bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological inhibition of titan-like cells formation suggests that accumulation of endogenous free radicals that correlate with mitochondrial changes are required to induce this transition inCryptococcus neoformans
Authors: García-Barbazán Irene , García-Rodas Rocío , Sachse Martin , Luque Daniel , Megías Diego , Zaragoza Oscar 
Published: April 2022

AbstractCryptococcus neoformansis an encapsulated yeast able to cause disease (mainly meningoencephalitis) among immunosuppressed patients, mostly HIV+. This yeast can form the so-called titan cellsin vivo, which are cells of an abnormal larger size due to an increase in both the capsule and the cell body size (total size reaching between 50-70 microns). This phenomenon can be partially reproducedin vitroto obtain cells of an intermediate size (25-30 um), which have been denominated titan-like cells. In this work, we have screened 1,520 compounds from the Prestwick Chemical Library and identified off-patent drugs that inhibited titan-like cell formationin vitro. We developed an automated fluorescence-based microscopy assay and identified 64 compounds as possible inhibitors of titan-like cellsin vitro. We chose 10 of these compounds to confirm their inhibitory effect and confirmed them as inhibitors of titan-like cells with dose-response curves. Several of the compounds identified had antioxidant properties (i.e., retinoic acid), indicating a possible role of free radicals during titan cell formation. Using fluorescent probes, we found that there was an endogenous accumulation of ROS during cell growth, which was inhibited in the presence of retinoic acid. Furthermore, we found that during titanization, there were significant changes in the mitochondria, which is the main organelle where ROS are produced. We hypothesize that an intracellular increase of free radicals at the mitochondria might be a triggering signal to induce titanization.ImportanceCryptococcus neoformansis an excellent model to investigate fungal pathogenesis. This yeast can produce “titan cells”, which are cells of an abnormal larger size that contribute to the persistence of the yeast in the host. In this work, we have used a new approach to characterize them, which is identifying drugs that inhibit this process. We have used a repurposing off- patent drug library, combined with an automatic method to image and analyse fungal cell size. In this way, we have identified many compounds that inhibit this transition. Interestingly, several compounds were antioxidants, allowing us to confirm that endogenous ROS and mitochondrial changes are important for titan cell formation. This work provides new evidences of the mechanisms required for titanization. Furthermore, the future characterization of the inhibitory mechanisms of the identified compounds by the scientific community will contribute to better understand the role of titan cells in virulence.
Cytoneme-mediated transport of active Wnt5b/Ror2 complexes in zebrafish gastrulation
Authors: Zhang Chengting , Brunt Lucy , Rogers Sally , Scholpp Steffen 
Published: April 2022

SummaryChemical signaling is the primary means by which cells communicate in the embryo. The underlying principle refers to a group of ligand-producing cells and a group of cells that respond to this signal because they express the appropriate receptors. In the zebrafish embryo, Wnt5b binds to the receptor Ror2 to trigger the Wnt/Planar Cell Polarity (Wnt/PCP) signaling pathway to regulate tissue polarity and cell migration. However, it is still unclear how this lipophilic ligand is transported from the source cells through the aqueous extracellular space to the target tissue. Here we show that Wnt5b, together with Ror2, is loaded on long protrusions. The active Wnt5b/Ror2 complexes are handed over from these cytonemes to the receiving cell to trigger Wnt/PCP signaling, regardless of whether the cell expresses functional receptors. On the tissue level, we show that cytoneme-dependent spreading of active Wnt5b/Ror2 affects convergence and extension in the zebrafish gastrula.
Development of an improved inhibitor of Lats kinases to promote regeneration of mammalian organs
Authors: Kastan Nathaniel R. , Oak Sanyukta , Liang Rui , Baxt Leigh , Myers Robert W. , Ginn John , Liverton Nigel , Huggins David J. , Pichardo John , Paul Matthew , Carroll Thomas S. , Nagiel Aaron , Gnedeva Ksenia , Hudspeth A. J. 
Published: April 2022

