bluuebunny/crossref_metadata_2025 huggingface dataset:
Generalizing Stepping Concepts To Non-Straight Walking
Authors: Dingwell Jonathan B. , Render Anna C. , Desmet David M. , Cusumano Joseph P.
Published: May 2023

People rarely walk in straight lines. Instead, we make frequent turns or other maneuvers. Spatiotemporal parameters fundamentally characterize gait. For straight walking, these parameters are well-defined for that task of walking on a straightpath. Generalizing these concepts tonon-straight walking, however, is not straightforward. People also follow non-straight paths imposed by their environment (store aisle, sidewalk, etc.) or choose readily-predictable, stereotypical paths of their own. People actively maintain lateral position to stay on their path and readily adapt their stepping when their path changes. We therefore propose a conceptually coherent convention that defines step lengths and widths relative to known walking paths. Our convention simply re-aligns lab-based coordinates to be tangent to a walker’s path at the mid-point between the two footsteps that define each step. We hypothesized this would yield results both morecorrectand more consistent with notions from straight walking. We defined several common non-straight walking tasks: single turns, lateral lane changes, walking on circular paths, and walking on arbitrary curvilinear paths. For each, we simulated idealized step sequences denoting “perfect” performance with known constant step lengths and widths. We compared results to path-independent alternatives. For each, we directly quantified accuracy relative to knowntruevalues. Results strongly confirmed our hypothesis. Our convention returned vastly smaller errors and introducednoartificial stepping asymmetries across all tasks. All results for our convention rationally generalized concepts from straight walking. Taking walking paths explicitly into account as important task goals themselves thus resolves conceptual ambiguities of prior approaches.
A new antibiotic from an uncultured bacterium binds to an immutable target
Authors: Shukla Rhythm , Peoples Aaron J. , Ludwig Kevin C. , Maity Sourav , Derks Maik G.N. , de Benedetti Stefania , Krueger Annika M , Vermeulen Bram J.A. , Lavore Francesca , Honorato Rodrigo V. , Grein Fabian , Bonvin Alexandre , Kubitscheck Ulrich , Breukink Eefjan , Achorn Catherine , Nitti Anthony , Schwalen Christopher J. , Spoering Amy L. , Ling Losee Lucy , Hughes Dallas , Lelli Moreno , Roos Wouter H. , Lewis Kim , Schneider Tanja , Weingarth Markus
Published: May 2023

Antimicrobial resistance is a leading mortality factor worldwide. Here we report the discovery of clovibactin, a new antibiotic, isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant bacterial pathogens without detectable resistance. Using biochemical assays, solid-state NMR, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (C55PP, Lipid II, LipidWTA). Clovibactin uses an unusual hydrophobic interface to tightly wrap around pyrophosphate, but bypasses the variable structural elements of precursors, accounting for the lack of resistance. Selective and efficient target binding is achieved by the irreversible sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups. Uncultured bacteria offer a rich reservoir of antibiotics with new mechanisms of action that could replenish the antimicrobial discovery pipeline.
Differentiating Agonists and Competitive Antagonists of the Serotonin Type 3A (5-HT3A) Receptor
Authors: Davolio Anthony J. , Jankowski W.J. , Várnai Csilla , Irwin B.W.J. , Payne M.C. , Chau P.-L.
Published: May 2023

What makes an agonist and a competitive antagonist? In this work, we aim to answer this question by performing parallel tempering Monte Carlo simulations on the serotonin type 3A (5-HT3A) receptor. We use linear response theory to predict conformational changes in the 5-HT3Areceptor active site after applying weak perturbations to its allosteric binding sites. A covariance tensor is built from conformational sampling of its apo state, and a harmonic approximation allows us to substitute the calculation of ligand-induced forces with the binding site’s displacement vector. We show that it is possible to differentiate between agonists and competitive antagonists for multiple ligands while running computationally expensive calculations only once for the protein.
Mass spectrometry imaging of natural carbonyl products directly from agar-based microbial interactions using 4-APEBA derivatization
Authors: Veličković Dušan , Zemaitis Kevin J. , Bhattacharjee Arunima , Anderton Christopher R.
Published: May 2023

Aliphatic carboxylic acids, aldehydes, and ketones play diverse roles in microbial adaptation to their microenvironment, from excretion as toxins to adaptive metabolites for membrane fluidity. However, the spatial distribution of these molecules throughout biofilms, and how microbes in these environments exchange these molecules remains elusive for many of these bioactive species due to inefficient molecular imaging strategies. Herein, we apply on-tissue chemical derivatization (OTCD) using 4-(2-((4-bromophenethyl)dimethylammonio)ethoxy)benzenaminium bromide (4-APEBA) on a co-culture of a soil bacterium (Bacillus subtilisNCIB 3610) and fungus (Fusariumsp. DS 682) grown on agar as our model system. Using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), we spatially resolved more than 300 different metabolites containing carbonyl-groups within this model system. Various spatial patterns are observable of these species, which indicate possible extracellular or intercellular processes of the metabolites, and their up or down regulation during microbial interaction. The unique chemistry of our approach allowed us to bring additional confidence in accurate carbonyl identification, especially when multiple isomeric candidates were possible, and this provided the ability to generate hypotheses about the potential role of some aliphatic carbonyls in thisB. subtilis/Fusariumsp. interaction. The results shown here demonstrate the utility of 4-ABEBA-based OCTD MALDI-MSI in probing interkingdom interactions directly from microbial co-cultures, and these methods will enable future microbial interactions studies with expanded metabolic coverage.

