bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanical forces at the kidney filtration barrier govern spatial orientation of podocyte processes on capillaries
Authors: Unnersjö-Jess David , Ramdedovic Amer , Butt Linus , Plagmann Ingo , Höhne Martin , Hackl Agnes , Blom Hans , Schermer Bernhard , Benzing Thomas
Published: February 2023

Mammalian kidneys filter enormous volumes of water and small solutes, a filtration driven by the very high hydrostatic pressure in glomerular capillaries. Interdigitating cellular processes of podocytes form the slits for fluid filtration. They are connected by the membrane-like slit diaphragm cell junction containing a mechanosensitive ion channel complex and allow filtration while counteracting hydrostatic pressure. Using high-resolution microscopy, we show that filtration-slit-generating secondary processes preferentially align along the capillaries’ longitudinal axis while primary processes are preferably perpendicular to the longitudinal direction. The preferential orientation requires maturation in development and is lost in disease states. We demonstrate that loss of proper orientation might contribute to impaired filtration by collapsing of the filtration slits and reducing the mechanical stability of podocyte processes. Together, these data suggest that podocytes sense mechanical strain to utilize circumferential hoop stress balancing the massive mechanical strain generated from fluid flow over the filtration slit.
Effects of Antibiotic Interaction on Antimicrobial Resistance Development in Wastewater
Authors: Sutradhar Indorica , Ching Carly , Desai Darash , Heins Zachary , Khalil Ahmad S. , Zaman Muhammad H.
Published: February 2023

While wastewater is understood to be a critically important reservoir of antimicrobial resistance due to the presence of multiple antibiotic residues from industrial and agricultural runoff, there is little known about the effects of antibiotic interactions in the wastewater on the development of resistance. We worked to fill this gap in quantitative understanding of antibiotic interaction in constant flow environments by experimentally monitoringE. colipopulations under subinhibitory concentrations of combinations of antibiotics with synergistic, antagonistic, and additive interactions. We then used these results to expand our previously developed computational model to account for the complex effects of antibiotic interaction. We found that whileE. colipopulations grown in additively interacting antibiotic combinations grew predictably according to the previously developed model, those populations grown under synergistic and antagonistic antibiotic conditions exhibited significant differences from predicted behavior.E. colipopulations grown in the condition with synergistically interacting antibiotics developed less resistance than predicted, indicating that synergistic antibiotics may have a suppressive effect on antimicrobial resistance development. FurthermoreE. colipopulations grown in the condition with antagonistically interacting antibiotics showed an antibiotic ratio-dependent development of resistance, suggesting that not only antibiotic interaction, but relative concentration is important in predicting resistance development. These results provide critical insight for quantitatively understanding the effects of antibiotic interactions in wastewater and provide a basis for future studies in modelling resistance in these environments.

Importance

Antimicrobial resistance (AMR) is a growing global threat to public health expected to impact 10 million people by 2050, driving mortality rates globally and with a disproportionate effect on low- and middle-income countries. Communities in proximity to wastewater settings and environmentally contaminated surroundings are at particular risk due to resistance stemming from antibiotic residues from industrial and agricultural runoff. Currently, there is a limited quantitative and mechanistic understanding of the evolution of AMR in response to multiple interacting antibiotic residues in constant flow environments. Using an integrated computational and experimental methods, we find that interactions between antibiotic residues significantly affect the development of resistant bacterial populations.
Integrated Constraint-Based Modeling ofE. coliCell-Free Protein Synthesis
Authors: Vilkhovoy Michael , Dammalapati Sruti , Vadhin Sandra , Adhikari Abhinav , Varner Jeffrey D.
Published: February 2023

Cell-free protein expression has become a widely used research tool in systems and synthetic biology and a promising technology for protein biomanufacturing. Cell-free protein synthesis relies onin-vitrotranscription and translation processes to produce a protein of interest. However, transcription and translation depend upon the operation of complex metabolic pathways for precursor and energy regeneration. Toward understanding the role of metabolism in a cell-free system, we developed a dynamic constraint-based simulation of protein production in the myTXTLE. colicell-free system with and without electron transport chain inhibitors. Time-resolved absolute metabolite measurements for ℳ = 63 metabolites, along with absolute concentration measurements of the mRNA and protein abundance and measurements of enzyme activity, were integrated with kinetic and enzyme abundance information to simulate the time evolution of metabolic flux and protein production with and without inhibitors. The metabolic flux distribution estimated by the model, along with the experimental metabolite and enzyme activity data, suggested that the myTXTL cell-free system has an active central carbon metabolism with glutamate powering the TCA cycle. Further, the electron transport chain inhibitor studies suggested the presence of oxidative phosphorylation activity in the myTXTL cell-free system; the oxidative phosphorylation inhibitors provided biochemical evidence that myTXTL relied, at least partially, on oxidative phosphorylation to generate the energy required to sustain transcription and translation for a 16-hour batch reaction.
An immune cell lipid atlas reveals the basis of susceptibility to ferroptosis
Authors: Pernes Gerard , Morgan Pooranee K , Huynh Kevin , Giles Corey , Paul Sudip , Smith Adam Alexander T , Mellett Natalie A , Veiga Camilla Bertuzzo , Collins Thomas JC , De Silva T Michael , Lee Man KS , Meikle Peter J , Lancaster Graeme I , Murphy Andrew J
Published: February 2023

