bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effects of Workplace Interventions on Low Back Pain in Workers: A Systematic Review and Meta-Analysis
Authors: Russo Fabrizio , Papalia Giuseppe Francesco , Vadalà Gianluca , Fontana Luca , Iavicoli Sergio , Papalia Rocco , Denaro Vincenzo
Published: December 2021

This systematic review and meta-analysis aimed to analyze the effects of workplace interventions (WI) on clinical outcomes related to low back pain (LBP) in a worker population, and to assess socio-economic parameters as participants on sick leave, days of sick leave, and return to work following WI. A systematic literature search was performed to select randomized clinical trials that investigated the effectiveness of WI on return to work, sick leave, and working capacity of workers affected by nonspecific LBP. Fourteen articles were included in the review and meta-analysis. The meta-analysis showed improvements in pain (p = 0.004), disability (p = 0.0008), fear-avoidance for psychical activity (p = 0.004), and quality of life (p = 0.001 for physical scale and p = 0.03 for mental scale) for patients who underwent WI compared to controls. Moreover, the pain reduction following WI was statistically significant in the healthcare workers’ group (p = 0.005), but not in the other workers’ group. The participants on sick leave and the number of days of sick leave decreased in the WI group without statistical significance (p = 0.85 and p = 0.10, respectively). Finally, LBP recurrence was significantly reduced in the WI group (p = 0.006). WI led to a significant improvement of clinical outcomes in a workers’ population affected by LBP.
Clustering of Socioeconomic Data in Hong Kong for Planning Better Community Health Protection
Authors: Huang Zhe , Chan Emily Ying Yang , Wong Chi Shing , Zee Benny Chung Ying
Published: December 2021

The concept of socioeconomic vulnerability has made a substantial contribution to the understanding and conceptualization of health risk. To assess the spatial distribution of multi-dimensional socioeconomic vulnerability in an urban context, a vulnerability assessment scheme was proposed to guide decision-making in disaster resilience and sustainable urban development to reduce health risk. A two-stage approach was applied in Hong Kong to identify subgroups among Tertiary Planning Units (TPU) (i.e., the local geographic areas) with similar characteristics. In stage 1, principal components analysis was used for dimension reduction and to de-noise the socioeconomic data for each TPU based on the variables selected, while in stage 2, Gaussian mixture modeling was used to partition all the TPUs into different subgroups based on the results of stage 1. This study summarized socioeconomic-vulnerability-related data into five principal components, including indigenous degree, family resilience, individual productivity, populous grassroots, and young-age. According to these five principal components, all TPUs were clustered into five subgroups/clusters. Socioeconomic vulnerability is a concept that could be used to help identify areas susceptible to health risk, and even identify susceptible groups in affluent areas. More attention should be paid to areas with high populous grassroots scores and low young-age score since they were associated with a higher mortality rate.
Promoting Construction Industrialisation with Policy Interventions: A Holistic Review of Published Policy Literature
Authors: Jin Xin , Shen Geoffrey Q. P. , Wang Qian-Cheng , Ekanayake E. M. A. C. , Fan Siqi
Published: December 2021

By adopting the concept of ‘factory assembly followed by onsite installation,’ construction industrialisation (CI) plays an increasingly important role in sustainable urban development. CI can enhance construction quality and efficiency while reducing environmental impacts. To promote the CI, several policy interventions have been developed and implemented in different countries and regions. This study reviews the global CI promoting regulations and policies to provide a comprehensive insight into its interrelationship and development tendency. The research selects 105 publications related to practical CI policy from widely utilised databases (i.e., Web of Science and Scopus). Based on the annual publication trend analysis, geospatial distribution, and citation analysis, seven interrelated critical CI policy formulation themes are identified and examined: regulatory policies, standardised policies, promotional policies, urban design and planning policies, technological policies, managerial and educational policies, and sustainability policies. In addition, internal correlations and mutual influence among these seven classified policies are explored and discussed, which helps scholars enhance their grasp of current CI policy research and guide future research. This review provides the research community and industrial practitioners with a comprehensive understanding of various CI-promoting policies and a roadmap to CI-promoting policy development and evaluation.
Cultural Variance in Reception and Interpretation of Social Media COVID-19 Disinformation in French-Speaking Regions
Authors: Hughes Brian , White Kesa , West Jennifer , Criezis Meili , Zhou Cindy , Bartholomew Sarah
Published: December 2021

Digital communication technology has created a world in which media are capable of crossing national boundaries as never before. As a result, language is increasingly the salient category determining individuals’ media consumption. Today, a single social media post can travel around the world, reaching anyone who speaks its language. This poses significant challenges to combatting the spread of disinformation, as an ever-growing pool of disinformation purveyors reach audiences larger than ever before. This dynamic is complicated, however, by the diversity of audience interpretations of message content within a particular language group. Both across and within national boundaries, a single message may be subject to a variety of interpretations depending on the cultural experiences and identities of its recipients. This study explores that dynamic through analysis of French language anti-vaccine and COVID-denialist disinformation. Using qualitative coding methodology, a team of researchers empirically identify common and far-reaching patterns of Francophone COVID disinformation narratives and rhetoric. These narratives and rhetorics are then subjected to hermeneutic close reading to determine likely variations in their reception across different French-speaking cultures. Data were gathered and analyzed between the dates of 24 March 2021 and 27 April 2021. Results of this study indicate the need for awareness on the part of public health officials combatting COVID disinformation online, for both the transnational reach of disinformation targeting speakers of a single language and for variations in meaning and salience across cultures within that language group.
Duration of Untreated Disorder and Cannabis Use: An Observational Study on a Cohort of Young Italian Patients Experiencing Psychotic Experiences and Dissociative Symptoms
Authors: Ricci Valerio , Martinotti Giovanni , Ceci Franca , Chiappini Stefania , Di Carlo Francesco , Burkauskas Julius , Susini Ottavia , Luciani Debora , Quattrone Diego , De Berardis Domenico , Pettorruso Mauro , Maina Giuseppe , Di Giannantonio Massimo
Published: December 2021