IMPORTANCE

The metabolic profiles within microbial biofilms and interkingdom interactions are extremely complex and serve a variety of functions, which include promoting colonization, growth, and survival within competitive and symbiotic environments. However, measuring and differentiating many of these molecules, especially in anin-situfashion, remains a significant analytical challenge. We demonstrate a chemical derivatization strategy that enabled highly sensitive, multiplexed mass spectrometry imaging of over 300 metabolites from a model microbial co-culture. Notably, this approach afforded us to visualize over two dozen classes of ketone-, aldehyde-, and carboxyl-containing molecules, which were previously undetectable from colonies grown on agar. We also demonstrate that this chemical derivatization strategy can enable discrimination of isobaric and isomeric metabolites, without the need for orthogonal separation (e.g.,online chromatography or ion mobility). We anticipate this approach will further enhance our knowledge of metabolic regulation within microbiomes and microbial systems used in bioengineering applications.
Profiling ubiquitin signaling with UBIMAX reveals DNA damage- and SCFβTRCP-dependent ubiquitylation of the actin-organizing protein Dbn1
Authors: Colding-Christensen Camilla S. , Kakulidis Ellen S. , Arroyo-Gomez Javier , Hendriks Ivo A. , Arkinson Connor , Fábián Zita , Gambus Agnieszka , Mailand Niels , Duxin Julien P. , Nielsen Michael L.
Published: May 2023

Ubiquitin widely modifies proteins, thereby regulating most cellular functions. The complexity of ubiquitin signalling necessitates unbiased methods enabling global detection of dynamic protein ubiquitylation. Here, we describe UBIMAX (UBiquitin target Identification byMass spectrometry inXenopusegg extracts), which enriches ubiquitin-conjugated proteins and quantifies regulation of protein ubiquitylation under precise and adaptable conditions. We benchmark UBIMAX by investigating DNA double-strand break-responsive ubiquitylation events, identifying previously known targets and revealing the actin-organising protein Dbn1 as a novel major target of DNA damage-induced ubiquitylation. We find that Dbn1 is targeted for proteasomal degradation by the SCFβ-Trcp1ubiquitin ligase, in a conserved mechanism driven by ATM-mediated phosphorylation of a previously uncharacterized β-Trcp1 degron containing an SQ motif. We further show that this degron is sufficient to induce DNA-damage dependent protein degradation of a model substrate. Collectively, we demonstrate UBIMAX’s ability to identify novel targets of stimulus-regulated ubiquitylation and reveal an SCFβ-Trcp1-mediated ubiquitylation mechanism controlled directly by the apical DNA damage response kinases.
Predictive Coding Networks for Temporal Prediction
Authors: Millidge Beren , Tang Mufeng , Osanlouy Mahyar , Harper Nicol S. , Bogacz Rafal
Published: May 2023

One of the key problems the brain faces is inferring the state of the world from a sequence of dynamically changing stimuli, and it is not yet clear how the sensory system achieves this task. A well-established computational framework for describing perceptual processes in the brain is provided by the theory of predictive coding. Although the original proposals of predictive coding have discussed temporal prediction, later work developing this theory mostly focused on static stimuli, and key questions on neural implementation and computational properties of temporal predictive coding networks remain open. Here, we address these questions and present a formulation of the temporal predictive coding model that can be naturally implemented in recurrent networks, in which activity dynamics rely only on local inputs to the neurons, and learning only utilises local Hebbian plasticity. Additionally, we show that temporal predictive coding networks can approximate the performance of the Kalman filter in predicting behaviour of linear systems, and behave as a variant of a Kalman filter which does not track its own subjective posterior variance. Importantly, temporal predictive coding networks can achieve similar accuracy as the Kalman filter without performing complex mathematical operations, but just employing simple computations that can be implemented by biological networks. Moreover, when trained with natural dynamic inputs, we found that temporal predictive coding can produce Gabor-like, motion-sensitive receptive fields resembling those observed in real neurons in visual areas. In addition, we demonstrate how the model can be effectively generalized to nonlinear systems. Overall, models presented in this paper show how biologically plausible circuits can predict future stimuli and may guide research on understanding specific neural circuits in brain areas involved in temporal prediction.

Author summary

While significant advances have been made in the neuroscience of how the brain processes static stimuli, the time dimension has often been relatively neglected. However, time is crucial since the stimuli perceived by our senses typically dynamically vary in time, and the cortex needs to make sense of these changing inputs. This paper describes a computational model of cortical networks processing temporal stimuli. This model is able to infer and track the state of the environment based on noisy inputs, and predict future sensory stimuli. By ensuring that these predictions match the incoming stimuli, the model is able to learn the structure and statistics of its temporal inputs and produces responses of neurons resembling those in the brain. The model may help in further understanding neural circuits in sensory cortical areas.
Willingness to pay for electronic transaction levy: empirical evidence from Ghana
Authors: Amoah Anthony , Kwablah Edmund , Amoah Benjamin , Adjei-Mantey Kwame
Published: May 2023

Purpose

In countries where the electronic levy (e-levy) has been implemented, one question that resonates with the populace is, “how much would you want to pay for e-levy per transaction?” In response, varied perspectives have been shared with no convergence. Against this background, this study seeks to estimate people's willingness to pay (WTP) for electronic transaction levy in Ghana, while analysing the associated determinants.