The cellular lipidome is comprised of thousands of unique lipid species. This complexity underpins the many roles of lipids in cellular biology. How lipidome composition varies between cell types and how such differences contribute to cell-specific functionality is poorly understood. Here, using mass spectrometry-based targeted lipidomics, we have characterised the cellular lipid landscape of the human and mouse immune systems (www.cellularlipidatlas.com). We find that myeloid and lymphoid cell lineages have unique lipid compositions, notably in the usage of ester and ether bonds within glycerophospholipids (PLs) and PL acyl chain composition. To determine if immune cell-specific lipid phenotypes promote cell-specific functional properties we focused on differences in poly-unsaturated fatty acid (PUFA)-containing PL, the levels of which are markedly higher in lymphoid cells relative to myeloid cells. We firstly show that differences in PUFA-PL content provides a mechanistic basis for previously described differences in immune cell susceptibility to ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, and secondly, that the low PUFA-PL content of neutrophils restrains NADPH oxidase-driven ferroptosis. In summary, we show that the lipid landscape is a defining feature of immune cell identity and that cell-specific lipid phenotypes underpin aspects of immune cell physiology.
Business process management applicability to destination country-brand management
Authors: Miyamaru Letícia , Lourenção Marina , Dallavale de Pádua Silvia Inês , de Moura Engracia Giraldi Janaina
Published: February 2023

Purpose

This study aims to analyze the business process management (BPM) applicability to a destination country-brand of a Latin American developing country and present a new process model for it.

Design/methodology/approach

This is a qualitative exploratory study whose unit of analysis is the BPM applicability to the destination country-brand of a Latin American developing country. Primary data were obtained through in-depth interview with the developing country's tourism international promotion agency. The secondary data were government reports and research papers on country-brand studies. Data analysis was carried out using stakeholder business context model, architecture processes, pain/gain matrix and BPMN for modelling.

Findings

The results present a new process model for country-brand management to reduce existing barriers. Three steps were carried out: analysis and modelling of the current processes of country-brand management; presentation of the current processes' problems and analysis and modelling of future processes country-brand management.

Research limitations/implications

A theoretical contribution is provided in the literature on processes and country-brands since no previous studies relate these concepts and present a process-oriented management analysis for country-brands.

Practical implications

The main practical contribution was to identify the country-brand management problems, propose solutions to them and generate a new process model for country-brands that can be used as a managerial tool for national tourism organizations to improve their brands.

Originality/value

The present study is original as it approaches the first analysis of country-brand development with an emphasis on its process management.
Performance at the cost of well-being? Testing the multi-level effects of HR practices on organisational performance via employee experiences and well-being
Authors: Sutton Anna , Atkinson Carol
Published: February 2023

Purpose

While the potential for HR practices (HRPs) to improve organisational performance is well-established, the mechanisms by which this occurs are complex. Individual HRPs may affect organisational performance either by mutual gains (improving both organisational performance and employee well-being) or by conflicting outcomes (organisational performance is improved at the expense of employee well-being). Models which combine HRPs may mask these differences and this study therefore tests pathways for four individual HRPs.

Design/methodology/approach

HRPs (employee involvement, pay, performance management and training) were hypothesised to influence organisational performance directly and indirectly via employee experiences of work (communication, autonomy) and employee well-being. The study used a large secondary dataset, the UK Workplace Employee Relations Survey 2011, to test these relationships in a multi-level model.

Findings

Employee experiences of work strongly predicted well-being. In addition, three different pathways from HRP to organisational performance were identified. Pay showed indirect negative effects, involvement had direct positive effects and performance management had a mixture of both positive direct and negative indirect effects on performance.

Originality/value

Using a disaggregated analysis of HRP and demonstrating their differing effects, this study questions the feasibility of a universal model of HRP effects. By using multi-level modelling (MLM), the study develops understanding of employee perspectives and integrates these into organisational-level models, demonstrating that performance effects are partially mediated by both employee experiences of work and employee well-being. Finally, the study highlights the complexity of performance effects achieved via both employee benefits and an intensification of employee experiences.
Parental unemployment and adolescents' academic performance
Authors: Drydakis Nick
Published: February 2023

Purpose

During the Great Recession, the increase in Greece's unemployment rate was the highest in the European Union (EU). However, there exists no multi-variate study which has assessed the association between parental unemployment and adolescents' grades. The present study aimed to examine whether parental unemployment is associated with deterioration in adolescents' grades during periods of economic decline.