Background: The Duration of Untreated Psychosis (DUP) is the time between the first-episode psychosis (FEP) and the initiation of antipsychotic treatment. It is an important predictor of several disease-related outcomes in psychotic disorders. The aim of this manuscript is investigating the influence of cannabis on the DUP and its clinical correlates. Methods: During years 2014–2019, sixty-two FEP patients with and without cannabis use disorder (CUD) were recruited from several Italian psychiatric hospitals. The subjects were then divided into two groups based on the duration of the DUP and assessed at the beginning of the antipsychotic treatment and after 3 and 6 months, using the Positive and Negative Syndrome Scale (PANSS), the Global Assessment of Functioning (GAF) scale, and the Dissociative Experiences Scale (DES-II). Results: As expected, a longer DUP was associated with worse symptoms and cannabis use did not seem to affect the DUP, but both were related with more dissociative symptoms at onset and over time. Discussion: According to our study, cannabis use can be a predictor of FEP and DUP, and of disease outcome. However, several factors might influence the relationship between cannabis use and DUP. Preventing cannabis use and early diagnosis of psychotic disorders might impact the disease by reducing the persistence of symptoms and limiting dissociative experiences.
Predicting Food Safety Compliance for Informed Food Outlet Inspections: A Machine Learning Approach
Authors: Oldroyd Rachel A. , Morris Michelle A. , Birkin Mark
Published: December 2021

Consumer food environments have transformed dramatically in the last decade. Food outlet prevalence has increased, and people are eating food outside the home more than ever before. Despite these developments, national spending on food control has reduced. The National Audit Office report that only 14% of local authorities are up to date with food business inspections, exposing consumers to unknown levels of risk. Given the scarcity of local authority resources, this paper presents a data-driven approach to predict compliance for newly opened businesses and those awaiting repeat inspections. This work capitalizes on the theory that food outlet compliance is a function of its geographic context, namely the characteristics of the neighborhood within which it sits. We explore the utility of three machine learning approaches to predict non-compliant food outlets in England and Wales using openly accessible socio-demographic, business type, and urbanness features at the output area level. We find that the synthetic minority oversampling technique alongside a random forest algorithm with a 1:1 sampling strategy provides the best predictive power. Our final model retrieves and identifies 84% of total non-compliant outlets in a test set of 92,595 (sensitivity = 0.843, specificity = 0.745, precision = 0.274). The originality of this work lies in its unique and methodological approach which combines the use of machine learning with fine-grained neighborhood data to make robust predictions of compliance.
What about the Consequences of the Use of Distance Learning during the COVID-19 Pandemic? A Survey on the Psychological Effects in Both Children and Parents
Authors: Maggio Maria Grazia , Stagnitti Maria Chiara , Calatozzo Patrizia , Cannavò Antonino , Bruschetta Daniele , Foti Cuzzola Marilena , Manuli Alfredo , Pioggia Giovanni , Calabrò Rocco Salvatore
Published: December 2021

Background: The COVID-19 pandemic implicated many social restrictions, including the use of distance learning (DL). Indeed, parents were obligated to support their children in online lessons and schoolwork. The aim of this study was to investigate the psycho-emotional impact of the COVID-19 pandemic on parents and children submitted to DL. Methods: One hundred and ninety-two participants (96 parents and 96 children) were enrolled in this study. Parents and children completed an online questionnaire, structured in four sections. Results: The results showed that parents had higher levels of stress and anxiety. In particular, the stress for DL was positively correlated with depression and anxiety. Parents’ jobs were negatively correlated with their levels of anxiety and stress. On the other hand, children reported higher levels of depressive symptoms and event-related anxiety, which increased as children got older. The stress and the anxiety in parents were positively correlated with the mood depression and anxiety of their children. Conclusions: The COVID-19 pandemic had a negative impact on the psychological well-being of children and parents who used DL. Although DL could be an alternative teaching method during pandemics, face-to-face teaching is fundamental and irreplaceable as it encourages dialogue, involvement, and human contact.
Organizational Health Literacy in a Hospital—Insights on the Patients’ Perspective
Authors: Lubasch Johanna Sophie , Voigt-Barbarowicz Mona , Ernstmann Nicole , Kowalski Christoph , Brütt Anna Levke , Ansmann Lena
Published: December 2021

