bluuebunny/crossref_metadata_2025 huggingface dataset:
Improved PIEZO1 agonism through 4‐benzoic acid modification of Yoda1
Authors: Parsonage Gregory , Cuthbertson Kevin , Endesh Naima , Murciano Nicoletta , Hyman Adam J. , Revill Charlotte H. , Povstyan Oleksandr V. , Chuntharpursat‐Bon Eulashini , Debant Marjolaine , Ludlow Melanie J. , Futers Timothy Simon , Lichtenstein Laeticia , Kinsella Jacob A. , Bartoli Fiona , Rotordam Maria Giustina , Becker Nadine , Brüggemann Andrea , Foster Richard , Beech David J.
Published: December 2022

Background and Purpose

The protein PIEZO1 forms mechanically activated, calcium‐permeable, non‐selective cation channels in numerous cell types from several species. Options for pharmacological modulation are limited and so we modified a small‐molecule agonist at PIEZO1 channels (Yoda1) to increase the ability to modulate these channels.

Experimental Approach

Medicinal chemistry generated Yoda1 analogues that were tested in intracellular calcium and patch‐clamp assays on cultured cells exogenously expressing human or mouse PIEZO1 or mouse PIEZO2. Physicochemical assays and wire myography assays on veins from mice with genetic disruption of PIEZO1.

Key Results

A Yoda1 analogue (KC159) containing 4‐benzoic acid instead of the pyrazine of Yoda1 and its potassium salt (KC289) have equivalent or improved reliability, efficacy and potency, compared with Yoda1 in functional assays. Tested against overexpressed mouse PIEZO1 in calcium assays, the order of potency (as EC50 values, nM) was KC289, 150 > KC159 280 > Yoda1, 600). These compounds were selective for PIEZO1 over other membrane proteins, and the physicochemical properties were more suited to physiological conditions than those of Yoda1. The vasorelaxant effects were consistent with PIEZO1 agonism. In contrast, substitution with 2‐benzoic acid failed to generate a modulator.

Conclusion and Implications

4‐Benzoic acid modification of Yoda1 improves PIEZO1 agonist activity at PIEZO1 channels. We suggest naming this new modulator Yoda2. It should be a useful tool compound in physiological assays and facilitate efforts to identify a binding site. Such compounds may have therapeutic potential, for example, in diseases linked genetically to PIEZO1 such as lymphatic dysplasia.
The flavonoid GL‐V9 alleviates liver fibrosis by triggering senescence by regulating the transcription factor GATA4 in activated hepatic stellate cells
Authors: Zhao Jiawei , Bai Dongsheng , Qi Lei , Cao Wangjia , Du Jiaying , Gu Chunyang , Zhou Chen , Gao Yuan , Zhang Lulu , Zhao Yue , Lu Na
Published: December 2022

Background and purpose

Liver fibrosis is a critical risk factor for the progression from chronic liver injury to hepatocellular carcinoma. Clinically, there is a lack of therapeutic drugs for liver fibrosis. Previous studies have confirmed that GL‐V9, a newly synthesized flavonoid derivative, exhibits anti‐inflammatory activity, but whether it has anti‐hepatic fibrosis actions remains unclear. This study aimed to investigate the anti‐fibrotic activities and potential mechanisms of GL‐V9.

Experimental approach

Bile duct ligation (BDL) and carbon tetrachloride (CCl4) challenges were used to assess the anti‐fibrotic effects of GL‐V9 in vivo. Mouse primary hepatic stellate cells (pHSCs) and the human HSC line LX2 also served as a liver fibrosis model in vitro. Cellular functions and molecular mechanism were analysed using senescence‐associated beta‐galactosidase staining, real‐time PCR, western blotting, immunofluorescence, and co‐immunoprecipitation.

Key results

GL‐V9 attenuated hepatic histopathological injury and collagen accumulation, as well as decreasing the expression of fibrotic genes in vivo. GL‐V9 promoted senescence and inhibited the expression of fibrogenic genes in HSCs in vitro. Mechanistic studies revealed that GL‐V9 induced senescence by upregulating GATA4 expression in HSCs. Further studies confirmed that GL‐V9 stabilized GATA4 by promoting autophagic degradation of P62.

Conclusion and implications

GL‐V9 exerted potent anti‐fibrotic effects both in vivo and in vitro by stabilizing GATA4, thereby promoting the senescence of HSCs, and by avoiding its activation and ultimately inhibiting liver fibrosis. This action indicated that the flavonoid GL‐V9 is a potential therapeutic candidate for the treatment of liver fibrosis.
Histone deacetylase activity is a novel target for epithelial barrier defects in patients with eosinophilic chronic rhinosinusitis with nasal polyps
Authors: Duan Su , Han Xinling , Jiao Jian , Wang Ming , Li Ying , Wang Yang , Zhang Luo
Published: December 2022

Background

Studies have independently indicated that eosinophils and histone deacetylases (HDACs) may compromise the integrity of the epithelial barrier in nasal polyps; however, the underlying mechanisms are not clear. In this study, we aimed to investigate the role of eosinophilia and HDACs in regulation of tight junctions (TJs) and nasal epithelial barrier integrity in chronic rhinosinusitis with nasal polyps (CRSwNP) patients.

