bluuebunny/crossref_metadata_2025 huggingface dataset:
Mutational hotspots lead to robust but suboptimal adaptive outcomes in certain environments
Authors: Flanagan Louise M. , Horton James S. , Taylor Tiffany B.
Published: June 2023

The observed mutational spectrum of adaptive outcomes can be constrained by many factors. For example, mutational biases can narrow the observed spectrum by increasing the rate of mutation at isolated sites in the genome. In contrast, complex environments can shift the observed spectrum by defining fitness consequences of mutational routes. We investigate the impact of different nutrient environments on the evolution of motility in the bacteriaPseudomonas fluorescensPf0-2x (an engineered non-motile derivative of Pf0-1) in the presence and absence of a strong mutational hotspot. Previous work has shown that this mutational hotspot can be built and broken via six silent mutations, which provide rapid access to a mutation that rescues swimming motility and confers the strongest swimming phenotype in specific environments. Here, we evolved a hotspot and non-hotspot variant strain of Pf0-2x for motility under nutrient rich (LB) and nutrient limiting (M9) environmental conditions. We observed the hotspot strain consistently evolved faster across all environmental conditions and its mutational spectrum was robust to environmental differences. However, the non-hotspot strain had a distinct mutational spectrum that changed depending on the nutrient environment. Interestingly, while alternative adaptive mutations in nutrient-rich environments were equal to, or less effective than, the hotspot mutation, the majority of these mutations in nutrient-limited conditions produced superior swimmers. Our competition experiments mirrored these findings, underscoring the role of environment in defining both the mutational spectrum and the associated phenotype strength. This indicates that while mutational hotspots working in concert with natural selection can speed up access to robust adaptive mutations (which can provide a competitive advantage in evolving populations) they can limit exploration of the mutational landscape, restricting access to potentially stronger phenotypes in specific environments.

DATA SUMMARY

All data is available at OSF: DOI 10.17605/OSF.IO/8BT2W, and in supplementary materials.
Dysfunctional T Follicular Helper Cells Cause Intestinal and Hepatic Inflammation in NASH
Authors: Wang Haiguang , Barrow Fanta , Fredrickson Gavin , Florczak Kira , Nguyen Huy , Parthiban Preethy , Herman Adam , Adeyi Oyedele , Staley Christopher , Ikramuddin Sayeed , Ruan Hai-Bin , Jameson Stephen C. , Revelo Xavier S.
Published: June 2023

Nonalcoholic steatohepatitis (NASH), characterized by hepatic inflammation and cellular damage, is the most severe form of nonalcoholic fatty liver disease and the fastest-growing indication for a liver transplant. The intestinal immune system is a central modulator of local and systemic inflammation. In particular, Peyer’s patches (PPs) contain T follicular helper (Tfh) cells that support germinal center (GC) responses required for the generation of high-affinity intestinal IgA and the maintenance of intestinal homeostasis. However, our understanding of the mechanisms regulating mucosal immunity during the pathogenesis of NASH is incomplete. Here, using a preclinical mouse model that resembles the key features of human disease, we discovered an essential role for Tfh cells in the pathogenesis of NASH. We have found that mice fed a high-fat high-carbohydrate (HFHC) diet have an inflamed intestinal microenvironment, characterized by enlarged PPs with an expansion of Tfh cells. Surprisingly, the Tfh cells in the PPs of NASH mice showed evidence of dysfunction, along with defective GC responses and reduced IgA+B cells. Tfh-deficient mice fed the HFHC diet showed compromised intestinal permeability, increased hepatic inflammation, and aggravated NASH, suggesting a fundamental role for Tfh cells in maintaining gut-liver homeostasis. Mechanistically, HFHC diet feeding leads to an aberrant increase in the expression of the transcription factor KLF2 in Tfh cells which inhibits its function. Thus, transgenic mice with reduced KLF2 expression in CD4 T cells displayed improved Tfh cell function and ameliorated NASH, including hepatic steatosis, inflammation, and fibrosis after HFHC feeding. Overall, these findings highlight Tfh cells as key intestinal immune cells involved in the regulation of inflammation in the gut-liver axis during NASH.
ER stress and lipid imbalance drive embryonic cardiomyopathy in a human heart organoid model of pregestational diabetes
Authors: Kostina Aleksandra , Lewis-Israeli Yonatan R. , Abdelhamid Mishref , Gabalski Mitchell A. , Volmert Brett D. , Lankerd Haley , Huang Amanda R. , Wasserman Aaron H. , Lydic Todd , Chan Christina , Olomu Isoken , Aguirre Aitor
Published: June 2023