Health literacy-sensitive communication has been found to be an important dimension of organizational health literacy measured from the patients’ perspective. Little is known about the role of health literacy-sensitive communication in complex care structures. Therefore, our aim was to assess which hospital characteristics (in terms of process organization) and patient characteristics (e.g., age, chronic illness, etc.) contribute to better perceptions of health literacy-sensitive communication, as well as whether better health literacy-sensitive communication is associated with better patient reported experiences. Data were derived from a patient survey conducted in 2020 in four clinical departments of a university hospital in Germany. Health literacy-sensitive communication was measured with the HL-COM scale. Data from 209 patients (response rate 24.2%) were analyzed with a structural equation model (SEM). Results revealed that no patient characteristics were associated with HL-COM scores. Better process organization as perceived by patients was associated with significantly better HL-COM scores, and, in turn, better HL-COM scores were associated with more patient-reported social support provided by physicians and nurses as well as fewer unmet information needs. Investing into good process organization might improve health literacy-sensitive communication, which in turn has the potential to foster the patient–provider relationship as well as to reduce unmet information needs of patients.
Validation of a Novel Predictive Algorithm for Kidney Failure in Patients Suffering from Chronic Kidney Disease: The Prognostic Reasoning System for Chronic Kidney Disease (PROGRES-CKD)
Authors: Bellocchio Francesco , Lonati Caterina , Ion Titapiccolo Jasmine , Nadal Jennifer , Meiselbach Heike , Schmid Matthias , Baerthlein Barbara , Tschulena Ulrich , Schneider Markus , Schultheiss Ulla T. , Barbieri Carlo , Moore Christoph , Steppan Sonja , Eckardt Kai-Uwe , Stuard Stefano , Neri Luca
Published: December 2021

Current equation-based risk stratification algorithms for kidney failure (KF) may have limited applicability in real world settings, where missing information may impede their computation for a large share of patients, hampering one from taking full advantage of the wealth of information collected in electronic health records. To overcome such limitations, we trained and validated the Prognostic Reasoning System for Chronic Kidney Disease (PROGRES-CKD), a novel algorithm predicting end-stage kidney disease (ESKD). PROGRES-CKD is a naïve Bayes classifier predicting ESKD onset within 6 and 24 months in adult, stage 3-to-5 CKD patients. PROGRES-CKD trained on 17,775 CKD patients treated in the Fresenius Medical Care (FMC) NephroCare network. The algorithm was validated in a second independent FMC cohort (n = 6760) and in the German Chronic Kidney Disease (GCKD) study cohort (n = 4058). We contrasted PROGRES-CKD accuracy against the performance of the Kidney Failure Risk Equation (KFRE). Discrimination accuracy in the validation cohorts was excellent for both short-term (stage 4–5 CKD, FMC: AUC = 0.90, 95%CI 0.88–0.91; GCKD: AUC = 0.91, 95% CI 0.86–0.97) and long-term (stage 3–5 CKD, FMC: AUC = 0.85, 95%CI 0.83–0.88; GCKD: AUC = 0.85, 95%CI 0.83–0.88) forecasting horizons. The performance of PROGRES-CKD was non-inferior to KFRE for the 24-month horizon and proved more accurate for the 6-month horizon forecast in both validation cohorts. In the real world setting captured in the FMC validation cohort, PROGRES-CKD was computable for all patients, whereas KFRE could be computed for complete cases only (i.e., 30% and 16% of the cohort in 6- and 24-month horizons). PROGRES-CKD accurately predicts KF onset among CKD patients. Contrary to equation-based scores, PROGRES-CKD extends to patients with incomplete data and allows explicit assessment of prediction robustness in case of missing values. PROGRES-CKD may efficiently assist physicians’ prognostic reasoning in real-life applications.
Parents’ and Children’s (6–12 Years Old) Physical Activity Association: A Systematic Review from 2001 to 2020
Authors: Matos Rui , Monteiro Diogo , Amaro Nuno , Antunes Raul , Coelho Luís , Mendes Diogo , Arufe-Giráldez Víctor
Published: December 2021

Worldwide, studies reveal that a significant proportion of adults and children do not meet the recommended guidelines for physical activity (PA). Therefore, it is crucial that proxy determinants for child physical activity enhancement could be identified. Parents have been considered to have a key role in child adherence to physical activity. Thus, this systematic review aimed to identify association between parents’ and children’s PA. The search of scientific papers was conducted from 31 October 2020 until 31 January 2021, on the Web of Science, Scopus, Psycinfo, SportDiscus, and Pubmed databases. The PRISMA protocol was used. Findings indicate a consistent association between parents’ and children’s (6–12 years old) PA. Despite the imbalance of the number of assessed fathers and mothers with the latter clearly overrepresented, a trend towards the same gender dyads on PA significant and positive association (father/son, mother/daughter) was evidenced. Results support the relevant importance of parents’ PA as role modeling (either explicitly or implicitly) for children’s PA. Besides, results revealed the importance of promoting PA in family for the enhancement of children’s PA. Moreover, and given the positive impact of exerting PA with the children on children’s PA, parents should spend more time practicing PA with their children, especially on MVPA and meeting the recommended guidelines for PA. Future studies should highlight the role of mediator variables on this interaction process, extending the knowledge on the contribution of other factors to the requested enhancement of children adherence to PA practice.
Assessing Esports Participation Intention: The Development and Psychometric Properties of the Theory of Planned Behavior-Based Esports Intention Questionnaire (TPB-Esport-Q)
Authors: Leung Ka-Man , Wong Ming-Yu-Claudia , Ou Kai-Ling , Chung Pak-Kwong , Lau Ka-Lai
Published: December 2021

