bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural Analysis of the Effect of Asn107Ser Mutation on Alg13 Activity and Alg13-Alg14 Complex Formation and Expanding the Phenotypic Variability of ALG13-CDG
Authors: Mitusińska Karolina , Góra Artur , Bogdańska Anna , Rożdżyńska-Świątkowska Agnieszka , Tylki-Szymańska Anna , Jezela-Stanek Aleksandra
Published: March 2022

Congenital Disorders of Glycosylation (CDG) are multisystemic metabolic disorders showing highly heterogeneous clinical presentation, molecular etiology, and laboratory results. Here, we present different transferrin isoform patterns (obtained by isoelectric focusing) from three female patients harboring the ALG13 c.320A>G mutation. Contrary to other known variants of type I CDGs, where transferrin isoelectric focusing revealed notably increased asialo- and disialotransferrin fractions, a normal glycosylation pattern was observed in the probands. To verify this data and give novel insight into this variant, we modeled the human Alg13 protein and analyzed the dynamics of the apo structure and the complex with the UDP-GlcNAc substrate. We also modeled the Alg13-Alg14 heterodimer and ran multiple simulations of the complex in the presence of the substrate. Finally, we proposed a plausible complex formation mechanism.
Identification of Metabolism-Associated Biomarkers for Early and Precise Diagnosis of Oral Squamous Cell Carcinoma
Authors: Wang Yuhan , Zhang Xiaoxin , Wang Shuai , Li Zihui , Hu Xinyang , Yang Xihu , Song Yuxian , Jing Yue , Hu Qingang , Ni Yanhong
Published: March 2022

The 5-year survival rate for oral squamous cell carcinoma (OSCC), one of the most common head and neck cancers, has not improved in the last 20 years. Poor prognosis of OSCC is the result of failure in early and precise diagnosis. Metabolic reprogramming, including the alteration of the uptake and utilisation of glucose, amino acids and lipids, is an important feature of OSCC and can be used to identify its biomarkers for early and precise diagnosis. In this review, we summarise how recent findings of rewired metabolic networks in OSCC have facilitated early and precise diagnosis of OSCC.
Brain Vascular Microenvironments in Cancer Metastasis
Authors: Tobar Lucas E. , Farnsworth Rae H. , Stacker Steven A.
Published: March 2022

Primary tumours, particularly from major solid organs, are able to disseminate into the blood and lymphatic system and spread to distant sites. These secondary metastases to other major organs are the most lethal aspect of cancer, accounting for the majority of cancer deaths. The brain is a frequent site of metastasis, and brain metastases are often fatal due to the critical role of the nervous system and the limited options for treatment, including surgery. This creates a need to further understand the complex cell and molecular biology associated with the establishment of brain metastasis, including the changes to the environment of the brain to enable the arrival and growth of tumour cells. Local changes in the vascular network, immune system and stromal components all have the potential to recruit and foster metastatic tumour cells. This review summarises our current understanding of brain vascular microenvironments, fluid circulation and drainage in the context of brain metastases, as well as commenting on current cutting-edge experimental approaches used to investigate changes in vascular environments and alterations in specialised subsets of blood and lymphatic vessel cells during cancer spread to the brain.
HSP70 Ameliorates Septic Lung Injury via Inhibition of Apoptosis by Interacting with KANK2
Authors: Pei Qing , Ni Wei , Yuan Yihang , Yuan Jing , Zhang Xiong , Yao Min
Published: March 2022

Acute lung injury is the most common type of organ damage with high incidence and mortality in sepsis, which is a poorly understood syndrome of disordered inflammation. The aims of this study are to explore whether heat shock protein 70 (HSP70), as a molecular chaperone, attenuates the septic lung injury, and to understand the underlying mechanisms. In our study, treatment with HSP70 ameliorated the survival rate, dysfunction of lung, inflammation, and apoptosis in cecal ligation and puncture (CLP)-treated mice as well as in LPS-treated human alveolar epithelial cells. Furthermore, HSP70 interacted with KANK2, leading to reversed cell viability and reduced apoptosis-inducing factor (AIF) and apoptosis. Additionally, knockdown of KANK2 in epithelial cells and deletion of hsp70.1 gene in CLP mice aggravated apoptosis and tissue damage, suggesting that interaction of KANK2 and HSP70 is critical for protecting lung injury induced by sepsis. HSP70 plays an important role in protection of acute lung injury caused by sepsis through interaction with KANK2 to reduce AIF release and apoptotic cell. HSP70 is a novel potential therapeutic approach for attenuation of septic lung injury.
β-Sheet to Random Coil Transition in Self-Assembling Peptide Scaffolds Promotes Proteolytic Degradation
Authors: Genové Elsa , Betriu Nausika , Semino Carlos E.
Published: March 2022