Congenital heart defects constitute the most common birth defect in humans, affecting approximately 1% of all live births. The incidence of congenital heart defects is exacerbated by maternal conditions, such as diabetes during the first trimester. Our ability to mechanistically understand these disorders is severely limited by the lack of human models and the inaccessibility to human tissue at relevant stages. Here, we used an advanced human heart organoid model that recapitulates complex aspects of heart development during the first trimester to model the effects of pregestational diabetes in the human embryonic heart. We observed that heart organoids in diabetic conditions develop pathophysiological hallmarks like those previously reported in mouse and human studies, including ROS-mediated stress and cardiomyocyte hypertrophy, among others. Single cell RNA-seq revealed cardiac cell type specific-dysfunction affecting epicardial and cardiomyocyte populations, and suggested alterations in endoplasmic reticulum function and very long chain fatty acid lipid metabolism. Confocal imaging and LC-MS lipidomics confirmed our observations and showed that dyslipidemia was mediated by fatty acid desaturase 2 (FADS2) mRNA decay dependent on IRE1-RIDD signaling. We also found that the effects of pregestational diabetes could be reversed to a significant extent using drug interventions targeting either IRE1 or restoring healthy lipid levels within organoids, opening the door to new preventative and therapeutic strategies in humans.
IL-22 promotes acute kidney injury through activation of the DNA damage response and cell death in proximal tubule cells
Authors: Taguchi Kensei , Sugahara Sho , Elias Bertha C. , Pabla Navjot , Canaud Guillaume , Brooks Craig R.
Published: June 2023

Acute kidney injury (AKI) affects over 13 million people world-wide annually and is associated with a fourfold increase in mortality. Our lab and others have shown that DNA damage response (DDR) governs the outcome of AKI in a bimodal manner. Activation of DDR sensor kinases protects against AKI, while hyperactivation of DDR effector proteins, such as p53, induces to cell death and worsens AKI. The factors that trigger the switch from pro-reparative to pro-cell death DDR remain to be resolved. Here we investigate the role of interleukin 22 (IL-22), an IL-10 family member whose receptor (IL-22RA1) is expressed on proximal tubule cells (PTCs), in DDR activation and AKI. Using cisplatin and aristolochic acid (AA) induced nephropathy as models of DNA damage, we identify PTCs as a novel source of urinary IL-22, making PTCs the only epithelial cells known to secret IL-22, to our knowledge. Functionally, IL-22 binding its receptor (IL-22RA1) on PTCs amplifies the DDR. Treating primary PTCs with IL-22 alone induces rapid activation of the DDRin vitro. The combination of IL-22 + cisplatin or AA treatment on primary PTCs induces cell death, while the same dose of cisplatin or AA alone does not. Global deletion of IL-22 protects against cisplatin or AA induced AKI. IL-22 deletion reduces expression of components of the DDR and inhibits PTC cell death. To confirm PTC IL-22 signaling contributes to AKI, we knocked out IL-22RA1 in renal epithelial cells by crossing IL-22RA1floxed mice with Six2-Cre mice. IL-22RA1 KO reduced DDR activation, cell death, and kidney injury. These data demonstrate that IL-22 promotes DDR activation in PTCs, switching pro-recovery DDR responses to a pro-cell death response and worsening AKI. Targeting IL-22 represents a novel therapeutic approach to prevent the negative consequences of the DDR activation while not interfering with the processes necessary for repair of damaged DNA.

Translational statement

Acute kidney injury, which affects 10-20% of hospitalized patients, is associated with a fourfold increase in mortality and predisposes patients to chronic kidney disease. In the present study, we identify interleukin 22 as a cofactor which worsens acute kidney injury. Interleukin 22 activates the DNA damage response, which in combination with nephrotoxic drugs amplifies the injury response in kidney epithelial cells and increases cell death. Deletion of interleukin 22 from mice or its receptor from mouse kidneys ameliorates cisplatin induced nephropathy. These findings may help clarify the molecular mechanisms of DNA damage induced kidney injury and identify interventions that can help treat acute kidney injury.
A mutational atlas for Parkin proteostasis
Authors: Clausen Lene , Voutsinos Vasileios , Cagiada Matteo , Johansson Kristoffer E. , Grønbæk-Thygesen Martin , Nariya Snehal , Powell Rachel L. , Have Magnus K. N. , Oestergaard Vibe H. , Stein Amelie , Fowler Douglas M. , Lindorff-Larsen Kresten , Hartmann-Petersen Rasmus
Published: June 2023

The delicate balance of protein homeostasis can be disturbed by mutations that affect folding and stability of the encoded protein. More than half of disease-causing missense variants are thought to lead to protein degradation, but determining which and the molecular mechanisms involved remain enigmatic. To examine these issues, we selected the ubiquitin-protein ligase Parkin, where known missense variants result in an autosomal recessive, early onset Parkinsonism. We used the variant abundance by massively parallel sequencing (VAMP-seq) approach to quantify the abundance of Parkin missense variants in cultured human cells. The resulting mutational map, covering 9219 out of the 9300 possible single-site amino acid substitutions and nonsense Parkin variants, show that most low abundance variants are located within the structured domains of the protein, while the flexible linker regions are more tolerant. The vast majority of low abundance Parkin variants are degraded through the ubiquitin-proteasome system and are stabilized at a lowered temperature. The cellular abundance data correlate with thermodynamic stability, evolutionary conservation, and show that half of the known disease-linked variants are found at low abundance. Systematic mapping of degradation signals (degrons) shows that inherent primary degrons in Parkin largely overlap with regions that are buried, and highly sensitive to mutations. An exposed degron region proximal to the so-called “activation element” is enhanced by substitutions to hydrophobic residues and destroyed by introduction of hydrophilic residues. The data provide examples of how missense variants may cause degradation either via destabilization of the native protein, or by introducing local signals for degradation. Combined with the computational methods based on Parkin structure and conservation, our abundance map sheds light on the mechanisms that cause loss of function, and points to variants where function potentially can be restored.
Evaluating the ileal and cecal microbiota composition of a 1940 heritage genetic line and a 2016 commercial line of white leghorns fed representative diets from 1940 and 2016
Authors: Wall D. C. , Dittoe Dana , Mahlerios Ramon D. , Anderson K. E. , Anthony N.
Published: June 2023

