's language, counselling and the staging of an intimate conversation with the masses. Modi uses more elitist and cosmopolitan SM sites in India, such as Twitter, to mitigate his populist credentials, and introduce himself as a respectable democratic leader favouring multilateral collaborations, banal nationalism and Gandhian peace‐building. The variability of his political rhetoric across seven address formats indicates that Modi is populist tactically rather than ideologically, which complicates the tenets of the dominant ‘ideational’ populist paradigm. To further ground our argument empirically, we venture into comparing Modi's and Trump's tweets. We suggest that due to the popularity of Twitter in the United States, it was strategically useful for the former President of the United States to act populist on the platform, while that is not the case for Modi. This tends to indicate that not enough attention is given to intermedium studies that complement comparisons between states/regions with comparisons nested within a coherent political space.
Assessment of abuse potential of carfentanil
Authors: Wei Jiayun , Lai Miaojun , Li Feng , Chen Yuanyuan , Li Xiangyu , Qiu Yi , Shen Haowei , Xu Peng , Di Bin
Published: January 2023

Carfentanil, as a fentanyl analogue, is a potent synthetic opioid. It has been controlled in many countries, and its emergence has been highlighted by many recent reports. However, although discriminative stimulus effects of carfentanil in rats had been reported, its abuse potential has not been fully evaluated. In this study, we evaluated the abuse potential of carfentanil via the tests of conditioned place preference (CPP), drug self‐administration and naloxone‐precipitated opioid withdrawal assay, compared with fentanyl and heroin. Carfentanil exhibited significant place preference at a minimum dose of 1 μg/kg in mice, whereas fentanyl and heroin induced significant place preference at the minimum doses of 100 μg/kg and 1000 μg/kg, respectively. In the drug‐substitution test in heroin self‐administered rats (50 μg/kg/infusion), carfentanil and fentanyl acquired significant self‐administrations above saline levels from 0.05–0.1 and 0.1–10.0 μg/kg/infusion, respectively. Carfentanil induced the maximum number of infusions at 0.1 μg/kg, whereas fentanyl and heroin at 1 and 25 μg/kg, respectively. In short, carfentanil showed the highest potency to induce CPP and self‐administration. Furthermore, repeated treatment with escalating doses of carfentanil, fentanyl or heroin induced typical withdrawal symptoms in mice, including a greater number of jumping and weight loss than saline group. This indicated that carfentanil could produce physical dependence similar to fentanyl and heroin. Taken together, the present study demonstrated the higher abuse potential of carfentanil compared with fentanyl and heroin. The rank order of abuse potential for these compounds is carfentanil > fentanyl > heroin.
Anatomy of the rabbit inner ear using computed tomography and magnetic resonance imaging
Authors: Abd El‐Hameed Zeinab Said , El‐Shafey Anwar Abd El‐Fattah , Metwally Mohamed Attia , Abd El‐Samie Hesham Abd El‐Rahman , Kassab A.
Published: January 2023

Anatomically, the inner ear is a highly complex organ of intricate design, composed of a bony labyrinth that encases the same‐shaped membranous labyrinth. It is difficult to study the three‐dimensional anatomy of the inner ear because the relevant structures are very small and embedded within the petrous temporal bone, one of the densest bones in the body. The current study aimed to provide a detailed anatomic reference for the normal anatomy of the rabbit's inner ear. As a study model, ten healthy adults New Zealand White rabbit heads were used. Six heads were used for macroscopic evaluation of the bony and membranous labyrinths. The remaining four heads were evaluated radiographically, where 3D images were generated of the bony and membranous labyrinths using data sets from computed tomography (CT) and magnetic resonance imaging (MRI), respectively. The anatomical structures were identified and labelled according to NominaAnatomicaVeterinaria (NAV). Our study revealed that CT and MRI are the optimal cross‐sectional imaging modalities for investigating such tiny and often inaccessible inner ear structures. As high‐quality scanners are not readily available to veterinarians, the CT and MRI images generated by this research were of lower quality; therefore, high‐quality dissections were used to identify/support structures seen in these images. In conclusion, this study provides one of the first investigations that uses multislice CT scans and MRI to study the rabbit's inner ear and its correlation with the corresponding anatomical images. Both anatomical, CT and MRI images will serve as a reference for interpreting pathologies relative to the rabbit's inner ear.
Effect of di(n‐butyl) phthalate on the blood–testis barrier during puberty onset
Authors: Molele Reneilwe A. , Zakariah Musa , Ibrahim Mohammed I. A. , Mahdy Mohamed A. A. , Fosgate Geoffrey T. , Brown Geoffrey
Published: January 2023