One of the most desirable properties that biomaterials designed for tissue engineering or drug delivery applications should fulfill is biodegradation and resorption without toxicity. Therefore, there is an increasing interest in the development of biomaterials able to be enzymatically degraded once implanted at the injury site or once delivered to the target organ. In this paper, we demonstrate the protease sensitivity of self-assembling amphiphilic peptides, in particular, RAD16-I (AcN-RADARADARADARADA-CONH2), which contains four potential cleavage sites for trypsin. We detected that when subjected to thermal denaturation, the peptide secondary structure suffers a transition from β-sheet to random coil. We also used Matrix-Assisted Laser Desorption/Ionization-Time-Of-Flight (MALDI-TOF) to detect the proteolytic breakdown products of samples subjected to incubation with trypsin as well as atomic force microscopy (AFM) to visualize the effect of the degradation on the nanofiber scaffold. Interestingly, thermally treated samples had a higher extent of degradation than non-denatured samples, suggesting that the transition from β-sheet to random coil leaves the cleavage sites accessible and susceptible to protease degradation. These results indicate that the self-assembling peptide can be reduced to short peptide sequences and, subsequently, degraded to single amino acids, constituting a group of naturally biodegradable materials optimal for their application in tissue engineering and regenerative medicine.
Hormones and Sex-Specific Medicine in Human Physiopathology
Authors: Tokatli Maria Raza , Sisti Leuconoe Grazia , Marziali Eleonora , Nachira Lorenza , Rossi Maria Francesca , Amantea Carlotta , Moscato Umberto , Malorni Walter
Published: March 2022

A prodigious increment of scientific evidence in both preclinical and clinical studies is narrowing a major gap in knowledge regarding sex-specific biological responses observed in numerous branches of clinical practices. Some paradigmatic examples include neurodegenerative and mental disorders, immune-related disorders such as pathogenic infections and autoimmune diseases, oncologic conditions, and cardiovascular morbidities. The male-to-female proportion in a population is expressed as sex ratio and varies eminently with respect to the pathophysiology, natural history, incidence, prevalence, and mortality rates. The factors that determine this scenario incorporate both sex-associated biological differences and gender-dependent sociocultural issues. A broad narrative review focused on the current knowledge about the role of hormone regulation in gender medicine and gender peculiarities across key clinical areas is provided. Sex differences in immune response, cardiovascular diseases, neurological disorders, cancer, and COVID-19 are some of the hints reported. Moreover, gender implications in occupational health and health policy are offered to support the need for more personalized clinical medicine and public health approaches to achieve an ameliorated quality of life of patients and better outcomes in population health.
S-Nitrosylation of Paraxonase 1 (PON1) Elevates Its Hydrolytic and Antioxidant Activities
Authors: Hajouj Hanin , Khattib Ali , Atrahimovich Dana , Musa Sanaa , Khatib Soliman
Published: March 2022

Covalent binding between nitric oxide (NO) and a protein’s free thiol group (SH) is termed protein S-nitrosylation. Protein S-nitrosylation is involved in cellular regulation mechanisms that underlie a wide range of critical functions, such as apoptosis, alteration of enzyme activities, and transcription-factor stability. Impaired protein S-nitrosylation is associated with a growing list of pathophysiological conditions, such as cardiovascular disease, multiple sclerosis, pulmonary hypertension, and sickle cell disease. The enzyme paraoxonase 1 (PON1) binds to high-density lipoprotein to provide many of its antiatherogenic properties. The enzyme has a strong antioxidant capacity, which protects fats, lipids, and lipoproteins from oxidation, in addition to breaking down oxidized fats. We investigated the effect of S-S transnitrosylation on PON1 activities. Incubation of recombinant PON1 (rePON1) with nitrosylated human serum albumin (HSA-NO) resulted in S-nitrosylation of about 70% of the rePON1, as measured by Q-TOF LC/MS. S-nitrosylation significantly increased rePON1 hydrolytic activities. It also increased rePON1’s ability to inhibit low-density lipoprotein oxidation induced by Cu2+. Finally, it increased the enzyme’s penetration into macrophage cells by 31%. Our findings suggest that S-nitrosylation of rePON1 improves its biological functions which may positively affect atherosclerosis disease progression.
Organosolv Treatment/Polyphenol Extraction from Olive Leaves (Olea europaea L.) Using Glycerol and Glycerol-Based Deep Eutectic Solvents: Effect on Metabolite Stability
Authors: Houasni Abdelhak , Grigorakis Spyros , Kellil Abdessamie , Makris Dimitris P.
Published: March 2022

Olive leaves (OLL) are an agri-food waste that may be regarded as a bioresource rich in bioactive polyphenolic metabolites. In this examination, simultaneous organosolv treatment/extraction of OLL polyphenols at elevated temperatures (>110 °C) has been optimized using glycerol, but also two glycerol-based deep eutectic solvents (DES). The assessment of the processes was based on the severity factor and the extraction efficiency factor. In any case, the treatment/extraction with a DES composed of glycerol and citric acid (GL-CA) was found to be the less severe and the most effective in recovering polyphenols from OLL, giving a yield of 69.35 mg gallic acid equivalents per g dry mass. On the other hand, liquid chromatography-mass spectrometry investigation revealed that extraction with either DES used provided extracts with differentiated polyphenolic profile than that obtained when water or 60% (v/v) aqueous ethanol was used as solvents. On the ground of these analysis, evidence emerged regarding hydrolysis of flavone glucosides when the treatment was performed with an alkaline DES composed of glycerol and sodium citrate. The extracts produced also exhibited diversified antioxidant activity, a fact putatively attributed to the different polyphenolic profiles. It was concluded that organosolv treatment/extraction of OLL for polyphenol recovery opens new endeavors in the valorization of this particular waste, but metabolite stability is an issue that merits profounder study.
Differential Transcriptome Profiling Unveils Novel Deregulated Gene Signatures Involved in Pathogenesis of Alzheimer’s Disease
Authors: Singh Himanshu Narayan , Swarup Vishnu , Dubey Navneet Kumar , Jha Niraj Kumar , Singh Anjani Kumar , Lo Wen-Cheng , Kumar Sanjay
Published: March 2022

Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by a progressive loss of cognitive functions at a higher level than normal aging. Although the apolipoprotein (APOE) gene is a major risk factor in developing AD, other genes have also been reported to be linked with complex phenotypes. Therefore, this genome-wide expression study explored differentially expressed genes as possible novel biomarkers involved in AD. The mRNA expression dataset, GSE28146, containing 15 sample data composed of 7 AD cases from the hippocampus region with age-matched control (n = 8, >80 years), was analyzed. Using “affy” R-package, mRNA expression was calculated, while pathway enrichment analysis was performed to determine related biological processes. Of 58 differentially expressed genes, 44 downregulated and 14 upregulated genes were found to be significantly (p < 0.001) altered. The pathway enrichment analysis revealed two altered genes, i.e., dynein light chain 1 (DYNLL1) and kalirin (KLRN), associated with AD in the elderly population. The majority of genes were associated with retrograde endocannabinoid as well as vascular endothelial growth factors affecting the complex phenotypes. The DYNLL1 and KLRN genes may be involved with AD and Huntington’s disease (HD) phenotypes and represent a common genetic basis of these diseases. However, the hallmark of AD is dementia, while the classic motor sign of HD includes chorea. Our data warrant further investigation to identify the role of these genes in disease pathogenesis.
Predictive Value of Urinary Aquaporin 2 for Acute Kidney Injury in Patients with Acute Decompensated Heart Failure
Authors: Chan Ming-Jen , Chen Yung-Chang , Fan Pei-Chun , Lee Cheng-Chia , Kou George , Chang Chih-Hsiang
Published: March 2022

Acute kidney injury (AKI) is frequently encountered in people with acute decompensated heart failure (ADHF) and is associated with increased morbidity and mortality. Early detection of a urinary biomarker of kidney injury might allow a prompt diagnosis and improve outcomes. Levels of urinary aquaporin 2 (UAQP2), which is also associated with several renal diseases, are increased with ADHF. We aimed to determine whether UAQP2 predicted AKI in patients with ADHF. We conducted a prospective observation study in the coronary care unit (CCU) in a tertiary care university hospital in Taiwan. Individuals with ADHF admitted to the CCU between November 2009 and November 2014 were enrolled, and serum and urinary samples were collected. AKI was diagnosed in 69 (36.5%) of 189 adult patients (mean age: 68 years). Area under the receiver operating characteristic curve (AUROC) of biomarkers was evaluated to evaluate the diagnostic power for AKI. Both brain natriuretic peptide and UAQP2 demonstrated acceptable AUROCs (0.759 and 0.795, respectively). A combination of the markers had an AUROC of 0.802. UAQP2 is a potential biomarker of AKI in CCU patients with ADHF. Additional research on this novel biomarker is required.
Air Plasma Functionalization of Electrospun Nanofibers for Skin Tissue Engineering
Authors: Mozaffari Abolfazl , Parvinzadeh Gashti Mazeyar
Published: March 2022

Nowadays, gelatin, a molecular derivative of collagen, has gained increasing interest in tissue engineering applications due to excellent biocompatibility, biodegradability, availability, process simplicity, and low costs. In this study, we fabricated tannic acid-crosslinked gelatin nanofibers by electrospinning method. In order to increase the bio-functionality of scaffolds, they were exposed to the atmospheric air plasma. Several analytical tools were used for evaluation of nanofibers including scanning electron microscopy (SEM), atomic force microscopy (AFM), attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy, X-ray diffraction (XRD), and water contact angle equipment (CA) together with biocompatibility study using fibroblast cells. Results demonstrated that atmospheric air plasma is not only able to improve the hydrophilicity of nanofibers but it also improves the bio-functionality against human skin fibroblast cells. Hence, we recommend atmospheric air plasma pre-treatment approach for the surface functionalization of gelatin nanofibers for skin tissue engineering applications.
Proteomic Studies of Psoriasis
Authors: Sobolev Vladimir V. , Soboleva Anna G. , Denisova Elena V. , Pechatnikova Eva A. , Dvoryankova Eugenia , Korsunskaya Irina M. , Mezentsev Alexandre
Published: March 2022

In this review paper, we discuss the contribution of proteomic studies to the discovery of disease-specific biomarkers to monitor the disease and evaluate available treatment options for psoriasis. Psoriasis is one of the most prevalent skin disorders driven by a Th17-specific immune response. Although potential patients have a genetic predisposition to psoriasis, the etiology of the disease remains unknown. During the last two decades, proteomics became deeply integrated with psoriatic research. The data obtained in proteomic studies facilitated the discovery of novel mechanisms and the verification of many experimental hypotheses of the disease pathogenesis. The detailed data analysis revealed multiple differentially expressed proteins and significant changes in proteome associated with the disease and drug efficacy. In this respect, there is a need for proteomic studies to characterize the role of the disease-specific biomarkers in the pathogenesis of psoriasis, develop clinical applications to choose the most efficient treatment options and monitor the therapeutic response.
Cuff-Less Blood Pressure Prediction from ECG and PPG Signals Using Fourier Transformation and Amplitude Randomization Preprocessing for Context Aggregation Network Training
Authors: Treebupachatsakul Treesukon , Boosamalee Apivitch , Shinnakerdchoke Siratchakrit , Pechprasarn Suejit , Thongpance Nuntachai
Published: March 2022