This study was conducted to identify and evaluate the differences between the microbiome composition of the ileum and ceca of 1940 and 2016 genetic strains of white leghorns fed representative contemporary diets from those times. Ileal and cecal samples were aseptically collected from both genetic lines at 69 weeks of age. The genomic DNA of the ileal and cecal contents were extracted and the V4 region of the 16S rDNA was sequenced on an Illumina Miseq. Microbiota data were filtered and aligned using the QIIME2 2020.2 pipeline. Alpha and beta diversity metrics were generated and the Analysis of Composition of Microbiomes (ANCOM) was utilized to determine significantly different taxa. Data were considered significant at P ≤ 0.05 for main effects and Q ≤ 0.05 for pairwise differences. Alpha diversity of the ileum and ceca were significantly different (P = 0.001; Q = 0.001; however, no differences between genetic lineage were observed (P > 0.05; Q > 0.05). The beta diversity between the ileum and ceca, as well as between the genetic lines (1940 vs. 2016) were significantly different from one another (P = 0.001; Q = 0.001). Using ANCOM,ProteobacteriaandActinobacteriotawere significantly different than other phyla (P ˂ 0.05) with a higher relative abundance ofProteobacteriabeing observed among treatment groups 2 and 3, whileActinobacteriotahad higher relative abundance in treatment groups 1 and 4. Among the significantly different genera in the ileum,Pseudomonas,Rhizobiaceae,Leuconostoc, andAeriscardoviawere different (P ˂ 0.05) with treatment groups 1 and 4 having a higher relative abundance ofAeriscardovia, while treatment groups 2 and 3 had higher relative abundance in bothPseudomonasandLeuconostoc. In the ceca,Proteobacteria,Firmicutes,Actinobacteriota, andEuryarchaeotawere significantly different phyla (P ˂ 0.05) withFirmicuteshaving the highest relative abundance across all treatment groups. Among the significantly different genera (Pseudomonas,Leuconostoc,Alloprevotella, andAeriscardovia),Alloprevotellahad the highest relative abundance across all treatment groups 1 and 2, whileLeuconostocandPseudomonashad the highest relative abundance in treatment group 4. Results from this study suggest that genetic makeup in conjunction with the nutritional composition of laying hens influences the cecal and ileal microbiota of corresponding hens.
Isolation of a putative sulfur comproportionating microorganism
Authors: Aronson Heidi S. , LaRowe Douglas E. , Macalady Jennifer L. , Amend Jan P.
Published: June 2023

Sulfur comproportionation is a heretofore undiscovered microbial catabolism that was predicted based on thermodynamic calculations. Here, we report the isolation of anAcidithiobacillus thiooxidansstrain from extremely low pH snottite biofilms in the karst at Frasassi, Italy. The strain grew to cell densities of >107cells mL-1in autotrophic sulfur comproportionation medium. Whole genome sequencing of the isolate revealed the presence of numerous genes involved in sulfur transformations that could be linked in a sulfur comproportionation pathway. We describe an experimental framework, including measurements of sulfate, sulfide, and S0concentrations, electron microscopy, and stable and radioisotope incubations coupled with NanoSIMS, scintillation counting and isotope ratio mass spectrometry, for future searches of sulfur comproportionators.

Significance

The prediction of and search for novel microbial catabolic reactions can be streamlined by using thermodynamics to identify energy-yielding redox reactions that may be catalyzed by microorganisms. This strategy has been used to successfully predict several previously overlooked microbial catabolic reactions, including anaerobic ammonia oxidation (anammox), anaerobic oxidation of methane (AOM), and complete ammonia oxidation (comammox). Sulfur comproportionation, or the coupled reduction of sulfate and oxidation of sulfide to form elemental sulfur, was predicted by thermodynamic calculations to exist as a microbial catabolism in low pH, low-temperature environments. In this study, we describe the isolation of the first putative sulfur comproportionating microorganism and provide a detailed experimental approach that can be applied to future investigations of this novel link in the biogeochemical sulfur cycle.
6,6′-Diheptyl-3,3′-bis[(pyridin-3-yl)ethynyl]-5H,5′H-dipyrrolo[1,2-b:1′,2′-g][2,6]naphthyridine-5,5′-dione
Authors: Xiang Juan , Gao Huan , Ma Zhengyu , Cai Xiaohua , Zhang Yu-Peng
Published: June 2023

The complete molecule of the title compound, C42H42N4O2, is generated by a crystallographic centre of symmetry. The pendant heptyl chains adopt extended conformations and the dihedral angle between the pyrrole and pyridine rings is 8.18 (15)°. In the crystal, the molecules are arranged in columnar stacks propagating in the [010] direction via slipped aromatic π–π stacking interactions.
Do geographical indications of agricultural products promote county-level economic growth?
Authors: Qie Hongkai , Chao Yudie , Chen Hui , Zhang Fan
Published: June 2023

Purpose

Intellectual property right constitutes play a forceful role to promote economic growth and create a fortune. However, it is not yet clear to what extent the agricultural intellectual property rights represented by geographical indications of agricultural products (AGIs) can affect the development of regional economy. The purpose of this paper is to analyze this impact and its mechanism as well as to draw policy implications from this empirical analysis.