Background: Esports is seen as an emerging industry that has enjoyed a surge in popularity worldwide. As a result, researchers have undertaken studies to try to understand the motivations and factors that impact Esports gameplay. Given the extensive utilization of TPB in many research projects to conceptualize and predict various behaviors, the current study aimed to further extend this theory to the Esports context by developing and validating an instrument that can illustrate the factors that impact the intention to participate in Esports, thus predicting Esports game playing behaviors. Methods: A total of 25 participants were involved in the development of the questionnaire using the qualitative approach, while 915 university students and 1164 secondary school students were involved in the survey for the questionnaire validation using the exploratory factor analysis and the confirmatory factor analysis. Results: All measurement models of the TPB subscales are considered as good fit. Conclusion: Hence, showing the newly designed TPB Esports Intention Questionnaire was found to be reliable and valid in revealing the level of intentions as well as the factors affecting Hong Kong students playing Esports.
Canadian Career Firefighters’ Mental Health Impacts and Priorities
Authors: MacDermid Joy C. , Lomotan Margaret , Hu Mostin A.
Published: December 2021

Firefighters’ perceptions of mental health can inform management. This qualitative study explored Canadian career firefighters’ experiences, needs, and research priorities with respect to mental health. Thirty-nine career firefighters (33 men, 6 women) of different ranks and geographic locales were interviewed using a semi-structured interview guide. The interviews were recorded, transcribed, and qualitatively analyzed using thematic analysis within an interpretive description approach. Firefighters reported that critical incidents and chronic job stressors contributed to mental health symptoms that led to burnout, compassion fatigue, and mental and physical injury. They were concerned with family impacts, like lack of full openness, reduced financial stability, and risk of divorce; and work impacts, like interpersonal conflict, lack of support to fellow firefighters, task avoidance, and absenteeism. A broad array of barriers and facilitators were found in firefighter work, culture, programs, social supports, health care, and societal factors. Variability in access to help, the changing fire service, and the complexity of knowing what to do to achieve mental health were evident across themes. Firefighters identified the need for research in four areas: awareness and monitoring, understanding etiology of mental health, better prevention and treatment, and access to care. Across domains of inquiry, context, “two sides to the coin”, and uncertainty were overarching themes.
Investigating Carnivore Guild Structure: Spatial and Temporal Relationships amongst Threatened Felids in Myanmar
Authors: Kyaw Pyae Phyoe , Macdonald David W. , Penjor Ugyen , Htun Saw , Naing Hla , Burnham Dawn , Kaszta Żaneta , Cushman Samuel A.
Published: December 2021

The co-occurrence of felid species in Southeast Asia provides an unusual opportunity to investigate guild structure and the factors controlling it. Using camera-trap data, we quantified the space use, temporal activity, and multi-dimensional niche overlap of the tiger, clouded leopard, Asiatic golden cat, marbled cat, and leopard cat in the Htamanthi Wildlife Sanctuary, Myanmar. We hypothesised that the spatio-temporal behaviour of smaller cats would reflect the avoidance of the larger cats, and similar-sized guild members would partition their niches in space or time to reduce resource competition. Our approach involved modelling single-species occupancy, pairwise spatial overlap using Bayesian inference, activity overlap with kernel density estimation, and multivariate analyses. The felid assembly appeared to be partitioned mainly on a spatial rather than temporal dimension, and no significant evidence of mesopredator release was observed. Nonetheless, the temporal association between the three mesopredators was inversely related to the similarity in their body sizes. The largest niche differences in the use of space and time occurred between the three smallest species. This study offers new insight into carnivore guild assembly and adds substantially to knowledge of five of the least known felids of conservation concern.
Impact of Multitemporal Land Use and Land Cover Change on Land Surface Temperature Due to Urbanization in Hefei City, China
Authors: Sun Jing , Ongsomwang Suwit
Published: December 2021

Land surface temperature (LST) is an essential parameter in the climate system whose dynamics indicate climate change. This study aimed to assess the impact of multitemporal land use and land cover (LULC) change on LST due to urbanization in Hefei City, Anhui Province, China. The research methodology consisted of four main components: Landsat data collection and preparation; multitemporal LULC classification; time-series LST dataset reconstruction; and impact of multitemporal LULC change on LST. The results revealed that urban and built-up land continuously increased from 2.05% in 2001 to 13.25% in 2020. Regarding the impact of LULC change on LST, the spatial analysis demonstrated that the LST difference between urban and non-urban areas had been 1.52 K, 3.38 K, 2.88 K and 3.57 K in 2001, 2006, 2014 and 2020, respectively. Meanwhile, according to decomposition analysis, regarding the influence of LULC change on LST, the urban and built-up land had an intra-annual amplitude of 20.42 K higher than other types. Thus, it can be reconfirmed that land use and land cover changes due to urbanization in Hefei City impact the land surface temperature.
Spatiotemporal Distribution Patterns and Local Driving Factors of Regional Development in Java
Authors: Pravitasari Andrea Emma , Rustiadi Ernan , Priatama Rista Ardy , Murtadho Alfin , Kurnia Adib Ahmad , Mulya Setyardi Pratika , Saizen Izuru , Widodo Candraningratri Ekaputri , Wulandari Siti
Published: December 2021