Design/methodology/approach

This study relies on a survey of 2,810 respondents obtained from February 9 to 16, 2022 in Ghana. A multivariate logit model was estimated with its marginal effects. Further, a robustness check was undertaken using the linear probability model to validate the results.

Findings

With respect to the sample, the authors find evidence that approximately 46% of the respondents are not willing to pay any amount per transaction for the e-levy. Second, about 21% of the respondents are willing to pay Ghs0.5% as e-levy per transaction. Furthermore, about 10% of the respondents are willing to pay 1% per transaction as e-levy. Those who indicated that they would pay rates above 1% (specifically, 1.50%–1.75%) per transaction are less than 5%. For flat rates, approximately 10% of the respondents were willing to pay Ghs5 per month for all transactions above Ghs100. All others who are interested in other flat rates together are less than 5% of the respondents. The key statistically significant determinants of the probability that an individual would be willing to pay for the e-levy are also provided. This study recommends a comprehensive dialogue between the government and all stakeholders to reach a reasonable conclusion on an acceptable e-levy rate and by extension, implementation strategies.

Originality/value

To the best of the researchers' knowledge, this is the first empirical study that estimates individuals' willingness to pay for e-levy on electronic transactions in a developing country.
What happens to others will happen to me! Examining the cross-lagged relationship between perceived overall justice and job insecurity
Authors: Lazauskaite-Zabielske Jurgita , Urbanaviciute Ieva , De Witte Hans
Published: May 2023

Purpose

Considering the adverse outcomes that job insecurity might have on employees and organizations (De Witte et al., 2016), this study aims to test the role of perceived justice in preventing job insecurity from occurring. Relying on social information processing theory (Salancik and Pfeffer, 1978) and fairness heuristic theory (Lind, 2001), the authors analyze both an assessment of the extent to which the person is treated fairly by the organization (i.e. self-focused justice) and an individual's evaluation of the extent to which the person's co-workers are treated fairly (i.e. other-focused justice). The authors expect other-focused and self-focused justice to be negatively related to job insecurity.

Design/methodology/approach

The hypotheses were tested using cross-lagged structural equation modelling based on two-wave data from 126 employees working in a public sector organization undergoing structural changes.

Findings

The study results revealed that other-focused overall justice but not self-focused overall justice predicted lower job insecurity one year later. Moreover, other-focused overall justice did have a cross-lagged effect on self-focused overall justice.

Originality/value

By investigating the relationship between other- and self-focused overall justice and job insecurity over time, this study provides solid evidence into so far neglected longitudinal relationships between justice and insecurity. The results show that in the context of organizational changes, other-focused overall justice predicted lower job insecurity as well as higher self-focused overall justice one year later.
Does M-payment service quality and perceived value co-creation participation magnify M-payment continuance usage intention? Moderation of usefulness and severity
Authors: Kumari Neha , Biswas Abhijeet
Published: May 2023

Purpose

Demonetization and pandemic-related restrictions in India propelled the usage of mobile payments (M-payments). The culture of online smartphone transactions is expected to rise over the coming years, even after things return to normal. This study aims to unveil the factors that escalate the satisfaction levels of M-payment users and eventually stimulate them to continue using M-payments for their daily activities.

Design/methodology/approach

This study evaluated the intention to continue using M-payments for 710 users utilizing structural equation modeling and augmenting the technology acceptance model (TAM) as well as the expectation confirmation model (ECM). Mediation and moderation analysis examined the proposed model's direct and indirect relationships.

Findings

The findings unveil that perceived value co-creation participation, service quality and cognitive processing magnify user satisfaction, significantly escalating M-payment continuance usage intention. Perceived value co-creation participation and user satisfaction with M-payment partially mediate the linkage among the constructs. Furthermore, perceived usefulness strengthens the link, while perceived severity of security threats weakens the linkage between user satisfaction with M-payment and continuance usage intention.

Research limitations/implications

The study's findings could benefit M-payment service providers, users, policymakers and the telecom industry to strengthen India's digital payment framework.

Originality/value

The perceived value co-creation participation and cognitive processing domain have not garnered much attention in the M-payment literature. The study strives to comprehend these constructs by widening the purview of TAM and ECM models. It also measures the moderating role of perceived severity of security threats and perceived usefulness to unfurl potential linkages between the identified constructs.
Managing empowerment: adjusting organisational units' autonomy to achieve corporate agility
Authors: Kahl Joachim , de Klerk Saskia , Whiteoak John
Published: May 2023

Purpose

Empowerment is recognised as being a key to achieving organisational agility. Typically associated with a particular leadership style, implications of empowerment for management have remained vague in the literature. Thus, this study aims at unpacking the facets and mechanisms of empowerment in the context of organisational units (OUs).

Design/methodology/approach

First, the authors review the extant literature and discuss the crucial concepts in the context empowerment. Then, the authors analyse qualitative data from interviews conducted in four research and development (R&D) departments in the industrial manufacturing industry.