Methods

Expression of mRNAs and proteins of TJs and HDACs of biopsy specimens and air‐liquid interface (ALI) human nasal epithelial cell cultures (HNECs) from eosinophilic and noneosinophilic CRSwNP patients and healthy controls was assessed. The ALI HNECs were also assessed for changes in transepithelial electrical resistance (TER) and paracellular flux of fluorescein isothiocyanate (FITC)‐labelled dextran. Meanwhile, the assessments for the effect of HDAC inhibitor in eosinophilic nasal polyps were also conducted.

Results

Decreased TER and increased paracellular flux of FITC‐labelled dextran in the ALI cultures were found in both eosinophilic and noneosinophilic CRSwNP, along with irregular, patchy and reduced expression of claudin‐1, 4, 7, occludin, zonula occludens (ZO)‐1 and ZO‐2 and increased expression of HDAC1, 9 and SIRT7 for both ALI culture cells and biopsy specimens, especially for the eosinophilic CRSwNP group. Treatment of eosinophilic CRSwNP ALI‐HNECs with an HDAC inhibitor improved the TJs expression and epithelial barrier integrity.

Conclusions

Our data suggest that eosinophilia and HDACs influence epithelial barrier function in CRSwNP patients by regulating TJ protein expression. Targeting HDACs with specific inhibitors may be a potential treatment option for patients with eosinophilic CRSwNP.
Gradual Route to Productivity: Evidence from Turkish Morphological Causatives
Authors: Ger Ebru , You Guanghao , Küntay Aylin C. , Göksun Tilbe , Stoll Sabine , Daum Moritz M.
Published: December 2022

Becoming productive with grammatical categories is a gradual process in children's language development. Here, we investigated this transition process by focusing on Turkish causatives. Previous research examining spontaneous and elicited production of Turkish causatives with familiar verbs attested the onset and early stages of productivity at ages 2 to 3 (Aksu‐Koç & Slobin, 1985; Nakipoğlu, Uzundag, & Sarıgül, 2021). So far, however, we know very little about children's understanding of causatives with novel verbs. In the present study, we asked: (a) When does the generalization of causative morphology in a novel context emerge? and (b) What role does child‐directed input play in this development? To answer the first question, we conducted comprehension‐judgment experiments with children aged 2;6–6;11 using pseudo‐verbs (Study 1 & 2). Results showed that children preferred the Turkish causative suffix ‐DIr over an unrelated or no suffix to denote caused events earliest at age 4;10. To answer the second question, we analyzed child‐directed speech from a longitudinal corpus of Turkish language acquisition (Study 3). Results showed that when addressing children younger than age 3, caregivers used the ‐DIr suffix with little variation considering the overall variability of verbs they could utter. Overall, these findings suggest that productivity with morphological causatives in a novel context emerges in a later stage of acquisition. This later development might partly be accounted for by the insufficient variation of morphological causatives in the early input.
Prediction of pine mistletoe infection using remote sensing imaging: A comparison of the artificial neural network model and logistic regression model
Authors: Usta Ayhan , Yilmaz Murat
Published: December 2022

In this study, the prediction of pine mistletoe distribution in Scots pine ecosystems was explored using remote sensing variables to compare the multilayer perceptron (MLP) artificial neural network (ANN) and logistic regression (LR) model performances. For this purpose, 109 sample plots were distinguished in pure Scots pine forests (natural) in the Eastern Black Sea Region of Turkey. Distinguishing mistletoe‐infected stands (69) and uninfected stands (40) was performed with field observations. The variables acquired from Landsat 8 (Level 1) images were used as independent variables for independent‐sample t‐test, MLP ANN and LR models. Remote sensing variables indicated that mistletoe‐infected stands were in drier areas with a lower vegetation‐leaf area index. Based on the performance results of both models, the sensitivity (SEN), specificity (SPE), positive predictive value (PPV), negative predictive value (NPV) and accuracy of the MLP ANN model were superior to those of the LR model. The prediction percentages (SEN, SPE, PPV and NPV) of mistletoe‐infected stands were better than the prediction percentages of uninfected stands. The prediction accuracies of LR and MLP ANN models were 74.3% and 89.6%, respectively. However, all remote sensing variables were included in the prediction equation of the MLP ANN model, while the thermal infrared 1 (TIRS1) variable was included in the LR model. In the MLP ANN model, the TIRS1 variable also had the highest normalized importance (100%). The area under the curve (AUC) value for identifying the mistletoe‐infected stands of Scots pine forests used by the MLP ANN model (0.892 ± 0.034) was higher than in the LR model (0.838 ± 0.039), explaining the more accurate predictions obtained from the MLP ANN model. The MLP ANN model showed much better performance than the LR model. The results of this study are expected to make important contributions to the identification of potential mistletoe‐infected areas.
CCL6 promotes M2 polarization and inhibits macrophage autophagy by activating PI3‐kinase/Akt signalling pathway during skin wound healing
Authors: Feng Xiao , Ji Yu , Zhang Ce , Jin Tingting , Li Jingyu , Guo Jincai
Published: December 2022

