bluuebunny/crossref_metadata_2025 huggingface dataset:
Lysosomes mediate the mitochondrial UPR via mTORC1-dependent ATF4 phosphorylation
Authors: Li Terytty Yang , Wang Qi , Gao Arwen W. , Li Xiaoxu , Mottis Adrienne , Shong Minho , Auwerx Johan
Published: November 2022

Lysosomes are central platforms for not only the degradation of macromolecules but also the integration of multiple signaling pathways. However, whether and how lysosomes mediate the mitochondrial stress response (MSR) remain largely unknown. Here, we demonstrate that lysosomal acidification via the vacuolar H+-ATPase (v-ATPase) is essential for the transcriptional activation of the mitochondrial unfolded protein response (UPRmt). Mitochondrial stress stimulates v-ATPase-mediated lysosomal activation of the mechanistic target of rapamycin complex 1 (mTORC1), which then directly phosphorylates the MSR transcription factor, activating transcription factor 4 (ATF4). Disruption of mTORC1-dependent ATF4 phosphorylation blocks the UPRmt, but not other similar stress responses, such as the UPRER. Finally, ATF4 phosphorylation downstream of the v-ATPase/mTORC1 signaling is indispensable for sustaining mitochondrial redox homeostasis and protecting cells from reactive oxygen species (ROS)-associated cell death upon mitochondrial stress. Thus, v-ATPase/mTORC1-mediated ATF4 phosphorylation via lysosomes links mitochondrial stress to UPRmtactivation and mitochondrial function resilience.
Robustness of a multivariate composite score when evaluating distress of animal models for gastrointestinal diseases
Authors: Talbot Steven R. , Kumstel Simone , Schulz Benjamin , Tang Guanglin , Abdelrahman Ahmed , Seume Nico , Wendt Edgar Heinz Uwe , Eichberg Johanna , Häger Christine , Bleich Andre , Vollmar Brigitte , Zechner Dietmar
Published: November 2022

The fundament of an evidence-based severity assessment in laboratory animal science is reliable distress parameters. Many readouts are used to evaluate and determine animal distress and the severity of experimental procedures. Therefore, we analyzed four distinct parameters like the body weight, burrowing behavior, nesting, and distress score in the four gastrointestinal animal models (pancreatic ductal adenocarcinoma (PDA), pancreatitis, CCl4intoxication, and bile duct ligation (BDL)). Further, we determined the parameters‘ robustness in various experimental subgroups due to slight variations like drug treatment or telemeter implantations. We used non-parametric bootstrapping to get robust estimates and 95 % confidence intervals for the experimental groups. It was found that the performance of the readout parameters is model-dependent and that the distress score is prone to experimental variation. On the other hand, we also found that burrowing and nesting can be more robust than, e.g., the body weight when evaluating PDA. However, the body weight still was highly robust in BDL, pancreatitis, and CCl4intoxication. To address the complex nature of the multi-dimensional severity space, we used the Relative Severity Assessment (RELSA) procedure to combine multiple distress parameters into a score and mapped the subgroups and models against a defined reference set obtained by telemeter implantation. This approach allowed us to compare the severity of individual animals in the experimental subgroups using the maximum achieved severity (RELSAmax). With this, the following order of severity was found for the animal models: CCl4< PDA ≈ Pancreatitis < BDL. Furthermore, the robustness of the RELSA procedure and outcome was externally validated with a reference set from another laboratory also obtained from telemeter implantation. Since the RELSA procedure reflects the multi-dimensional severity information and is highly robust in estimating the quantitative severitywithinandbetweenmodels, it can be deemed a valuable tool for laboratory animal severity assessment.
The nature-nurture transform underlying the emergence of reliable cortical representations
Authors: Trägenap Sigrid , Whitney David E. , Fitzpatrick David , Kaschube Matthias
Published: November 2022

The fundamental structure of cortical networks arises early in development prior to the onset of sensory experience. However, how endogenously generated networks respond to the onset of sensory experience, and how they form mature sensory representations with experience remains unclear. Here we examine this ‘nature-nurture transform’ usingin vivocalcium imaging in ferret visual cortex. At eye-opening, visual stimulation evokes robust patterns of cortical activity that are highly variable within and across trials, severely limiting stimulus discriminability. Initial evoked responses are distinct from spontaneous activity of the endogenous network. Visual experience drives the development of low-dimensional, reliable representations aligned with spontaneous activity. A computational model shows that alignment of novel visual inputs and recurrent cortical networks can account for the emergence of reliable visual representations.