Design/methodology/approach

Using county-level panel data from 2006 to 2020, this paper employed the difference-in-differences (DID) model.

Findings

The authors find that AGIs can significantly improve economic development at the county level. The AGIs can stimulate the flow of commercial and industrial capital to the countryside, thus fueling county-level economic development. Unlike AGIs for cereals and cash crops, AGIs for aquatic products and animal products cannot influence or have a negative impact on county-level economic. Compared with Eastern regions, the acquisition of AGIs in Western regions can more significantly boost county-level economic development. Therefore, AGIs can pronouncedly narrow down the gap of cross-county economic growth.

Originality/value

Conclusions of this paper can provide references for building the county-level countryside into a main ground of agricultural economic development and brand construction, continuously promoting the agricultural supply-front structural reform and boosting realization of all-around rural revitalization.
Communication challenges and blockchain in building energy efficiency retrofits: Croatia case
Authors: Cerić Anita , Ivić Ivona
Published: June 2023

Purpose

As climate change has become a growing concern, sustainable development has become increasingly important. Emissions reduction is a key step for more efficient energy use. In the last few years, the residential building sector in Croatia has received financial support for multi-dwelling building energy efficiency retrofits (EERs). However, some of these projects encountered difficulties due to information asymmetry between the key participants. This study aims to address the problem from the perspective of the principal-agent theory, which is concerned with information asymmetry and the asymmetry's repercussions.

Design/methodology/approach

A social network analysis is conducted to reflect the operation and management (OM) details of Croatian multi-dwelling buildings. The key stakeholders of EER are mapped, along with the contractual and communication ties between them. Using the Gephi software, relationship data are visually represented and statistically evaluated.

Findings

The analysis indicated two different clusters or groups of stakeholders in EERs in Croatia and enabled the mapping of key relationships between stakeholders. The findings stress the importance of the key relationship between owner representatives (ORs) and property managers (PMs).

Originality/value

The contribution of this study is the development of framework for blockchain implementation in EERs, which can be adapted for use in different markets and/or projects. Blockchain is proposed for minimization of information asymmetry between different stakeholders. Blockchain enables communication and cooperation during project development and enhances trust among stakeholders.
Study on the milling performance of ball-end milling cutter under the combined action of micro-texture of rake and flank face
Authors: Yang Shucai , Xing Shiwen , Yu Yang , Han Pei , Guo Chaoyang , Liu Lukai
Published: June 2023

Purpose

It was verified that the micro-texture in the front and back of the tool at the same time had a positive effect on improving the milling behavior and surface quality of the tool. The purpose of this study is to explore the rationality of simultaneous placement of micro-textures on the front and rear surfaces of ball-end milling cutters, analyze the influence of micro-texture parameters on tool milling behavior and workpiece surface quality, reveal its internal mechanism, and obtain the best micro-texture parameters by optimization.

Design/methodology/approach

First, the mechanism of micro-texture is studied based on the energy loss model. Second, the orthogonal experiment is designed to analyze the influence of micro-texture parameters on tool milling behavior and reveal its mechanism by combining simulation technology and cutting experiment. Finally, the parameters are optimized based on the artificial bee colony algorithm.

Findings

The results show that the simultaneous placement of micro-texture on the rake face and flank face of the tool has a positive effect on improving the milling behavior and surface quality of the tool. Taking milling force, tool wear and surface roughness as the evaluation criteria, the optimal parameter combination is obtained: the rake face micro-texture diameter is 50 µm, the distance from the micro-texture is 200 µm and the distance from the cutting edge is 110 µm; the diameter of the micro-textured flank is 40 µm, the distance from the micro-texture is 170 µm and the distance from the cutting edge is 130 µm.

Originality/value

Taking milling force, tool wear and surface roughness as the evaluation criteria, the optimal parameter combination is obtained: the rake face micro-texture diameter is 50 µm, the distance from the micro-texture is 200 µm and the distance from the cutting edge is 110 µm; the diameter of the micro-textured flank is 40 µm, the distance from the micro-texture is 170 µm and the distance from the cutting edge is 130 µm, which provides theoretical support for the further study of the micro-textured tool.

Peer review

The peer review history for this article is available at: https://publons.com/publon/10.1108/ILT-01-2023-0022/
Effect of gender equality on financial stability and financial inclusion
Authors: Ozili Peterson K.
Published: June 2023

Purpose

This study aims to examine the effect of gender equality on financial stability and financial inclusion for 14 developing countries using yearly data from 2005 to 2021.

Design/methodology/approach

The two-stage least squares regression estimation and the generalized linear model regression estimation were used to investigate the effect of gender equality on financial stability and financial inclusion.