The transition of macrophages from the proinflammatory M1 to the anti‐inflammatory M2 phenotype is crucial during the wound healing process. In this study, we assess the role of chemokine (C‐C motif) ligand 6 (CCL6) in modulating macrophage polarization and wound healing. Initially, we observed significantly upregulated CCL6 expression in the skin tissue on the edge of the wound during the inflammation and proliferation phases. Furthermore, we discovered that the mice treated with rCCL6 had significantly accelerated wound healing and increased levels of M2‐type macrophages. Using in vitro models, we found that CCL6 promotes the M2 polarization of macrophages by activating the PI3‐kinase/Akt signalling pathway. Additionally, our results showed that CCL6 inhibited macrophage autophagy and accelerated wound healing, whereas the autophagy inducer rapamycin delayed wound healing. Finally, we determined that the PI3‐kinase inhibitor LY294002 promoted macrophage autophagy and decreased M2 macrophages, indicating the importance of PI3‐kinase in M2 polarization, and this process was reversed by CCL6. Taken together, our study demonstrates that CCL6 promotes M2 polarization, inhibits macrophage autophagy, and accelerates skin wound healing by activating the PI3‐kinase/Akt signalling pathway.
c‐Src activation as a potential marker of chemical‐induced skin irritation using tissue‐engineered skin equivalents
Authors: Harding Amy L. , Colley Helen E. , Vazquez Inmaculada Barragan , Danby Simon , Hasan Md Zobaer , Nakanishi Hirofumi , Furuno Tetsuo , Murdoch Craig
Published: December 2022

Skin irritancy to topically applied chemicals is a significant problem that affects millions of people worldwide. New or modified chemical entities must be tested for potential skin irritancy by industry as part of the safety and toxicity profiling process. Many of these tests have now moved to a non‐animal‐based format to reduce experiments on animals. However, these tests for irritancy potential often rely on monolayer cultures of keratinocytes that are not representative of the skin architecture or tissue‐engineered human skin equivalents (HSE) using complex multi‐gene expression panels that are often cumbersome and not amenable for high throughput. Here, we show that human skin equivalents increase abundance of several phosphorylated kinases (c‐Src, c‐Jun, p53, GSK3α/β) in response to irritant chemical stimulation by phosphokinase array analysis. Specific phosphorylation of c‐SrcY419 was confirmed by immunoblotting and was plasma membrane‐associated in basal/spinous cells by phospho‐specific immunohistochemistry. Moreover, c‐SrcY419 phosphorylation in response to the irritants lactic acid and capsaicin was inhibited by the c‐Src inhibitors KB‐SRC and betaine trimethylglycine. These data provide the first evidence for c‐Src specific activation in response to chemical irritants and point to the development of new modes of rapid testing by immunodetection for first‐pass screening of potential irritants.
Impact of Covid‐19 pandemic on the transnationalization of LGBT* activism in Japan and beyond
Authors: Yamamura Sakura
Published: December 2022

The global Covid‐19 pandemic has strongly impacted social practices, relocating communications and social networks into the digital space. Contextualized in such impact of the Covid‐19 pandemic, the local LGBT* activism in Japan achieved a special momentum: both the acceleration of the socio‐spatial relocation of LGBT* activism to the digital space and the postponement of the Tokyo Olympics 2020 by 1 year enabled activists to mobilize people domestically and globally. The pandemic was not the actual cause or driver of the local LGBT* activism, yet it has been an important catalyst for the transnationalization of the local movement in Japan, pushing evidently the spatial boundaries to achieve broader public outreach but in turn also receiving stronger support from the global community through transnational networks. This study explores novel dynamics of spatiality and temporality of social transformations through the Covid‐19‐induced increase in global digital connectedness as well as transnationalization of local actions.
‘We want it all’:ARTpreferences assessed byDesirability ofOutcomeRanking
Authors: Homerova Ivana , Patel Avani , Macallan Derek C.
Published: December 2022

Objectives

Understanding how people living with HIV (PLWH) view antiretroviral therapy (ART) prescribing choices is fundamental to patient‐centred care. We used the Desirability of Outcome Ranking (DOOR) approach to explore patient ART preferences.

Methods

Seventy‐four PLWH entered the study, 20 into the ‘pilot study’, and 54 in the ‘comparative study’. Participants ranked five different hypothetical patient stories by desirability. Each story comprised five narrative lines, each line addressing one treatment characteristic drawn from one of five pre‐selected domains (treatment failure, treatment difficulty, adverse effects, long‐term complications, life events). Narrative lines could be favourable or adverse. In the pilot study the number of adverse domains varied from one to five. Comparative study stories were fixed at two adverse versus three favourable domains, to test the relative ranking of different domains.

Results

The pilot study identified a relationship between the number of adverse domains and rank (R2 = 0.54;p < 0.0001, Friedman test), however pairwise differences in ranking were not significant beyond three adverse domains. In the comparative study, all domains were ranked equally across the cohort (p = 0.88; Friedman test). In pre‐defined demographic subgroup analyses, women ranked the ‘treatment failure’ domain significantly less desirable than men (p = 0.0014, Mann–Whitney test).