One sentence summary

The reliability of cortical representations emerges from experience-driven reorganization of endogenous networks
Dendritic degeneration and altered synaptic innervation of a central auditory neuron during age-related hearing loss
Authors: Wang Meijian , Zhang Chuangeng , Lin Shengyin , Xie Ruili
Published: November 2022

Cellular morphology and synaptic configuration are key determinants of neuronal function and are often modified under pathological conditions. In the first nucleus of the central auditory system, the cochlear nucleus (CN), principal bushy neurons specialize in processing temporal information of sound critical for hearing. These neurons alter their physiological properties during aging that contribute to age-related hearing loss (ARHL). The structural basis of such changes remains unclear, especially age-related modifications in their dendritic morphology and the innervating auditory nerve (AN) synapses. Using young (2-5 months) and aged (28-33 months) CBA/CaJ mice of either sex, we filled individual bushy neurons with fluorescent dye in acute brain slices to characterize their dendritic morphology, followed by immunostaining against vesicular glutamate transporter 1 (VGluT1) and calretinin (CR) to identify innervating AN synapses. We found that dendritic morphology of aged bushy neurons had significantly reduced complexity, suggesting age-dependent dendritic degeneration, especially in neurons with predominantly non-CR-expressing synapses on the soma. These dendrites were innervated by AN bouton synapses, which were predominantly non-CR-expressing in young mice but had increased proportion of CR-expressing synapses in old mice. While somatic AN synapses degenerated substantially with age, as quantified by VGluT1-labeled puncta volume, no significant difference was observed in the total volume of dendritic synapses between young and old mice. Consequently, synaptic density on dendrites was significantly higher in old mice. The findings suggest that dendritic degeneration and altered synaptic innervation in bushy neurons during aging may underlie their changed physiological activity and contribute to the development of ARHL.

HIGHLIGHTS

Dendrites of bushy neurons degenerate during aging with reduced complexity

Bushy dendrites receive AN input primarily from SGNs with medium/high threshold

Dendritic synapses show similar total volume but increased density during aging

Dendritic degeneration in bushy neurons and altered AN input may underlie ARHL
Fisetin Attenuates Cellular Senescence Accumulation During Culture Expansion of Human Adipose-Derived Stem Cells
Authors: Mullen Michael , Goff Alexander , Billings Jake , Kloser Heidi , Huard Charles , Mitchell John , Hambright William Sealy , Ravuri Sudheer , Huard Johnny
Published: November 2022

Mesenchymal stem cells (MSCs) have long been viewed as a promising therapeutic for musculoskeletal repair. However, regulatory concerns including tumorgenicity, inconsistencies in preparation techniques, donor-to-donor variability, and the accumulation of senescence during culture expansion have hindered the clinical application of MSCs. Senescence, in particular, is a driving mechanism for MSC dysfunction with advancing age. Often characterized by increased reactive oxygen species, senescence-associated heterochromatin foci, inflammatory cytokine and chemokine secretion, and reduced proliferative capacity, senescence directly inhibits MSCs efficacy as a therapeutic for musculoskeletal regeneration and repair. Furthermore, autologous delivery of senescent MSCs can further induce disease and aging progression through the secretion of the senescence-associated secretory phenotype (SASP) and mitigate the regenerative potentetial of MSCs. To combat these issues, the use of senolytic agents to selectively clear senescent cell populations has become popular. However, their benefits to human MSCs during the culture expansion process have not yet been elucidated. To address this, analyzed markers of senescence during culturing of human primary adipose-derived stem cells (ADSCs), a population of fat-resident MSCs commonly used in regenerative medicine applications. Next, we used the senolytic agent fisetin to determine if we can reduce these markers of senescence within our culture-expanded ADSC populations. Our results indicate that ADSCs acquire common markers of cellular senescence including increased reactive oxygen species, senescence-associated β-galactosidase, and senescence-associated heterochromatin foci. Furthermore, we found that the senolytic agent fisetin works in a dose-dependent manner and selectively attenuates these markers of senescence while maintaining the differentiation potential of the expanded ADSCs.

Signficance Statement

The accumulation of dysfunctional, senescent cells throughout aging is not confined to specific tissues and cell types, but instead effects the whole body, including stem cells. Similarly, during culture expansion stem cells accumulate senescence while concurrently losing their regenerative potential. In this study, we found that fisetin (a well known senotherapeutic agent) can reduce the number of senescent cells during stem cell expansion. The current results indicate that fisetin may be used not only as a promising therapeutic to remove senescent cells in stem cell isolates from older individuals but also to reduce the accumulation of senescence during culture expansion.
Automatic tolerance analyses by generation of assembly graph and mating edges from STEP AP 242 file of mechanical assembly
Authors: S. Mukunthan , R. Manu , Lawrence K. Deepak
Published: November 2022

Purpose

This paper aims to propose a method to automate the tolerance analyses of mechanical assembly using STandard for the Exchange of Product model data-Application Protocol Part 242 (STEP AP 242) files derived from the 3-D computer-aided design (CAD) models.

Design/methodology/approach

Product manufacturing information and mating information available in ISO 10303 STEP AP242 files resulting from the 3-D CAD model of mechanical assembly are extracted. The extracted geometric attributes, geometric dimensioning and tolerancing (GD&T) and mating information are used to automatically generate assembly graph and mating edges required for the tolerance analyses of the mechanical assembly by using the matrix approach.