Design/methodology/approach

The study utilised panel data from the same upper high schools in the periods 2011–2013 and 2017–2019 to assess whether the grades of adolescents were associated with parental unemployment. A variety of empirical specifications and robustness tests were employed to offer better informed evaluations.

Findings

The exogeneity of parental unemployment with respect to adolescents' grade was confirmed. The analysis revealed that parental unemployment was associated with a decline in adolescents' grades. Periods of economic decline, i.e. in 2011–2013, were found to be associated with deterioration in adolescents' grades. Moreover, during periods of economic decline, parental unemployment was associated with deterioration in adolescents' grades. Furthermore, parental unemployment was associated with lower adolescents' grades for those households that were not homeowners and whose schools were located in working-class areas. The outcomes were found to be robust, even after including information for government expenditure on education and social protection.

Originality/value

This is the first Greek study, and amongst the first international studies, to evaluate whether parental unemployment can lead to a deterioration in adolescents' grades during an economic decline. The potential long-lasting effects of parental unemployment on children's human capital should be considered by policymakers, as should educational interventions to support households experiencing adverse economic conditions.
Tradeoff between well-being of students and cost of greening schools in arid regions
Authors: Elkhapery Basel , Kianmehr Peiman , Doczy Ryan
Published: February 2023

Purpose

Schools should be adequately built and operated to protect students' health. Green building rating systems, including Leadership in Energy and Environmental Design (LEED), assist the construction industry in improving both the resource efficiency and indoor environmental quality of its buildings. Construction professionals may waive some green modifications and available optional credits due to their high costs or construction complexities. This study investigates whether cost-effective green modifications can adequately address the student health.

Design/methodology/approach

In an effort to identify how school projects in Dubai, UAE prioritized LEED credits related to occupant well-being, the study identified eight LEED credits (called “Health and wellbeing” credits). Cost data from a sample of nine Dubai schools were used to develop an indicator, named the Feasibility Index Score (FIS), to quantify the attractiveness of LEED credits based on their cost and implementation complexity. Physical measurements taken from the sample schools give a window into current indoor environmental quality (IEQ) conditions of schools in the local region, while FIS provides insight into potential financial barriers towards improving these conditions.

Findings

The authors identified eight “Health and wellbeing” credits, which may net up to 14 points or 13% of all possible LEED points. Despite this, assessments of the sample schools revealed that six of the “Health and wellbeing” credits exhibited relatively low FIS values. This may cause these credits to be waived when lower tiers of LEED certifications are desired.

Research limitations/implications

A sample of nine schools was chosen for this research; further investigation using a greater sample size is recommended.

Practical implications

The paper's IEQ assessment indicates the importance of health-related credits and suggests implementing them regardless of their FIS.

Originality/value

This paper recognizes the importance of providing more weight to credits that directly impact the health of occupants, particularly when upgrading existing structures.
Should I stay or should I go? Benefits of crowd-checking technology for a face-to-face shopping experience
Authors: Marikyan Davit , Pantano Eleonora , Scarpi Daniele
Published: February 2023

Purpose

Long sales periods (i.e. Christmas time, Black Friday, etc.) and the risk of contagion while shopping (i.e. during pandemics like COVID-19) showed the extent to which crowded shopping environments have negative effects on consumers’ behavior. Hence, using terror management theory (TMT) and stimulus–organism–response (S–O–R) approach, the authors aims to develop a new model to investigate the effect of crowd-checking technology on shopping anxiety, the perceived value of shopping experience and willingness to pay.

Design/methodology/approach

Using a cross-sectional research design and with a help of an independent research company, the authors collected 1,000 valid responses from individuals residing in the UK.

Findings

Results showed that crowd-checking technology cues reduce shopping anxiety, improve value perceptions and increase willingness to pay. In addition, the efficacy of technology in reducing shopping anxiety is moderated by customers’ shopping orientation.

Originality/value

To the best of the authors’ knowledge, this research is the first one investigating crowd monitoring systems used at the initial stage of consumers’ journey to show the number of consumers in-store in real-time. It contributes to the literature on technology applications in retailing by providing evidence that technology cues reduce shopping anxiety, which in turn enhances customer-perceived value from the shopping experience and increases the willingness to pay in stores with embedded crowd-checker technology. The study also extends the application of TMT in a new context.
Population‐specific effects of temperature and photoperiod on development and body mass in Cassida vibex (Coleoptera: Chrysomelidae)
Authors: Kutcherov Dmitry , Lopatina Elena B.
Published: February 2023