This research proposes an algorithm to preprocess photoplethysmography (PPG) and electrocardiogram (ECG) signals and apply the processed signals to the context aggregation network-based deep learning to achieve higher accuracy of continuous systolic and diastolic blood pressure monitoring than other reported algorithms. The preprocessing method consists of the following steps: (1) acquiring the PPG and ECG signals for a two second window at a sampling rate of 125 Hz; (2) separating the signals into an array of 250 data points corresponding to a 2 s data window; (3) randomizing the amplitude of the PPG and ECG signals by multiplying the 2 s frames by a random amplitude constant to ensure that the neural network can only learn from the frequency information accommodating the signal fluctuation due to instrument attachment and installation; (4) Fourier transforming the windowed PPG and ECG signals obtaining both amplitude and phase data; (5) normalizing both the amplitude and the phase of PPG and ECG signals using z-score normalization; and (6) training the neural network using four input channels (the amplitude and the phase of PPG and the amplitude and the phase of ECG), and arterial blood pressure signal in time-domain as the label for supervised learning. As a result, the network can achieve a high continuous blood pressure monitoring accuracy, with the systolic blood pressure root mean square error of 7 mmHg and the diastolic root mean square error of 6 mmHg. These values are within the error range reported in the literature. Note that other methods rely only on mathematical models for the systolic and diastolic values, whereas the proposed method can predict the continuous signal without degrading the measurement performance and relying on a mathematical model.
Recent Progress of Fluorescence Sensors for Histamine in Foods
Authors: Wu Gan , Dou Xilin , Li Dapeng , Xu Shihan , Zhang Jicheng , Ding Zhaoyang , Xie Jing
Published: March 2022

Biological amines are organic nitrogen compounds that can be produced by the decomposition of spoiled food. As an important biological amine, histamine has played an important role in food safety. Many methods have been used to detect histamine in foods. Compared with traditional analysis methods, fluorescence sensors as an adaptable detection tool for histamine in foods have the advantages of low cost, convenience, less operation, high sensitivity, and good visibility. In terms of food safety, fluorescence sensors have shown great utilization potential. In this review, we will introduce the applications and development of fluorescence sensors in food safety based on various types of materials. The performance and effectiveness of the fluorescence sensors are discussed in detail regarding their structure, luminescence mechanism, and recognition mechanism. This review may contribute to the exploration of the application of fluorescence sensors in food-related work.
Altered Pain Processing Associated with Administration of Dopamine Agonist and Antagonist in Healthy Volunteers
Authors: Martin Sarah L. , Jones Anthony K. P. , Brown Christopher A. , Kobylecki Christopher , Whitaker Grace A. , El-Deredy Wael , Silverdale Monty A.
Published: March 2022

Striatal dopamine dysfunction is associated with the altered top-down modulation of pain processing. The dopamine D2-like receptor family is a potential substrate for such effects due to its primary expression in the striatum, but evidence for this is currently lacking. Here, we investigated the effect of pharmacologically manipulating striatal dopamine D2 receptor activity on the anticipation and perception of acute pain stimuli in humans. Participants received visual cues that induced either certain or uncertain anticipation of two pain intensity levels delivered via a CO2 laser. Rating of the pain intensity and unpleasantness was recorded. Brain activity was recorded with EEG and analysed via source localisation to investigate neural activity during the anticipation and receipt of pain. Participants completed the experiment under three conditions, control (Sodium Chloride), D2 receptor agonist (Cabergoline), and D2 receptor antagonist (Amisulpride), in a repeated-measures, triple-crossover, double-blind study. The antagonist reduced an individuals’ ability to distinguish between low and high pain following uncertain anticipation. The EEG source localisation showed that the agonist and antagonist reduced neural activations in specific brain regions associated with the sensory integration of salient stimuli during the anticipation and receipt of pain. During anticipation, the agonist reduced activity in the right mid-temporal region and the right angular gyrus, whilst the antagonist reduced activity within the right postcentral, right mid-temporal, and right inferior parietal regions. In comparison to control, the antagonist reduced activity within the insula during the receipt of pain, a key structure involved in the integration of the sensory and affective aspects of pain. Pain sensitivity and unpleasantness were not changed by D2R modulation. Our results support the notion that D2 receptor neurotransmission has a role in the top-down modulation of pain.
Study on Stress Field Distribution during the Construction of a Group of Tunnels Using the Pile–Beam–Arch Method
Authors: Huang Bo , Du Yihan , Zeng Yu , Cao Bing , Zou Yu , Yu Qian
Published: March 2022