Findings

The feasibility of the proposed method is verified through two mechanical assembly case studies. The results of manual calculations and tolerance values computed by the automated method are very closely matching.

Practical implications

Tolerance analysis is an integral part of product development that directly influences the cost and performance of a product. Apart from the academic interest, the work is expected to have positive implications for the digital design and smart manufacturing industry that involve in the development of solutions for automation of design and manufacturing system functions.

Originality/value

The approach presented in the paper that aids the automation of tolerance analyses of mechanical assembly is an innovative application of the STEP AP 242 file. The automation of tolerance analyses would improve the productivity and efficiency of the product realization process.
Employability skills of the next generation of Chinese factory workers
Authors: Froese Fabian Jintae , Hong Lin-Ya
Published: November 2022

Purpose

The main purpose of this study was to develop and test an employability scale in a Chinese context. Moreover, the authors investigated how socioeconomic status indicators (education and occupation of parents, household income and hukou, i.e. household registration location) affect the endowment and development of adolescents' employability skills in China.

Design/methodology/approach

Data were collected via paper-based surveys from 1,146 vocational school students in rural and urban areas in China at two points in time one year apart. The authors developed a scale to measure employability skills in China and conducted general linear modeling to test the hypotheses.

Findings

The findings indicate that adolescents whose parents have more education, highly skilled occupations, relatively affluent household income and urban hukou are more likely to attain higher employability skills than those from lower socioeconomic status backgrounds. Moreover, adolescents with these background characteristics tend to improve their employability skills more than those without such characteristics. This suggests that social capital may further widen the inequality gap among adolescents.

Research limitations/implications

The framework of employability skills focuses on the general basic transferable employability skills of vocational students. Future studies could develop measures of employability skills for college graduates and widen the measurements of social capital based on the study’s findings. The findings suggest that higher education institutions should be encouraged to integrate resources to improve education inequality between rural and urban regions to the disparity in adolescents' employability skills development.

Originality/value

Building on Western frameworks, the study defines and develops an employability scale in the Chinese context that can be a practical measurement tool for researchers, educators and policymakers. The authors investigated the endowment and development of employability skills in relation to social capital. Exposure to social capital tends to affect an individual's skills and capability development at an early stage, and in the long term, this calls attention to access to quality education between rural and urban youth.
Investigating the impact of emerging technologies on construction safety performance
Authors: Dobrucali Esra , Demirkesen Sevilay , Sadikoglu Emel , Zhang Chengyi , Damci Atilla
Published: November 2022

Purpose

Construction safety is heavily affected by using new technologies in this growing trend of technology adoption. Especially, safety performance is enhanced through the utilization of some effective technologies such as artificial intelligence, virtual reality, BIM and wearable devices. Therefore, the main purpose of this study is to investigate the influence of emerging technologies on construction safety performance and quantify the relationship between those. The proposed components of emerging technologies are BIM, GIS, VR, RFID, AI, ML, eye tracking and serious games and wearable devices, whereas the dimensions of construction safety performance are safety planning, safety training, safety inspection and monitoring, safety audits and reviews and safety leadership.

Design/methodology/approach

A structural model was composed consisting of emerging technologies and safety performance indicators. Then, a questionnaire was designed and administered to construction professionals, and data from 167 projects were analyzed using structural equation modeling. The data were analyzed by using software, called SPSS AMOS.

Findings

The analysis of the structural model proves that there is a positive and significant relationship between emerging technologies and construction safety performance. Moreover, the factor loadings for each factor were found to be high indicating a good representation of the construct by the components developed. Among the technologies, BIM, robotics and automation, AI and wearable devices were detected to be the most significant technologies in terms of impacting safety performance.

Originality/value

The study contributes to the body of knowledge in that it develops a conceptual framework consisting of specific technologies in terms of emerging technologies, reveals the impact of such technologies on safety performance and proposes several tools and strategies for enabling effective safety management along the project lifecycle. Industry practitioners may benefit from the framework developed by adopting such technologies to enhance their safety performance on construction projects.
Transformational leadership, employee self-efficacy, employee innovativeness, customer-centricity, and organizational competitiveness among insurance firms
Authors: Iddris Faisal , Dogbe Courage Simon Kofi , Kparl Emmanuel Mensah
Published: November 2022

Purpose

This study aims to assess how employee innovativeness, employee self-efficacy and customer-centricity intervene in the relationship between transformational leadership and organizational competitiveness of insurance firms.

Design/methodology/approach

This study was a survey, with data collected using a structured questionnaire. The population was the insurance firms in Ghana, and the target respondents were employees. The sample comprises 218 employees drawn from 19 insurers. Data was analyzed using structural equation modeling.

Findings

This study concludes that transformational leadership had a direct effect on organizational competitiveness. Employee innovativeness partially mediated the relationship between transformational leadership and organizational competitiveness. Employee self-efficacy moderated the effect of transformational leadership on employee innovativeness. Finally, customer-centricity moderated the effect of employee innovativeness on the organizational competitiveness of insurance firms.

