bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial Expansion of Built-Up Areas in the Beijing–Tianjin–Hebei Urban Agglomeration Based on Nighttime Light Data: 1992–2020
Authors: Zhang Hua , Liang Chen , Pan Yuxuan
Published: March 2022

Built-up areas are one of the most intuitive and important indicators used to assess urbanization, the spatial expansion of which is of great significance in depicting the evolution of urban spatial structures. Based on the harmonized Defense Meteorological Satellite Program (DMSP) nighttime light dataset, this paper extracts the spatial distribution of built-up areas and explores the spatial expansion patterns and spatiotemporal evolution regularity of the Beijing–Tianjin–Hebei urban agglomeration from 1992 to 2020. The results show that the spatial comparison method, comparing the extracted area with the government’s statistical area, can accurately determine the optimal threshold of nighttime light and extract urban built-up areas. According to the spatial comparison method, the built-up areas of the Beijing–Tianjin–Hebei urban agglomeration are expanding rapidly from 1992 to 2020, and both expansion speed and expansion intensity have experienced an inverted “U-shaped” growth process. As the core cities of the Beijing–Tianjin–Hebei urban agglomeration, Beijing and Tianjin have been in the later stage of spatial expansion with slower expansion speed but better quality. In contrast, prefecture-level cities and other node cities have rapid expansion speed. The urban space structure of the Beijing–Tianjin–Hebei urban agglomeration has changed from a “monocentric model” to a “polycentric model” to a “metropolitan model”. High-tech industry parks around node cities have become important strongholds of urban space development, leading cities to evolve from monocentric structures to polycentric structures of downtown and industrial parks. The radiation range of core cities expands and spreads to surrounding districts and counties, which inevitably lead to the formation of metropolitan areas.
Impact of Short-Term Exposure to Extreme Temperatures on Mortality: A Multi-City Study in Belgium
Authors: Demoury Claire , Aerts Raf , Vandeninden Bram , Van Schaeybroeck Bert , De Clercq Eva M.
Published: March 2022

In light of climate change, health risks are expected to be exacerbated by more frequent high temperatures and reduced by less frequent cold extremes. To assess the impact of different climate change scenarios, it is necessary to describe the current effects of temperature on health. A time-stratified case-crossover design fitted with conditional quasi-Poisson regressions and distributed lag non-linear models was applied to estimate specific temperature-mortality associations in nine urban agglomerations in Belgium, and a random-effect meta-analysis was conducted to pool the estimates. Based on 307,859 all-cause natural deaths, the mortality risk associated to low temperature was 1.32 (95% CI: 1.21–1.44) and 1.21 (95% CI: 1.08–1.36) for high temperature relative to the minimum mortality temperature (23.1 °C). Both cold and heat were associated with an increased risk of cardiovascular and respiratory mortality. We observed differences in risk by age category, and women were more vulnerable to heat than men. People living in the most built-up municipalities were at higher risk for heat. Air pollutants did not have a confounding effect. Evidence from this study helps to identify specific populations at risk and is important for current and future public health interventions and prevention strategies.
The Effect of Worktime Control on Overtime Employees’ Mental Health and Work-Family Conflict: The Mediating Role of Voluntary Overtime
Authors: Yu Jiaoyang , Leka Stavroula
Published: March 2022

Overtime has become a widespread phenomenon in the current information age that creates a high speed working pace and fierce competition in the high technology global economy. Based on the time-regulation mechanism and effort-recovery model, we examined the effect of worktime control (WTC) on mental health and work-family conflict (WFC) among overtime employees, and whether voluntary overtime mediated the relationships. We also examined two separate dimensions of WTC (control over time-off and control over daily hours). The results showed that control over time-off was related to decreased depression, anxiety, stress and WFC, while control over daily hours was related to decreased stress and WFC. Generally, control over time-off was beneficial to females and employees with dependents. Furthermore, mediation results showed that voluntary overtime was a complete mediator of relationships between WTC and depression and anxiety as well as a partial mediator of the relationship between WTC and stress. However, this study did not find a mediating effect of voluntary overtime on the WTC-WFC relationship. Limitations and practical implications are discussed.
VAD Patients’ Perception of Potential Telemedicine Support
Authors: Berg Thomas , Benstoem Carina , Moza Ajay K.
Published: March 2022

Technical possibilities for patient support must be user-friendly. This includes acceptance on the part of the patients, and safe function that must not lead to the user being overtaxed. In a study of Ventricular Assist Device (VAD) patients at the Department of Thoracic and Cardiovascular Surgery at the University Hospital RWTH Aachen, a questionnaire was used to investigate the current situation in dealing with the VAD system. This was followed by a query about ideas, wishes, and fears regarding the increased use of telemedical applications. An adapted Service User Technology Acceptability Questionnaire (SUTAQ) was used and the evaluation was carried out with the help of Office-based applications. As a result, it can be stated that the patients do not want to see personal contacts and care be completely replaced by telemedical remote support. If the application is stable and functioning, the majority is very much open to such support.
Client’s Experiences Using a Location-Based Technology ICT System during Gambling Treatments’ Crucial Components: A Qualitative Study
Authors: Diaz-Sanahuja Laura , Miralles Ignacio , Granell Carlos , Mira Adriana , González-Pérez Alberto , Casteleyn Sven , García-Palacios Azucena , Bretón-López Juana
Published: March 2022