Findings

This study finds that the empowerment of business entities is crucial when operating in turbulent conditions. However, empowerment must be accompanied by a clear focus when aiming at higher agile performance. Moreover, different autonomy types and their interplay with critical factors of middle management empowerment could be identified. The research results also reveal important details about the effects of autonomy on motivation and performance and the role of OUs' dependencies.

Practical implications

The model proposed in this paper can help senior and middle managers better manage the empowerment of OUs required to enhance middle management agility and, in turn, increase overall organisational adaptability.

Originality/value

Beyond regarding empowerment as a leadership style, this paper takes a middle management perspective and unfolds the facets of empowerment in the context of OUs. Adding to the theory of self-organisation, a model is proposed to capture the key factors to determine and manage the autonomy of OUs. These insights are essential to managing autonomy successfully at the middle management level.
Engagement and consumption behavior of eSports gamers
Authors: Abbasi Amir Zaib , Asif Muhammad , Shamim Amjad , Ting Ding Hooi , Rather Raouf Ahmad
Published: May 2023

Purpose

The purpose of this study is to present a conceptual model where consumer electronic sports (eSports) engagement (CeSE) acts a predictor for gamers’ online engagement in eSports-related products/firm either through direct contribution (purchase intention) or indirect contribution (co-production, community engagement, word-of-mouth and recruitment).

Design/methodology/approach

Data from 262 eSports consumers aged 18–24 years were collected and analyzed through WarpPLS 8.0.

Findings

The findings of this study confirm that CeSE significantly influences all dimensions of the consumption behaviors (purchase intention, co-production, community engagement, word-of-mouth and recruitment).

Originality/value

This study provides empirical support for a conceptual framework developed through the social exchange theory and engagement theory. Besides, hierarchical component model approach is applied to estimate the composite model of CeSE.
Distinct spatiotemporal succession of bacterial generalists and specialists in the lacustrine plastisphere
Authors: Yang Yuyi , Suyamud Bongkotrat , Liang Shuxin , Liang Xinjin , Wan Wenjie , Zhang Weihong
Published: May 2023

The assembly processes of generalists and specialists and their driving mechanisms during spatiotemporal succession is a central issue in microbial ecology but a poorly researched subject in the plastisphere. We investigated the composition variation, spatiotemporal succession, and assembly processes of bacterial generalists and specialists in the plastisphere, including non‐biodegradable (NBMPs) and biodegradable microplastics (BMPs). Although the composition of generalists and specialists on NBMPs differed from that of BMPs, colonization time mainly mediated the composition variation. The relative abundance of generalists and the relative contribution of species replacement were initially increased and then decreased with colonization time, while the specialists initially decreased and then increased. Besides, the richness differences also affected the composition variation of generalists and specialists in the plastisphere, and the generalists were more susceptible to richness differences than corresponding specialists. Furthermore, the assembly of generalists in the plastisphere was dominated by deterministic processes, while stochastic processes dominated the assembly of specialists. The network stability test showed that the community stability of generalists on NBMPs and BMPs was lower than corresponding specialists. Our results suggested that different ecological assembly processes shaped the spatiotemporal succession of bacterial generalists and specialists in the plastisphere, but were less influenced by polymer types.
Structural Factors and Racial/Ethnic Inequities in Travel Times to Acute Care Hospitals in the Rural US South, 2007–2018
Authors: PLANEY ARRIANNA MARIE , PLANEY DONALD A. , WONG SANDY , MCLAFFERTY SARA L. , KO MICHELLE J.
Published: May 2023

Policy Points

Policymakers should invest in programs to support rural health systems, with a more targeted focus on spatial accessibility and racial and ethnic equity, not only total supply or nearest facility measures.

Health plan network adequacy standards should address spatial access to nearest and second nearest hospital care and incorporate equity standards for Black and Latinx rural communities.

Black and Latinx rural residents contend with inequities in spatial access to hospital care, which arise from fundamental structural inequities in spatial allocation of economic opportunity in rural communities of color. Long‐term policy solutions including reparations are needed to address these underlying processes.

Context

The growing rate of rural hospital closures elicits concerns about declining access to hospital‐based care. Our research objectives were as follows: 1) characterize the change in rural hospital supply in the US South between 2007 and 2018, accounting for health system closures, mergers, and conversions; 2) quantify spatial accessibility (in 2018) for populations most at risk for adverse outcomes following hospital closure—Black and Latinx rural communities; and 3) use multilevel modeling to examine relationships between structural factors and disparities in spatial access to care.

Methods

To calculate spatial access, we estimated the network travel distance and time between the census tract–level population‐weighted centroids to the nearest and second nearest operating hospital in the years 2007 and 2018. Thereafter, to describe the demographic and health system characteristics of places in relation to spatial accessibility to hospital‐based care in 2018, we estimated three‐level (tract, county, state‐level) generalized linear models.

Findings

We found that 72 (10%) rural counties in the South had ≥1 hospital closure between 2007 and 2018, and nearly half of closure counties (33) lost their last remaining hospital to closure. Net of closures, mergers, and conversions meant hospital supply declined from 783 to 653. Overall, 49.1% of rural tracts experienced worsened spatial access to their nearest hospital, whereas smaller proportions experienced improved (32.4%) or unchanged (18.5%) access between 2007 and 2018. Tracts located within closure counties had longer travel times to the nearest acute care hospital compared with tracts in nonclosure counties. Moreover, rural tracts within Southern states with more concentrated commercial health insurance markets had shorter travel times to access the second nearest hospital.