Research limitations/implications

Future studies should pay particular attention to the individual dimensions of transformational leadership (individualized consideration, intellectual stimulation, inspirational motivation and idealized influence), in combination with the other constructs studied.

Practical implications

Insurance is a service industry, which sells mostly unsolicited products. Customer-centricity is therefore very crucial in achieving organizational competitiveness. Attention should also be paid to transformational leadership and employee self-efficacy, as they enhanced employee innovativeness needed for competitive advantage.

Originality/value

This study contributed to the understanding of the relationship between transformational leadership and organizational competitiveness, by identifying employee innovativeness, employee self-efficacy and customer centricity, as intervening variables.
Alliance learning process and alliance success: the moderating role of openness
Authors: Waheed Abdul , Shafiq Saad , Mirza Bilal
Published: November 2022

Purpose

Industry and academia are interested to understand how companies develop alliance capabilities through managing the knowledge, for alliance success. This study aims to investigate how alliance learning process is related to the overall success of any alliance, and how openness culture moderates the relationship of alliance learning process and alliance success.

Design/methodology/approach

English language questionnaires were sent to top executives of 400 companies because English is a commonly understood language at managerial level in Pakistani companies. In total, 186 usable answers were received. Hierarchical linear regression was used for hypothesis testing.

Findings

Alliance learning is significantly and positively related to alliance success. Openness plays a role as moderator between the relationship of alliance learning process and alliance success. Contrary to the literature, at low level of alliance learning, high level of openness increases the chances of alliance but as we move toward high level of alliance leaning, low level of openness is more effective to achieve the alliance success.

Research limitations/implications

The data in this study was collected from Pakistan. The results may not be generalized to other regions, especially to developed countries.

Practical implications

The results have implications for managers involved in alliances. They can be benefitted by this study to understand the role of alliance (knowledge) learning process on alliance success and contingent role of openness on this relationship.

Originality/value

This study is an important contribution to understand the notion of organizational learning and knowledge management in alliance context. To the best of the authors’ knowledge, this is the first study to investigate openness as a moderator of the relationship between alliance learning process and alliance success.
Task information types related to data gathering in media studies
Authors: Korkeamäki Laura , Keskustalo Heikki , Kumpulainen Sanna
Published: November 2022

Purpose

The purpose of this paper is to examine what types of task information media scholars need while gathering research data to create new knowledge.

Design/methodology/approach

The research design is qualitative and user-oriented. A total of 25 media scholars were interviewed about their research processes and interactions with their research data. The interviews were semi-structured, complemented by critical incident interviews. The analysis focused on the activity of gathering research data. A typology of information (task, domain and task-solving information) guided the analysis of information types related to data gathering, with further analysis focusing only on task information types.

Findings

Media scholars needed the following task information types while gathering research data to create new knowledge: (1) information about research data (aboutness of data, characteristics of data, metadata and secondary information about data), (2) information about sources of research data (characteristics of sources, local media landscapes) and (3) information about cases and their contexts (case information, contextual information). All the task information types should be considered when building data services and tools to support media scholars' work.

Originality/value

The paper increases understanding of the concept of task information in the context of gathering research data to create new knowledge and thereby informs the providers of research data services about the task information types that researchers need.
New bed configurations and discharge timing policies: A hospital‐wide simulation
Authors: Hassanzadeh Hamed , Khanna Sankalp , Boyle Justin , Jensen Felicity , Murdoch Allison
Published: November 2022

Objective

Optimising patient flow is becoming an increasingly critical issue as patient demand fluctuates in healthcare systems with finite capacity. Simulation provides a powerful tool to fine‐tune policies and investigate their impact before any costly intervention.

Methods

A hospital‐wide discrete event simulation is developed to model incoming flow from ED and elective units in a busy metropolitan hospital. The impacts of two different policies are investigated using this simulation model: (i) varying inpatient bed configurations and a load sharing strategy among a cluster of wards within a medical department and (ii) early discharge strategies on inpatient bed access. Several clinically relevant bed configurations and early discharge scenarios are defined and their impact on key performance metrics are quantified.

Results

Sharing beds between wards reduced the average and total ED length of stay (LOS) by 21% compared to having patients queue for individual wards. The current baseline performance level could be maintained by using fewer beds when the load sharing approach was imposed. Earlier discharge of inpatients resulted in reducing average patient ED LOS by approximately 16% and average patient waiting time by 75%. Specific time‐based discharge targets led to greater improvements in flow compared to blanket approaches of discharging all patients 1 or 2 hours earlier.