An interplay of genetic divergence and phenotypic plasticity in shaping geographic variation is increasingly receiving attention in the entomological literature. Two major environmental variables that govern life histories are temperature and photoperiod. Studies of thermal and photoperiodic reaction norms help us understand how insect diversity evolved and how insects respond to environmental change. We studied survival, development, and body mass in three geographic populations of the beetle Cassida vibex reared in the laboratory under several combinations of constant temperature (16, 19, 22, 25, and 28 °C) and photoperiod (short‐day and long‐day). The three collection sites are situated along a climatic gradient and separated by hundreds of kilometers. Each population subtly but significantly differs in the absolute values of survival rate, developmental rate, and body mass as well as in the thermal and photoperiodic plasticity of these traits, but the geographic differences do not form a latitudinal cline. The southernmost population from a relatively warm climate survives worse at low temperatures than the other two, but the overall survival is lowest in the latitudinally intermediate population. Short‐day conditions tend to accelerate postembryonic development and increase the slope of the developmental rate–temperature relationship, especially so in the intermediate population, followed by the southernmost population and then by the northernmost population. The latter, which inhabits a harsh climate, has the fastest and most temperature‐sensitive development, regardless of photoperiod, and attains the largest body mass among the three populations. The intermediately located and photoperiodically plastic population, which lives in a cool but mild climate, in contrast, has the smallest body size. Hence, although the importance of short‐day conditions as a seasonal cue increases poleward, the photoperiodic responses do not always become more pronounced in colder, high‐latitude environments. Our results emphasize that insect life‐history traits can exhibit quite sophisticated patterns of variation along climatic gradients.
Improvement in bioconversion efficiency and reduction of ammonia emission by introduction of fruit fermentation broth in a black soldier fly larvae and kitchen waste conversion system
Authors: Li Lusheng , Chen Lifei , Shang Rongsheng , Wang Guiying , Zhang Jibin
Published: February 2023

The black soldier fly (BSF), Hermetia illucens (Diptera: Stratiomyidae), is an insect commonly used for the bioconversion of various organic wastes. Not only can the BSF convert organic waste into macromolecular organic substances, such as insect proteins, but it can also lessen the pollution associated with these waste products by reducing ammonia emissions, for example. In this study, we measured the effects of adding fruit fermentation broth (Fer) and commercial lactic acid bacteria fermentation broth (Em) to kitchen waste (KW), as deodorizing auxiliary substances, on the growth performance of black soldier fly larvae (BSFL), the intestinal flora structure of BSFL, the ammonia emission from the KW substrate, and the microbial community structure of the KW substrate. We found that the addition of Fer or Em increased the body weight of BSFL after 6 d of culture, increasing the growth rate by 9.96% and 7.96%, respectively. The addition of Fer not only reduced the pH of the KW substrate but also increased the relative abundance of probiotics, such as Lactobacillus, Lysinibacillus, and Vagococcus, which inhibited the growth of ammonifiers such as Bacillus, Oligella, Paenalcaligenes, Paenibacillus, Pseudogracilibacillus, and Pseudomonas, resulting in the reduction of ammonia emission in the KW substrate. Moreover, the addition of Fer or Em significantly increased the relative abundances of Bacteroides, Campylobacter, Dysgonomonas, Enterococcus, and Ignatzschineria in the gut of BSFL and increased the species diversity and richness in the KW substrate. Our findings provide a novel way to improve the conversion rate of organic waste and reduce the environmental pollution caused by BSF.
Port first vs. Tip first: does difference in portacath insertion techniques reduce complication rates
Authors: Tang Hannah , Bhutia Sherab
Published: February 2023

Background

Accurate placement of central venous access devices is important to avoid complications such as infection, thrombosis and migration. This audit aims to determine if there is a difference in complication rates and accuracy of tip position between two different intravenous jugular (IVJ) port device insertion techniques: fixation of port first (PF) versus tip first (TF).

Methods

Patients who underwent port device insertions from 2019 to 2021 at the Cairns Hospital were identified from the Australia Vascular Audit database. The primary outcome of accurate catheter tip placement (based on radiological criteria), secondary outcomes of line infection, thrombosis and other outcomes such as removal rates were gathered and compared between the 2 groups of port first (PF) versus tip first (TF) insertion.

Results

Two‐hundred and twenty‐seven patients underwent port device insertions during the period of interest. 98 (43.2%) patients had a PF insertion technique and 129 (56.8%) had a TF insertion technique. In the PF group, 81.6% (P < 0.05) of lines were accurately placed compared to 69.8% (P < 0.05) in the TF group. The line related thrombosis rate was 1% (P < 0.05) in the PF group compared to 6.2% (P < 0.05) in the TF group. Rate of line infections in the PF group was 5.1% (P = 0.92) compared to 6.2% (P = 0.92) in the TF group.

Conclusion

The port first technique for IVJ port device placement was associated with higher accuracy and lower thrombosis rates and this was statistically significant. Further studies should involve larger multicentre populations to compare results between practitioners.
Postcode osteoarthritis: geographic inequities in hip and knee arthroplasty
Authors: Stowers Marinus D. J. , Gibson Alexandria , Gupta Anshuman , Pohl Margy J.
Published: February 2023

Background

It is suspected that there are differences in access to orthopaedic care within New Zealand (NZ), due to inter‐hospital differences in scoring thresholds for surgical eligibility. We aimed to evaluate those patients who meet the threshold for publicly funded surgery with regard to both functional disability and severity of radiographic arthritis across three different public hospitals to assess any discrepancies.