Conclusions

Rural places affected by rural hospital closures have greater travel burdens for acute care. Across the rural South, racial/ethnic inequities in spatial access to acute care are most pronounced when travel times to the second nearest open acute care hospital are accounted for.
Rational clinical approach to transient ischaemic attack, stroke and associated mimics: A retrospective cohort study
Authors: Goh Rudy , Bacchi Stephen , Lam Lydia , Kleinig Timothy , Jannes Jim
Published: May 2023

Objective

The present study was performed to identify the individual clinical features and risk factors most strongly associated with the diagnosis of transient neurological symptoms with a cerebrovascular cause (transient ischaemic attack (TIA) or stroke), as compared to common TIA mimics (including retinal ischaemia, migraine and seizure).

Methods

In a retrospective cohort study, consecutive patients presenting with transient neurological symptoms to TIA clinic in Royal Adelaide Hospital were included. Clinical features and risk factors were recorded in a standardised form, categorised into subgroups, and analysed using descriptive statistics and diagnostic performance indicators, such as sensitivity, specificity and likelihood ratios.

Results

For 218/1273 individuals diagnosed with stroke, the three features with the highest positive likelihood ratio were the presence of diffusion weighted imaging positive lesion on magnetic resonance imaging (23.66, 95% confidence interval (CI) 14.35–51.08), extracranial carotid atherosclerosis (3.98, 95% CI 1.19–6.87) and a history of peripheral vascular disease (3.33, 95% CI 1.64–6.27). For TIA, the three features with the highest positive likelihood ratio were extracranial carotid atherosclerosis (3.98, 95% CI 1.19–8.27), presence of atrial fibrillation (2.43, 95% CI 1.54–3.46) and pre‐existing anticoagulant therapy (2.39, 95% CI 1.61–3.29). For stroke and TIA, the respective features with the lowest negative likelihood ratios were limb weakness (0.71, 95% CI 0.65–0.77) and hypertension (0.66, 95% CI 0.49–0.84).

Conclusions

The present study demonstrated that specific clinical features and risk factors were associated with the final diagnosis at TIA clinic. These clinical features may assist with diagnosis of TIA in centres without access to a vascular neurologist.
Exosomal ERBB2IP contributes to tumor growth via elevating PSAT1 expression in non‐small cell lung carcinoma
Authors: Peng Xijuan , Zhao Lanfu , Yao Linong , Dong Jingzhi , Wu Wei , Luo Tao
Published: May 2023

Background

Both exosomes and circular RNAs (circRNAs) are involved in tumor growth. Hsa_circ_0001492 (circERBB2IP) has been reported to be overexpressed in plasma exosomes from patients with lung adenocarcinoma, but the biological role of exosomal circERBB2IP in non‐small cell lung carcinoma (NSCLC) is indistinct.

Methods

Exosomes isolated from serums and medium samples were validated by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blotting. Relative expression of circERBB2IP was detected by RT‐qPCR. Loss‐of‐function was done to determine the effect of circERBB2IP on NSCLC cell proliferation and migration. Molecular mechanisms associated with circERBB2IP were predicted by bioinformatic analysis and validated by dual‐luciferase reporter, RIP, and RNA pulldown assays. In vivo experiments were performed to identify the function of circERBB2IP in NSCLC.

Results

We discovered that circERBB2IP expression was correlated with TNM grade, lymph node metastasis and tumor size of NSCLC patients. Upregulation of circERBB2IP was observed in exosomes derived from NSCLC patient's serum and circERBB2IP might be a potential diagnostic biomarker for NSCLC. CircERBB2IP was transmitted between carcinoma cells through exosomes. Knockdown of circERBB2IP lowered cell growth in mouse models and restrained NSCLC cell proliferation and migration. CircERBB2IP could mediate PSAT1 expression via sponging miR‐5195‐3p.

Conclusion

In conclusion, circERBB2IP may drive NSCLC growth by the miR‐5195‐3p/PSAT1 axis in NSCLC, shedding light on a diagnostic biomarker and therapeutic target for NSCLC.
Circ_0069094 regulates malignant phenotype and paclitaxel resistance in breast cancer cells via targeting the miR‐136‐5p/YWHAZ axis
Authors: Kong Zhihua , Han Qi , Zhu Bisheng , Wan Long , Feng Enrong
Published: May 2023

Background

Breast cancer is one of the most malignant cancers. Increasing evidence suggests that circular RNAs (circRNAs) are involved in breast cancer progression through sponging microRNA (miRNA). However, the underlying molecular mechanisms of circ_0069094 in breast cancer are unclear. This study aimed to reveal the effect of the circ_0069094/miR‐136‐5p/tyrosine 3‐monooxygenase/tryptophan 5‐monooxygenase activation protein zeta (YWHAZ) pathway on the malignant progression of breast cancer.