To study stress field distributions during the construction of a group of tunnels using the pile–beam–arch method, the excavation for an underground station of Beijing subway line 7 was taken as an engineering problem, and a numerical structural model of a tunnel group was built with the aid of software. In this model, four stress-monitoring planes were set up to extract the data obtained from monitoring stress. The construction of the pilot tunnels was simulated according to six established construction schemes, and images were generated for the stress field distribution on each monitoring plane using different schemes. Finally, a verification of physical model tests was carried out. The results show that the effect of excavation on vertical stress in pilot tunnels has a range that is essentially equal to twice the width of the station. After the excavation of pilot tunnels, peaks appeared both at the tops of the pilot tunnels and between the bottoms of the tunnels; moreover, valleys appeared both at the bottoms of the pilot tunnels and between the tops of the tunnels. Pilot tunnels located at the top of the group were less affected during excavation than the tunnels located at the bottom of the group both in stress concentration factor and in the point of extreme stress. Finally, the model verified the numerical simulation results of the stress variation law.
Semi-Supervised Clustering for Architectural Modularisation
Authors: Feist Sofia , Sanhudo Luís , Esteves Vítor , Pires Miguel , Costa António Aguiar
Published: March 2022

Modular construction allows for a faster, safer, better controlled, and more productive construction process, yielding quality results with low risk and controlled costs. However, despite the potential advantages of this methodology, its adoption has remained slow due to the reasonably high degree of standardisation and repetition that projects require, inexorably clashing with the unique building designs created to meet the clients’ needs. The present article proposes performing a modularisation process after the building design is complete, reaping most benefits of modular construction while preserving the unique vision and design of the building. This objective is achieved by implementing a semi-supervised methodology reliant on the clustering of individual rooms and subsequent user validation of the obtained clusters to identify base modules representative of each cluster. The proposed methodology is applied in a case study of an existing apartment complex, in which the modularisation process was previously performed manually—thus serving as a baseline. The acquired results display a 99.6% reduction in the modularisation process’ duration, while maintaining a 96.4% Normalised Mutual Information Score and a 93.3% Adjusted Mutual Information Score, justifying the continuous development and assessment of the methodology in future works.
Exploration for Spatial Sustainability of Microalgae Façades Based on Mock-Up Cultivation Settings
Authors: Choe Seung-Ju , Han Seung-Hoon
Published: March 2022

Microalgae are third-generation biomasses that can be used to extract bio-fuel with various advantages from an ecological perspective. In addition, since it is cultivated in an underwater space, it can be used as a microalgae culture space by using building facades. Architectural applications of microalgae are being carried out from various points of view in other countries such as America, Israel, and Germany. As a result, successful cases (such as Germany’s BIQ House) are emerging. However, research studies related to microalgae facade are mainly conducted in terms of culture environment and efficiency. The degree of inflow concerning external resources for a microalgae facade remains unclear. The question concerning how the environment of an indoor space where microalgae facade is installed could be changed is unclear too. Thus, the objective of this study was to analyze the impact of the space in which the microalgae facade was installed from the perspective of the lighting environment. This study also examined effects of creating a lighting environment compared to existing windows, applicable space, and supplementary points through mock-up tests on microalgae facade. As a result, it was found that the standard microalgae facade suggested by the Korean Intellectual Property Office (KIPO) could inflow 22.7–41.3% of illumination compared to general windows. If the analysis result is compared with Korean Standard A 3011 (Normal), the microalgae facade can only be applied to spaces that do not have natural light such as ‘warehouses’ and ‘stairs’. Accordingly, it is concluded that if the microalgae facade is to be used creatively, the thickness should be thinner than the standard of patent to set the standard of comfort and consider the user’s comfort in the design stage.
Relationships between Physical, Mechanical and Acoustic Properties of Asphalt Mixtures Using Ultrasonic Testing
Authors: Hou Shuguang , Deng Yong , Jin Rui , Shi Xijun , Luo Xue
Published: March 2022

Ultrasonic testing can be used for a nondestructive and rapid determination of material properties. In this study, twelve asphalt mixture samples of four different types were fabricated and used in conventional material property tests and two ultrasonic wave tests. Physical properties such as bulk specific gravity and air void content, mechanical properties such as dynamic modulus and phase angle, and acoustic properties such as wave velocity were measured. Relationships between these properties were established and analyzed as a tool for the future material property determination. In addition, the dynamic modulus and phase angle, measured in a standard laboratory test, were used to construct two master curve models to predict their values at arbitrary temperatures and frequencies. Furthermore, a theoretical model for wave velocity in a linear isotropic viscoelastic material was utilized with measured density, Poisson’s ratio, phase angle and ultrasonic wave velocity to predict the dynamic modulus. Good agreement has been achieved between laboratory measurements and model predictions. It indicates that ultrasonic testing can serve as a rapid method for material property determination.
Instantaneous Spectral Entropy: An Application for the Online Monitoring of Multi-Storey Frame Structures
Authors: Civera Marco , Surace Cecilia
Published: March 2022

Damage assessment techniques based on entropy measurements have been recently proposed for the structural health monitoring of civil structures and infrastructures. A quasi-real-time approach, based on the use of instantaneous spectral entropy (ISE) over an uninterrupted stream of data, is discussed here. The methodology is proposed for the detection of sudden damage-related structural changes (more specifically, linear stiffness reductions and nonlinear breathing cracks). The method operates by framing the continuous stream of vibration signals and comparing the single frames to a known baseline. The approach is also suitable for nonstationary signals originating from nonlinearly behaving structures. The procedure is validated on an experimental benchmark: a laboratory-scaled model of a three-storey single-span frame metallic structure. Three different definitions of entropy and six candidate time–frequency/time-scale transforms have been tested to find the optimal settings.
Analysis of Behavioral Strategies of Construction Safety Subjects Based on the Evolutionary Game Theory
Authors: Wu Fan , Xu Haiying , Sun Kuo-Shun , Hsu Wei-Ling
Published: March 2022