Methods

A retrospective review of prospectively collected data over a 12 month period (2018–2019) across three public hospitals (Auckland City, North Shore and Whangārei hospitals) in NZ was performed. Patients undergoing primary hip and knee arthroplasty for OA were eligible for the study. Preoperative Oxford Score and the Tonnis and Kellgren‐Lawrence classification systems for hip and knees, respectively, were compared.

Results

A total of 274 scheduled total arthroplasties (161 hips and 113 knees) in 273 patients were included for analysis. The mean Preoperative Oxford scores for individuals with hip OA in Auckland, North Shore and Whangārei were 15.9 (SD 10.5), 14.5 (SD 6.9) and 11.9 (SD 5.7), respectively. The mean Preoperative Oxford scores for individuals with knee OA in Auckland, North Shore and Whangārei were 17.4 (SD 11.9), 18.2 (SD 6.2) and 12.7 (SD 6.9), respectively.

Conclusion

Patients undergoing hip and knee joint replacement surgery in Whangārei hospital are, on average, more functionally impaired and have more severe radiographic arthritis than those having the same proposed surgery in Auckland and North Shore hospitals.
Morphology of the optic nerve head and factors affecting it in the Northern Finland birth cohort
Authors: Pitkänen Joel , Liinamaa Johanna , Leiviskä Ilmari , Saarela Ville
Published: February 2023

Purpose

To assess topographic characteristics of the optic nerve head (ONH) and retinal nerve fibre layer (RNFL) and study the effect of ocular and physiological factors on them in a middle‐aged population.

Methods

A 1552‐person randomised sample from Northern Finland population aged 45–49 was examined. Laser scanning tomography and optical coherency tomography were performed to obtain measurements for ONH and RNFL morphology. Measurements of the RNFL included global thickness and the six zones used in automated structure–function analysis (S–F analysis). Influence of central corneal thickness (CCT), refractive correction, intraocular pressure (IOP), anterior chamber angle, gender, blood pressure, height, weight and body mass index (BMI) on tomographic data was analysed.

Results

The optic disc area had a strong correlation with all other parameters of ONH morphology (R = 0.261 to 0.706) as did spherical equivalent (R = −0.280 to 0.280). The correlations between ONH and RNFL measurements were weaker (R = 0.057 to 0.180). Gender, CCT, anterior chamber angle, blood pressure, height and BMI had statistically significant, yet feeble, correlations with a number of ONH parameters.

Conclusion

Other than spherical equivalent, the studied anatomical and physiological attributes had little predictive value on the ONH morphology. The optic disc area itself had a significant effect on other measurements of ONH tomography and should be taken into consideration when the thresholds for normal ONH morphology are calculated.
Perceptions of the COVID‐19 pandemic as demonstrated in drawings of Swedish children aged 4–6 years
Authors: Sarkadi Anna , Thell Maria , Jirblom Klara
Published: February 2023

Aim

To explore the perceptions of the COVID‐19 pandemic, as expressed in the drawings of Swedish children aged 4–6 years.

Methods

We analysed 91 drawings with associated descriptions submitted to the Swedish Archive of Children's Art from April 2020 to February 2021.

Results

The visual and text analysis resulted in three themes. First, illustrating the virus and embodying the danger showed that young children understood the invisible enemy, combining realistic elements of the virus particle with fantasies of the ‘virus monster’ that needs to be fought off. Second, life has changed for the worse describes the profound effect the pandemic had on young children's lives also in Sweden, with comparatively mild restrictions and no school closures. Third, the virus spreads across the world, affects people and infects their bodies conveys young children's understanding of the pandemic as an existential challenge affecting the whole world. Children displayed surprisingly high levels of health literacy related to COVID‐19, including contagion routes and the importance of hand hygiene.

Conclusion

The drawings of Swedish children aged 4–6 years demonstrated the profound, practical and emotional effects of the pandemic on their lives. Drawings also illuminated young children's level of health literacy regarding COVID‐19.
A generational perspective of family firms' social capital: Interplay between ethical leadership and firm performance
Authors: Sanchez‐Famoso Valeriano , Maseda Amaia , Iturralde Txomin , Alayo Mikel
Published: February 2023

This study proposes and tests a model that integrates ethical leadership, internal social capital, and firm performance in small‐ and medium‐sized family firms at different generational stages. Using the upper echelons theory and the social capital perspective of familiness, this study shows that ethical leadership can explain the effectiveness of certain behaviors in relation to family firm performance. Moreover, social capital helps spread a leader's business ethics to firm members, thus improving the family firm's performance. Our results show that founders' personalities and identities determine high internal social capital, which decreases over generations. The study also shows that internal social capital is a communicative element crucial to ethical leadership, facilitating the absorption of the culture and values of the family in the firm. This powerful resource should be promoted and supported by coherent behavior over time by senior leaders.
Unravelling G protein‐coupled receptor signalling networks using global phosphoproteomics
Authors: Pokhrel Rina , Morgan Alexandra L. , Robinson Harley R. , Stone Martin J. , Foster Simon R.
Published: February 2023