Methods

The quantitative real‐time polymerase chain reaction and western blot were used to assess the expression of circRNA/miRNA/mRNA. The functional effects of circ_0069094 on the cell processes of breast cancer were investigated by cell counting kit‐8, colony‐forming assay, 5‐ethynyl‐2′‐deoxyuridine (EdU) assay, flow cytometry, and transwell invasion assay. The interactions among circ_0069094, miR‐136‐5p, and YWHAZ were assessed by dual‐luciferase reporter assay. A xenograft experiment was performed to determine the effects of circ_0069094 on tumor formation.

Results

Circ_0069094 was overexpressed in paclitaxel (PTX)‐resistant breast cancer tissues and cells, and the silencing of circ_0069094 decreased tumor growth, cell proliferation and cell invasion while increasing PTX sensitivity and cell apoptosis in PTX‐resistant cells. In addition, miR‐136‐5p was a target of circ_0069094, and miR‐136‐5p inhibition abolished circ_0069094 knockdown‐induced effects in PTX‐resistant cells. MiR‐136‐5p expression was decreased in PTX‐resistant breast cancer tissues and cells, and the overexpression of miR‐136‐5p suppressed the malignant behaviors of breast cancer cells by targeting YWHAZ. Importantly, circ_0069094 regulated YWHAZ expression in breast cancer by targeting miR‐136‐5p.

Conclusion

Circ_0069094 silencing improved PTX sensitivity in breast cancer progression through competitively sponging miR‐136‐5p.
CEO career concerns in early tenure and corporate social responsibility reporting
Authors: Chen Long , Liao Chih‐Hsien , Tsang Albert , Yu Li
Published: May 2023

The literature on corporate social responsibility (CSR) disclosure focuses on its economic consequences, but little is known about motivations—especially CEO personal incentives—behind such disclosure. Using an array of CSR reporting measures, we find that career concerns of CEOs early in their tenure motivate them to use voluntary CSR reporting as a signaling mechanism. The negative association between CEO tenure and CSR reporting is more pronounced in firms with stronger information intermediaries—that is, a higher level of socially responsible investors, a higher number of analysts following, and a higher level of media coverage. We also find that CEOs early in their tenure receive more personal benefits after voluntary CSR reporting, in terms of higher total compensation, better reputation, and less turnover, than CEOs later in their tenure. Taken together, the findings of our study lend support to the conjecture that CEO career concerns early in their tenure can be an important determinant of firms' voluntary CSR reporting.
Natural progression of deep pelvic endometriosis in women who opt for expectant management
Authors: Knez Jure , Bean Elisabeth , Nijjar Simrit , Tellum Tina , Chaggar Prubpreet , Jurkovic Davor
Published: May 2023

Introduction

The natural history of endometriosis is poorly understood, and despite numerous studies, the rate of the disease progression and optimal treatment planning in women who are asymptomatic or experience mild symptoms not requiring treatment are unknown. The aim of this study was to assess the behavior of deep endometriosis in women who are managed expectantly without any medical or surgical intervention.

Material and methods

A retrospective cohort study of women diagnosed with deep endometriosis on transvaginal ultrasound scan at the Department of Gynecology, University College London Hospitals and The Gynecology Ultrasound Centre, London, UK, from April 2007 to April 2022. All women attended for at least two ultrasound scans which were carried out by a single expert ultrasound examiner and at least 6 months apart. The number and position of endometriotic nodules were recorded, and the mean diameter of each nodule was calculated from measurements taken in three orthogonal planes.

Results

During the study period, 1922 women were found to have moderate or severe deep endometriosis on pelvic ultrasound examination. A total of 135 premenopausal women who were managed expectantly fitted the inclusion criteria. The median number of endometriotic nodules per woman at the initial visit was 2 (range: 0–7), and the median follow‐up time was 666 days (181–2984). In the follow‐up period, 50/135 women (37%, 95% CI: 29–46) developed additional nodules or experienced an increase in nodule size, and 17/135 women (13%, 95% CI: 8–19) had a regression in the number or size of the nodules. In the remaining 68/135 women (50%, 95% CI: 42–59) the disease remained static during the follow‐up. The median change in mean diameter of nodules during the study period per woman was +0.13 mm (−11.67 − +5.83), with an annual growth rate of +0.09 mm/year (−6.65 − +6.45).

Conclusions

In our study we found evidence of deep endometriosis progression in just over a third of women. In view of this, asymptomatic or mildly symptomatic women diagnosed with deep endometriosis could be reassured that their disease is unlikely to worsen with time.
Urinary angiotensinogen is associated with albuminuria in adults with sickle cell anaemia
Authors: Elsherif Laila , Kanthakumar Praghalathan , Afolabi Jeremiah , Stratton Ashley F. , Ogu Ugochi , Nelson Marquita , Mukhopadhyay Ayesha , Smeltzer Matthew P. , Adebiyi Adebowale , Ataga Kenneth I.
Published: May 2023

We explored the association of novel urinary biomarkers with albumin‐creatinine ratio (ACR) in adults with sickle cell anaemia. Of 37 participants, 13 (35.2%) had persistent albuminuria (PA). Urinary levels of clusterin (p = 0.002), retinol‐binding protein 4 (p = 0.008), alpha‐1 microglobulin (p = 0.002) and angiotensinogen (p = 0.006) were significantly higher in participants with PA than in those without PA. Although univariate analysis showed significant associations between both alpha‐1 microglobulin (p = 0.035) and angiotensinogen (p = 0.0021) with ACR, only angiotensinogen was associated with ACR in multivariable analysis (p = 0.04). Our results suggest that urinary angiotensinogen may identify sickle cell anaemia patients at risk for kidney disease.
Emerging strategies for cancer therapy by ATR inhibitors
Authors: Yano Kimiyoshi , Shiotani Bunsyo
Published: May 2023