Conclusions

ED access performance for admitted patients can be improved by modifying downstream capacity or inpatient discharge times. The simulation model was able to quantify the potential impacts of such policies on patient flow and to provide insights for future strategic planning.
CRISPR/Cas9‐mediated knockout of period reveals its function in the circadian rhythms of the diamondback moth Plutella xylostella
Authors: Wang Danfeng , Chen Jing , Yuan Yao , Yu Lingqi , Yang Guang , Chen Wenfeng
Published: November 2022

Circadian clocks control the rhythmicity of many behaviors and physiological features of insects. To study the circadian clock of the moth Plutella xylostella, we employed CRISPR/Cas9‐mediated genome editing to investigate the effect of loss of the clock gene period on the circadian rhythms. P. xylostella harbors a single copy of period. Phylogenetic analysis showed that P. xylostella PERIOD is more homologous to mouse PERIOD than the PERIOD proteins from bees, flies, mosquitos, and many other Lepidoptera, such as Danaus plexippus and Bombyx mori. The circadian rhythms in adult locomotor activity were altered in the period knockout strain of P. xylostella under light–dark (LD) and continuous dark (DD) conditions. Under the LD cycle, the wild‐type moths displayed nocturnal activity with activity peaking very early after lights off and quickly declining after lights on. In contrast, the period knockout strain had no peak in activity when the lights were turned off and exhibited steady activity throughout the hours of darkness. Interestingly, under DD conditions, our results showed that the locomotor rhythm can be maintained without period gene, but at a lower rhythmicity ratio than wild‐type. In addition, knockout of period in P. xylostella changed circadian rhythms patterns related to pupal eclosion, mating, egg‐laying, and egg hatching. Mechanistically, loss of PERIOD disrupted the molecular rhythm of period and changed the clock transcription rhythm in the heads of the moths under LD and DD conditions. Together, our study indicates that the PERIOD is required for normal expression of many behavioral rhythms in P. xylostella.
Weak Emission Standards and Australia's Low Takeup of Electric Vehicles
Authors: Martin Peter
Published: November 2022

Australia is unusual among developed countries both in lacking fleet‐wide vehicle carbon dioxide emission standards and in having a very low takeup of all‐electric vehicles. This paper outlines how fleet‐wide vehicle carbon dioxide emission standards operate and identifies mechanisms by which their absence might lead to a low takeup of electric vehicles in countries such as Australia. Although hard to verify one of those mechanisms in Australia (higher prices charged for all‐electric vehicles), it is easy to verify the unusually low number of models of all‐electric models made available for sale. The paper also outlines Australia's slow 15‐year journey towards standards, pointing to the possible role of political machinations and political caution in delaying their introduction. It identifies one group of employees with much to lose from a rapid uptake of electric vehicles—motor mechanics.
Circulating CD200 is increased in the secretory phase of women with endometriosis as is endometrial mRNA, and endometrial stromal cell CD200R1 is increased in spite of reduced mRNA
Authors: Hamilton Matthew , Turpin Victoria , Ayoub Anmar , Reihani Amir , Arredondo Jorge , Ask Kjetil , Clark David A. , Foster Warren G.
Published: November 2022

Problem

Estrogen‐dependent extrauterine implantation and growth of menstrual endometrial tissue affects roughly 10% of reproductive age women and depends on suppression of local innate immune defenses to prevent ectopic tissue rejection. Immunohistochemistry has shown the immune check‐point inhibitor CD200 which can suppress rejection is expressed in eutopic endometrium and in ectopic deposits. Soluble CD200 accumulated in venules draining eutopic and ectopic endometrium of endometriosis cases in the secretory phase but not proliferative phase of the menstrual cycle, and should be increased in the circulation.

Method of Study

Sera from endometriosis and non‐endometriosis controls were tested by ELISA for CD200. Endometrial CD200, CD200R1 and CD200R2 mRNA in eutopic was quantified by RT‐PCR and localized by in situ hybridization. CD200R1 protein was quantified by immunohistochemistry.

Results

Secretory phase serum CD200 was elevated in women with endometriosis compared to controls. Serum CD200 correlated with matched endometrial CD200 mRNA levels. Expression of mRNA for CD200R1 which signals immune suppression was decreased whereas mRNA for the CD200R2 activating receptor was increased. In situ staining of CD200R1 and CD200R2 mRNA showed both receptors were expressed and the fraction of CD200R that is CD200R1 was reduced in secretory and menstrual phase endometriosis endometrium consistent with the RT‐PCR result. By contrast, CD200R1 protein and CD200R1 fraction of total CD200R protein were increased in endometriosis.

Conclusions

Failure to suppress circulating CD200 levels in the secretory phase had an 87% specificity and 90% sensitivity for endometriosis. CD200 and increased CD200R1 expression may facilitate development of ectopic deposits by suppressing rejection mechanisms.
Non‐invasive monitoring and treat‐to‐target approach are cost‐effective in patients with mild–moderate ulcerative colitis
Authors: Cortesi Paolo Angelo , Fiorino Gionata , Peyrin‐Biroulet Laurent , Mantovani Lorenzo Giovanni , Jairath Vipul , Paridaens Kristine , Andersson Fredrik L. , Danese Silvio
Published: November 2022

Background

There are no data to assess the value associated with a treat‐to‐target (T2T) strategy based on tight control of mild–moderate ulcerative colitis (UC).