Cognitive Behavioral Therapy is the treatment of choice for Gambling Disorder (GD), with stimulus control (SC) and exposure with response prevention (ERP) being its two core components. Despite their efficacy, SC and ERP are not easy to deliver, so it is important to explore new ways to enhance patient compliance regarding SC and ERP. The aim of this study is to describe and assess the opinion of two patients diagnosed with problem gambling and GD that used the Symptoms app, a location-based ICT system, during SC and ERP. A consensual qualitative research study was conducted. We used a semi-structured interview, developed ad-hoc based on the Expectation and Satisfaction Scale and System Usability Scale. A total of 20 categories were identified within six domains: usefulness, improvements, recommendation to other people, safety, usability, and opinion regarding the use of the app after completing the intervention. The patients considered the app to be useful during the SC and ERP components and emphasized that feeling observed and supported at any given time helped them avoid lapses. This work can offer a starting point that opens up new research paths regarding psychological interventions for gambling disorder, such as assessing whether location-based ICT tools enhance commitment rates.
Factors Associated with Advance Directives Documentation: A Nationwide Cross-Sectional Survey of Older Adults in Korea
Authors: Kim Boram , Choi Jiyeon , Lee Ilhak
Published: March 2022

Advance directives (ADs) can support autonomy in making healthcare decisions and minimize unnecessary discomfort during the treatment process at the end of life (EOL). This study aimed to investigate the factors that influence AD documentation among community-dwelling older adults. We used data from the National Survey of Older Koreans which was conducted nationwide in 2020. Data from participants aged 65 years or older were extracted using stratified multistage cluster sampling and the survey was conducted through one-on-one interviews. A total of 9920 older adults were included in this study: 421 respondents (4.7%) claimed that they had prepared for AD. Multivariable logistic regression analysis showed that being 75 years or older, having higher educational attainment, higher income, having any chronic disease(s), being screened for dementia in the past, being against futile life-sustaining treatment, taking a lecture on death and being registered for organ donation were positively associated with AD. Furthermore, when health was rated as average, it was associated with reduced odds of AD documentation compared when health was rated as good. These results suggest that more targeted efforts are required to promote EOL discussions among older adults.
Elderly People’s Perceptions of Heat Stress and Adaptation to Heat: An Interview Study
Authors: Malmquist Anna , Hjerpe Mattias , Glaas Erik , Karlsson-Larsson Hulda , Lassi Tina
Published: March 2022

Objectives: Heatwaves are having a disproportionate impact on the elderly population, as demonstrated by pronounced mortality and morbidity. The present study aimed to explore elders’ subjective experiences of heat impacts and adaptive strategies. Methods: Semi-structured interviews with 19 elderly Swedes were conducted, focusing on their experiences of the extremely hot summer of 2018. Results: Most informants suffered during the heatwave, although some found it pleasant. The readiness to implement adaptive measures was generally high among the healthiest, who were able to avoid excessive heat and adjust their daily routines. In contrast, those highly dependent on care from others had limited options for avoiding the heat, and little capacity to take up adaptive measures. Discussion: With heat becoming an increasing problem, it is important to adjust elderly care so that the most vulnerable elderly people can avoid excessive heat exposure.
Validation of the Patient Health Questionnaire-9 for Screening Depressive Disorders among Korean Employees: A Longitudinal Study of the National Health Examination Data
Authors: Lee Jihye , Lee Kyeong-Eun , Park Sungkyun , Jun Kyo Yeon
Published: March 2022

This nationwide longitudinal study examined the screening utility of the Patient Health Questionnaire-9 (PHQ-9) for Korean workers (aged 20, 30, 40, 50, 60, and 70 years) who completed the questionnaire in 2018. Data on disease names and health-related behaviors were collected from the National Health Insurance Service (NHIS). Follow-up began on 1 January 2018, and the primary endpoint was the hospitalization date for depression, self-harm, or suicide or 31 December 2019. Of the 766,351 participants, 741,423 received depression screening. Those screened were classified into normal (n = 716,760) and high-risk groups (n = 24,663) based on PHQ-9 scores. The incidence of hospital admissions for depression, self-harm, or suicide in the non-screened, normal, and high-risk groups was analyzed, and the PHQ-9′s validity was examined. There were more females in the high-risk group than in the normal group, and the income distribution differed. The two-year cumulative incidence was highest for the high-risk group (4.21%), followed by the normal (0.89%) and non-screened groups (0.80%). The PHQ-9′s sensitivity was low (males: 14.2%; females: 13.8%). Its specificity for males and females was 97.1% and 96.3%, respectively. Our findings may help develop a system to prevent suicides and hospitalizations attributed to workplace depression.
Sclerocarya birrea (Marula) Extract Inhibits Hepatic Steatosis in db/db Mice
Authors: Mabasa Lawrence , Kotze Anri , Shabalala Samukelisiwe , Kimani Clare , Gabuza Kwazi , Johnson Rabia , Sangweni Nonhlakanipho F. , Maharaj Vinesh , Muller Christo J. F.
Published: March 2022