Findings

Gender equality has a significant positive effect on financial stability and financial inclusion in developing countries. Gender equality has a significant positive effect on financial stability and financial inclusion in African countries. Gender equality has a significant positive effect on financial stability but not on financial inclusion in non-African countries.

Originality/value

Little attention has been paid to the role of gender equality in promoting financial stability and financial inclusion. The authors address this issue in this study.
Barriers and facilitators to implementing self‐directed therapy activities in inpatient rehabilitation settings
Authors: Brusco Natasha K. , Walpole Brianna , Kugler Helen , Tilley Louise , Thwaites Claire , Devlin Alicia , Dorward Emma , Dulfer Fiona , Lee Annemarie L. , Morris Meg E. , Taylor Nicholas F. , Dawes Helen , Whittaker Sara L. , Ekegren Christina L.
Published: June 2023

Background

Self‐directed therapy activities are not currently part of routine care during inpatient rehabilitation. Understanding patient and clinician perspectives on self‐directed therapy is key to increasing implementation. The aim of this study was to investigate barriers and facilitators to implementing a self‐directed therapy programme (“My Therapy”) in adult inpatient rehabilitation settings.

Methods

My Therapy was recommended by physiotherapists and occupational therapists and completed by rehabilitation inpatients independently, outside of supervised therapy sessions. Physiotherapists, occupational therapists, and patients were invited to complete an online questionnaire comprising open‐ended questions on barriers and facilitators to prescribing and participating in My Therapy. A directed content analysis of free‐text responses was undertaken, with data coded using categories of the Capability, Opportunity, and Motivation Model of Behaviour (COM‐B model).

Results

Eleven patients and 20 clinicians completed the questionnaire. Patient capability was reported to be facilitated by comprehensive education by clinicians, with mixed attitudes towards the format of the programme booklet. Clinician capability was facilitated by staff collaboration. One benefit was the better use of downtime between the supervised therapy sessions, but opportunities for patients to engage in self‐directed therapy were compromised by the lack of space to complete the programme. Clinician opportunity was reported to be provided via organisational support but workload was a reported barrier. Patient motivation to engage in self‐directed therapy was reported to be fostered by feeling empowered, engaged, and encouraged to participate. Clinician motivation was associated with belief in the value of the programme.

Conclusion

Despite some barriers to rehabilitation patients independently practicing therapeutic exercises and activities outside of supervised sessions, both clinicians and patients agreed it should be considered as routine practice. To do this, patient time, ward space, and staff collaboration are required. Further research is needed to scale‐up the implementation of the My Therapy programme and evaluate its effectiveness.
Tax morale and social capital: An empirical investigation among European citizens
Authors: Cascavilla Alessandro , Ripollés Jordi , Morone Andrea
Published: June 2023

Despite the extensive literature examining determinants of tax morale, little is still known about the relationship between the associational involvement of citizens and their willingness to pay taxes. Given the insights offered by the social capital literature regarding the role of voluntary organizations in shaping civic engagement, this study empirically investigates how membership of different types of associations could influence individual tax morale in Europe. With this in mind, we exploit the information available in the fifth wave of the European Values Study for citizens of 34 countries. Unlike previous studies on tax morale, we classify the types of voluntary associations depending on their potential to build out‐group “bridging” or in‐group “bonding” social ties. In this study, to carry out the classification, three alternative approaches are considered which are based on the sociodemographic heterogeneity within associations, the interconnections between them, and a combination of both. Our findings show that, after controlling for different individual characteristics and country‐specific unobserved heterogeneity, those survey respondents involved in bridging associations tend to exhibit higher levels of tax morale, while the opposite is found for bonding associations. The results are quite robust for the three approaches and different estimation strategies, including an instrumental‐variables methodology.
Antimicrobial resistance of Pseudomonas aeruginosa in a cystic fibrosis population after introduction of a novel cephalosporin/β‐lactamase inhibitor combination
Authors: Katzenstein Terese L. , Faurholt‐Jepsen Daniel , Qvist Tavs , Jensen Peter Østrup , Pressler Tacjana , Johansen Helle Krogh , Kolpen Mette
Published: June 2023

Ceftolozane‐tazobactam is a new β‐lactam/β‐lactamase inhibitor combination approved by the U.S. Food and Drug Administration in 2019 for the treatment of hospital‐acquired and ventilator‐associated pneumonia. The combination is a particularly potent inhibitor of penicillin‐binding proteins with higher affinity than other β‐lactam agents. Persons with cystic fibrosis (pwCF) often harbour resistant Gram‐negative bacteria in the airways and need antibiotics to prevent declining lung function. To test whether the introduction of ceftolozane‐tazobactam in the period 2015–2020 led to a bacterial population level increase in cephalosporin resistance in a Danish CF population. In vitro, activity of ceftolozane‐tazobactam was evaluated by susceptibility testing of clinical Pseudomonas aeruginosa isolated from pwCF from January 1, 2015, to June 1, 2020. Six thousand three hundred thirty two isolates collected from 210 adult pwCF were included. Thirty pwCF were treated with ceftolozane‐tazobactam at least once. Ceftolozane‐tazobactam exposure did not increase cephalosporin resistance on an individual or population level. However, resistance to ceftolozane‐tazobactam was recorded despite no prior exposure in four pwCF. Compared to ceftazidime, ceftolozane‐tazobactam had a better in vitro activity on P. aeruginosa. The percentage of non‐mucoid P. aeruginosa isolates susceptible to ceftolozane‐tazobactam were higher or equal to 5 other β‐lactams. Ceftolozane‐tazobactam expands the armamentaria against P. aeruginosa with acceptable levels for a selection of drug resistance.
Sustainable marketing: an exploratory study of a sustain‐centric, versus profit‐centric, approach
Authors: Dyck Bruno , Manchanda Rajesh V. , Vagianos Savanna , Bernardin Michèle
Published: June 2023