Aim

To assess the cost‐effectiveness of a T2T approach based on the normalisation of clinical signs and faecal calprotectin (FC)

Methods

A decision analytical Markov model was developed to compare T2T algorithm combining clinical symptoms and FC levels to define treatment response and the possible switch to the next treatment line (T2T‐FC), and the reference strategy based only on symptoms. The model included five treatment lines and was conducted from the Italian national health service (NHS) perspective using a 3‐year time horizon. The model calculated the incremental cost‐effectiveness ratio as € per relapse avoided. Deterministic and probabilistic sensitivity analyses were conducted.

Results

The cost‐effectiveness analysis produced an increased time spent by a patient in clinical remission and FC ≤ 100 level (+0.177 years; about 2 months) and a decreasing number of relapses (−0.1937; −20.9%) per patient using a T2T‐FC approach compared to only symptoms. Furthermore, the T2T‐FC was associated with higher cost (+€1795). The ICER estimated was €9263 per relapse avoided. These results were confirmed by sensitivity analyses.

Conclusions

T2T‐FC approach resulted in a higher benefit for mild–moderate UC patients in terms of time in remission and incidence of relapse but was associated with higher costs. Clinical trials and real‐world clinical studies are needed to provide additional data on the cost–benefit of this approach.
Successful combined laparoscopic and thoracoscopic surgery for esophago‐mediastinal fistulae
Authors: Takise Shuhei , Nakajima Masanobu , Muroi Hiroto , Ihara Keisuke , Kubo Tsukasa , Kikuchi Maiko , Fujita Junki , Matsudera Shotaro , Inoue Noboru , Yamaguchi Takeshi , Ogino Kei , Nakagawa Masatoshi , Suzuki Kan , Morita Shinji , Nakamura Takatoshi , Kojima Kazuyuki
Published: November 2022

Minimally invasive surgeries have been developed, not only for gastrointestinal cancer, but also for benign or emergency cases. We report the case of a 62‐year‐old male who underwent laparoscopic and thoracoscopic combined surgery for an esophago‐mediastinal fistula caused by a press‐through package. In the initial laparoscopic phase, transhiatal dissection of the lower thoracic esophagus and harvesting of the greater omentum were performed. In the thoracoscopic phase, resection of the fistula and esophageal wall closure were performed. Thereafter, the greater omentum was lifted via the esophageal hiatus and wrapped around the repaired part of the esophagus for reinforcement. The total operative time was 371 min, with 163 and 208 min for the laparoscopic and thoracoscopic phases, respectively. In total, 20 ml of blood was lost. No perioperative complications or recurrences were observed. Laparoscopic and thoracoscopic combined omentoplasty was effective for refractory esophago‐mediastinal fistula.
Pulmonary transit time has close relation with pulmonary pulse wave transit time in normal subjects
Authors: Zhang Jun , Zheng Xiao‐Zhi , Wu Xu‐Chu
Published: November 2022

Background

Pulmonary transit time (PTT) and pulmonary pulse wave transit time (pPTT) are useful parameters for the evaluation of cardiopulmonary circulation and vascular alterations, but their relationship remains unknown. The aim of this study was to investigate the correlation between PTT and pPTT.

Methods

A total of 60 healthy volunteers were involved in this study. They were divided into two groups (30 participants per group): <50 years and >50 years. They all underwent Doppler echocardiography of pulmonary vein flow and contrast echocardiography with the measurement of pPTT and PTT, respectively. The correlation between PTT and pPTT was deduced.

Results

Compared with Group of <50 years, there was a significant increment in left atrial volume index, left atrial pressure and pulmonary artery stiffness but a significant reduction in acceleration times of pulmonary artery flow in Group of >50 years (p < 0.05). Group >50 years had longer PTT and but reduced normalized PTT by R‐R interval (NPTT), reduced normalized pPTT by R‐R interval (NpPTT) than Group <50 years (p < 0.05), while there was no significant difference in pPTT between the two groups (p > 0.05). PTT and NPTT were all negatively correlated with pPTT and NpPTT. The statistically significant strongest correlation was observed between PTT and NpPTT (r = −0.886, p < 0.0001). The regression equation for them was y = 7.4396–13.095x (R2 = 0.785; p < 0.001), where x and y represent NpPTT and PTT, respectively.