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of hepatic metabolic perturbations ranging from simple steatosis to steatohepatitis, cirrhosis and hepatocellular carcinoma. Currently, lifestyle modifications to reduce weight gain are considered the most effective means of preventing and treating the disease. The aim of the present study was to determine the therapeutic benefit of Sclerocarya birrea (Marula leaf extract, MLE) on hepatic steatosis. Obese db/db mice were randomly stratified into the obese control, metformin (MET) or MLE-treated groups. Mice were treated daily for 29 days, at which point all mice were euthanized and liver samples were collected. Hematoxylin and eosin staining was used for histological assessment of the liver sections, while qRT-PCR and Western blot were used to determine hepatic mRNA and protein expression, respectively. Thereafter, the association between methylenetetrahydrofolate reductase (Mthfr a key enzyme in one-carbon metabolism and DNA-methylation-induced regulation of gene transcription) and lipogenic genes was evaluated using Pearson’s correlation coefficient. Mice treated with MLE presented with significantly lower body and liver weights as compared with the obese control and MET-treated mice (p ≤ 0.05). Further, MLE treatment significantly inhibited hepatic steatosis as compared with the obese control and MET-treated mice (p ≤ 0.05). The reduced lipid accumulation was associated with low expression of fatty acid synthase (Cpt1; p ≤ 0.05) and an upregulation of the fatty acid oxidation gene, carnitine palmitoyltransferase (Cpt1; p ≤ 0.01), as compared with the obese control mice. Interestingly, MLE treatment improved the correlation between Mthfr and Cpt1 mRNA expression (r = 0.72, p ≤ 0.01). Taken together, the results suggest that Marula leaf extracts may inhibit hepatic steatosis by influencing the association between Mthfr and genes involved in hepatic lipid metabolism. Further studies are warranted to assess DNA methylation changes in lipid metabolism genes.
Delay in Vaccine Access in ASEAN Countries
Authors: Subsittipong Nilubon , Choi Junjeong , Kim Tae Hyun , Han Euna
Published: March 2022

Background: The introduction of new vaccines has been delayed in some countries in the Asia-Pacific region, which has led to delays in accessing vaccines for target patients. However, the approval lag of vaccines in the Asia-Pacific region has not been assessed. The objective of this study is to assess the availability and approval lag of vaccines in Asia-Pacific countries and compare them among Asia-Pacific countries, the United States (US), and Europe (EU). Methods: The information on vaccines prequalified by the World Health Organization (WHO) between 2010 and 2019 was obtained primarily from the WHO website. The date of approval of the WHO prequalified vaccine in Australia, India, South Korea, Thailand, Singapore, Malaysia, the US, and EU was retrieved from the official website of national regulatory agencies. The vaccines were divided into two groups based on their first approval pathway, that is, vaccines that were first approved by SRA (Stringent Regulatory Authority including the US, EU, and WHO) and those that were first approved by non-SRA. The absolute approval lag represented the availability of the vaccine. Relative approval lag represented the lag time between the approval date of the country of interest and the first global approval date and was measured as the median approval lag. A Mann–Whitney U test was used to examine statistical differences between relative approval lag between the SRA first and the non-SRA first groups. Results: A total of 92 vaccines were prequalified by the WHO between 2010 and 2019, but only 61 vaccines were included in the analysis. Over 50% of vaccines were first licensed by non-SRAs. Of all the WHO-prequalified vaccines, the median approval lag in the ASEAN countries in this study was longer than those in the US and EU, with a median of 30 months in Australia, 15 months in South Korea, 52 months in Thailand, and 23 months in Singapore, compared to 0 months in the US and EU. The differences in approval lags between SRA first vaccines and non-SRA first vaccines were statistically significant in South Korea and Thailand (p < 0.05). Conclusions: The approval lag of vaccines was observed in the Asia-Pacific region, indicating a gap between the Asia-pacific region and the US and EU in regard to access to new vaccines. Future studies need to analyze the background factors related to the gap in availability and vaccine approval lag in the Asia-Pacific region and assess the impact of vaccine approval lag in the region.
The Point Cloud Semantic Segmentation Method for the Ming and Qing Dynasties’ Official-Style Architecture Roof Considering the Construction Regulations
Authors: Dong Youqiang , Li Yihao , Hou Miaole
Published: March 2022

Point cloud semantic segmentation has played an important role in the scan-to-BIM process of the Ming and Qing Dynasties’ official-style architecture roof. To overcome the complexity of roof components’ shape and the scale differences between different roof component types, a point cloud semantic segmentation method for the MQDOAs roof considering the construction regulations is proposed in this paper. This method is composed of two stages. In the first stage, the features from the construction rules of MQDOAs, including the normalized symmetrical distance (NSD), relative height (RH) and local height difference (LHD), are extracted alongside the regular geometric features. To lower the influence of scale differences, a multi-scale feature connection strategy is also applied to construct the feature classification vector. In the second stage, RF method is applied to classify the point cloud. To verify the efficiency of the proposed method, we took the Hall of Complete Harmony as the study case. The experiments showed that our method achieved segmentation result in overall classification accuracy and reached 96.8%.
Intelligent Mining of Urban Ventilated Corridor Based on Digital Surface Model under the Guidance of K-Means
Authors: Chen Chaoxiang , Ye Shiping , Bai Zhican , Wang Juan , Nedzved Alexander , Ablameyko Sergey
Published: March 2022