Although uneven regional development has long been an issue in Java, most parts of the territory experienced an increased level of development over the last two decades. Due to the variance in local background and spatial heterogeneity, the driving factors of the development level should, theoretically, vary over space. Therefore, in this study, we aim to investigate the local factors that influence the development level of Java’s regions. We used the spatiotemporal pattern analysis, ordinary least squares (OLS) regression, and geographically weighted regression (GWR), utilizing the regional development index as the predicted variable, and the social level, economy, infrastructure, land use, and environmental barriers as predictors. As per our results, it was found that the level of development in Java has improved over the past two decades. Metropolitan areas continued to lead this improvement. All the predictors that we examined significantly affected regional development. However, the spatial pattern of the local regression coefficients of Human Development Index (HDI), landslide, paddy conversion, and crime shifted due to changes in the spatial concentration of development activities.
3D Structures of IgA, IgM, and Components
Authors: Pan Shunli , Manabe Noriyoshi , Yamaguchi Yoshiki
Published: December 2021

Immunoglobulin G (IgG) is currently the most studied immunoglobin class and is frequently used in antibody therapeutics in which its beneficial effector functions are exploited. IgG is composed of two heavy chains and two light chains, forming the basic antibody monomeric unit. In contrast, immunoglobulin A (IgA) and immunoglobulin M (IgM) are usually assembled into dimers or pentamers with the contribution of joining (J)-chains, which bind to the secretory component (SC) of the polymeric Ig receptor (pIgR) and are transported to the mucosal surface. IgA and IgM play a pivotal role in various immune responses, especially in mucosal immunity. Due to their structural complexity, 3D structural study of these molecules at atomic scale has been slow. With the emergence of cryo-EM and X-ray crystallographic techniques and the growing interest in the structure-function relationships of IgA and IgM, atomic-scale structural information on IgA-Fc and IgM-Fc has been accumulating. Here, we examine the 3D structures of IgA and IgM, including the J-chain and SC. Disulfide bridging and N-glycosylation on these molecules are also summarized. With the increasing information of structure–function relationships, IgA- and IgM-based monoclonal antibodies will be an effective option in the therapeutic field.
No Intercellular Regulation of the Cell Cycle among Human Cervical Carcinoma HeLa Cells Expressing Fluorescent Ubiquitination-Based Cell-Cycle Indicators in Modulated Radiation Fields
Authors: Fukunaga Hisanori , Kaminaga Kiichi , Hirose Eri , Watanabe Ritsuko , Usami Noriko , Prise Kevin M. , Yokoya Akinari
Published: December 2021

The non-targeted effects of radiation have been known to induce significant alternations in cell survival. Although the effects might govern the progression of tumor sites following advanced radiotherapy, the impacts on the intercellular control of the cell cycle following radiation exposure with a modified field, remain to be determined. Recently, a fluorescent ubiquitination-based cell-cycle indicator (FUCCI), which can visualize the cell-cycle phases with fluorescence microscopy in real time, was developed for biological cell research. In this study, we investigated the non-targeted effects on the regulation of the cell cycle of human cervical carcinoma (HeLa) cells with imperfect p53 function that express the FUCCI (HeLa–FUCCI cells). The possible effects on the cell-cycle phases via soluble factors were analyzed following exposure to different field configurations, which were delivered using a 150 kVp X-ray irradiator. In addition, using synchrotron-generated, 5.35 keV monochromatic X-ray microbeams, high-precision 200 μm-slit microbeam irradiation was performed to investigate the possible impacts on the cell-cycle phases via cell–cell contacts. Collectively, we could not detect the intercellular regulation of the cell cycle in HeLa–FUCCI cells, which suggested that the unregulated cell growth was a malignant tumor. Our findings indicated that there was no significant intercellular control system of the cell cycle in malignant tumors during or after radiotherapy, highlighting the differences between normal tissue and tumor characteristics.
SB203580—A Potent p38 MAPK Inhibitor Reduces the Profibrotic Bronchial Fibroblasts Transition Associated with Asthma
Authors: Paw Milena , Wnuk Dawid , Nit Kinga , Bobis-Wozowicz Sylwia , Szychowski Rafał , Ślusarczyk Alicja , Madeja Zbigniew , Michalik Marta
Published: December 2021

Subepithelial fibrosis is a component of the remodeling observed in the bronchial wall of patients diagnosed with asthma. In this process, human bronchial fibroblasts (HBFs) drive the fibroblast-to-myofibroblast transition (FMT) in response to transforming growth factor-β1 (TGF-β1), which activates the canonical Smad-dependent signaling. However, the pleiotropic properties of TGF-β1 also promote the activation of non-canonical signaling pathways which can affect the FMT. In this study we investigated the effect of p38 mitogen-activated protein kinase (MAPK) inhibition by SB203580 on the FMT potential of HBFs derived from asthmatic patients using immunocytofluorescence, real-time PCR and Western blotting methods. Our results demonstrate for the first time the strong effect of p38 MAPK inhibition on the TGF-β1-induced FMT potential throughout the strong attenuation of myofibroblast-related markers: α-smooth muscle actin (α-SMA), collagen I, fibronectin and connexin 43 in HBFs. We suggest the pleiotropic mechanism of SB203580 on FMT impairment in HBF populations by the diminishing of TGF-β/Smad signaling activation and disturbances in the actin cytoskeleton architecture along with the maturation of focal adhesion sites. These observations justify future research on the role of p38 kinase in FMT efficiency and bronchial wall remodeling in asthma.
Determination of CYP450 Expression Levels in the Human Small Intestine by Mass Spectrometry-Based Targeted Proteomics
Authors: Grangeon Alexia , Clermont Valérie , Barama Azemi , Gaudette Fleur , Turgeon Jacques , Michaud Veronique
Published: December 2021