Di(n‐butyl) phthalate (DBP) is considered a substance of serious concern because of its reproductive toxicity and endocrine‐disrupting properties. Exposure to DBP causes morphological and functional changes in the male reproductive system of birds and mammals. However, there are no detailed reports on the effects of DBP on the Sertoli cell and junctional complexes of the blood–testis barrier (BTB) in birds. The present study investigated dose‐related ultrastructural changes in Sertoli cells and junctional complexes of the BTB in adult Japanese quail (Coturnix coturnix japonica) exposed to DBP prior to puberty. A total of 25 Japanese quail were used for the study. Exposure to DBP doses of 50, 200 and 400 mg DBP/kg/d caused dose‐related ultrastructural changes in junctional complexes including dilation and separation, while disruption of cytoplasmic membranes and mitochondria was observed in Sertoli cells. There was a significant difference in the sum of vacuoles, vacuole diameter, nuclear width, nuclear length, nuclear area, sum of damaged spherical mitochondria, width of elongated mitochondria and the sum of damaged elongated mitochondria among the five treatment groups (p ˂ 0.05). Prepubertal exposure to DBP at doses of 50, 200 and 400 mg DBP/kg/d for 30 days led to adverse effects in the adult male Japanese quail reproductive system by inducing structural changes in the Sertoli cells and junctional complexes. Such changes might disrupt the BTB and potentially interfere with spermatogenesis. Results indicated that the Sertoli cell is sensitive to DBP exposure and might be an important cellular target for DBP‐induced testicular toxicity.
Staphylococcus aureus causes aberrant epidermal lipid composition and skin barrier dysfunction
Authors: Kim Jihyun , Kim Byung Eui , Berdyshev Evgeny , Bronova Irina , Bin Lianghua , Bae Jaewoong , Kim Seokjin , Kim Hye‐Young , Lee Un Ha , Kim Myoung Shin , Kim Hyunmi , Lee Jinyoung , Hall Clifton F. , Hui‐Beckman Jessica , Chang Yunhee , Bronoff Anna Sofia , Hwang Dasom , Lee Hae‐Young , Goleva Elena , Ahn Kangmo , Leung Donald Y. M.
Published: January 2023

Background

Staphylococcus (S) aureus colonization is known to cause skin barrier disruption in atopic dermatitis (AD) patients. However, it has not been studied how S. aureus induces aberrant epidermal lipid composition and skin barrier dysfunction.

Methods

Skin tape strips (STS) and swabs were obtained from 24 children with AD (6.0 ± 4.4 years) and 16 healthy children (7.0 ± 4.5 years). Lipidomic analysis of STS samples was performed by mass spectrometry. Skin levels of methicillin‐sensitive and methicillin‐resistant S. aureus (MSSA and MRSA) were evaluated. The effects of MSSA and MRSA were evaluated in primary human keratinocytes (HEKs) and organotypic skin cultures.

Results

AD and organotypic skin colonized with MRSA significantly increased the proportion of lipid species with nonhydroxy fatty acid sphingosine ceramide with palmitic acid ([N‐16:0 NS‐CER], sphingomyelins [16:0–18:0 SM]), and lysophosphatidylcholines [16:0–18:0 LPC], but significantly reduced the proportion of corresponding very long‐chain fatty acids (VLCFAs) species (C22–28) compared to the skin without S. aureus colonization. Significantly increased transepidermal water loss (TEWL) was found in MRSA‐colonized AD skin. S. aureus indirectly through interleukin (IL)‐1β, tumor necrosis factor (TNF)‐α, IL‐6, and IL‐33 inhibited expression of fatty acid elongase enzymes (ELOVL3 and ELOVL4) in HEKs. ELOVL inhibition was more pronounced by MRSA and resulted in TEWL increase in organotypic skin.

Conclusion

Aberrant skin lipid profiles and barrier dysfunction are associated with S. aureus colonization in AD patients. These effects are attributed to the inhibition of ELOVLs by S. aureus‐induced IL‐1β, TNF‐α, IL‐6, and IL‐33 seen in keratinocyte models and are more prominent in MRSA than MSSA.
Maternal autonomy and prenatal harm
Authors: Howard Nathan Robert
Published: January 2023

This paper offers an account of why prenatal harms seem particularly objectionable. It identifies structural similarities between key cases of prenatal harm and the recently characterized “all‐or‐nothing” problem from Joe Horton. According to the account defended by the paper, a willingness to parent incurs a duty to protect the fetus from harm. This implication provides independent support for so‐called “voluntarist” or “intentionalist” accounts of parental role obligations, according to which, roughly, a mother's autonomous choice to parent a child suffices for having the obligations distinctive of parenthood toward the child.
Stromal bone marrow fibroblasts and mesenchymal stem cells support acute myeloid leukaemia cells and promote therapy resistance
Authors: Miari Katerina E. , Williams Mark T. S.
Published: January 2023

The bone marrow (BM) is the primary site of adult haematopoiesis, where stromal elements (e.g. fibroblasts and mesenchymal stem cells [MSCs]) work in concert to support blood cell development. However, the establishment of an abnormal clone can lead to a blood malignancy, such as acute myeloid leukaemia (AML). Despite our increased understanding of the pathophysiology of the disease, patient survival remains suboptimal, mainly driven by the development of therapy resistance. In this review, we highlight the importance of bone marrow fibroblasts and MSCs in health and acute myeloid leukaemia and their impact on patient prognosis. We discuss how stromal elements reduce the killing effects of therapies via a combination of contact‐dependent (e.g. integrins) and contact‐independent (i.e. secreted factors) mechanisms, accompanied by the establishment of an immunosuppressive microenvironment. Importantly, we underline the challenges of therapeutically targeting the bone marrow stroma to improve acute myeloid leukaemia patient outcomes, due to the inherent heterogeneity of stromal cell populations.