With the acceleration of urbanization, climate problems affecting human health and safe operation of cities have intensified, such as heat island effect, haze, and acid rain. Using high-resolution remote sensing mapping image data to design scientific and efficient algorithms to excavate and plan urban ventilation corridors and improve urban ventilation environment is an effective way to solve these problems. In this paper, we use unmanned aerial vehicle (UAV) tilt photography technology to obtain high-precision remote sensing image digital elevation model (DEM) and digital surface model (DSM) data, count the city’s dominant wind direction in each season using long-term meteorological data, and use building height to calculate the dominant wind direction. The projection algorithm calculates the windward area density of this dominant direction. Under the guidance of K-means, the binarized windward area density map is used to determine each area and boundary of potential ventilation corridors within the threshold range, and the length and angle of each area’s fitted elliptical long axis are calculated to extract the ventilation corridors that meet the criteria. On the basis of high-precision stereo remote sensing data from UAV, the paper uses image classification, segmentation, fitting, and fusion algorithms to intelligently mine potential urban ventilation corridors, and the effectiveness of the proposed method is demonstrated through a case study in Zhuji City, Zhejiang Province.
NKX2-5 Variant in Two Siblings with Thyroid Hemiagenesis
Authors: Szczepanek-Parulska Ewelina , Budny Bartłomiej , Borowczyk Martyna , Zhukov Igor , Szutkowski Kosma , Zawadzka Katarzyna , Tahir Raiha , Minczykowski Andrzej , Niedziela Marek , Ruchała Marek
Published: March 2022

Thyroid hemiagenesis (THA) is an inborn absence of one thyroid lobe of largely unknown etiopathogenesis. The aim of the study was to reveal genetic factors responsible for thyroid maldevelopment in two siblings with THA. None of the family members presented with congenital heart defect. The samples were subjected to whole-exome sequencing (WES) (Illumina, TruSeq Exome Enrichment Kit, San Diego, CA 92121, USA). An ultra-rare variant c.839C>T (p.Pro280Leu) in NKX2-5 gene (NM_004387.4) was identified in both affected children and an unaffected father. In the mother, the variant was not present. This variant is reported in population databases with 0.0000655 MAF (GnomAD v3, dbSNP rs761596254). The affected amino acid position is moderately conserved (positive scores in PhyloP: 1.364 and phastCons: 0.398). Functional prediction algorithms showed deleterious impact (dbNSFP v4.1, FATHMM, SIFT) or benign (CADD, PolyPhen-2, Mutation Assessor). According to ACMG criteria, variant is classified as having uncertain clinical significance. For the first time, NKX2-5 gene variants were found in two siblings with THA, providing evidence for its potential contribution to the pathogenesis of this type of thyroid dysgenesis. The presence of the variant in an unaffected parent, carrier of p.Pro280Leu variant, suggests potential contribution of yet unidentified additional factors determining the final penetrance and expression.
Divergences of the RLR Gene Families across Lophotrochozoans: Domain Grafting, Exon–Intron Structure, Expression, and Positive Selection
Authors: Yao Shanshan , Chan Jiulin , Xu Yue , Wu Shimei , Zhang Linlin
Published: March 2022

Invertebrates do not possess adaptive immunity but have evolved a variety of unique repertoires of innate immune sensors. In this study, we explored the immune diversity and specificity of invertebrates based on the lophotrochozoan RLRs, a major component in antiviral immune recognition. By annotating RLRs in the genomes of 58 representative species across metazoan evolution, we explored the gene expansion of RLRs in Lophotrochozoa. Of note, the N-terminal domains of lophotrochozoan RLRs showed the most striking diversity which evolved independently by domain grafting. Exon–intron structures were revealed to be prevalent in the domain grafting of lophotrochozoan RLRs based on an analysis of sibling paralogs and orthologs. In more than half of the cases, the mechanism of ‘exonization/pseudoexonization’ led to the generation of non-canonical N-terminal domains. Transcriptomic studies revealed that many non-canonical RLRs display immune-related expression patterns. Two of these RLRs showed obvious evidence of positive selection, which may be the result of host defense selection pressure. Overall, our study suggests that the complex and unique domain arrangement of lophotrochozoan RLRs might result from domain grafting, exon–intron divergence, expression diversification, and positive selection, which may have led to functionally distinct lophotrochozoan RLRs.
The Role of mTOR and eIF Signaling in Benign Endometrial Diseases
Authors: Driva Tatiana S. , Schatz Christoph , Sobočan Monika , Haybaeck Johannes
Published: March 2022

Adenomyosis, endometriosis, endometritis, and typical endometrial hyperplasia are common non-cancerous diseases of the endometrium that afflict many women with life-impacting consequences. The mammalian target of the rapamycin (mTOR) pathway interacts with estrogen signaling and is known to be dysregulated in endometrial cancer. Based on this knowledge, we attempt to investigate the role of mTOR signaling in benign endometrial diseases while focusing on how the interplay between mTOR and eukaryotic translation initiation factors (eIFs) affects their development. In fact, mTOR overactivity is apparent in adenomyosis, endometriosis, and typical endometrial hyperplasia, where it promotes endometrial cell proliferation and invasiveness. Recent data show aberrant expression of various components of the mTOR pathway in both eutopic and ectopic endometrium of patients with adenomyosis or endometriosis and in hyperplastic endometrium as well. Moreover, studies on endometritis show that derangement of mTOR signaling is linked to the establishment of endometrial dysfunction caused by chronic inflammation. This review shows that inhibition of the mTOR pathway has a promising therapeutic effect in benign endometrial conditions, concluding that mTOR signaling dysregulation plays a critical part in their pathogenesis.
Inhaled Placental Mesenchymal Stromal Cell Secretome from Two- and Three-Dimensional Cell Cultures Promotes Survival and Regeneration in Acute Lung Injury Model in Mice
Authors: Kudinov Vasily A. , Artyushev Rafael I. , Zurina Irina M. , Zorina Elena S. , Lapshin Roman D. , Snopova Ludmila B. , Mukhina Irina V. , Saburina Irina N.
Published: March 2022