In construction safety management practices, identifying key stakeholders and specifying their safety behavior patterns are critical to avoid unsafe practices, which are the major cause of construction accidents. This paper argues that the main contractor and construction workers are key safety stakeholders in the construction safety management in China. The purpose of this paper is to develop an evolutionary game model to explore the safety behavior strategies of the main contractor and construction workers. In this framework, we explored the effects of model parameter changes on the evolution of safety behavior strategies and verify the evolution paths under different initial values by numerical simulations. The findings of this paper are as follows: Firstly, the safety and stability of construction projects are related to the possible losses caused by accidents, the amount of work required by construction workers to comply with safety regulations, the gain of bravado, the probability of accidents, and cost savings from the main contractor’s lax supervision. Secondly, the role of restraining the unsafe behavior of construction workers through the form of fines is limited, and increasing the fines to the main contractor cannot effectively reduce the unsafe behaviors. Thirdly, strengthening safety education, creating a safe atmosphere, and optimizing operating procedures are effective measures to improve the effectiveness of safety behavior. This study further extends the application of evolutionary game theory to construction safety management, and the findings can provide clear guidance for the development of effective incentives and constraints on safety behavior.
How Do the Chinese New Farmers’ Entrepreneurial Talents Drive the Business Model Innovation of Agricultural Business Organizations? Case Study Based on Grounded Research
Authors: Zheng Ke , Li Yufeng , Wu Chaodang
Published: March 2022

BMI in the field of agriculture has attracted more and more attention; it is argued that BMI will help in improving development quality of agricultural business sectors, as well as addressing sustainable development issues. In China’s agricultural business area, the emergence of new farmers has resulted in a large number of BMI actions. This study focuses on how Chinese new-farmer entrepreneurs in the agricultural field promote the BMI of agricultural business organizations. Based on the field survey of 32 agricultural maker spaces (“maker spark”) located in Sichuan Province, China, we followed the research paradigm of grounded theory. After research, we have clarified the core categories of new farmers’ entrepreneurial talent and BMI-innovation behavior, respectively. The network relationship between the two groups of core categories is discussed in order to clearly identify its complex influence mechanism. This study helps us understand how agricultural entrepreneurs promote business model innovation in specific situations.
Single-Cell RNA Sequencing Uncovers Heterogeneous Circulating Tumor Cell Subsets in Breast Cancer
Authors: Papadaki Maria A. , Agelaki Sofia
Published: March 2022

Metastasis remains the main cause of death for breast cancer (BC) patients, and conceivably, a huge effort has been directed toward the understanding of the metastatic process [...]
Discovery of a New CaMKII-Targeted Synthetic Lethal Therapy against Glioblastoma Stem-like Cells
Authors: Han Jang Mi , Kim Yu Jin , Jung Hye Jin
Published: March 2022

Glioblastoma stem-like cells (GSCs) drive tumor initiation, cancer invasion, immune evasion, and therapeutic resistance and are thus a key therapeutic target for improving treatment for glioblastoma multiforme (GBM). We previously identified calcium/calmodulin-dependent protein kinase II (CaMKII) as an emerging molecular target for eliminating GSCs. In this study, we aim to explore a new CaMKII-targeted synthetic lethal therapy for GSCs. Through high-throughput drug combination screening using CaMKII inhibitors and a bioactive compound library in GSCs, neurokinin 1 receptor (NK1R) inhibitors such as SR 140333 and aprepitant are found to be potential anticancer agents that exhibit chemical synthetic lethal interactions with CaMKII inhibitors, including hydrazinobenzoylcurcumin (HBC), berbamine, and KN93. Combined treatment with NK1R and CaMKII inhibitors markedly suppresses the viability and neurosphere formation of U87MG- and U373MG-derived GSCs. In addition, the combination of HBC and NK1R inhibitors significantly inhibits U87MG GSC tumor growth in a chick embryo chorioallantoic membrane (CAM) model. Furthermore, the synthetic lethal interaction is validated using RNA interference of CaMKIIγ and NK1R. Notably, the synthetic lethal effects in GSCs are associated with the activation of caspase-mediated apoptosis by inducing p53 expression and reactive oxygen species generation, as well as the suppression of stemness marker expression by reducing nuclear factor-kappa B (NF-κB) activity. This follows the downregulation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling and a decrease in intracellular calcium concentration. Moreover, NK1R affects CaMKIIγ activation. These findings demonstrate that NK1R is a potential synthetic lethal partner of CaMKII that is involved in eradicating GSCs, and they suggest a new CaMKII-targeted combination therapy for treating GBM.
Role of Neural (N)-Cadherin in Breast Cancer Cell Stemness and Dormancy in the Bone Microenvironment
Authors: Maurizi Antonio , Ciocca Michela , Giuliani Cristiano , Di Carlo Ilaria , Teti Anna
Published: March 2022