The human small intestine can be involved in the first-pass metabolism of drugs. Under this condition, members of the CYP450 superfamily are expected to contribute to drug presystemic biotransformation. The aim of this study was to quantify protein expression levels of 16 major CYP450 isoforms in tissue obtained from nine human organ donors in seven subsections of the small intestine, i.e., duodenum (one section, N = 7 tissue samples), jejunum (three subsections (proximal, mid and distal), N = 9 tissue samples) and ileum (three subsections, (proximal, mid and distal), N = 9 tissue samples), using liquid chromatography tandem mass spectrometry (LC-MS/MS) based targeted proteomics. CYP450 absolute protein expression levels were compared to mRNA levels and enzyme activities by using established probe drugs. Proteins corresponding to seven of sixteen potential CYP450 isoforms were detected and quantified in various sections of the small intestine: CYP2C9, CYP2C19, CYP2D6, CYP2J2, CYP3A4, CYP3A5 and CYP4F2. Wide inter-subject variability was observed, especially for CYP2D6. CYP2C9 (p = 0.004) and CYP2C19 (p = 0.005) expression levels decreased along the small intestine. From the duodenum to the ileum, CYP2J2 (p = 0.001) increased, and a trend was observed for CYP3A5 (p = 0.13). CYP3A4 expression was higher in the jejunum than in the ileum (p = 0.03), while CYP4F2 expression was lower in the duodenum compared to the jejunum and the ileum (p = 0.005). CYP450 protein levels were better correlated with specific isoform activities than with mRNA levels. This study provides new data on absolute CYP450 quantification in human small intestine that could improve physiologically based pharmacokinetic models. These data could better inform drug absorption profiles while considering the regional expression of CYP450 isoforms.
The Role of Membrane Transporters in Plant Growth and Development, and Abiotic Stress Tolerance
Authors: Gill Rafaqat Ali , Ahmar Sunny , Ali Basharat , Saleem Muhammad Hamzah , Khan Muhammad Umar , Zhou Weijun , Liu Shengyi
Published: December 2021

The proteins of membrane transporters (MTs) are embedded within membrane-bounded organelles and are the prime targets for improvements in the efficiency of water and nutrient transportation. Their function is to maintain cellular homeostasis by controlling ionic movements across cellular channels from roots to upper plant parts, xylem loading and remobilization of sugar molecules from photosynthesis tissues in the leaf (source) to roots, stem and seeds (sink) via phloem loading. The plant’s entire source-to-sink relationship is regulated by multiple transporting proteins in a highly sophisticated manner and driven based on different stages of plant growth and development (PG&D) and environmental changes. The MTs play a pivotal role in PG&D in terms of increased plant height, branches/tiller numbers, enhanced numbers, length and filled panicles per plant, seed yield and grain quality. Dynamic climatic changes disturbed ionic balance (salt, drought and heavy metals) and sugar supply (cold and heat stress) in plants. Due to poor selectivity, some of the MTs also uptake toxic elements in roots negatively impact PG&D and are later on also exported to upper parts where they deteriorate grain quality. As an adaptive strategy, in response to salt and heavy metals, plants activate plasma membranes and vacuolar membrane-localized MTs that export toxic elements into vacuole and also translocate in the root’s tips and shoot. However, in case of drought, cold and heat stresses, MTs increased water and sugar supplies to all organs. In this review, we mainly review recent literature from Arabidopsis, halophytes and major field crops such as rice, wheat, maize and oilseed rape in order to argue the global role of MTs in PG&D, and abiotic stress tolerance. We also discussed gene expression level changes and genomic variations within a species as well as within a family in response to developmental and environmental cues.
The Cytokine Mediated Molecular Pathophysiology of Psoriasis and Its Clinical Implications
Authors: Singh Rohan , Koppu Sindhuja , Perche Patrick O. , Feldman Steven R.
Published: December 2021

Psoriasis is the result of uncontrolled keratinocyte proliferation, and its pathogenesis involves the dysregulation of the immune system. The interplay among cytokines released by dendritic, Th1, Th2, and Th17 cells leads to the phenotypical manifestations seen in psoriasis. Biological therapies target the cytokine-mediated pathogenesis of psoriasis and have improved patient quality of life. This review will describe the underlying molecular pathophysiology and biologics used to treat psoriasis. A review of the literature was conducted using the PubMed and Google Scholar repositories to investigate the molecular pathogenesis, clinical presentation, and current therapeutics in psoriasis. Plaque psoriasis’, the most prevalent subtype of psoriasis, pathogenesis primarily involves cytokines TNF-α, IL-17, and IL-23. Pustular psoriasis’, an uncommon variant, pathogenesis involves a mutation in IL-36RN. Currently, biological therapeutics targeted at TNF-α, IL-12/IL-23, IL-17, and IL-23/IL-39 are approved for the treatment of moderate to severe psoriasis. More studies need to be performed to elucidate the precise molecular pathology and assess efficacy between biological therapies for psoriasis. Psoriasis is a heterogenous, chronic, systemic inflammatory disease that presents in the skin with multiple types. Recognizing and understanding the underlying molecular pathways and biological therapeutics to treat psoriasis is important in treating this common disease.
New Therapeutic Targets for Hepatic Fibrosis in the Integrin Family, α8β1 and α11β1, Induced Specifically on Activated Stellate Cells
Authors: Yokosaki Yasuyuki , Nishimichi Norihisa
Published: December 2021