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is a common clinical problem, leading to significant morbidity and mortality, and no effective pharmacotherapy exists. The problem of ARDS causing mortality became more apparent during the COVID-19 pandemic. Biotherapeutic products containing multipotent mesenchymal stromal cell (MMSC) secretome may provide a new therapeutic paradigm for human healthcare due to their immunomodulating and regenerative abilities. The content and regenerative capacity of the secretome depends on cell origin and type of cultivation (two- or three-dimensional (2D/3D)). In this study, we investigated the proteomic profile of the secretome from 2D- and 3D-cultured placental MMSC and lung fibroblasts (LFBs) and the effect of inhalation of freeze-dried secretome on survival, lung inflammation, lung tissue regeneration, fibrin deposition in a lethal ALI model in mice. We found that three inhaled administrations of freeze-dried secretome from 2D- and 3D-cultured placental MMSC and LFB protected mice from death, restored the histological structure of damaged lungs, and decreased fibrin deposition. At the same time, 3D MMSC secretome exhibited a more pronounced trend in lung recovery than 2D MMSC and LFB-derived secretome in some measures. Taking together, these studies show that inhalation of cell secretome may also be considered as a potential therapy for the management of ARDS in patients suffering from severe pneumonia, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), however, their effectiveness requires further investigation.
Molecular Biological and Clinical Understanding of the Statin Residual Cardiovascular Disease Risk and Peroxisome Proliferator-Activated Receptor Alpha Agonists and Ezetimibe for Its Treatment
Authors: Yanai Hidekatsu , Adachi Hiroki , Hakoshima Mariko , Katsuyama Hisayuki
Published: March 2022

Several randomized, double blind, placebo-controlled trials (RCTs) have demonstrated that low-density lipoprotein cholesterol (LDL-C) lowering by using statins, including high-doses of strong statins, reduced the development of cardiovascular disease (CVD). However, among the eight RCTs which investigated the effect of statins vs. placebos on the development of CVD, 56–79% of patients had the residual CVD risk after the trials. In three RCTs which investigated the effect of a high dose vs. a usual dose of statins on the development of CVD, 78–87% of patients in the high-dose statin arms still had the CVD residual risk after the trials. An analysis of the characteristics of patients in the RCTs suggests that elevated triglyceride (TG) and reduced high-density lipoprotein cholesterol (HDL-C), the existence of obesity/insulin resistance, and diabetes may be important metabolic factors which determine the statin residual CVD risk. To understand the association between lipid abnormalities and the development of atherosclerosis, we show the profile of lipoproteins and their normal metabolism, and the molecular and biological mechanisms for the development of atherosclerosis by high TG and/or low HDL-C in insulin resistance. The molecular biological mechanisms for the statin residual CVD risk include an increase of atherogenic lipoproteins such as small dense LDL and remnants, vascular injury and remodeling by inflammatory cytokines, and disturbed reverse cholesterol transport. Peroxisome proliferator-activated receptor alpha (PPARα) agonists improve atherogenic lipoproteins, reverse the cholesterol transport system, and also have vascular protective effects, such as an anti-inflammatory effect and the reduction of the oxidative state. Ezetimibe, an inhibitor of intestinal cholesterol absorption, also improves TG and HDL-C, and reduces intestinal cholesterol absorption and serum plant sterols, which are increased by statins and are atherogenic, possibly contributing to reduce the statin residual CVD risk.
EAPB0503, an Imidazoquinoxaline Derivative Modulates SENP3/ARF Mediated SUMOylation, and Induces NPM1c Degradation in NPM1 Mutant AML
Authors: Skayneh Hala , Jishi Batoul , Hleihel Rita , Hamie Maguy , El Hajj Rana , Deleuze-Masquefa Carine , Bonnet Pierre-Antoine , El Sabban Marwan , El Hajj Hiba
Published: March 2022

Nucleophosmin-1 (NPM1) is a pleiotropic protein involved in numerous cellular processes. NPM1 shuttles between the nucleus and the cytoplasm, but exhibits a predominant nucleolar localization, where its fate and functions are exquisitely controlled by dynamic post-translational modifications (PTM). Sentrin/SUMO Specific Peptidase 3 (SENP3) and ARF are two nucleolar proteins involved in NPM1 PTMs. SENP3 antagonizes ARF-mediated NPM1 SUMOylation, to promote ribosomal biogenesis. In Acute Myeloid Leukemia (AML), NPM1 is frequently mutated, and exhibits an aberrant cytoplasmic localization (NPM1c). NPM1c mutations define a separate AML entity with good prognosis in some AML patients, rendering NPM1c as a potential therapeutic target. SENP3-mediated NPM1 de-SUMOylation induces resistance to therapy in NPM1c AML. Here, we demonstrate that the imidazoquinoxaline EAPB0503 prolongs the survival and results in selective reduction in the leukemia burden of NPM1c AML xenograft mice. Indeed, EAPB0503 selectively downregulates HDM2 expression and activates the p53 pathway in NPM1c expressing cells, resulting in apoptosis. Importantly, we unraveled that NPM1c expressing cells exhibit low basal levels of SUMOylation paralleled with high SENP3 and low ARF basal levels. EAPB0503 reverted these molecular players by inducing NPM1c SUMOylation and ubiquitylation, leading to its proteasomal degradation. EAPB0503-induced NPM1c SUMOylation is concurrent with SENP3 downregulation and ARF upregulation in NPM1c expressing cells. Collectively, these results provide a strong rationale for testing therapies modulating NPM1c post-translational modifications in the management of NPM1c AML.
A Dual Anti-Inflammatory and Anti-Proliferative 3-Styrylchromone Derivative Synergistically Enhances the Anti-Cancer Effects of DNA-Damaging Agents on Colon Cancer Cells by Targeting HMGB1-RAGE-ERK1/2 Signaling
Authors: Tanuma Sei-ichi , Oyama Takahiro , Okazawa Miwa , Yamazaki Hiroaki , Takao Koichi , Sugita Yoshiaki , Amano Shigeru , Abe Takehiko , Sakagami Hiroshi
Published: March 2022