Breast cancer cells that interact with spindle-shaped N-Cadherin+ Osteoblasts (SNOs) are recognised to become dormant through a Notch2-dependent mechanism. We found that Notch2High human BrCa MDA-MB231 (MDA) cells also expressed high level of N-Cadherin. This prompted us to hypothesize that N-Cadherin could have a role in MDA-SNO interaction. Of note, the expression of N-Cadherin in MDA cells reduced tumour incidence and bone osteolysis in BrCa mouse model. Moreover, similarly to Notch2High MDA cells, the N-CadherinHigh MDA cells revealed a high expression of the canonical Haematopoietic Stem cell (HSC) markers, suggesting an HSC mimicry, associated with higher ability to form mammospheres. Interestingly, N-CadherinHigh MDA cells showed greater capacity to adhere to SNOs, while the inhibition of SNO-mediating MDA cell proliferation was unremarkable. To investigate whether these features were shared by mouse BrCa, we used the 4T1 cell line in which N-Cadherin expression was abolished and then rescued. At variance with MDA cells, 4T1 cells expressing N-Cadherin revealed that the latter was associated with a lower expression of the HSC marker, Cxcr4, along with a lower capacity to form mammospheres. Furthermore, the rescue of N-Cadherin expression increased cell-cell adhesion and reduced proliferation of 4T1 cells when they were co-plated with SNOs. In conclusion, we demonstrated that: (i) N-CadherinHigh and Notch2High MDA cells showed similar HSC mimicry and dormancy features; (ii) N-Cadherin mediated BrCa-SNO adhesion; (iii) N-Cadherin had a positive Notch2-dependent role on SNO-induced dormancy and HSC mimicry in MDA cells, and a negative role in 4T1 cell stemness and HSC mimicry.
Direct Targeting KRAS Mutation in Non-Small Cell Lung Cancer: Focus on Resistance
Authors: Reita Damien , Pabst Lucile , Pencreach Erwan , Guérin Eric , Dano Laurent , Rimelen Valérie , Voegeli Anne-Claire , Vallat Laurent , Mascaux Céline , Beau-Faller Michèle
Published: March 2022

KRAS is the most frequently mutated oncogene in non-small cell lung cancers (NSCLC), with a frequency of around 30%, and encoding a GTPAse that cycles between active form (GTP-bound) to inactive form (GDP-bound). The KRAS mutations favor the active form with inhibition of GTPAse activity. KRAS mutations are often with poor response of EGFR targeted therapies. KRAS mutations are good predictive factor for immunotherapy. The lack of success with direct targeting of KRAS proteins, downstream inhibition of KRAS effector pathways, and other strategies contributed to a focus on developing mutation-specific KRAS inhibitors. KRAS p.G12C mutation is one of the most frequent KRAS mutation in NSCLC, especially in current and former smokers (over 40%), which occurs among approximately 12–14% of NSCLC tumors. The mutated cysteine resides next to a pocket (P2) of the switch II region, and P2 is present only in the inactive GDP-bound KRAS. Small molecules such as sotorasib are now the first targeted drugs for KRAS G12C mutation, preventing conversion of the mutant protein to GTP-bound active state. Little is known about primary or acquired resistance. Acquired resistance does occur and may be due to genetic alterations in the nucleotide exchange function or adaptative mechanisms in either downstream pathways or in newly expressed KRAS G12C mutation.
The Skin Microbiome and Influencing Elements in Cutaneous T-Cell Lymphomas
Authors: Jost Marion , Wehkamp Ulrike
Published: March 2022

Since the 1970s, a connection between the skin’s microbiota and cutaneous T-cell lymphomas (CTCL) was suggested. New techniques such as next-generation sequencing technologies enable the examination of the nuanced interplay between microbes and their host. The purpose of this review is an updated description of the current knowledge on the composition of the microbiome, relevant bacteria, or other stimuli, and their potential role in CTCL with a focus on the most frequent subtype, mycosis fungoides. Some findings suggest that the skin barrier—or the deficiency hereof—and host-microbiota might be involved in disease progression or etiopathogenesis. In addition, information on the current knowledge of antimicrobial peptide expression in CTCL, as well as treatment considerations with antiseptics and antibiotics, are included. Further studies are needed to provide more insight and potentially contribute to the development of new treatment approaches.
Management and Outcome of Young Women (≤40 Years) with Breast Cancer in Switzerland
Authors: Montagna Giacomo , Schaffar Robin , Bordoni Andrea , Spitale Alessandra , Terribile Daniela A. , Rossi Lorenzo , Bergeron Yvan , van der Linden Bernadette W. A. , Konzelmann Isabelle , Rohrmann Sabine , Staehelin Katharina , Maspoli-Conconi Manuela , Bulliard Jean-Luc , Meani Francesco , Pagani Olivia , Rapiti Elisabetta
Published: March 2022