A huge effort has been devoted to developing drugs targeting integrins over 30 years, because of the primary roles of integrins in the cell-matrix milieu. Five αv-containing integrins, in the 24 family members, have been a central target of fibrosis. Currently, a small molecule against αvβ1 is undergoing a clinical trial for NASH-associated fibrosis as a rare agent aiming at fibrogenesis. Latent TGFβ activation, a distinct talent of αv-integrins, has been intriguing as a therapeutic target. None of the αv-integrin inhibitors, however, has been in the clinical market. αv-integrins commonly recognize an Arg-Gly-Asp (RGD) sequence, and thus the pharmacophore of inhibitors for the 5-integrins is based on the same RGD structure. The RGD preference of the integrins, at the same time, dilutes ligand specificity, as the 5-integrins share ligands containing RGD sequence such as fibronectin. With the inherent little specificity in both drugs and targets, “disease specificity” has become less important for the inhibitors than blocking as many αv-integrins. In fact, an almighty inhibitor for αv-integrins, pan-αv, was in a clinical trial. On the contrary, approved integrin inhibitors are all specific to target integrins, which are expressed in a cell-type specific manner: αIIbβ3 on platelets, α4β1, α4β7 and αLβ2 on leukocytes. Herein, “disease specific” integrins would serve as attractive targets. α8β1 and α11β1 are selectively expressed in hepatic stellate cells (HSCs) and distinctively induced upon culture activation. The exceptional specificity to activated HSCs reflects a rather “pathology specific” nature of these new integrins. The monoclonal antibodies against α8β1 and α11β1 in preclinical examinations may illuminate the road to the first medical agents.
Regulation of Gene Expression by Telomere Position Effect
Authors: Lee Kyung-Ha , Kim Do-Yeon , Kim Wanil
Published: December 2021

Many diseases that involve malignant tumors in the elderly affect the quality of human life; therefore, the relationship between aging and pathogenesis in geriatric diseases must be under-stood to develop appropriate treatments for these diseases. Recent reports have shown that epigenetic regulation caused by changes in the local chromatin structure plays an essential role in aging. This review provides an overview of the roles of telomere shortening on genomic structural changes during an age-dependent shift in gene expression. Telomere shortening is one of the most prominent events that is involved in cellular aging and it affects global gene expression through genome rearrangement. This review provides novel insights into the roles of telomere shortening in disease-affected cells during pathogenesis and suggests novel therapeutic approaches.
YES1 as a Therapeutic Target for HER2-Positive Breast Cancer after Trastuzumab and Trastuzumab-Emtansine (T-DM1) Resistance Development
Authors: Fujihara Miwa , Shien Tadahiko , Shien Kazuhiko , Suzawa Ken , Takeda Tatsuaki , Zhu Yidan , Mamori Tomoka , Otani Yusuke , Yoshioka Ryo , Uno Maya , Suzuki Yoko , Abe Yuko , Hatono Minami , Tsukioki Takahiro , Takahashi Yuko , Kochi Mariko , Iwamoto Takayuki , Taira Naruto , Doihara Hiroyoshi , Toyooka Shinichi
Published: December 2021

Trastuzumab-emtansine (T-DM1) is a therapeutic agent molecularly targeting human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), and it is especially effective for MBC with resistance to trastuzumab. Although several reports have described T-DM1 resistance, few have examined the mechanism underlying T-DM1 resistance after the development of acquired resistance to trastuzumab. We previously reported that YES1, a member of the Src family, plays an important role in acquired resistance to trastuzumab in HER2-amplified breast cancer cells. We newly established a trastuzumab/T-DM1-dual-resistant cell line and analyzed the resistance mechanisms in this cell line. At first, the T-DM1 effectively inhibited the YES1-amplified trastuzumab-resistant cell line, but resistance to T-DM1 gradually developed. YES1 amplification was further enhanced after acquired resistance to T-DM1 became apparent, and the knockdown of the YES1 or the administration of the Src inhibitor dasatinib restored sensitivity to T-DM1. Our results indicate that YES1 is also strongly associated with T-DM1 resistance after the development of acquired resistance to trastuzumab, and the continuous inhibition of YES1 is important for overcoming resistance to T-DM1.
Genetically Modified Cellular Therapies for Malignant Gliomas
Authors: Kilian Michael , Bunse Theresa , Wick Wolfgang , Platten Michael , Bunse Lukas
Published: December 2021