LINKED ARTICLES

This article is part of a themed issue on Cancer Microenvironment and Pharmacological Interventions. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.2/issuetoc
Lenvatinib enhances antitumor immunity by promoting the infiltration of TCF1+CD8+ T cells in HCC via blocking VEGFR2
Authors: Mei Zhibin , Gao Xingxing , Pan Caixu , Wu Qinchuan , Wang Shuai , Qian Junjie , Xu Zhentian , Xu Kangdi , Zhou Lin , Zhen Shushen
Published: January 2023

Lenvatinib is the favorable treatment for advanced hepatocellular carcinoma (HCC), and it is currently undergoing phase III clinical trials. However, the specific effects of lenvatinib on PD1+ CD8+ T cells in HCC microenvironment have not been systematically studied. Here, we established an orthotopic hepa1‐6 mouse model treated with lenvatinib to investigate CD8+ T cells’ role in the tumor and spleen. We found an increasing proportion of TCF‐1+ in PD1+ CD8+ T cells and proliferation of PD1+ CD8+ T cells after lenvatinib treatment. Meanwhile, lenvatinib treatment upregulated the expression of granzyme B on PD1+ CD8+ T cells both in vitro and in vivo. Lenvatinib activated the endogenous mTOR pathway of exhausted CD8+ T cells, and mTOR pathway blockade eliminated the antitumor effect of lenvatinib and function of PD1+ CD8+ T cells. The effects of the mTOR pathway on PD1+ CD8+ T cells after lenvatinib treatment were mediated by VEGFR2 inhibition. Overall, our work provides insight into the mechanism of lenvatinib's antitumor efficacy through exhausted CD8+ T cells in HCC treatment.
Mutational analysis of DNMT3A improves the prognostic stratification of patients with acute myeloid leukemia
Authors: Wakita Satoshi , Marumo Atsushi , Morita Kaoru , Kako Shinichi , Toya Takashi , Najima Yuho , Doki Noriko , Kanda Junya , Kuroda Junya , Mori Shinichiro , Satake Atsushi , Usuki Kensuke , Ueki Toshimitsu , Uoshima Nobuhiko , Kobayashi Yutaka , Kawata Eri , Nakayama Kazutaka , Nagao Yuhei , Shono Katsuhiro , Shibusawa Motoharu , Tadokoro Jiro , Hagihara Masao , Uchiyama Hitoji , Uchida Naoyuki , Kubota Yasushi , Kimura Shinya , Nagoshi Hisao , Ichinohe Tatsuo , Kurosawa Saiko , Motomura Sayuri , Hashimoto Akiko , Muto Hideharu , Sato Eriko , Ogata Masao , Mitsuhashi Kenjiro , Ando Jun , Tashiro Haruko , Sakaguchi Masahiro , Yui Shunsuke , Arai Kunihito , Kitano Tomoaki , Miyata Miho , Arai Haruka , Kanda Masayuki , Itabashi Kako , Fukuda Takahiro , Kanda Yoshinobu , Yamaguchi Hiroki
Published: January 2023

Nucleophosmin1 (NPM1) mutations are the most frequently detected gene mutations in acute myeloid leukemia (AML) and are considered a favorable prognostic factor. We retrospectively analyzed the prognosis of 605 Japanese patients with de novo AML, including 174 patients with NPM1‐mutated AML. Although patients with NPM1‐mutated AML showed a high remission rate, this was not a favorable prognostic factor for overall survival (OS); this is contrary to generally accepted guidelines. Comprehensive gene mutation analysis showed that mutations in codon R882 of DNA methyltransferase 3A (DNMT3AR882 mutations) were a strong predicative factor indicating poor prognosis in all AML (p < 0.0001) and NPM1‐mutated AML cases (p = 0.0020). Furthermore, multivariate analysis of all AML cases showed that DNMT3AR882 mutations and the co‐occurrence of internal tandem duplication in FMS‐like tyrosine kinase 3 (FLT3‐ITD), NPM1 mutations, and DNMT3AR882 mutations (triple mutations) were independent factors predicting a poor prognosis related to OS, with NPM1 mutations being an independent factor for a favorable prognosis (hazard ratios: DNMT3AR882 mutations, 1.946; triple mutations, 1.992, NPM1 mutations, 0.548). Considering the effects of DNMT3AR882 mutations and triple mutations on prognosis and according to the classification of NPM1‐mutated AML into three risk groups based on DNMT3AR882/FLT3‐ITD genotypes, we achieved the improved stratification of prognosis (p < 0.0001). We showed that DNMT3AR882 mutations are an independent factor for poor prognosis; moreover, when confounding factors that include DNMT3AR882 mutations were excluded, NPM1 mutations were a favorable prognostic factor. This revealed that ethnological prognostic discrepancies in NPM1 mutations might be corrected through prognostic stratification based on the DNMT3A status.