AbstractThe Hippo signaling pathway acts as a brake on regeneration in many tissues. This cascade of kinases culminates in the phosphorylation of the transcriptional cofactors Yap and Taz, whose concentration in the nucleus consequently remains low. Various types of cellular stress can reduce phosphorylation, however, resulting in the accumulation of Yap and Taz in the nucleus and subsequently in mitosis. We earlier identified a small molecule, TRULI, that blocks the final kinases in the pathway, Lats1 and Lats2, and thus elicits proliferation of several cell types that are ordinarily post-mitotic and aids regeneration in mammals. In the present study we present the results of chemical modification of the original compound and demonstrate that a derivative, TDI-011536, is an effective blocker of Lats kinases in vitro at nanomolar concentrations. The compound fosters extensive proliferation in retinal organoids derived from human induced pluripotent stem cells. Intraperitoneal administration of the substance to mice suppresses Yap phosphorylation for several hours and induces transcriptional activation of its target genes in the heart, liver, and skin. Moreover, the compound initiates the proliferation of cardiomyocytes in adult mice following cardiac cryolesions. After further chemical refinement, related compounds might prove useful in protective and regenerative therapies.Significance StatementIn humans and other mammals, many organs regenerate through the proliferation of cells that replace those that have succumbed to aging or injury. However, proliferation is largely absent in certain critical organs, including the heart, the central nervous system, and sensory organs such as the inner ear and retina. The Hippo-Yap biochemical signaling pathway, a cascade of proteins that—when active—inhibits cell division, constitutes one impediment to proliferation. We earlier identified a small molecule that interrupts Hippo-Yap signaling and thus relieves this block for some non-proliferating cells in vitro. In the present investigation, we have chemically modified the original substance to yield a more potent analog that is effective for several hours in mammalian tissues in vivo and initiates the proliferation of heart-muscle cells after cryolesioning. After further refinements, compounds of this family might prove useful in regenerative therapies.
Mathematical models of tumor volume dynamics in response to radiotherapy
Authors: Mohsin Nuverah , Enderling Heiko , Brady-Nicholls Renee , Zahid Mohammad U. 
Published: April 2022

AbstractFrom the beginning of the usage of radiotherapy (RT) for cancer treatment, mathematical modeling has been integral to understanding radiobiology and for designing treatment approaches and schedules. There has been extensive modeling of response to RT with the inclusion of various degrees of biological complexity. Here we focus on models of tumor volume dynamics. There has been much discussion on the implications of different models of tumor growth, and it is just important to consider the implications of selecting different models for response to RT. In this study, we compare three models of tumor volume dynamics: (1) exponential growth with RT directly reducing tumor volume, (2) logistic growth with direct tumor volume reduction, and (3) logistic growth with RT reducing the tumor carrying capacity. For all three models, we: performed parameter sensitivity and identifiability analyses; investigated the impact of the parameter sensitivity on the tumor volume trajectories; and examined the rates of change in tumor volume (ΔV/Δt) during and RT treatment course. The parameter identifiability and sensitivity analyses revealed the interdependence of the different model parameters and may inform parameter calibration in any further usage of these models. In examining the ΔV/Δt trends, we coined a new metric – the point of maximum reduction of tumor volume (MRV) – to quantify the magnitude and timing of the expected largest impact of RT during a treatment course. Ultimately, the results of these analyses help us to better understand the implications of model selection while simultaneously generating many hypotheses about the underlying radiobiology that need to be tested on time-resolved measurements of tumor volume from appropriate pre-clinical or clinical data. The answers to these questions and more detailed study of these and similar models of tumor volume dynamics may enable more appropriate model selection on a disease-site or patient-by-patient basis.
Interoperability of RTN1A in dendrite dynamics and immune functions in human Langerhans cells
Authors: Cichoń Małgorzata Anna , Pfisterer Karin , Leitner Judith , Wagner Lena , Staud Clement , Steinberger Peter , Elbe-Bürger Adelheid 
Published: April 2022

AbstractSkin is an active immune organ where professional antigen-presenting cells such as epidermal Langerhans cells (LCs) link innate and adaptive immune responses. While Reticulon 1A (RTN1A) was recently identified in LCs and dendritic cells in cutaneous and lymphoid tissues of humans and mice, its function is still unclear. Here, we studied the involvement of this protein in cytoskeletal remodeling and immune responses towards pathogens by stimulation of Toll-like receptors (TLRs) in resident LCs (rLCs) and emigrated LCs (eLCs) in human epidermis ex vivo and in a transgenic THP-1 RTN1A+cell line. Hampering RTN1A functionality through an inhibitory antibody induced significant dendrite retraction of rLCs and inhibited their emigration. Similarly, expression of RTN1A in THP-1 cells significantly altered their morphology, enhanced aggregation potential and inhibited the Ca2+flux. Differentiated THP-1 RTN1A+macrophages exhibited long cell protrusions and a larger cell body size in comparison to wild type cells. Further, stimulation of epidermal sheets with bacterial lipoproteins (TLR1/2 and TLR2) and single-stranded RNA (TLR7) resulted in the formation of substantial clusters of rLCs and a significant decrease of RTN1A expression in eLCs. Together, our data indicate involvement of RTN1A in dendrite dynamics and structural plasticity of primary LCs. Moreover, we discovered a relation between activation of TLRs, clustering of LCs and downregulation of RTN1A within the epidermis, thus indicating an important role of RTN1A in LC residency and maintaining tissue homeostasis.Graphical abstractHighlightsBlocking of RTN1A induces dendrite retraction of resident LCs (rLCs) in epidermal explants.Despite a roundish morphology rLCs exhibit reduced migration capacity.RTN1A has an inhibitory effect on the calcium flux.Toll-like receptor-activated rLCs form vast clusters and significantly diminish RTN1A expression after emigration.RTN1A plays a central role in LC residency and maintaining tissue homeostasis.
Participation Factor based analysis of PVSC type Multi-Input Zeta-SEPIC dc-dc converter
Authors: Thota Phanindra , Bhimavarapu Amarendra Reddy , Chintapalli V.V.S. Bhaskara Reddy 
Published: April 2022