Despite extensive preclinical research on immunotherapeutic approaches, malignant glioma remains a devastating disease of the central nervous system for which standard of care treatment is still confined to resection and radiochemotherapy. For peripheral solid tumors, immune checkpoint inhibition has shown substantial clinical benefit, while promising preclinical results have yet failed to translate into clinical efficacy for brain tumor patients. With the advent of high-throughput sequencing technologies, tumor antigens and corresponding T cell receptors (TCR) and antibodies have been identified, leading to the development of chimeric antigen receptors (CAR), which are comprised of an extracellular antibody part and an intracellular T cell receptor signaling part, to genetically engineer T cells for antigen recognition. Due to efficacy in other tumor entities, a plethora of CARs has been designed and tested for glioma, with promising signs of biological activity. In this review, we describe glioma antigens that have been targeted using CAR T cells preclinically and clinically, review their drawbacks and benefits, and illustrate how the emerging field of transgenic TCR therapy can be used as a potent alternative for cell therapy of glioma overcoming antigenic limitations.
Differential Role of p53 in Oligodendrocyte Survival in Response to Various Stresses: Experimental Autoimmune Encephalomyelitis, Cuprizone Intoxication or White Matter Stroke
Authors: Luo Fucheng , Zhang Zhen , Luo Yu
Published: December 2021

Promoting oligodendrocyte viability has been proposed as a therapeutic strategy for alleviating many neuronal diseases, such as multiple sclerosis and stroke. However, molecular pathways critical for oligodendrocyte survival under various stresses are still not well known. p53 is a strong tumor suppressor and regulates cell cycle, DNA repair and cell death. Our previous studies have shown that p53 plays an important role in promoting neuronal survival after insults, but its specific role in oligodendrocyte survival is not known. Here, we constructed the mice with oligodendrocyte-specific p53 loss by crossing TRP53flox/flox mice and CNP-cre mice, and found that p53 was dispensable for oligodendrocyte differentiation and myelin formation under physiological condition. In the experimental autoimmune encephalomyelitis (EAE) model, p53 loss of function, specifically in oligodendrocytes, did not affect the EAE disease severity and had no effect on demyelination in the spinal cord of the mice. Interestingly, p53 deficiency in oligodendrocytes significantly attenuated the demyelination of corpus callosum and alleviated the functional impairment of motor coordination and spatial memory in the cuprizone demyelination model. Moreover, the oligodendrocyte-specific loss of p53 provided protection against subcortical white matter damage and mitigated recognition memory impairment in mice in the white matter stroke model. These results suggest that p53 plays different roles in the brain and spinal cord or in response to various stresses. Thus, p53 may be a therapeutic target for oligodendrocyte prevention in specific brain injuries, such as white matter stroke and multiple sclerosis.
Overlap and Specificity in the Substrate Spectra of Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3
Authors: Gebauer Lukas , Jensen Ole , Neif Maria , Brockmöller Jürgen , Dücker Christof
Published: December 2021

Human monoamine transporters (MATs) are cation transporters critically involved in neuronal signal transmission. While inhibitors of MATs have been intensively studied, their substrate spectra have received far less attention. Polyspecific organic cation transporters (OCTs), predominantly known for their role in hepatic and renal drug elimination, are also expressed in the central nervous system and might modulate monoaminergic signaling. Using HEK293 cells overexpressing MATs or OCTs, we compared uptake of 48 compounds, mainly phenethylamine and tryptamine derivatives including matched molecular pairs, across noradrenaline, dopamine and serotonin transporters and OCTs (1, 2, and 3). Generally, MATs showed surprisingly high transport activities for numerous analogs of neurotransmitters, but their substrate spectra were limited by molar mass. Human OCT2 showed the broadest substrate spectrum, and also the highest overlap with MATs substrates. Comparative kinetic analyses revealed that the radiotracer meta-iodobenzylguanidine had the most balanced uptake across all six transporters. Matched molecular pair analyses comparing MAT and OCT uptake using the same methodology could provide a better understanding of structural determinants for high cell uptake by MATs or OCTs. The data may result in a better understanding of pharmacokinetics and toxicokinetics of small molecular organic cations and, possibly, in the development of more specific radiotracers for MATs.
The Flavonoid Biosynthesis Network in Plants
Authors: Liu Weixin , Feng Yi , Yu Suhang , Fan Zhengqi , Li Xinlei , Li Jiyuan , Yin Hengfu
Published: December 2021

Flavonoids are an important class of secondary metabolites widely found in plants, contributing to plant growth and development and having prominent applications in food and medicine. The biosynthesis of flavonoids has long been the focus of intense research in plant biology. Flavonoids are derived from the phenylpropanoid metabolic pathway, and have a basic structure that comprises a C15 benzene ring structure of C6-C3-C6. Over recent decades, a considerable number of studies have been directed at elucidating the mechanisms involved in flavonoid biosynthesis in plants. In this review, we systematically summarize the flavonoid biosynthetic pathway. We further assemble an exhaustive map of flavonoid biosynthesis in plants comprising eight branches (stilbene, aurone, flavone, isoflavone, flavonol, phlobaphene, proanthocyanidin, and anthocyanin biosynthesis) and four important intermediate metabolites (chalcone, flavanone, dihydroflavonol, and leucoanthocyanidin). This review affords a comprehensive overview of the current knowledge regarding flavonoid biosynthesis, and provides the theoretical basis for further elucidating the pathways involved in the biosynthesis of flavonoids, which will aid in better understanding their functions and potential uses.