Conclusions

People living with HIV appear to care equally about all aspects of ART. The observation that male and female PLWH have different treatment priorities merits further investigation in larger studies. Interindividual differences highlight the importance of individualized shared decision‐making and treatment personalization. DOOR may have a role as a pre‐treatment assessment tool as well as a research technique.
Effect of recombinant buckwheat trypsin inhibitor on gel properties of chicken meat emulsion
Authors: Li Chen , Liu Xin , Li Anzhi , Li Fang
Published: December 2022

The aim of this study was to investigate the effects of purified recombinant buckwheat trypsin inhibitor (rBTI) on gelling properties of chicken meat emulsion. Recombinant BTI was obtained by culturing and inducing an M15 strain containing pQE30‐BTI plasmid, and then purified by Ni2+ affinity chromatography. rBTI exhibited good thermal stability and retained 67.7% ± 4.0% of its initial activity even after heating in a boiling water bath for 100 min. Results showed that the breaking force, deformation, penetration force and water‐holding capacity of chicken meat gels increased with the increase of rBTI (0‰–0.10‰), indicating that rBTI could improve the gel‐forming ability of chicken meat. Meanwhile, trichloroacetic acid (TCA)‐soluble peptide content decreased with rBTI addition and more myosin heavy chain (MHC) was retained on SDS‐PAGE. Compared with the group without rBTI, the content of TCA‐soluble peptide in the group with rBTI (0.10‰) decreased by 52.4%. rBTI is a specific inhibitor for trypsin, one of the dominant proteases resulting in myosin degradation. Thus, we concluded that rBTI improved the gel properties by deducing the degradation of myosin by endogenous enzymes. Furthermore, the addition of rBTI had no significant influence on the whiteness of the gels. With the advantages of good thermal stability, no unpleasant smell and the function of improving gel properties of meat emulsion, rBTI could be used as a potential candidate for food additives in food processing.
The Philippines and seafaring labour export: State, non‐state and international actors in the assembly and employability of Filipino seafarers
Authors: Galam Roderick
Published: December 2022

Based on interviews, this article examines the Philippines as a sending state from the perspective of seafaring labour export. It analyses how the outsourcing of seafaring labour and global regulation of standards of seafarer education, training and certification have broadened and deepened the involvement of international actors in Filipino seafaring labour. It situates these developments in two phases of seafaring labour migration, thereby clarifying the role of these international actors and their relationship with state and non‐state actors. These international actors have influenced Philippine policy on seafaring labour and employment, are vitally involved in assembling Filipino seafaring labour through their investment in maritime education and training and are determining Filipino seafarers' employability through their inspection of Philippine compliance with the STCW convention. Compliance with this international instrument mobilised the state to reshape the functioning of its agencies to revitalise its capacity as a sending state.
Some aspects of improving the legal regulation of labour relations: Thirty years of experience in the Baltic States
Authors: Mačernytė‐Panomariovienė Ingrida , Krasauskas Rytis , Mačiulaitis Vilius , Kārkliņa Annija , Tavits Gaabriel , Erikson Merle
Published: December 2022

In the context of globalisation processes, technological changes, and business mobility, Lithuania, Latvia, and Estonia are facing the necessity to modify their approach towards the legal regulation of employment relations. Labour laws of the Baltics States, namely concerning new forms of work, work–life balance, and social dialogue, were systematised, rectified, and clarified by analysing texts that consist of primary and secondary sources. The research conducted in the article showed that the move from strict regulation to more flexible arrangements between employer and employee in these states is an ongoing process, which has been delayed for more than 10 years, because during that period the old Soviet laws inherited from the past (with appropriate amendments) were in force. Therefore, the search for new forms of work is slow, the regulation of working time remains rather strict and inflexible, and the involvement of social partners in the processes of collective bargaining remains very formal and segmented. This legal research of transformation of legal regulation of labour relations in the Baltic States might be used to forecast future developments of such legal regulation, as well as to enrich the imagination and increase the set of alternatives to be considered when drafting possible future rules.
Self‐advocates with Down syndrome research the lived experiences of COVID‐19 lockdowns in Aotearoa New Zealand
Authors: Vaccarino Franco , Vaccarino Zandra , Armstrong Duncan , Borkin Edward , Hewitt Alexandra , Oswin Andrew , Quick Caroline , Smith Erin , Glew Averill
Published: December 2022

Background

Individuals with Down syndrome are particularly vulnerable to COVID‐19 because they are recognised as significantly immunocompromised. Yet their voices regarding their lived experiences of pandemic lockdowns have not been sought or heard.

Aim

This study aims to describe the lived experiences of people with Down syndrome during the pandemic lockdowns in Aotearoa New Zealand to add evidence in order to inform systemic advocacy.

Method

A mixed‐methods approach positioned within an inclusive research paradigm was used, in which a group of self‐advocates with Down syndrome co‐designed a structured interview schedule and conducted 40 face‐to‐face interviews. Key themes were identified by using content analysis.

Results

Despite the difficulties associated with lockdowns and participants not receiving their usual supports and having to make significant adjustments, they remained positive, adapted well, and demonstrated a high level of resilience and adaptability.

Conclusions

The findings add to the limited research on the lived experiences of people with Down syndrome during pandemic lockdowns. This research has given them a voice to contribute to policy, government initiatives, and service providers; particularly on issues around support during lockdown and staying connected with others.
Environmental effects, gene flow and genetic drift: Unequal influences on genetic structure across landscapes
Authors: Chiu Ming‐Chih , Nukazawa Kei , Resh Vincent H. , Watanabe Kozo
Published: December 2022

Aim

Both gene flow and genetic drift can affect the genetic diversity of interacting populations. However, the influence of the complex evolutionary histories of species may be obscured by simplified assumptions about how these roles operate in nature. To examine this issue, we mechanistically explored the relative importance of environment‐mediated gene flow and genetic drift in determining genetic structure and diversity.

Location

Northeast Japan.

Taxon

Caddisflies (Hydropsyche orientalis and Stenopsyche marmorata; Insecta: Trichoptera).

