bluuebunny/crossref_metadata_2025 huggingface dataset:
Aging Induces Hepatic Oxidative Stress and Nuclear Proteomic Remodeling in Liver from Wistar Rats
Authors: Bárcena Brenda , Salamanca Aurora , Pintado Cristina , Mazuecos Lorena , Villar Margarita , Moltó Eduardo , Bonzón-Kulichenko Elena , Vázquez Jesús , Andrés Antonio , Gallardo Nilda
Published: September 2021

Aging is a continuous, universal, and irreversible process that determines progressive loss of adaptability. The liver is a critical organ that supports digestion, metabolism, immunity, detoxification, vitamin storage, and hormone signaling. Nevertheless, the relationship between aging and the development of liver diseases remains elusive. In fact, although prolonged fasting in adult rodents and humans delays the onset of the disease and increases longevity, whether prolonged fasting could exert adverse effects in old organisms remains incompletely understood. In this work, we aimed to characterize the oxidative stress and nuclear proteome in the liver of 3-month- and 24-month-old male Wistar rats upon 36 h of fasting and its adaptation in response to 30 min of refeeding. To this end, we analyzed the hepatic lipid peroxidation levels (TBARS) and the expression levels of genes associated with fat metabolism and oxidative stress during aging. In addition, to gain a better insight into the molecular and cellular processes that characterize the liver of old rats, the hepatic nuclear proteome was also evaluated by isobaric tag quantitation (iTRAQ) mass spectrometry-based proteomics. In old rats, aging combined with prolonged fasting had great impact on lipid peroxidation in the liver that was associated with a marked downregulation of antioxidant genes (Sod2, Fmo3, and Cyp2C11) compared to young rats. Besides, our proteomic study revealed that RNA splicing is the hepatic nuclear biological process markedly affected by aging and this modification persists upon refeeding. Our results suggest that aged-induced changes in the nuclear proteome could affect processes associated with the adaptative response to refeeding after prolonged fasting, such as those involved in the defense against oxidative stress.
Intermittent FOCV Using an I-V Curve Tracer for Minimizing Energy Loss
Authors: Im Yun Chan , Kwak Seung Soo , Park Jonghyun , Kim Yong Sin
Published: September 2021

Conventional fractional open-circuit voltage (FOCV) methods in maximum power point tracking (MPPT) are widely adopted for their simple structure and low computing power requirements. However, under mismatch and environmental changing conditions, the FOCV methods introduce a large amount of energy loss due to their maximum power point being fixed at the initial setup. To reduce energy loss, the intermittent FOCV MPPT proposed in this paper regularly refreshes all the parameters for each condition in time by using an I-V curve tracer. The proposed intermittent FOCV consists of two phases: the scan and set phases. In scan phase, the I-V curve of a photovoltaic (PV) cell is scanned and its power is calculated. In set phase, the global MPP of the PV cell is extracted and set by controlling the 8-bit capacitance array. Simulation and calculation based on experimental results with a single PV cell show that the energy loss of the proposed intermittent FOCV under daily temperature and illuminance distributions decreased by up to 99.9% compared to that of the conventional FOCV.
Temperature Compensated Wide-Range Micro Pressure Sensor with Polyimide Anticorrosive Coating for Harsh Environment Applications
Authors: Jiao Mengru , Wang Minghao , Fan Ye , Guo Bangbang , Ji Bowen , Cheng Yuhua , Wang Gaofeng
Published: September 2021

In this work, a MEMS piezoresistive micro pressure sensor (1.5 × 1.5 × 0.82 mm) is designed and fabricated with SOI-based micromachining technology and assembled using anodic bonding technology. In order to optimize the linearity and sensitivity over a wide effective pressure range (0–5 MPa) and temperature range (25–125 °C), the diaphragm thickness and the insulation of piezoresistors are precisely controlled by an optimized micromachining process. The consistency of the four piezoresistors is greatly improved by optimizing the structure of the ohmic contact pads. Furthermore, the probability of piezoresistive breakdown during anodic bonding is greatly reduced by conducting the top and bottom silicon of the SOI. At room temperature, the pressure sensor with 40 µm diaphragm demonstrates reliable linearity (0.48% F.S.) and sensitivity (33.04 mV/MPa) over a wide pressure range of 0–5.0 MPa. In addition, a polyimide protection layer is fabricated on the top surface of the sensor to prevent it from corrosion by a moist marine environment. To overcome the linearity drift due to temperature variation in practice, a digital temperature compensation system is developed for the pressure sensor, which shows a maximum error of 0.43% F.S. in a temperature range of 25–125 °C.
QHAR: Q-Holonic-Based ARchitecture for Self-Configuration of Cyber–Physical Production Systems
Authors: Macherki Douha , Diallo Thierno M. L. , Choley Jean-Yves , Guizani Amir , Barkallah Maher , Haddar Mohamed
Published: September 2021

Production systems must be able to adapt to increasingly frequent internal and external changes. Cyber-Physical Production Systems (CPPS), thanks to their potential capacity for self-reconfiguration, can cope with this need for adaptation. To implement the self-reconfiguration functionality in economical and safe conditions, CPPS must have appropriate tools and contextualized information. This information can be organized in the form of an architecture. In this paper, after the analysis of several holonic and nonholonic architectures, we propose a holonic architecture that allows for reliable and efficient reconfiguration. We call this architecture QHAR (Q-Holonic-based ARchitecture). QHAR is constructed based on the idea of a Q-holon, which has four dimensions (physical, cyber, human, and energy) and can exchange three flows (energy, data, and materials). It is a generic Holon that can represent any entity or actor of the supply chain. The QHAR is structured in three levels: centralized control level, decentralized control level, and execution level. QHAR implements the principle of an oligarchical control architecture by deploying both hierarchical and heterarchical control approaches. This ensures the overall system performance and reactivity to hazards. The proposed architecture is tested and validated on a case study.
Metal Nanozymes: New Horizons in Cellular Homeostasis Regulation
Authors: Lewandowska Hanna , Wójciuk Karolina , Karczmarczyk Urszula
Published: September 2021