Purpose
This study aims to propose a new non-isolated Multi-Input Zeta-SEPIC (MIZS) dc–dc converter for renewable energy sources integration with different voltage levels (low-voltage source, high-voltage source). The chosen configuration of the converter is capable of performing bucking as well as boosting operations in various modes of operation.

Design/methodology/approach
Parameters of the selected MIZS converter are designed using the time-domain analysis. The selected converter belongs to the sixth-order family with two switches and six energy storage elements. State-space model of the converter is developed for each mode of operation, and using these individual state-space models, an average state-space model of the converter useful to carry out detailed analysis for different operating conditions is developed. Analysis related to operational stability of the converter is also carried out using Participation Factor (PaF)-based Eigen value analysis.

Findings
Using the PaF-based Eigen analysis, participation of the various state variables in different Eigen modes and vice versa is carried out. Performance of the converter for different parameter variations in the allowable range is determined and the same has been used to find the operational stability of the converter under different modes of operation. The selected converter has low inductor ripple currents and output voltage ripples when delivering the power to load.

Originality/value
Because operational stability of the converter under various operating conditions is one of the key performance indicators for selecting a particular type of converter, PaF-based Eigen value analysis has been carried out using the average state-space model developed for the selected MIZS converter. Operational stability analysis of the converter is carried out for parameter variations also. In addition, participation of the various states in each Eigen mode and vice versa have been analyzed for designed parameter values and also variation within the specified range of variations.
SMEs and the regionalization of global value chains: an untold story from the Italian industrial districts
Authors: Bettiol Marco , Burlina Chiara , Chiarvesio Maria , Di Maria Eleonora 
Published: April 2022

Purpose
Within the theoretical framework of global value chains (GVCs), much importance has been given to industrial districts (IDs) and their role as localized manufacturing systems. The regionalization of GVC has opened new questions on the location of manufacturing activities and the potential consequences at the ID level. The reshoring phenomenon challenges internationalization processes, changing the configuration in trade dynamics for IDs. This paper aims to investigate which are the main internationalization patterns followed by district small and medium enterprises (SMEs) under the perspective of the regionalization of GVCs. This will help both practitioners and policymakers to better understand internationalization trajectories aimed at sustaining the economic development of district firms and territories.

Design/methodology/approach
The analysis has been conducted using a survey carried out on 210 ID SMEs in the furniture, mechanics and fashion industries located in Veneto and Friuli Venezia Giulia regions, in northeastern Italy. Moreover, data released from the Italian Customs Agency have been merged to detect the trends of interviewed firms’ internationalization between 2005 and 2019.

Findings
The results highlight how the geography of internationalization has changed over time, in particular following the regionalization of the GVCs. There are also differences among the industry specializations of IDs. This could be attributable to the strategy pursued by each firm to control the competition both in the domestic market and abroad, also in relation to GVC lead firms’ location strategies.

Originality/value
This paper applies new data on the analysis of ID SMEs related to international transactions over a long period of time. In doing this, this paper adds new insights to the GVC literature and future policies to be implemented to foster the participation of district firms in the global scenario.
Content analysis of e-inspection implementation for highway infrastructure construction projects
Authors: Mohamed Mamdouh , Tran Dai Q. 
Published: April 2022

PurposeThe use of digital inspection or e-inspection of transportation projects has been proven as an efficient method over the last decade. A wide range of studies were dedicated to developing and applying e-inspection techniques and technologies. However, there is a lack of a comprehensive systematic review and content analysis of using e-inspection in highway construction and maintenance projects. The main objectives of this study were to explore the current trend and identify relevant inspection technologies and their applications for highway construction projects.Design/methodology/approachA systematic review of 172 articles from 16 high-ranked academic journals in construction engineering and management published during 2000–2021 was conducted. This process resulted in 67 relevant articles included in the detailed content analysis. The analysis involved synthesizing six main construction elements and work types, nine typical inspection activities, and 23 technologies.FindingsThe result of the analysis showed that among the six construction elements and work types, bridge and hot mix asphalt (HMA) recorded the largest share of e-inspection research. For the nine inspection activities, progress monitoring of construction operations was the highest focused area of e-inspection research. The most common e-inspection technologies are geospatial tools, 3D modeling, and unmanned aircraft systems (UASs). Camera-based inspection has existed for decades, however, has limited research development. The critical success factors in implementing e-inspection in highway projects are sharing data among different technologies, inspector training, and reducing the cost of technology purchase.Originality/valueThis study is one of the first attempts to conduct a content analysis of the e-inspection implementation for highway projects. The findings of this study expose knowledge gaps in contemporary research related to implementation barriers such as cost of purchase and operation of e-inspection technologies and transferring data between technologies.
Winterizing the Egyptian spring: why might business schools fail to develop responsible leaders?
Authors: Mousa Mohamed 
Published: April 2022

Purpose
This paper aims to theoretically answer the question: why might business schools in Egypt fail to develop responsible leaders?