DNA replication stress (RS) causes genomic instability and vulnerability in cancer cells. To counteract RS, cells have evolved various mechanisms involving the ATR kinase signaling pathway, which regulates origin firing, cell cycle checkpoints, and fork stabilization to secure the fidelity of replication. However, ATR signaling also alleviates RS to support cell survival by driving RS tolerance, thereby contributing to therapeutic resistance. Cancer cells harboring genetic mutations and other changes that disrupt normal DNA replication increase the risk of DNA damage and the levels of RS, conferring addiction to ATR activity for sustainable replication and susceptibility to therapeutic approaches using ATR inhibitors (ATRis). Therefore, clinical trials are currently being conducted to evaluate the efficacy of ATRis as monotherapies or in combination with other drugs and biomarkers. In this review, we discuss recent advances in the elucidation of the mechanisms by which ATR functions in the RS response and its therapeutic relevance when utilizing ATRis.
The SHH‐GLI1 pathway is required in skin expansion and angiogenesis
Authors: Zhang Xinling , Chen Yujie , Ding Pengbing , Lin Zhiyu , Sun Zhixuan , Jin Mengying , Li Chong , Zhao Zhenmin , Bi Hongsen
Published: May 2023

To investigate the role of GLI1 on skin proliferation and neovascularization during skin expansion in mice. We constructed GLI1‐cre/R26‐Tdtomato and GLI1‐cre/R26‐mtmg gene‐tagged skin expansion mouse models. Using a two‐photon in vivo imaging instrument to observe the changes in the number and distribution of GLI1(+) cells during the expansion process and to clarify the spatial relationship between GLI1(+) cells and blood vessels during the expansion process. In vitro proliferation assays were performed to further validate the effects of SHH (sonic hedgehog) and its downstream component GLI1 on cell proliferation viability. Finally, qRT‐PCR was used to verify the changes in proliferation, angiogenesis‐related factors, SHH signalling pathway‐related factors, and the role of GLI1 cells in the process of skin expansion in mice. The number of GLI1(+) cells increased during dilation and were attached to the outer membrane of the vessel. The epidermis was thickened and the dermis thinned after the dilated skin was taken, while the epidermal thickening was suppressed and the dermis became thinner after the GLI1 cells were inhibited. The non‐inhibited group showed a significant increase in PCNA positivity with prolonged dilation compared to the GANT61(GLI specificity inhibitor) inhibited group; CD31 immunofluorescence showed a significant increase in the number of dilated skin vessels and a significant decrease in the number of vessels after treatment with GANT61 inhibitor. In vitro proliferation results showed that SHH signalling activator significantly increased the proliferation viability of GLI1(+) hair follicle mesenchymal stem cells, while GNAT61 significantly inhibited the proliferation viability of GLI1(+) hair follicle mesenchymal stem cells. GLI1 is necessary for proliferation and neovascularization in expansion skin of mice through activation of the SHH signalling pathway.
Deus Ludus: The Christocentric Games of Nicholas of Cusa and Blaise Pascal
Authors: Ashlock Garrett Lincoln
Published: May 2023

Nicholas of Cusa and his daringly speculative theology seem odd matches for Blaise Pascal, the constant critic of the philosophies en vogue during his life. A commonality they share is their mutual concern for the apparent disproportion between the infinite God and the finite human. In this paper, I compare and analyse the shape this question takes in Cusanus's De ludo globi and Pascal's Pensées. Both men observe a sort of ‘ludic’ character inherent to the pursuit of bridging finite and infinite. Cusanus's ‘ball game’ realises the universe and the human being's pursuit of salvation as a circular field in which the player seeks to reach the vanishing point of its centre. Pascal likewise portrays human life as a cosmic game that everyone must ‘play’ with their ethical decisions. Ultimately, they both come to register Christ as the agent and object of their games, the divine player who fashions finitude into infinity. I conclude by sketching a way to reconcile Pascal with natural theology based on his universal game.
Tocilizumab increases regulatory T cells, reduces natural killer cells and delays graft‐versus‐host disease development in humanized mice treated with post‐transplant cyclophosphamide
Authors: Sligar Chloe , Cuthbertson Peter , Miles Nicole A , Adhikary Sam R , Elhage Amal , Zhang Geoff , Alexander Stephen I , Sluyter Ronald , Watson Debbie
Published: May 2023