G protein‐coupled receptor (GPCR) activation initiates signalling via a complex network of intracellular effectors that combine to produce diverse cellular and tissue responses. Although we have an advanced understanding of the proximal events following receptor stimulation, the molecular detail of GPCR signalling further downstream often remains obscure. Unravelling these GPCR‐mediated signalling networks has important implications for receptor biology and drug discovery. In this context, phosphoproteomics has emerged as a powerful approach for investigating global GPCR signal transduction. Here, we provide a brief overview of the phosphoproteomic workflow and discuss current limitations and future directions for this technology. By highlighting some of the novel insights into GPCR signalling networks gained using phosphoproteomics, we demonstrate the utility of global phosphoproteomics to dissect GPCR signalling networks and to accelerate discovery of new targets for therapeutic development.

LINKED ARTICLES

This article is part of a themed issue Therapeutic Targeting of G Protein‐Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc
Safe space in the woods: Mechanistic spatial models for predicting risks of human–bear conflicts in India
Authors: Puri Mahi , Srivathsa Arjun , Karanth Krithi K. , Patel Imran , Kumar N. Samba
Published: February 2023

Human–wildlife interactions can have negative consequences when they involve large carnivores. Spatial risk modelling could serve as a useful management approach for predicting and pre‐emptively mitigating negative interactions. We present a mechanistic modelling framework and examine interactions between humans and sloth bears (Melursus ursinus) in a multi‐use forest landscape of central India. We first assessed patterns and determinants of bear distribution across the landscape using indirect sign surveys. At the same spatial scale, we then estimated spatial probabilities of bear attacks on people using information from 675 interviews with local residents, incorporating estimates of distribution probabilities from the previous step. We found the average occupancy probability across 128 grid‐cells to be 0.77 (SE = 0.03). Bear occupancy was influenced by terrain ruggedness, forest composition and configuration, vegetation productivity and size of human settlements. The average probability of a bear attack in any given grid‐cell was 0.61 (SE = 0.03), mostly determined by bear occurrence patterns, forest cover, terrain ruggedness, and size of human settlements. Using spatial information on people's dependence on forest resources, we identified locations with the highest risk of bear attacks. Our study demonstrates that human attacks by bears—generally believed to be random or incidental—in fact showed deterministic patterns. Our framework can be applied to other scenarios involving human–wildlife conflicts. Based on our findings, we propose that a proactive co‐management approach which involves collaboration between wildlife managers and local residents could help better manage human–bear conflicts in central India and elsewhere across the species' range.
Mind the GAP—But make it better: Improving the U.S. Gap Analysis Project's protected‐area classification system to better reflect biodiversity conservation
Authors: Dietz Matthew S. , Belote R. Travis , Aplet Gregory H.
Published: February 2023

Protected areas are foundational to the conservation of biological diversity, and many scientists have called for increased protections in the face of the current extinction and climate‐change crises. Currently in the United States, the most recognized way to track the amount of protected land is the Gap Analysis Project classification system, which we argue is deficient in three ways: it does not, in a systematic way, specify the typical uses and constraints associated with each conservation designation; it is not fine‐tuned or nuanced enough to distinguish the levels of protection among designations within “protected” or “unprotected” areas that allow quite different human activities; and it largely ignores the durability of the designations, failing to account for an area's vulnerability to downsizing, downgrading, or degazetting. We propose a new classification system to address these deficiencies and demonstrate this method for several of the most common federal land designations in the United States.
Concentration QTc analysis of giredestrant: Overcoming QT/heart rate confounding in the presence of drug‐induced heart rate changes
Authors: Brooks Logan , Dolton Michael , Langenhorst Jurgen , Yoshida Kenta , Lien Yi Ting (Kayla) , Malhi Vikram , Li Chunze , Perez‐Moreno Pablo , Bond John , Chen Ya‐Chi , Yu Jiajie
Published: February 2023