The current anti-cancer treatments are not enough to eradicate tumors, and therefore, new modalities and strategies are still needed. Most tumors generate an inflammatory tumor microenvironment (TME) and maintain the niche for their development. Because of the critical role of inflammation via high-mobility group box 1 (HMGB1)–receptor for advanced glycation end-products (RAGE) signaling pathway in the TME, a novel compound possessing both anti-cancer and anti-inflammatory activities by suppressing the HMGB1-RAGE axis provides an effective strategy for cancer treatment. A recent work of our group found that some anti-cancer 3-styrylchromones have weak anti-inflammatory activities via the suppression of this axis. In this direction, we searched such anti-cancer molecules possessing potent anti-inflammatory activities and discovered 7-methoxy-3-hydroxy-styrylchromone (C6) having dual suppressive activities. Mechanism-of-action studies revealed that C6 inhibited the increased phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) under the stimulation of HMGB1-RAGE signaling and thereby suppressed cytokine production in macrophage-like RAW264.7 cells. On the other hand, in colorectal cancer HCT116 cells, C6 inhibited the activation of ERK1/2, cyclin-dependent kinase 1, and AKT, down-regulated the protein level of XIAP, and up-regulated pro-apoptotic Bax and caspase-3/7 expression. These alterations are suggested to be involved in the C6-induced suppression of cell cycle/proliferation and initiation of apoptosis in the cancer cells. More importantly, in cancer cells, the treatment of C6 potentiates the anti-cancer effects of DNA-damaging agents. Thus, C6 may be a promising lead for the generation of a novel class of cancer therapeutics.
Autotaxin/Lysophosphatidic Acid Axis: From Bone Biology to Bone Disorders
Authors: Alioli Candide , Demesmay Léa , Peyruchaud Olivier , Machuca-Gayet Irma
Published: March 2022

Lysophosphatidic acid (LPA) is a natural bioactive phospholipid with pleiotropic activities affecting multiple tissues, including bone. LPA exerts its biological functions by binding to G-protein coupled LPA receptors (LPA1-6) to stimulate cell migration, proliferation, and survival. It is largely produced by autotaxin (ATX), a secreted enzyme with lysophospholipase D activity that converts lysophosphatidylcholine (LPC) into active LPA. Beyond its enzymatic activity, ATX serves as a docking molecule facilitating the efficient delivery of LPA to its specific cell surface receptors. Thus, LPA effects are the result of local production by ATX in a given tissue or cell type. As a consequence, the ATX/LPA axis should be considered as an entity to better understand their roles in physiology and pathophysiology and to propose novel therapeutic strategies. Herein, we provide not only an extensive overview of the relevance of the ATX/LPA axis in bone cell commitment and differentiation, skeletal development, and bone disorders, but also discuss new working hypotheses emerging from the interplay of ATX/LPA with well-established signaling pathways regulating bone mass.
Sperm Physiological Response to Female Serum—Potential New Insights into the Reproductive Incompatibility Diagnostics
Authors: Łukasiewicz Aleksandra , Huhta Kari , Ritari Jarmo , Peräsaari Juha , Allinen Pia , Malinen Marjo , Jokiniemi Annalaura , Turunen Tanja , Partanen Jukka , Kekäläinen Jukka
Published: March 2022

Infertility is assumed to arise exclusively from male- and female-dependent pathological factors. However, recent studies have indicated that reproductive failure may also result from the reproductive incompatibility of the partners. Selection against such incompatibilities likely occurs via female-derived reproductive secretions, including follicular fluid (FF), that mediate gamete-level mate choice towards the sperm of specific males. To facilitate potential development of diagnostic tests for human reproductive incompatibility, we examined whether sperm physiological response to female serum indicate male–female compatibility in the presence of FF. We performed a full-factorial experiment, in which the sperm of 10 males were treated with the FF and serum of 6 healthy females. We found that sperm motility and viability in both biofluids were highly similar and that in 70% of the males, sperm serum treatment predicted male–female compatibility. We also identified male human leucocyte antigen (HLA) alleles and female (FF and serum) anti-HLA antibodies and tested whether the number of allele–antibody matches predict sperm physiological response to female fluids. However, no association was found between measured sperm traits and the number of allele–antibody matches. Overall, the present results may open novel possibilities for the future development of reproductive incompatibility tests and may pave the way towards more accurate infertility diagnostics and treatments.
Identification and Expression Analysis of R2R3-MYB Family Genes Associated with Salt Tolerance in Cyclocarya paliurus
Authors: Zhang Zijie , Zhang Lei , Liu Yang , Shang Xulan , Fang Shengzuo
Published: March 2022