As the need for business to address pressing social and ecological issues intensifies, so does the importance of enhancing the development of sustainable marketing. The current dominant approach to sustainable marketing is based on a Triple Bottom Line (TBL) profit‐centric worldview, which suggests that firms can simultaneously improve their financial well‐being as they reduce negative social and ecological externalities. However, whereas the scope of TBL marketing is limited to sustainability initiatives that enhance profits, there is a growing need for—and interest in—developing a sustain‐centric approach to marketing that relaxes the need to maximize financial well‐being in order to optimize social and ecological well‐being. Even so, because of the dominance of the profit‐centric worldview, hallmarks of sustain‐centric marketing practices remain under‐developed and may even lend themselves to becoming inauthentically mimicked on a piecemeal basis by greenwashing profit‐centric firms. We provide an exploratory empirical study of marketing practices evident in two sustain‐centric firms and draw implications to advance theory for both sustain‐centric and profit‐centric marketing.
Effect of ophiopogonin D on the pharmacokinetics and transport of cryptotanshinone during their co‐administration and the potential mechanism
Authors: Wang Ling , Gu Hong , Chen Kaixia
Published: June 2023

Cryptotanshinone and ophiopogonin D are sourced from herbs with similar indications. It is necessary to evaluate their interaction to provide a reference for their clinical prescriptions. The co‐administration of cryptotanshinone (30 and 60 mg/kg) and ophiopogonin D was carried out in Sprague–Dawley rats and the pharmacokinetics of cryptotanshinone were analyzed. The Caco‐2 cells were employed to evaluate the transport of cryptotanshinone, and the metabolic stability was studied in the rat liver microsomes. Ophiopogonin D significantly increased the Cmax (from 5.56 ± 0.26 to 8.58 ± 0.71 μg/mL and from 15.99 ± 1.81 to 185.12 ± 1.43 μg/mL), half‐life (21.72 ± 10.63 vs. 11.47 ± 3.62 h and 12.58 ± 5.97 vs. 8.75 ± 2.71 h) and decreased the clearance rate (0.697 ± 0.36 vs. 1.71 ± 0.15 L/h/kg) and (60 mg/kg and 0.101 ± 0.02 vs. 0.165 ± 0.05 L/h/kg) of cryptotanshinone. In vitro, ophiopogonin D significantly suppressed the transport of cryptotanshinone with the decreasing efflux rate and enhanced the metabolic stability with the reducing intrinsic clearance. The combination of cryptotanshinone and ophiopogonin D induced prolonged exposure and suppressed the transport of cryptotanshinone, which indicated the decreased bioavailability of cryptotanshinone.
Patterns of species richness and turnover in endemic amphibians of the Guineo‐Congolian rain forest
Authors: Nneji Lotanna M. , Azevedo Josué A. R. , Oyebanji Oyetola O. , Ma Liang , Elsen Paul R. , Oladipo Segun O. , Salako Gabriel , Puschendorf Robert , Pringle Robert M.
Published: June 2023

Aim

The African Guineo‐Congolian (GC) region is a global biodiversity hotspot with high species endemism, bioclimatic heterogeneity, complex landscape features, and multiple biogeographic barriers. Bioclimatic and geographic variables influence global patterns of species richness and endemism, but their relative importance varies across taxa and regions and is poorly understood for many faunas. Here, we test the hypothesis that turnover in endemic amphibians of the GC biodiversity hotspot is influenced mainly by the geographic distance between grid cells and secondarily by rainfall‐ and temperature‐related variables.

Location

West and Central Africa.

Major Taxa Studied

Amphibians.

Methods

We compiled species‐occurrence records via field sampling, online databases, and taxonomic literature. Our study used 1205 unique georeferenced records of 222 amphibian species endemic to the GC region. Patterns of species richness were mapped onto a grid with a spatial resolution of 0.5° × 0.5°. We estimated weighted endemism and tested whether endemism was higher than the expected species richness (randomization test). We quantified species turnover using generalized dissimilarity modelling to evaluate the processes underlying observed patterns of species richness in GC endemic amphibians. We explored bioregionalization using agglomerative hierarchical clustering based on the unweighted pair group method with arithmetic averages.

Results

We identified seven areas within the lower GC region – forests in Cameroon, Gabon, Southern Nigeria, Equatorial Guinea, Republic of Congo, Democratic Republic of Congo, and Cote d'Ivoire – as having high species richness of endemic amphibians. The randomization test returned four major areas of significant weighted endemism: Nigeria‐Cameroon mountains, forest regions of the Democratic Republic of Congo, Cote d'Ivoire, and Ghana. Our analysis revealed five bioregions for amphibian endemism, four of which were located within the lower Guineo‐Congolian forest. Species turnover was strongly related to the geographic distance between grid cells; contributing bioclimatic variables included precipitation of the warmest quarter, mean temperature of the wettest quarter, and mean diurnal temperature range.