Background: An increase in breast cancer (BC) incidence in young women (YW) as well as disparities in BC outcomes have been reported in Switzerland. We sought to evaluate treatment and outcome differences among YW with BC (YWBC). Methods: YW diagnosed with stage I-III BC between 2000–2014 were identified through nine cancer registries. Concordance with international guidelines was assessed for 12 items covering clinical/surgical management, combined in a quality-of-care score. We compared score and survival outcome between the two linguistic-geographic regions of Switzerland (Swiss-Latin and Swiss-German) and evaluated the impact of quality-of-care on survival. Results: A total of 2477 women were included. The median age was 37.3 years (IQR 34.0–39.4 years), with 50.3% having stage II BC and 70.3% having estrogen receptor positive tumors. The mean quality-of-care score was higher in the Latin region compared to the German region (86.0% vs. 83.2%, p < 0.0005). Similarly, 5- and 10-year overall survival rates were higher in the Latin compared to the German region (92.3% vs. 90.2%, p = 0.0593, and 84.3% vs. 81.5%, p = 0.0025, respectively). There was no difference in survival according to the score. In the univariate analysis, women in the Latin region had a 28% lower mortality risk compared to women in the German region (hazard ratio 0.72; 95% CI 0.59–0.89). In the multivariable analysis, only stage, differentiation, tumor subtype and treatment period remained independently associated with survival. Conclusions: We identified geographic disparities in the treatment and outcome of YWBC in Switzerland. National guidelines for YWBC should be implemented to standardize treatment. Awareness should be raised among YW and clinicians that BC does not discriminate by age.
Stem-Cell Theory of Cancer: Implications for Antiaging and Anticancer Strategies
Authors: Tu Shi-Ming , Pisters Louis L.
Published: March 2022

A stem-cell theory of cancer predicates that not only does the cell affect the niche, the niche also affects the cell. It implicates that even though genetic makeup may be supreme, cellular context is key. When we attempt to solve the mystery of a long cancer-free life, perhaps we need to search no further than the genetics and epigenetics of the naked mole-rat. When we try to unlock the secrets in the longevity and quality of life, perhaps we need to look no further than the lifestyle and habits of the super centenarians. We speculate that people with Down’s syndrome and progeria age faster but have fewer cancers, because they are depleted of stem cells, and, as a consequence, have fewer opportunities for stem cell defects that could predispose them to the development of cancer. We contemplate whether these incredible experiments of nature may provide irrefutable evidence that cancer is a stem-cell disease—fewer aberrant stem cells, fewer cancers; no defective stem cells, no cancer. In this perspective, we investigate a stem-cell origin of aging and cancer. We elaborate an intriguing inverse relationship between longevity and malignancy in the naked mole-rat, in Down’s syndrome, and in progeria. We postulate that stem-cell pools and stemness factors may affect aging and dictate cancer. We propose that a healthy microbiome may protect and preserve stem cell reserves and provide meaningful antiaging effects and anticancer benefits.
CK1 Is a Druggable Regulator of Microtubule Dynamics and Microtubule-Associated Processes
Authors: Roth Aileen , Gihring Adrian , Bischof Joachim , Pan Leiling , Oswald Franz , Knippschild Uwe
Published: March 2022

Protein kinases of the Casein Kinase 1 family play a vital role in the regulation of numerous cellular processes. Apart from functions associated with regulation of proliferation, differentiation, or apoptosis, localization of several Casein Kinase 1 isoforms to the centrosome and microtubule asters also implicates regulatory functions in microtubule dynamic processes. Being localized to the spindle apparatus during mitosis Casein Kinase 1 directly modulates microtubule dynamics by phosphorylation of tubulin isoforms. Additionally, site-specific phosphorylation of microtubule-associated proteins can be related to the maintenance of genomic stability but also microtubule stabilization/destabilization, e.g., by hyper-phosphorylation of microtubule-associated protein 1A and RITA1. Consequently, approaches interfering with Casein Kinase 1-mediated microtubule-specific functions might be exploited as therapeutic strategies for the treatment of cancer. Currently pursued strategies include the development of Casein Kinase 1 isoform-specific small molecule inhibitors and therapeutically useful peptides specifically inhibiting kinase-substrate interactions.
Testing for Lynch Syndrome in Endometrial Carcinoma: From Universal to Age-Selective MLH1 Methylation Analysis
Authors: Pasanen Annukka , Loukovaara Mikko , Kaikkonen Elina , Olkinuora Alisa , Pylvänäinen Kirsi , Alhopuro Pia , Peltomäki Päivi , Mecklin Jukka-Pekka , Bützow Ralf
Published: March 2022

International guidelines recommend universal screening of endometrial carcinoma (EC) patients for Lynch syndrome (LS). This screening is generally based on mismatch repair (MMR) protein immunohistochemistry followed by MLH1 methylation analysis of MLH1-negative cases to exclude the likely sporadic cases from germline testing. As LS-associated EC is uncommon in the elderly, age-selective methylation testing could improve cost-efficiency. We performed MMR immunohistochemistry on 821 unselected ECs (clinic-based cohort) followed by a MLH1 promoter methylation test of all MLH1/PMS2-negative tumors. Non-methylated MLH1-deficient cases underwent NGS and MLPA-based germline analyses to identify MLH1 mutation carriers. A reduction in the test burden and corresponding false negative rates for LS screening were investigated for various age cut-offs. In addition, the age distribution of 132 MLH1 mutation carriers diagnosed with EC (registry-based cohort) was examined. A germline MLH1 mutation was found in 2/14 patients with non-methylated MLH1-deficient EC. When compared to a universal methylation analysis, selective testing with a cut-off age of 65 years, would have reduced the testing effort by 70.7% with a false negative rate for LS detection of 0% and 3% in the clinic and registry-based cohorts, respectively. The use of age-selective methylation analysis is a feasible way of reducing the costs and laboratory burden in LS screening for EC patients.