Methods

We developed a novel Bayesian framework to evaluate the individual and joint effects of these two evolutionary processes that operate through environmental networks on genetic structuring of these populations. Modelling was performed using genetic information on the two sympatric species of stream—macroinvertebrates having aerial‐dispersing adult stages. Genotyping data for samples from 41 and 30 locations were used at 98 and 162 neutral amplified fragment length polymorphism loci in H. orientalis and S. marmorata, respectively.

Results

Environmental conditions and habitat quality can mediate gene flow by providing different levels of resistance to interpopulation dispersal. Similarly, genetic drift may be altered through variable environmental limitations on population size. Compared to the role of genetic drift, gene flow has a greater influence on the genetic diversity of both species examined. The elevated gene‐flow levels generally increase the genetic diversity in S. marmorata, whereas no obvious trend is evident across the various degrees of gene flow in H. orientalis.

Main Conclusions

Information on environmentally mediated gene flow and genetic drift, coupled with different dispersal strategies in habitat networks, may influence management efforts and success. Consequently, evolutionary processes that act individually or jointly in determining genetic structure are important in the effectiveness of management strategies used for restoration and conservation efforts.
Cloner 3D photogrammetric facial scanner: Assessment of accuracy in a controlled clinical study
Authors: Nogueira Básia R. , Oliveira Junior Osmir B. , de Sousa Gomes Costa Joatan L. , Zanetti Thomaz Faraco , Pretel Hermes
Published: December 2022

Objective

To evaluate the accuracy of facial measurements on three‐dimensional images obtained using a new photogrammetric scanner.

Material and Methods

A total of 11 participants were included in the study. Nine customized adhesive labels were used to identify the facial landmarks: Trichion (Tri), Glabella (G), Right (Exr) and Left (Exl), Pronasal (Pn), Subnasal (Sn), Chelion right (Chr) and left (Chl) and Mentonian (Me). Two trained and calibrated examiners were responsible for performing seven linear measurements for each participant (Tri‐G, Sn‐Me, Exr‐Exl, Chr‐Chl, Exr‐Chr, Exl‐Chl, Pn‐Sn) first with a digital caliper and later with a three‐dimensional model obtained after digitalization with photogrammetric technology. The intraclass correlation coefficient (ICC), mean difference, SD, and Bland–Altman correlation were used to compare the measurements performed.

Results

Intra and inter‐examiner reliability were excellent (ICC >0.9). In general, the measurements presented a variation of a minor 2.0 mm. However, only three measures (Sn‐Me, Exr‐Exl, and Exr‐Chr) were outside the clinical acceptability range.

Conclusions

The 3D Cloner scanner showed clinically acceptable accuracy comparable to the digital caliper with a variation of −0.8 ± 1.2 mm. Inter‐ and intra‐examiner agreement on digital measurements was also observed.

Clinical Significance

Scanners with accurate 3D model reproductions associated with reliable digital measurements provide a more precise diagnosis and better planning in orofacial treatment.
Clinical presentation, investigation, underlying causes, and subsequent pregnancy outcomes among different phenotypes of second trimester miscarriage
Authors: Cheung Ka Wang , Seto Mimi Tin Yan , Wang Weilan , Mok Yin Kwan , Cheung Vincent Y. T.
Published: December 2022

Aim

To evaluate the causes of miscarriage and subsequent pregnancy outcomes among different phenotypes of second trimester miscarriage.

Methods

Retrospective analysis of 170 consecutive second trimester miscarriages between 14 + 0 and 23 + 6 weeks recorded in the Clinical Data Analysis and Reporting System from 2012 to 2021. Cases were excluded if miscarriages occurred before 14 + 0 weeks of gestation, data were incomplete, or passage of the fetus happened before the clinical assessment. Cases were classified with a stepwise approach into three phenotypic groups including silent miscarriages (ST‐SM), rupture of membranes (ST‐ROM), and inevitable miscarriages (ST‐IM) depending on the fetal heart pulsation and leakage of liquor at presentation. Clinical investigation of the underlying causes and the outcome of the subsequent pregnancy was then reviewed.

Results

There were 97 cases of ST‐SM, 21 cases of ST‐ROM, and 52 cases of ST‐IM. Placental histology and karyotype examination were more likely to yield significant results in the cases of ST‐ROM and ST‐SM (p < 0.05). The phenotypic examination identified different underlying causes including fetal anomaly, suspected cervical insufficiency, diabetes mellitus, and unknown causes (p < 0.001).

Sixty‐four cases achieved a subsequent pregnancy. Although women with history of ST‐ROM and ST‐IM received more cervical length monitoring and cervical cerclage than those with ST‐SM (66.7% vs. 44.4% vs. 7.5%, p = 0.0002; and 16.7% vs. 22.2% vs. 2.5%, p = 0.031, respectively), the risk of recurrent second trimester miscarriage was higher in ST‐ROM and ST‐IM than in ST‐SM (16.7% vs. 0%, p = 0.018).