Concentration‐QTc (C‐QTc) analysis has become a common approach for evaluating proarrhythmic risk and delayed cardiac repolarization of oncology drug candidates. Significant heart rate (HR) change has been associated with certain classes of oncology drugs and can result in over‐ or underestimation of the true QT prolongation risk. Because oncology early clinical trials typically lack a placebo control arm or time‐matched, treatment‐free baseline electrocardiogram collection, significant HR change brings additional challenges to C‐QTc analysis in the oncology setting. In this work, a spline‐based correction method (QTcSPL) was explored to mitigate the impact of HR changes in giredestrant C‐QTc analysis. Giredestrant is a selective estrogen receptor degrader being developed for the treatment of patients with estrogen receptor‐positive (ER+) breast cancer. A dose‐related HR decrease has been observed in patients under giredestrant treatment, with significant reductions (>10 bpm) observed at supratherapeutic doses. The QTcSPL method demonstrated superior functionality to reduce the correlation between QTc and HR as compared with the Fridericia correction (QTcF). The effect of giredestrant exposure on QTc was evaluated at the clinical dose of 30 mg and supratherapeutic dose of 100 mg based on a prespecified linear mixed effect model. The upper 90% confidence interval of ΔQTcSPL and ΔQTcF were below the 10 ms at both clinical and supratherapeutic exposures, suggesting giredestrant has a low risk of QT prolongation at clinically relevant concentrations. This work demonstrated the use case of QTcSPL to address HR confounding challenges in the context of oncology drug development for the first time.
T follicular helper phenotype mycosis fungoides associated with acanthosis nigricans
Authors: Spigariolo Cristina B. , Berti Emilio , Cerri Amilcare , Venegoni Luigia , Croci Giorgio , Violetti Silvia Alberti
Published: February 2023

The association between acanthosis nigricans (AN) and mycosis fungoides (MF) has rarely been described, but it is known that MF may appear as AN‐like vegetating and papillomatous plaques in skin folds, or may be associated with paraneoplastic AN. There have also been recent descriptions of a form of “intertriginous MF” that is characterized by skin fold involvement and the expression of T follicular helper (TFH) markers, and that often has an aggressive course. We describe the case of a 48‐year‐old man affected by MF associated with AN, whose lesions were characterized by a TFH immunophenotype and the expression of the GATA‐3 nuclear master regulator that may be related to a TFH‐2 subpopulation or possible disease progression.
Transgenic skin biomechanical properties following first lifesaving epidermal regeneration using combined gene and cell therapy
Authors: Yeni Burcu , Dermietzel Alexander , Varnava Charalampos , Wiebringhaus Philipp , Aitzetmueller Matthias , Klietz Marie‐Luise , Hirsch Tobias , Kueckelhaus Maximilian
Published: February 2023

Background

In 2017, we reported the first life‐saving regeneration of virtually an entire epidermis by combined gene and stem cell therapy. Recently, we demonstrated excellent long‐term stability of this transgenic epidermis. Skin quality in this experimental approach and its potential application in other conditions were elucidated here regarding long‐term outcomes of biomechanical properties.

Patients and methods

Analysis of biomechanical properties including skin elasticity, anisotropy and friction was performed on multiple body sites 24, 36 and 60 months following transplantation. Firstly, the sites were matched against and compared to remaining stable non‐transgenic areas as well as to a control group of 13 healthy subjects. Parameters for skin elasticity, deformation and friction were assessed non‐invasively.

Results

Biomechanical properties of the transgenic epidermis showed encouraging results in comparison to both the remaining stable non‐transgenic skin as well as healthy controls. Skin elasticity was comparable to the controls. Skin friction showed some decrease in both transgenic and non‐transgenic areas as compared to the controls.

Conclusions

The excellent functional outcomes of the transgenic epidermis demonstrate stable long‐term results of this novel combined gene and stem cell therapy for epidermal regeneration. Thus, other applications for this technology, such as treatment of specific burns, should be explored.
The potential of telemedicine for dermatological care of pediatric patients in Germany
Authors: Hansen Inga , Abeck Dietrich , Kött Julian , Schneider Stefan W. , Abeck Finn
Published: February 2023

Background and Objectives

Skin diseases are a common reason for consultations in pediatric practice. The present study aims to characterize the dermatological requests of resident pediatric specialists using teledermatology in Germany.

Patients and Methods

This analysis of consultation requests, submitted by pediatricians to a designated pediatric dermatologist via a telemedical consultation system (PädExpert) using the store‐and‐forward technology, was performed between February 2021 and December 2021.

Results

The study analysis included 504 telemedical consultation requests. The mean age of the patients was 6.5 ± 5.0 years with 45.5% of the patients being female. Telemedicine was useful in providing a definite diagnosis in 88.3%. The diagnoses were most frequently assigned to the group of infectious skin diseases (28.8%). Referral to a dermatologist was recommended in 11.5%. The requests were answered on the same day in 63.8% of the cases.