Main Conclusions

Our results indicate that geographic distance between grid cells is the primary determinant of turnover in GC endemic amphibians, with secondary but significant effects of rainfall‐ and temperature‐related variables. Our study identifies key areas of endemic amphibian richness that could be prioritized for conservation actions.
Tight spatial coupling of a marine predator with soniferous fishes: Using joint modelling to aid in ecosystem approaches to management
Authors: Roberts Sarah M. , Jacoby Ann‐Marie , Roberts Jason J. , Leslie Jaelyn , Payne Khadijah L. , Read Andrew J. , Halpin Patrick N. , Barco Susan , Garrison Lance , McLellan William , Palka Debra , Nye Janet A.
Published: June 2023

Aim

Understanding the distribution of marine organisms is essential for effective management of highly mobile marine predators that face a variety of anthropogenic threats. Recent work has largely focused on modelling the distribution and abundance of marine mammals in relation to a suite of environmental variables. However, biotic interactions can largely drive distributions of these predators. We aim to identify how biotic and abiotic variables influence the distribution and abundance of a particular marine predator, the bottlenose dolphin (Tursiops truncatus), using multiple modelling approaches and conducting an extensive literature review.

Location

Western North Atlantic continental shelf.

Methods

We combined widespread marine mammal and fish and invertebrate surveys in an ensemble modelling approach to assess the relative importance and capacity of the environment and other marine species to predict the distribution of both coastal and offshore bottlenose dolphin ecotypes. We corroborate the modelled results with a systematic literature review on the prey of dolphins throughout the region to help explain patterns driven by prey availability, as well as reveal new ones that may not necessarily be a predator–prey relationship.

Results

We find that coastal bottlenose dolphin distributions are associated with one family of fishes, the Sciaenidae, or drum family, and predictions slightly improve when using only fish versus only environmental variables. The literature review suggests that this tight coupling is likely a predator–prey relationship. Comparatively, offshore dolphin distributions are more strongly related to environmental variables, and predictions are better for environmental‐only models. As revealed by the literature review, this may be due to a mismatch between the animals caught in the fish and invertebrate surveys and the predominant prey of offshore dolphins, notably squid.

Main Conclusions

Incorporating prey species into distribution models, especially for coastal bottlenose dolphins, can help inform ecological relationships and predict marine predator distributions.
Touch to learn: Multisensory input supports word learning and processing
Authors: Seidl Amanda H. , Indarjit Michelle , Borovsky Arielle
Published: June 2023

Infants experience language in rich multisensory environments. For example, they may first be exposed to the word applesauce while touching, tasting, smelling, and seeing applesauce. In three experiments using different methods we asked whether the number of distinct senses linked with the semantic features of objects would impact word recognition and learning. Specifically, in Experiment 1 we asked whether words linked with more multisensory experiences were learned earlier than words linked fewer multisensory experiences. In Experiment 2, we asked whether 2‐year‐olds’ known words linked with more multisensory experiences were better recognized than those linked with fewer. Finally, in Experiment 3, we taught 2‐year‐olds labels for novel objects that were linked with either just visual or visual and tactile experiences and asked whether this impacted their ability to learn the new label‐to‐object mappings. Results converge to support an account in which richer multisensory experiences better support word learning. We discuss two pathways through which rich multisensory experiences might support word learning.
When social assistance meets market power: A mixed duopoly view of health insurance in the United States
Authors: Ranasinghe Ashantha , Su Xuejuan
Published: June 2023

We develop a mixed duopoly model with quality‐differentiated products. The public firm offers its product for free to eligible individuals, while the private firm chooses its product quality and price to maximize profit. We calibrate the model to health insurance for the U.S. working‐age population, with Medicaid being the public firm. We examine distributional implications of policies that expand Medicaid to various degrees. Despite potentially significant inefficiency of Medicaid, its expansion is welfare improving. Central to these findings is the significant market power of the private firm when left unchecked, which is increasingly disciplined as more individuals become Medicaid eligible.
The 2022 European postgraduate (residency) programme in neurology in a historical and international perspective
Authors: Bassetti Claudio L. A. , Soffietti Riccardo , Vodušek David B. , Schoser Benedikt , Kuks Jan B. M. , Rakusa Martin , Cras Patrick , Boon Paul A. J. M.
Published: June 2023

Background and purpose

Neurology residency programmes, which were first established at the beginning of the 20th century, have become mandatory all over Europe in the last 40–50 years. The first European Training Requirements in Neurology (ETRN) were published in 2005 and first updated in 2016. This paper reports the most recent revisions of the ETRN.

Methods

Members of the EAN board performed an in depth revision of the ETNR 2016‐version, which was reviewed by members of the European Board and Section of Neurology of the UEMS, the Education and Scientific Panels, the Resident and Research Fellow Section and the Board of the EAN, as well as the presidents of the 47 European National Societies.