Conclusion

The classification can differentiate different second trimester miscarriage phenotypes, which offers essential information to guide investigation panels of the underlying cause of miscarriages, and the prognosis and management of subsequent pregnancy. Future researches focused on second trimester miscarriage should report their findings according to different phenotypes.
Dynamic resource‐acquisition strategies: Analysis of survivor betweenness centrality relationships after downsizing
Authors: Moore Ozias A. , Susskind Alex M. , Margolin Drew
Published: December 2022

This paper investigates dynamic changes in instrumental (i.e., work‐related) tie‐seeking patterns and the structure of a communication network following a downsizing event—whereby many employees are simultaneously eliminated from a network. Our analysis spans a two‐year period and applies a resource‐ and network‐change approach to examine how survivors develop revised resource‐acquisition strategies while repositioning themselves after a downsizing. Our results demonstrate that two temporary logics of tie formation—a suspension of within‐unit homophily and a preference for seeking ties with long‐tenured employees—help employees acquire betweenness centrality during the disruption period. Specifically, we find that disruption initiates a transitional period after downsizing in which new tie‐making logics are employed, including seeking out ties with long‐tenured employees and employees outside of one's department. We observed post‐disruption, during the stabilization period after downsizing, where logics used for tie‐making in the disruption period were abandoned, pre‐disruption tie‐making logics were resumed, and betweenness centrality remained relatively constant. We discuss the theoretical and managerial implications of these results and suggest future research directions.
Glutamine promotes the proliferation of epithelial cells via mTOR/S6 pathway in oral lichen planus
Authors: Hu Jiaqi , Ling Zihang , Li Wei , Su Zhangci , Lu Jingyi , Zeng Qi , Cheng Bin , Tao Xiaoan
Published: December 2022

Background

Although abnormal cell proliferation and apoptosis are associated with the pathogenesis of oral lichen planus (OLP), the exactly mechanism of which is not yet known. It has been reported that glutamine (Gln) can promote cell proliferation and inhibit apoptosis of various tumor cells. This study aims to evaluate the effect of Gln metabolism on the balance of proliferation and apoptosis in epithelial cells of OLP.

Methods

Thirty human OLP specimens and 11 normal controls were stained by immunohistochemistry to detect the levels of proliferation and Gln metabolism related proteins. Then, the critical role of Gln in cell proliferation and apoptosis was determined by Gln deprivation or treatment with glutaminase inhibitor (CB‐839) to intervene Gln metabolism in human gingival epithelial cells. Cell proliferation was detected using CCK8, p‐mTOR and p‐S6 proteins were detected using Western Blot, cell apoptosis and cell cycle were detected using flow cytometry, and cell stress was detected using immunofluorescence.

Results

Compared with normal controls, OLP specimens showed higher levels of Ki‐67 and Gln metabolism‐related proteins, including Gln transporter (ASCT2), glutaminase (GLS), and pathway proteins (p‐mTOR and p‐S6). In vitro, Gln promoted cell proliferation and simultaneously upregulated the activity of mTOR/S6 pathway. Moreover, rapamycin, an mTOR pathway inhibitor, could effectively block the Gln‐induced cell proliferation. MHY1485, an mTOR pathway agonist, could effectively reverse the decline of cell proliferation under Gln deprivation. In addition, inhibiting Gln metabolism caused the accumulation of intracellular radical oxygen species (ROS) and induced cell apoptosis. However, N‐acetylcysteine reversed this state and then decreased cell apoptosis by eliminating intracellular ROS.

Conclusion

Gln metabolism is essential to maintain the balance of proliferation and apoptosis in oral epithelial cells, and inhibition of Gln metabolism may have a beneficial effect on OLP treatment.
Saliva‐based cell‐free DNA and cell‐free mitochondrial DNA in head and neck cancers have promising screening and early detection role
Authors: Sayal Lana , Hamadah Omar , Almasri Aroub , Idrees Majdy , Thomson Peter , Kujan Omar
Published: December 2022

Background

Cell‐free DNA (cfDNA) and cell‐free mitochondrial DNA (cf‐mtDNA) have been postulated as potential diagnostic and prognostic biomarkers for different human malignancies. Early detection of head and neck malignancies is fundamental for optimal patient management. This study, therefore, aimed to assess the utility of saliva‐based liquid biopsy as a noninvasive source of cfDNA and cf‐mtDNA for detecting head and neck cancer (HNSCC).

Methods

One hundred thirty‐three patients diagnosed with either oral leukoplakia (OLK) or HNSCC were compared with 137 healthy volunteers. An unstimulated whole saliva sample was collected from each participant. The absolute copy numbers of salivary cf‐mtDNA and cfDNA were quantified using Multiplex Quantitative PCR. Two diagnostic indices based on the investigated molecules were assessed for their ability to differentiate between different diagnostic categories.

Results

The median scores of cfDNA and cf‐mtDNA were statistically significantly higher among HNSCC patients (p < 0.05), revealing area under the curve values of 0.758 and 0.826, respectively. The associated accuracy for this test in discriminating HNSCC from other diagnostic categories was 77.37% for the cfDNA‐based index and 80.5% for the cf‐mtDNA‐based index. The median score of cfDNA was statistically significantly higher for patients with severe epithelial dysplasia (OED) compared to those with epithelial keratosis with no OED and mild OED. However, there was no significant difference between controls and OLK individuals.