Conclusion

PTT had close relation with pPTT in normal subjects. From the regression equation for them, we can get the value of PTT simply and easily by non‐invasively measured pPTT.
Trans‐gnetin H isolated from the seeds of Paeonia species induces autophagy via inhibiting mTORC1 signalling through AMPK activation
Authors: Xia Chao , Wang Guoyan , Chen Lei , Geng Huijun , Yao Junhu , Bai Zhangzhen , Deng Lu
Published: November 2022

Paeonia is a well‐known species of ornamental plants, traditional Chinese medicines, and emerging oilseed crops. Apart from nutritional unsaturated fatty acids, the seeds of peonies are rich in stilbenes characterized by their wide‐ranging health‐promoting properties. Although the typical stilbene resveratrol has been widely reported for its multiple bioactivities, it remains uncertain whether the trimer of resveratrol trans‐gnetin H has properties that regulate cancer cell viability, let alone the underlying mechanism. Autophagy regulated by trans‐gnetin H was detected by western blotting, immunofluorescence, and quantitative real‐time PCR. The effects of trans‐gnetin H on apoptosis and proliferation were examined by flow cytometry, colony formation and Cell Counting Kit‐8 assays. Trans‐gnetin H significantly inhibits cancer cell viability through autophagy by suppressing the phosphorylation of TFEB and promoting its nuclear transport. Mechanistically, trans‐gnetin H inhibits the activation and lysosome translocation of mTORC1 by inhibiting the activation of AMPK, indicating that AMPK is a checkpoint for mTORC1 inactivation induced by trans‐gnetin H. Moreover, the binding of TSC2 to Rheb was markedly increased in response to trans‐gnetin H stimulation. Similarly, trans‐gnetin H inhibited the interaction between Raptor and RagC in an AMPK‐dependent manner. More importantly, trans‐gnetin H‐mediated autophagy highly depends on the AMPK‐mTORC1 axis. We propose a regulatory mechanism by which trans‐gnetin H inhibits the activation of the mTORC1 pathway to control cell autophagy.
Cover Image
Authors: Olaniru Oladapo E. , Hook Philippa , Persaud Shanta J.
Published: November 2022

The cover image is based on the Invited Review Using single‐cell multi‐omics screening of human fetal pancreas to identify novel players in human beta cell development by Oladapo E. Olaniru et al., https://doi.org/10.1111/dme.14992

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Breast cancer classification and segmentation framework using multiscale CNN and U‐shaped dual decoded attention network
Authors: Umer Muhammad Junaid , Sharif Muhammad , Wang Shui‐Hua
Published: November 2022

Breast cancer is a mostly diagnosed deadly disease with a high mortality rate that can effectively be cured by early diagnosis and proper treatment. Ultrasound imaging modality is being utilized at a large scale for early diagnosis of this disease due to quick results and cheapness. Manual diagnosis of breast cancer is a laborious task that needs experts and is also subjective which necessitates the accurate diagnosis solution of this disease with help of the computer. This work proposed a combined framework for the classification and segmentation of breast cancer to automate manual diagnosis. A multiscale classification model for the classification of breast cancer into three classes is developed. For the segmentation task, an autoencoder‐based U‐shaped DDA‐Net segmentation model consisting of a dual‐decoded attention mechanism is proposed. For experiments two publically available datasets namely BUSI and UDIAT are utilized. Before the classification task feature selection method of the whale optimization algorithm is implemented and for the classification task different machine learning algorithms are utilized. The proposed method achieved the segmentation dice of 88.68% on the UDIAT dataset and dice of 87.95% on the BUSI dataset with a classification accuracy of 97.89% with a precision score of 97.9%. Results validated that the proposed combined classification and segmentation technique can reliably be implemented to accurately diagnose breast cancer at its initial level.
Monitoring concept for the propagation of compressive fatigue in externally prestressed concrete beams using digital image correlation and fiber optic sensors
Authors: Becks Henrik , Baktheer Abedulgader , Marx Steffen , Classen Martin , Hegger Josef , Chudoba Rostislav
Published: November 2022

The fatigue of concrete has been the subject of research for many years, and yet, there are still open questions. In particular, the fatigue‐induced damage evolution accompanied by a stress redistribution process propagating through the concrete structure is still not fully understood. So far, there are only few experimental studies addressing the fatigue propagation through a material zone occurring, for example, in beams with a pulsating, nonuniform stress profile. To investigate the influence of such stress configurations on the material and structural degradation process, a measuring concept has been developed combining digital image correlation, fiber optic sensors, and conventional strain gauges. The presented experiments visualize the propagating fatigue degradation in the compression zone of prestressed concrete beams subjected to fatigue loading. Based on the developed measurement concept, the quantitative foundation for a comprehensive validation of design rules and material models accounting for concrete fatigue can be significantly extended.
On the use of milled shell‐only specimens to study the effect of fiber orientation on the fatigue behavior of a short fiber‐reinforced polyamide
Authors: Canegrati Andrea , Martulli Luca Michele , Hine Peter J. , Grassini Carlo , Bernasconi Andrea
Published: November 2022

The interpretation of the fiber orientation effects on the fatigue behavior of short fiber‐reinforced polymers using specimens extracted from injection‐molded plates is hampered by the typical shell‐core‐shell structure, which affects the stress distribution through the sample's thickness. In this work, local fatigue strength values are obtained using specimens machined to leave only the outer shell layers, thus having a more homogeneous fiber orientation. Results of the finite element analysis of integer and shell‐only specimens, accounting for locally measured fiber orientations, are compared. Conclusions are drawn about the role of the core layer and the limitations of milled specimens in the evaluation of the fatigue strength.
Practice what you preach: Adoption of internal campus innovations at Dutch research‐intensive universities
Authors: Rymarzak Małgorzata , den Heijer Alexandra , Arkesteijn Monique , Du Preez Mathilda
Published: November 2022