R2R3-MYB transcription factors are most abundant in the MYB superfamily, while the R2R3-MYB genes play an important role in plant growth and development, especially in response to environmental stress. Cyclocarya paliurus is a multifunction tree species, and the existing resources cannot meet the requirement for its leaf production and medical use. Therefore, lands with some environmental stresses would be potential sites for developing C. paliurus plantations. However, the function of R2R3-MYB genes in C.paliurus in response to environmental stress remains unknown. In this study, to identify the roles of R2R3-MYB genes associated with salt stress response, 153 CpaMYB genes and their corresponding protein sequences were identified from the full-length transcriptome. Based on the comparison with MYB protein sequences of Arabidopsis thaliana, 69 R2R3-MYB proteins in C. paliurus were extracted for further screening combined with conserved functional domains. Furthermore, the MYB family members were analyzed from the aspects of protein sequences alignment, evolution, motif prediction, promoter cis-acting element analysis, and gene differential expression under different salt treatments using both a pot experiment and hydroponic experiment. The results showed that the R2R3-MYB genes of C.paliurus conserved functional domains, whereas four R2R3-MYB genes that might respond to salt stress via regulating plant hormone signals were identified in this study. This work provides a basis for further functional characterization of R2R3-MYB TFs in C. paliurus.
40 Years after the Registration of Acyclovir: Do We Need New Anti-Herpetic Drugs?
Authors: Majewska Anna , Mlynarczyk-Bonikowska Beata
Published: March 2022

Herpes simplex virus types 1 and 2 HSV1 and 2, namely varicella-zoster VZV and cytomegalovirus CMV, are among the most common pathogens worldwide. They remain in the host body for life. The course of infection with these viruses is often asymptomatic or mild and self-limiting, but in immunocompromised patients, such as solid organ or bone marrow transplant recipients, the course can be very severe or even life-threatening. Unfortunately, in the latter group, the highest percentage of infections with strains resistant to routinely used drugs is observed. On the other hand, frequent recurrences of genital herpes can be a problem even in people with normal immunity. Genital herpes also increases the risk of acquiring sexually transmitted diseases, including HIV infection and, if present in pregnant women, poses a risk to the fetus and newborn. Even more frequently than herpes simplex, congenital infections can be caused by cytomegalovirus. We present the most important anti-herpesviral agents, the mechanisms of resistance to these drugs, and the associated mutations in the viral genome. Special emphasis was placed on newly introduced drugs such as maribavir and brincidofovir. We also briefly discuss the most promising substances in preclinical testing as well as immunotherapy options and vaccines currently in use and under investigation.
The Path to Therapeutic Furin Inhibitors: From Yeast Pheromones to SARS-CoV-2
Authors: Thomas Gary , Couture Frédéric , Kwiatkowska Anna
Published: March 2022

The spurious acquisition and optimization of a furin cleavage site in the SARS-CoV-2 spike protein is associated with increased viral transmission and disease, and has generated intense interest in the development and application of therapeutic furin inhibitors to thwart the COVID-19 pandemic. This review summarizes the seminal studies that informed current efforts to inhibit furin. These include the convergent efforts of endocrinologists, virologists, and yeast geneticists that, together, culminated in the discovery of furin. We describe the pioneering biochemical studies which led to the first furin inhibitors that were able to block the disease pathways which are broadly critical for pathogen virulence, tumor invasiveness, and atherosclerosis. We then summarize how these studies subsequently informed current strategies leading to the development of small-molecule furin inhibitors as potential therapies to combat SARS-CoV-2 and other diseases that rely on furin for their pathogenicity and progression.
A Strategic and Worldwide Cooperative Challenge Required for the Next Generation of Platelet Concentrates
Authors: Kawase Tomoyuki
Published: March 2022

Blood-derived biomaterials, which are represented by platelet-rich plasma (PRP) or more recently by platelet-rich fibrin (PRF), have been used in regenerative therapy for almost 30 years [...]
Photocatalytic Degradation of 4,4′-Isopropylidenebis(2,6-dibromophenol) on Magnetite Catalysts vs. Ozonolysis Method: Process Efficiency and Toxicity Assessment of Disinfection By-Products
Authors: Kisała Joanna , Tomaszewska Anna , Barylyak Adriana , Bobitski Yaroslav , Balawejder Maciej
Published: March 2022

Flame retardants have attracted growing environmental concern. Recently, an increasing number of studies have been conducted worldwide to investigate flame-retardant sources, environmental distribution, living organisms’ exposure, and toxicity. The presented studies include the degradation of 4,4′-isopropylidenebis(2,6-dibromophenol) (TBBPA) by ozonolysis and photocatalysis. In the photocatalytic process, nano- and micro-magnetite (n-Fe3O4 and μ-Fe3O4) are used as a catalyst. Monitoring of TBBPA decay in the photocatalysis and ozonolysis showed photocatalysis to be more effective. Significant removal of TBBPA was achieved within 10 min in photocatalysis (ca. 90%), while for ozonation, a comparable effect was observed within 70 min. To determine the best method of TBBPA degradation concentration on COD and TOC, the removals were examined. The highest oxidation state was obtained for photocatalysis on μ-Fe3O4, whereas for n-Fe3O4 and ozonolysis, the COD/TOC ratio was lower. Acute toxicity results show noticeable differences in the toxicity of TBBPA and its degradation products to Artemia franciscana and Thamnocephalus platyurus. The EC50 values indicate that TBBPA degradation products were toxic to harmful, whereas the TBPPA and post-reaction mixtures were toxic to the invertebrate species tested. The best efficiency in the removal and degradation of TBBPA was in the photocatalysis process on μ-Fe3O4 (reaction system 1). The examined crustaceans can be used as a sensitive test for acute toxicity evaluation.
How miRNAs Regulate Schwann Cells during Peripheral Nerve Regeneration—A Systemic Review
Authors: Borger Anton , Stadlmayr Sarah , Haertinger Maximilian , Semmler Lorenz , Supper Paul , Millesi Flavia , Radtke Christine
Published: March 2022