Results

The new (2022) ETRN suggest a 5‐year training subdivided in three phases: a first phase (2 years) of general neurology training, a second phase (2 years) of training in neurophysiology/neurological subspecialties and a third phase (1 year) to expand clinical training (e.g., in other neurodisciplines) or for research (path for clinical neuroscientist). The necessary theoretical and clinical competences as well as learning objectives in diagnostic tests have been updated, are newly organized in four levels and include 19 neurological subspecialties. Finally, the new ETRN require, in addition to a programme director, a team of clinician‐educators who regularly review the resident's progress.

The 2022 update of the ETRN reflects emerging requirements for the practice of neurology and contributes to the international standardization of training necessary for the increasing needs of residents and specialists across Europe.
Catering and cash savings
Authors: Chen Hsuan‐Chi , Chou Robin K. , Lu Chien‐Lin
Published: June 2023

We examine the catering of managers to investors' preference for cash holdings. We find that cash is positively related to the cash‐holding premium as represented by the difference in the market‐to‐book ratios between cash‐rich and noncash‐rich firms. This positive effect can be attributed to different sources such as internal and external financing, and firms may switch their sources for holding cash when catering to investors' preference. Issuing firms benefit from catering to cash holdings by obtaining higher valuations from the stock market. The catering theory helps explain cash savings especially for firms without a good timing window or financing need.
Pellino‐1 expression is associated with epidermal proliferation and enhanced Th17 cell infiltration in psoriatic lesions
Authors: Cho Haeyon , Park Nora Jee‐Young , Ko Jiwon , Lee Chang‐Woo , Lee Jin‐Kwan , Maeng Young‐In , Go Heounjeong
Published: June 2023

Pellino‐1 plays a crucial role in cellular proliferation and regulates inflammatory processes. This study investigated Pellino‐1 expression patterns and their relationship with CD4+ T‐cell subsets in psoriasis patients. Group 1 comprised primarily biopsied psoriasis lesions from 378 patients, multiplex‐immunostained for Pellino‐1, CD4 and representative T helper (Th) cells (T‐bet [Th1], GATA3 [Th2], and RORγt [Th17] and regulatory T cell [FoxP3] markers). Ki‐67 labeling was evaluated in the epidermis. Group 2 comprised 43 Pellino‐1‐positive cases immunostained for Pellino‐1 in both lesion and non‐lesion skin biopsy samples. Five normal skin biopsies served as controls. Among 378 psoriasis cases, 293 (77.5%) were positive for Pellino‐1 in the epidermis. Pellino‐1‐positivity was higher in psoriasis lesions than in non‐lesions and normal skin (52.55% vs. 40.43% vs. 3.48%, p < 0.001; H‐score, 72.08 vs. 47.55 vs. 4.40, p < 0.001, respectively). Pellino‐1‐positive cases also had a significantly higher Ki‐67 labeling index (p < 0.001). Epidermal Pellino1‐positivity was significantly associated with higher RORγt+ (p = 0.001) and FoxP3+ (p < 0.001) CD4+ T cell ratios but not T‐bet+ and GATA3+ CD4+ T cell ratios. Among the CD4+Pellino‐1+ T‐cell subsets, the CD4+Pellino‐1+RORγt+ ratio was significantly associated with epidermal Pellinio‐1 expression (p < 0.001). Pellino‐1 expression is thus increased in psoriasis lesions and associated with increased epidermal proliferation and CD4+ T‐cell subset infiltration, especially Th17 cells. This suggests that Pellino‐1 could be a therapeutic target that simultaneously regulates psoriasis epidermal proliferation and immune interactions.
Nursing home caregivers' acceptance of, and experiences with, a new digital intervention for oral healthcare: A qualitative feasibility study
Authors: Lee Hannah Haewon , Melbye Elisabeth Lind
Published: June 2023

Objectives

The objectives of the present study were to qualitatively investigate nursing home caregivers' acceptance of, and experiences with, a new digital intervention for oral healthcare after a period of real‐life testing in three nursing homes located in Rogaland county, Norway.

Background

Nursing home caregivers report numerous barriers when it comes to provision of adequate oral care for care‐dependent older adults. Among the reported barriers are lack of knowledge and skills, care‐resistant behaviours, lack of adequate routines and documentation systems for oral health, a high workload, and unclear responsibilities. To overcome these barriers, a digital tool named SmartJournal was developed to assist caregivers in preserving nursing home residents' oral health.

Materials and methods

Semistructured interviews were performed with selected caregivers (n = 12) taking part in SmartJournal testing. A theory‐driven thematic analysis based on technology acceptance model was conducted.

Results

SmartJournal was generally described as a userfriendly and useful tool. The initial reaction of the participants was mixed; some were positive, some had concerns, but many seemed to have a neutral stance to the intervention. Both barriers and facilitating factors for SmartJournal usage were revealed. Interestingly, the usage gradually changed from norm‐based to routine‐based behaviour during the test period. Although the tool was well‐accepted, as demonstrated with study participants' willingness to use it in the future, they had several suggestions for improvements to further adapt it to a nursing home setting.

Conclusion

Results from the present study provide valuable information on questions about SmartJournal acceptance and intervention delivery, thereby preparing the ground for a larger scale evaluation study assessing measurable effects of SmartJournal usage in nursing homes.