Campus decision makers are increasingly expected to adopt ‘campus innovations’ (affecting real estate and different facilities), not only from the market and demand‐led (external campus innovations), but also developed by the university's own scientists (internal campus innovations). The adoption of the latter can be driven and hindered by many unique factors that campus decision makers have not dealt with before. To provide insight into them, qualitative data were collected from 13 out of 14 Dutch research‐intensive universities. The results indicate that internal campus innovations are driven by co‐creation stimulation, collaborative partnership, transparency and accountability, and local development contribution. Their adoption, however, may be obstructed by barriers embedded in the interaction between campus decision makers and scientists, organizational university context, funds unavailability and innovations' supply‐pushed characteristics. An increased understanding of these barriers and the practices to overcome them is crucial for universities' campus decision makers to actively engage in the adoption of internal campus innovations.
Narrative review of inpatient nutritional management of anorexia nervosa with management recommendations for Australian tertiary health services
Authors: Hoo Phoebe , Goldschlager Romi , Katsoulis John , Newnham Evan , Harun Nur‐Shirin , Gwee Karen , Silberberg Carol , Russell Nick , Lam Simon , Adithama Esti , Cook Natasha , Weickhardt Andrew
Published: November 2022

Background

Patients with anorexia nervosa (AN) may experience life‐threatening malnutrition‐related complications requiring inpatient medical stabilisation. Several management guidelines have been developed but discrepancies exist because of limited high‐level evidence.

Aims

To review the evidence base for recommendations contained in Victorian health services guidelines for the nutritional management of inpatients with AN.

Methods

MEDLINE and Embase databases were searched for published studies on the nutritional management of inpatients with AN, combined with a manual search through citations. Studies including patients with AN aged 16 years and older were included. Case reports, small case series of <10 patients, studies of nonmedical management and studies with an exclusive paediatric population were excluded. The search results were compared with AN inpatient medical management guidelines sourced from large tertiary health services across Victoria, Australia.

Results

The search yielded 584 studies, subsequently reduced to nine studies using the inclusion and exclusion criteria. The results suggest that commencing refeeding at a higher caloric value allows faster weight gain and shorter hospitalisation. Enteral tube feeding is preferential to parenteral nutrition because of infrequent and milder complications. Zinc supplementation showed a doubled rate of body mass index increase compared with placebo. Comparison with Victorian health services guidelines revealed inconsistent recommendations for high‐calorie refeeding and micronutrient supplementation.

Conclusion

The evidence supports high‐calorie refeeding of 2000 kcal/day in AN inpatient medical management and zinc supplementation in improving the rate of weight restoration. This is inconsistently reflected in different Victorian health services guidelines. Updated national consensus guidelines could assist in improving consistency of evidence‐based health care.
The PI3K inhibitor pictilisib and the multikinase inhibitors pazopanib and sorafenib have an impact on Rac1 level and migration of medulloblastoma in vitro
Authors: Schoen Leonie F. , Craveiro Rogerio B. , Pietsch Torsten , Moritz Thomas , Troeger Anja , Jordans Silvia , Dilloo Dagmar
Published: November 2022

Metastatic disease is the leading cause of death in children suffering from medulloblastoma and a major treatment challenge. The evidence of leptomeningeal dissemination defines the most aggressive tumours and is associated with increased mortality; thus, inhibition of migration as a factor involved in the process of metastatic disease is fundamental for the treatment and prevention of metastatic dissemination. Targeting the small Rho GTPases Rac1 has been shown to effectively impair medulloblastoma cell migration in vitro. Yet clinically applicable selective Rac1 inhibitors are still lacking. In view of the pertinent oncogenic role of the PI3K signalling cascade and tyrosine kinase‐mediated signalling pathways in medulloblastoma, we explored clinically available targeted therapeutics to this effect. Here, we show that Rac1 is expressed in both the cytoplasm and nucleus in the medulloblastoma cell lines Daoy and MEB‐Med‐8A representative of two high risk medulloblastoma entities. We demonstrate that activated Rac1 is subject to substantial downmodulation following administration of the clinically available inhibitor of the PI3K pathway Pictilisib (GDC‐0941) and the multityrosine kinase inhibitors Pazopanib and Sorafenib. The application of those drugs was associated with reduced mobility of the medulloblastoma cells and alterations of the actin skeleton. Of note, PI3K inhibition reveals the strongest anti‐migratory effect in Daoy cells. Thus, our in vitro observations provide new insights into different strategies of blocking Rac1 and inhibiting migration in medulloblastoma employing clinically available agents paving the way for confirmatory studies in in vivo models.