A growing body of studies indicate that small noncoding RNAs, especially microRNAs (miRNA), play a crucial role in response to peripheral nerve injuries. During Wallerian degeneration and regeneration processes, they orchestrate several pathways, in particular the MAPK, AKT, and EGR2 (KROX20) pathways. Certain miRNAs show specific expression profiles upon a nerve lesion correlating with the subsequent nerve regeneration stages such as dedifferentiation and with migration of Schwann cells, uptake of debris, neurite outgrowth and finally remyelination of regenerated axons. This review highlights (a) the specific expression profiles of miRNAs upon a nerve lesion and (b) how miRNAs regulate nerve regeneration by acting on distinct pathways and linked proteins. Shedding light on the role of miRNAs associated with peripheral nerve regeneration will help researchers to better understand the molecular mechanisms and deliver targets for precision medicine.
Tolerogenic IDO1+CD83− Langerhans Cells in Sentinel Lymph Nodes of Patients with Melanoma
Authors: Gerlini Gianni , Di Gennaro Paola , Pimpinelli Nicola , Sestini Serena , Borgognoni Lorenzo
Published: March 2022

Langerhans cells (LCs) are crucial regulators of anti-cancer immune responses. Cancer, however, can alter DCs functions leading to tolerance. The enzyme indoleamine 2,3-dioxygenase (IDO1) plays a crucial role in this process. In sentinel lymph nodes (SLNs) of patients with melanoma, LCs show phenotypical and functional alterations favoring tolerance. Herein we aimed to investigate IDO1 expression in SLN LCs from patients with melanoma. We showed by immunofluorescence analysis that a portion of Langerin+ LCs, located in the SLN T cell-rich area, displayed the typical dendritic morphology and expressed IDO1. There was no significant difference in the expression of IDO between SLN with or without metastases. Double IDO1/CD83 staining identified four LCs subsets: real mature IDO1−CD83+ LCs; real immature IDO1−CD83− LCs; tolerogenic mature IDO1+CD83+ LCs; tolerogenic immature IDO1+CD83− LCs. The latter subset was significantly increased in metastatic SLNs as compared to negative ones (p < 0.05), and in SLN LCs of patients with mitotic rate (MR) > 1 in primary melanoma, as compared to MR ≤ 1 (p < 0.05). Finally, immature SLN LCs, after in vitro stimulation by inflammatory cytokines, acquired a maturation profile by CD83 up-regulation. These results provide new input for immunotherapeutic approaches targeting in vivo LC of patients with melanoma.
Atherosclerosis: From Molecular Biology to Therapeutic Perspective
Authors: Perrotta Ida
Published: March 2022

Atherosclerosis is a chronic and progressive inflammatory disease of the arteries initiated by the functional and structural alteration of the endothelial layer responsible for promoting the subendothelial retention of modified low-density lipoproteins (LDL), which in turn generate an active proinflammatory state in which environmental factors, such as oxidizing agents, growth factors, cytokines, monocyte-macrophages and smooth muscle cells (SMCs), work in cooperation to promote the formation of plaque [...]
Pleiotropic Roles of Scavenger Receptors in Circadian Retinal Phagocytosis: A New Function for Lysosomal SR-B2/LIMP-2 at the RPE Cell Surface
Authors: Rieu Quentin , Bougoüin Antoine , Zagar Yvrick , Chatagnon Jonathan , Hamieh Abdallah , Enderlin Julie , Huby Thierry , Nandrot Emeline F.
Published: March 2022

The retinal phagocytic machinery resembles the one used by macrophages to clear apoptotic cells. However, in the retina, the permanent contact between photoreceptor outer segments (POS) and retinal pigment epithelial (RPE) cells requires a tight control of this circadian machinery. In addition to the known receptors synchronizing POS internalization, several others are expressed by RPE cells. Notably, scavenger receptor CD36 has been shown to intervene in the internalization speed. We thus investigated members of the scavenger receptor family class A SR-AI and MARCO and class B CD36, SR-BI and SR-B2/LIMP-2 using immunoblotting, immunohisto- and immunocytochemistry, lipid raft flotation gradients, phagocytosis assays after siRNA/antibody inhibition, RT-qPCR and western blot analysis along the light:dark cycle. All receptors were expressed by RPE cell lines and tissues and colocalized with POS, except SR-BI. All receptors were associated with lipid rafts, and even more upon POS challenge. SR-B2/LIMP-2 inhibition suggested a role in the control of the internalization speed similar to CD36. In vivo, MARCO and CD36 displayed rhythmic gene and protein expression patterns concomitant with the phagocytic peak. Taken together, our results indicate that CD36 and SR-B2/LIMP-2 play a direct regulatory role in POS phagocytosis dynamics, while the others such as MARCO might participate in POS clearance by RPE cells either as co-receptors or via an indirect process.