Graft‐versus‐host disease (GVHD) is a life‐threatening complication following donor hematopoietic stem cell transplantation, where donor T cells damage host tissues. This study investigated the effect of tocilizumab (TOC) combined with post‐transplant cyclophosphamide (PTCy) on immune cell engraftment and GVHD development in a humanized mouse model. NOD‐scid‐IL2Rγnull (NSG) mice were injected intraperitoneally with 2 × 107 human (h) peripheral blood mononuclear cells and cyclophosphamide (33 mg kg−1) or saline on days 3 and 4, then TOC or control antibody (0.5 mg mouse−1) twice weekly for 28 days. Mice were monitored for clinical signs of GVHD for either 28 or 70 days. Spleens and livers were assessed for human leukocyte subsets, and serum cytokines and tissue histology were analyzed. In the short‐term model (day 28), liver and lung damage were reduced in PTCy + TOC compared with control mice. All groups showed similar splenic hCD45+ leukocyte engraftment (55–60%); however, PTCy + TOC mice demonstrated significantly increased (1.5–2‐fold) splenic regulatory T cells. Serum human interferon gamma was significantly reduced in PTCy + TOC compared with control mice. Long‐term (day 70), prolonged survival was similar in PTCy + TOC (median survival time, > 70 days) and PTCy mice (median survival time, 56 days). GVHD onset was significantly delayed in PTCy + TOC, compared with TOC or control mice. Notably, natural killer cells were reduced (77.5%) in TOC and PTCy + TOC mice. Overall, combining PTCy with TOC increases regulatory T cells and reduces clinical signs of early GVHD, but does not improve long‐term survival compared with PTCy alone.
Insights into phenotypic and functional CD8+ TRM heterogeneity
Authors: Heeg Maximilian , Goldrath Ananda W.
Published: May 2023

Cytotoxic CD8+ T cells recognize and eliminate infected or cancerous cells. A subset of CD8+ memory T cells called tissue‐resident memory T cells (TRM) resides in peripheral tissues, monitors the periphery for pathogen invasion, and offers a rapid and potent first line of defense at potential sites of re‐infection. TRM cells are found in almost all tissues and are transcriptionally and epigenetically distinct from circulating memory populations, which shows their ability to acclimate to the tissue environment to allow for long‐term survival. Recent work and the broader availability of single‐cell profiling have highlighted TRM heterogeneity among different tissues, as well as identified specialized subsets within individual tissues, that are time and infection dependent. TRM cell phenotypic and transcriptional heterogeneity has implications for understanding TRM function and longevity. This review aims to summarize and discuss the latest findings on CD8+ TRM heterogeneity using single‐cell molecular profiling and explore the potential implications for immune protection and the design of immune therapies.
ALENDRONATE: A NEW BISPHOSPHONATE FOR THE TREATMENT OF OSTEOPOROSIS
Authors: Keen RW , Spector TD
Published: May 2023

SUMMARY Alendronate is a drug with considerable potential. It is likely to work best in elderly patients with moderate to severe osteoporosis. Long‐term studies and comparison with other therapeutic agents are needed before its exact role is established.
CONFERENCE REVIEW: SCIENTIFIC SESSION OF THE AMERICAN COLLEGE OF CARDIOLOGY 1996
Authors: Purcell H
Published: May 2023

SUMMARY Several truly ‘landmark’ studies were presented duting the 45th Annual Scientific Session of the American College of Cardiology (ACC). This report reviews studies of markers of atherosclerosis and some of the trials in endothelial dysfunction (TREND), lipid lowering (CARE), coronary angioplasty and unstable angina (EPILOG, CAPTURE, RESTORE), acute myocardial infarction (HERO, GUSTO 11b), post‐myocardial infarction (EMIAT, CAMIAT), and heart failure (DIG trial).
ACALCULOUS CHOLECYSTITIS IN PATIENTS WITH ACUTE LEUKAEMIA
Authors: Topeli A , Demiroglu H , Dundar S
Published: May 2023

SUMMARY Cases of acalculous cholecystitis in patients with acute leukaemia are rare. Manifestations of the primary disease often mask the acute cholecystitis symptoms. A high index of suspicion and ultrasonographic examination in leukaemic patients with abdominal pain and unexplained fever may allow earlier diagnosis, before the development of complications. We report two cases of acute acalculous cholecystitis during the course of acute leukaemia.
A RANDOMISED STUDY TO COMPARE THE EFFICACY AND SAFETY OF A NEW 17β‐OESTRADIOL TRANSDERMAL MATRIX PATCH WITH ESTRADERM TTS 50 IN HYSTERECTOMISED POSTMENOPAUSAL WOMEN
Authors: Al‐Azzawi F , van der Mooren MJ , Rolland R , Hirvonen E ,   The Lyrelle Study Group
Published: May 2023

SUMMARY This study was designed to compare the efficacy and safety of two sizes of Lyrelle, a new matrix design transdermal oestrogen patch, with Estraderm TTS 50, a reservoir system. Three hundred and ninety‐four (394) hysterectomised postmenopausal women between 30 and 65 years of age participated in this open‐label, randomised, multicentre clinical trial. The main efficacy criterion was the reduction in the mean number of hot flushes per day at six months. Secondary efficacy end points included other climacteric symptoms as well as various psychofunctional and genitourinary disorders. A significant decrease from baseline in the mean number of hot flushes/day was observed in all three groups from the end of cycle 1, reaching 90% at the end of cycle 7. There was no statistically significant difference between Lyrelle 50 and Estraderm at any time point for any parameter; however, between‐group differences between Lyrelle 80 and Estraderm for various parameters were seen in the first three cycles in favour of Lyrelle 80. A similar impact on blood lipid levels was observed in all three groups, without significant between‐group differences. We conclude that the new Lyrelle patch is a highly effective system for transdermal oestrogen replacement therapy that may enhance long‐term patient compliance