Conclusion

cfDNA and cf‐mtDNA showed potential for use as precision medicine tools to detect HNSCC. Further multi‐centre prospective studies are warranted to assess the prognostic utility of these molecules.
An aphid symbiont confers protection against a specialized RNA virus, another increases vulnerability to the same pathogen
Authors: Higashi Clesson H. V. , Nichols William L. , Chevignon Germain , Patel Vilas , Allison Suzanne E. , Kim Kyungsun Lee , Strand Michael R. , Oliver Kerry M.
Published: December 2022

Insects often harbour heritable symbionts that provide defence against specialized natural enemies, yet little is known about symbiont protection when hosts face simultaneous threats. In pea aphids (Acyrthosiphon pisum), the facultative endosymbiont Hamiltonella defensa confers protection against the parasitoid, Aphidius ervi, and Regiella insecticola protects against aphid‐specific fungal pathogens, including Pandora neoaphidis. Here, we investigated whether these two common aphid symbionts protect against a specialized virus A. pisum virus (APV), and whether their antifungal and antiparasitoid services are impacted by APV infection. We found that APV imposed large fitness costs on symbiont‐free aphids and these costs were elevated in aphids also housing H. defensa. In contrast, APV titres were significantly reduced and costs to APV infection were largely eliminated in aphids with R. insecticola. To our knowledge, R. insecticola is the first aphid symbiont shown to protect against a viral pathogen, and only the second arthropod symbiont reported to do so. In contrast, APV infection did not impact the protective services of either R. insecticola or H. defensa. To better understand APV biology, we produced five genomes and examined transmission routes. We found that moderate rates of vertical transmission, combined with horizontal transfer through food plants, were the major route of APV spread, although lateral transfer by parasitoids also occurred. Transmission was unaffected by facultative symbionts. In summary, the presence and species identity of facultative symbionts resulted in highly divergent outcomes for aphids infected with APV, while not impacting defensive services that target other enemies. These findings add to the diverse phenotypes conferred by aphid symbionts, and to the growing body of work highlighting extensive variation in symbiont‐mediated interactions.
From high masked to high realized genetic load in inbred Scandinavian wolves
Authors: Smeds Linnéa , Ellegren Hans
Published: December 2022

When new mutations arise at functional sites they are more likely to impair than improve fitness. If not removed by purifying selection, such deleterious mutations will generate a genetic load that can have negative fitness effects in small populations and increase the risk of extinction. This is relevant for the highly inbred Scandinavian wolf (Canis lupus) population, founded by only three wolves in the 1980s and suffering from inbreeding depression. We used functional annotation and evolutionary conservation scores to study deleterious variation in a total of 209 genomes from both the Scandinavian and neighbouring wolf populations in northern Europe. The masked load (deleterious mutations in heterozygote state) was highest in Russia and Finland with deleterious alleles segregating at lower frequency than neutral variation. Genetic drift in the Scandinavian population led to the loss of ancestral alleles, fixation of deleterious variants and a significant increase in the per‐individual realized load (deleterious mutations in homozygote state; an increase by 45% in protein‐coding genes) over five generations of inbreeding. Arrival of immigrants gave a temporary genetic rescue effect with ancestral alleles re‐entering the population and thereby shifting deleterious alleles from homozygous into heterozygote genotypes. However, in the absence of permanent connectivity to Finnish and Russian populations, inbreeding has then again led to the exposure of deleterious mutations. These observations provide genome‐wide insight into the magnitude of genetic load and genetic rescue at the molecular level, and in relation to population history. They emphasize the importance of securing gene flow in the management of endangered populations.
Scratching beneath the surface: How organisational culture influences curricular reform
Authors: Shah Adarsh P. , Walker Kim A. , Hawick Lorraine , Walker Kenneth G. , Cleland Jennifer
Published: December 2022

Introduction

Curricular reform is often proposed as the means to improve medical education and training. However, reform itself may not lead to noticeable change, possibly because the influence of organisational culture on change is given insufficient attention. We used a national reform of early‐years surgical training as a natural opportunity to examine the interplay between organisational culture and change in surgical education. Our specific research question was: in what ways did organisational culture influence the implementation of Improving Surgical Training (IST)?

Methods

This is a qualitative study underpinned by social constructivism. Interviews were conducted with core surgical trainees (n = 46) and their supervising consultants (n = 25) across Scotland in 2020–2021. Data coding and analysis were initially inductive. The themes indicated the importance of many cultural factors as barriers or enablers to IST implementation. We therefore carried out a deductive, secondary data analysis using Johnson's (1988) cultural web model to identify and examine the different elements of organisational culture and their impact on IST.

Results

The cultural web enabled a detailed understanding of how organisational culture influenced IST implementation as per Johnson's six elements—Rituals and Routines (e.g. departmental rotas), Stories (e.g. historical training norms and culture), Symbols (e.g. feedback mechanisms, visibility and value placed on education), Power Structures (e.g. who has the power in local contexts), Organisational Structures (e.g. relationships and accountability) and the Control System (e.g. consultant job plans and service targets)—and how these interact. However, it did not shed light on the influence of exogenous events on change.

Conclusion

Our data reveal cultural reasons why this curricular reform met with varying degrees of success across different hospital sites, reinforcing that curricular reform is not simply about putting recommendations into practice. Many different aspects of context must be considered when planning and evaluating change in medical education and training.
Correlation of plasma levels of itraconazole with treatment response at 4 weeks in chronic dermatophytosis: Results of a randomised controlled trial
Authors: Bhalavi Hitesh , Shaw Dipika , Mehta Hitaishi , Narang Tarun , Sachdeva Naresh , Shafiq Nusrat , Rudramurthy Shivaprakash M. , Dogra Sunil
Published: December 2022

Background

Itraconazole in varying doses and duration is being frequently used for the management of dermatophytosis. There is a scarcity of studies on the bioavailability of various itraconazole brands available in the market.