Conclusions

The study data shows the great potential of teledermatology to improve access for children with skin diseases to specialized dermatological care. Another advantage is its function as a triage instrument. Since most cases could be managed by teledermatology only, it is possible to reduce the need for an in‐person visit to the dermatologist, thus saving resources.
A (paid) passage to India: Migration and revealed willingness to pay for upper‐caste status
Authors: Persaud Alexander
Published: February 2023

How much are individuals willing to pay for privileged status in a society with systemic discrimination? Utilizing unique data on indentured Indians in Fiji paying to return to India, I calculate how much upper‐caste individuals were willing to pay historically for their status. I show the lower bound of the value of the uppermost castes in north India equaled almost 2.5 years' gross wages. The ordering follows hypothesized inter‐caste hierarchies and shows diminishing effects as caste status falls. Men entirely drive the effects. My results show some of the first evidence quantifying caste status values and speak to caste's persistence.
Modifiable vascular risk factors in patients with cerebral and spinal cavernous malformations: a complete 10‐year follow‐up study
Authors: Rauscher Steffen , Santos Alejandro N. , Gull Hanah Hadice , Rauschenbach Laurèl , Chen Bixia , Schmidt Börge , Deuschl Cornelius , Benet Arnau , Jabbarli Ramazan , Wrede Karsten H. , Siegel Adrian M. , Lawton Michael , Sure Ulrich , Dammann Philipp
Published: February 2023

Background and purpose

The aim was to investigate the effect of modifiable vascular risk factors on the risk of first and recurrent bleeding for patients with a cavernous malformation (CM) of the central nervous system (CNS) over a 10‐year period.

Methods

A retrospective review of our CM institutional database was performed spanning from 2003 to 2021. The inclusion criteria were non‐missing serial magnetic resonance imaging studies and clinical baseline metrics such as vascular risk factors. The exclusion criteria were patients who underwent surgical CM removal and patients with less than a decade of follow‐up. Kaplan–Meier and Cox regression analyses were performed to determine the cumulative risk (10 years) of hemorrhage.

Results

Eighty‐nine patients with a CM of the CNS were included. Our results showed a non‐significant increased risk of hemorrhage during 10 years of follow‐up in patients using nicotine (hazard ratio 2.11, 95% confidence interval 0.86–5.21) and in patients with diabetes (hazard ratio 3.25, 95% confidence interval 0.71–14.81). For the presence of modifiable vascular risk factors at study baseline different cumulative 10‐year risks of bleeding were observed: arterial hypertension 42.9% (18.8%–70.4%); diabetes 66.7% (12.5%–98.2%); hyperlipidemia 30% (8.1%–64.6%); active nicotine abuse 50% (24.1%–76%); and obesity 22.2% (4%–59.8%). Overall cumulative (10‐year) hemorrhage risk was 30.3% (21.3%–41.1%).

Conclusions

The probability of hemorrhage in untreated CNS CM patients increases progressively within a decade of follow‐up. None of the modifiable vascular risk factors showed strong indication for an influence on hemorrhage risk, but our findings may suggest a more aggressive course in patients with active nicotine abuse or suffering from diabetes.
Atypical intrinsic neural timescales in temporal lobe epilepsy
Authors: Xie Ke , Royer Jessica , Lariviere Sara , Rodriguez‐Cruces Raul , de Wael Reinder Vos , Park Bo‐yong , Auer Hans , Tavakol Shahin , DeKraker Jordan , Abdallah Chifaou , Caciagli Lorenzo , Bassett Dani S. , Bernasconi Andrea , Bernasconi Neda , Frauscher Birgit , Concha Luis , Bernhardt Boris C.
Published: February 2023

Objective

Temporal lobe epilepsy (TLE) is the most common pharmacoresistant epilepsy in adults. Here we profiled local neural function in TLE in vivo, building on prior evidence that has identified widespread structural alterations. Using resting‐state functional magnetic resonance imaging (rs‐fMRI), we mapped the whole‐brain intrinsic neural timescales (INT), which reflect temporal hierarchies of neural processing. Parallel analysis of structural and diffusion MRI data examined associations with TLE‐related structural compromise. Finally, we evaluated the clinical utility of INT.

Methods

We studied 46 patients with TLE and 44 healthy controls from two independent sites, and mapped INT changes in patients relative to controls across hippocampal, subcortical, and neocortical regions. We examined region‐specific associations to structural alterations and explored the effects of age and epilepsy duration. Supervised machine learning assessed the utility of INT for identifying patients with TLE vs controls and left‐ vs right‐sided seizure onset.

Results

Relative to controls, TLE showed marked INT reductions across multiple regions bilaterally, indexing faster changing resting activity, with strongest effects in the ipsilateral medial and lateral temporal regions, and bilateral sensorimotor cortices as well as thalamus and hippocampus. Findings were similar, albeit with reduced effect sizes, when correcting for structural alterations. INT reductions in TLE increased with advancing disease duration, yet findings differed from the aging effects seen in controls. INT‐derived classifiers discriminated patients vs controls (balanced accuracy, 5‐fold: 76% ± 2.65%; cross‐site, 72%–83%) and lateralized the focus in TLE (balanced accuracy, 5‐fold: 96% ± 2.10%; cross‐site, 95%–97%), with high accuracy and cross‐site generalizability. Findings were consistent across both acquisition sites and robust when controlling for motion and several methodological confounds.

Significance

Our findings demonstrate atypical macroscale function in TLE in a topography that extends beyond mesiotemporal epicenters. INT measurements can assist in TLE diagnosis, seizure focus lateralization, and monitoring of disease progression, which emphasizes promising clinical utility.