Design/methodology/approach
The author starts by discussing modernization theory (Lipset, 1959) – which highlights the idea that the more educated people there are in a given society/nation, the more calls for democracy, social citizenship and social justice will be launched – to address the strong association between the quality of business learning and the development of responsible leadership norms. Moving forward by focusing on the theory of education (Dewey, 1916) and institutional theory (DiMaggio and Powell, 1983), the author finds the main conditions needed to develop responsible leadership norms among business school students.

Findings
The author identified the following three necessary conditions: implementing responsible management education, sustaining management learning and ensuring that a purposive hidden curriculum is well-planned in business schools. The author sees these as the main priorities for developing responsible leadership skills among business school students in Egypt and similar post revolution countries.

Originality/value
This paper contributes by filling a gap in responsible leadership, public administration and higher education literature, in which conceptual studies on the role of business schools in post-revolution periods and conflict zones has been limited until now.
Female representation on boards of directors and environmental disclosure: evidence of the Brazilian GHG protocol program
Authors: Fabrício Sarah Amaral , Ferreira Denize Demarche Minatti , Rover Suliani 
Published: April 2022

Purpose
This study aims to identify a relationship between the presence of women on the board of directors (BOD) of Brazilian companies and the firms’ disclosure and participation in projects or initiatives to reduce greenhouse gas (GHG) emissions.

Design/methodology/approach
The research used an adaptation of the model by Ben-Amar et al. (2017), added two other gender variables and analyzed a sample of 42 companies listed on the Brazilian stock exchange that participate in the Brazilian GHG protocol program. As for the models with the variables of interest, the most significant was the female percentage, Blau’s index, the dummy of female presence, the number of women on BOD, total years with the woman on board and the number of committees the board women were.

Findings
The results for the sample showed that women were present on the BOD 475 times, against a male presence of 4,538 times. Empirical evidence confirms the research hypothesis that there is a positive relationship between the presence of women on the BOD and the likelihood of participation in the Brazilian GHG protocol program.

Research limitations/implications
The fact that few companies are listed on Brasil, Bolsa and Balcão and participate in the Brazilian GHG protocol program. Therefore, the impact of these findings may be reduced when compared with countries presenting more listed companies that have joined this type of program to diminish GHG emissions.

Originality/value
This study contributes to the literature on accounting, discussing carbon accounting in the field of environmental accounting and emphasizing that climate change-related risks greatly influence business and corporate assets. According to an article published by the World Resources Institute Brasil (2019), Brazil is the seventh country with the highest GHG emissions in the world.
Carbon footprint of maize planting under intensive subsistence cultivation in South Korea
Authors: Li Zhirun , Yang Yinsheng , So Namho , Lee Jong-In 
Published: April 2022

Purpose
During the planting process, agricultural products produce large amounts of greenhouse gas (GHG) emissions. This has placed tremendous pressure on sustainable global development. Many countries and regions in the world have adopted intensive subsistence cultivation methods when planting maize; however, limited studies exist on these methods. The main purpose of this research is to show the impact of climate change on maize yields and carbon footprint (CF) in South Korea over 10 years, find the proper operating method and promote the advanced combination of inputs for the sustainable development of maize farmers.

Design/methodology/approach
This study used survey data from the South Korea Rural Development Administration of 2010, 2014 and 2019 to estimate the CF of maize planting under intensive subsistence cultivation. Life-cycle assessment was used to determine the CF. Farmers were grouped according to significant differences in yield and GHG emissions. Linear regression was used to measure the dependence of the main contributors on the CF production and carbon efficiency.

Findings
In South Korean maize planting, N in chemical fertiliser was the most significant contributor to the CF and organic fertiliser was the most significant input. The use of chemical and organic fertilisers significantly affects the production of the CF and carbon efficiency. Households in the high-yield and low-GHG emission groups are more sustainable because they generate the least GHG when producing and earning through maize cultivation. Globally, maize production in South Korea has a relatively low CF and maize production produces fewer GHG.

Originality/value
This study provides information for policymakers to determine key operational options for reducing GHG emissions using intensive subsistence cultivation of maize production in South Korea and other countries.