Aims and Objectives

The aim of this study was to determine the plasma concentration of itraconazole of various brands and its correlation with clinical efficacy in chronic dermatophytosis.

Materials and Methods

One hundred patients with chronic dermatophytosis with age >18 years were studied at the outpatient clinic of our tertiary care hospital. Plasma itraconazole level was estimated on Week 2 and Week 4 after randomly dividing the patients into Groups A, B and C who received cap itraconazole 100 mg twice a day of innovator, multinational and local generic brands, respectively, for 4 weeks. Both efficacy (cure, partial cure or no cure), safety and recurrence were compared between the three groups.

Results

At 4 weeks, number of patients classified as ‘cured’ were 10/26 (38.4%) in Group A, 5/22 in Group B (22.7%) and 3/21 (14.2%) in Group C (p = .002). Mycological cure rates at Week 4 in Groups A, B and C were 21 (80.8%), 17 (81.0%) and 5 (26.3%), respectively (p = .006). Plasma levels of itraconazole were comparable between the three groups at Week 2 and Week 4. No statistically significant correlation was found between itraconazole levels and treatment response in any of the groups at 4 weeks. Incidence of adverse effects and recurrence rates was also similar among the three groups.

Conclusion

Cure rates for chronic dermatophytosis were poor with all three itraconazole brands at 4 weeks of treatment. Higher cure rates were obtained with innovator drug as compared to multinational and local generic brands at 4 weeks. Plasma levels of the three drugs were however similar, indicating that factors other than serum bioavailability are at play in determining response of chronic dermatophyte infections to oral itraconazole.
Productivity and Performance: A GMM approach
Authors: Tsionas Mike G. , Kumbhakar Subal C.
Published: December 2022

In this paper we propose a single‐step generalized method of moments (GMM) approach to estimate a production function with multiple quasi‐fixed and variable inputs as well as productivity and inefficiency. Our approach relies on the system consisting of the production function, the first‐order conditions of expected profit maximization with respect to the variable inputs, as well as general formulations for dynamic productivity and inefficiency. The estimation procedure takes care of correlations of both productivity and inefficiency with the variable inputs without using any distributional assumptions on the error terms (including inefficiency) in the system. We use Indonesian manufacturing census data to illustrate workings of our procedure.
Assessing adolescents' readiness for action and attitudes toward obesity prevention: Instrument development and psychometric properties
Authors: Grewal Navnit Kaur , Klepp Knut‐Inge , Banik Anna , Bröer Christian , Holbæk Helene , Luszczynska Aleksandra , Macauley Talia , Rutter Harry , Lien Nanna
Published: December 2022

Engaging adolescents in obesity prevention is a main objective of the CO‐CREATE project. This paper presents the development of a questionnaire to assess readiness for action and attitudes toward obesity prevention among adolescents. The questionnaire was developed based on literature searches and internal discussions with experts in the CO‐CREATE consortium. The questionnaire was translated, back translated, and pretested for time and comprehensiveness by adolescents from five countries (the Netherlands, Norway, Poland, Portugal, and the United Kingdom). Exploratory factor analysis was performed, and internal reliability of the resulting factors was determined using baseline data from Poland and Norway. Furthermore, test–retest reliability was assessed in a sample of Norwegian adolescents. The exploratory factor analysis on readiness for action identified four factors. Analysis on attitudes toward obesity prevention identified four factors on responsibility and five factors on drivers of behavior. Six of the factors had a Cronbach's alpha value above 0.70, five factors had a value between 0.60–0.70, whereas the remaining two factors were below 0.60. The test–retest correlation ranged from 0.46 to 0.87. The exploratory factor analyzes on readiness for action identified the same factors as hypothesized in the development of the questionnaire, whereas attitudes toward obesity prevention identified more factors than initially assumed. The questionnaire is considered reliable as a tool for measuring adolescents' readiness for action and attitudes toward obesity prevention.
Screening of functionalized collagen membranes with a porcine periodontal regeneration model
Authors: Quan Bryan D. , Sadeghi Rokhsareh , Ikeda Yuichi , Ganss Bernhard , Hamilton Douglas W. , McCulloch Christopher A. , Sone Eli D.
Published: December 2022

Objectives

Current methods for periodontal regeneration do not promote collagen fiber insertions into new bone and cementum. We used a pig wound model to screen different functionalized collagen membranes in promoting periodontal reattachment to root surfaces.

Methods

Treatment groups included (1) control with no membranes, (2) collagen‐coated membranes, (3) membranes with insulin‐like growth factor‐1 (IGF‐1), (4) membranes with amelotin, or (5) membranes attached with calcium phosphate cement (CPC), or with CPC combined with IGF‐1. Flap procedures were performed on mandibular and maxillary premolars of each pig.

Results

Histomorphometric, micro‐CT, and clinical measurements obtained at 4 and 12 weeks after surgery showed cementum formation on denuded roots and reformation of alveolar bone, indicating that the pig model can model healing responses in periodontal regeneration. Calcium phosphate cement simplified procedures by eliminating the need for sutures and improved regeneration of alveolar bone (p < 0.05) compared with other treatments. There was a reduction (p < 0.05) of PD only for the IGF group. Large observed variances between treatment groups indicated that a priori power analyses should be conducted to optimize statistical analysis.

Conclusions

Pigs can model discrete elements of periodontal healing using collagen‐based, functionalized membranes. Screening indicates that membrane anchorage with calcium phosphate cements improve regeneration of alveolar bone.