Nanomaterials with enzyme-like activity (nanozymes) have found applications in various fields of medicine, industry, and environmental protection. This review discusses the use of nanozymes in the regulation of cellular homeostasis. We also review the latest biomedical applications of nanozymes related to their use in cellular redox status modification and detection. We present how nanozymes enable biomedical advances and demonstrate basic design strategies to improve diagnostic and therapeutic efficacy in various diseases. Finally, we discuss the current challenges and future directions for developing nanozymes for applications in the regulation of the redox-dependent cellular processes and detection in the cellular redox state changes.
The Impact of Orthodontic Treatment on Pre-Existing Gingival Recessions: A Retrospective Study
Authors: Antanavičienė Guostė , Zasčiurinskienė Eglė , Smailienė Dalia , Basevičienė Nomeda
Published: September 2021

(1) Background: This retrospective study aimed to examine the change of gingival recessions (GR) before and after orthodontic treatment (OT). (2) Methods: Patients who had at least one GR on the vestibular surface of maxillary/mandibular teeth mesial to first molars were included. GR was measured on good quality plaster models before and after OT. (3) Results: Significant improvement of mean GR at patient level was found between T0 and T1 (0.45 mm, 95% CI: 0.28, 0.62) (p < 0.001). In 51.4% of patients GRs became better, in 37.8% GRs did not change. and in 10.8% GRs became worse. At tooth level the mean GR improvement was 0.54 mm (CI: 0.42, 0.65; median 0.55 mm Q1; Q3: 0.12, 0.96) (p < 0.001). GR improved in 67 teeth (58.7%), did not change in 41 (36.0%), and worsened in 6 (5.3%). Full healing was observed in 15 teeth. A reduced GR improvement was found in cases with pre-treatment open bite (OR 3.89; CI: 1.35, 11.16; p = 0.008) and dental Class III patients (OR 2.6; CI: 1.11, 6.0; p = 0.026). (4) Conclusions: There was an improvement of GR after OT in more than half of the patients. Class III malocclusion and reduced pre-treatment overbite had a negative impact on GR improvement.
Analysis of Changes in Spectral Signal According to Gas Flow Rate in Laser-Induced Breakdown Spectroscopy
Authors: Yoon Sangwoo , Choi Hae-Woon , Kim Joohan
Published: September 2021

In a laser-induced breakdown spectroscopy (LIBS) system that performs elemental analysis of a target by acquiring the emission of plasma generated on the material surface by a focused laser, the plasma signal may be affected by the flow of the surrounding gas. A flow of gas may be present when LIBS measurements are performed in a special environment where an inert gas is normally applied. In such an environment, the flow of gas may affect the intensity of emission generated in plasma. The LIBS spectral intensity in the gas flow field changes according to the direction of the gas flow and the signal detector of the LIBS. In this case, the correlation between the flow rate and intensity of the spectral line can be confirmed both theoretically and experimentally. In this study, changes in the signal according to the flow rate were theoretically evaluated using the view factor and wave equation. In addition, LIBS signals were examined based on the flow of Ar, N2, and He gases in the experiment. The experimental results confirmed the range of effective gas flow rates over which the correlation between the flow rate and intensity of the LIBS spectral line could be inferred. These results could be used for calibration to achieve accurate measurement of LIBS signals in gas flow fields. In addition, this analysis has the potential to shed light on the properties of flowing gases that affect plasma by reversibly tracking changes in the signal of LIBS in a confined environment.
Spatio-Temporal Dynamic Fields Estimating and Modeling of Missing Points in Data Sets Using a Flexible State-Space Model
Authors: Shi Zhichao , Zhou Xiaoguang
Published: September 2021

Modelling and estimating spatio-temporal dynamic field are common challenges in much applied research. Most existing spatio-temporal interpolation methods require massive prior calculations and consistent observational data, resulting in low interpolation efficiency. This paper presents a flexible state-space model for iteratively fitting time-series from random missing points in data sets, namely Flexible Universal Kriging state-space model(FUKSS). In this work, a recursive method similar to Kalman filter is used to estimate the time-series, avoiding the problem of increasing data caused by Kriging space-time extension. Based on the statistical characteristics of Kriging, this method introduces a spatial selection matrix to make the different observation data and state vectors identical at different times, which solves the problem of missing data and reduces the calculation complexity. In addition, a dynamic linear autoregressive model is introduced to solve the problem that the universal Kriging state-space model cannot predict. We have demonstrated the superiority of our method by comparing it with different methods through experiments, and verified the effectiveness of this method through practical cases.
Canal Transportation and Volumetric Dentin Removal Abilities of Ni-Ti Rotary File Systems in Curved Primary Root Canals: CBCT Study
Authors: İslam Aylin , Ünsal Gürkan , Almashharawi Alaa
Published: September 2021

Current improvements in nickel-titanium (Ni-Ti) rotary file systems have created a paradigm shift in the root canal therapy of primary teeth. Therefore, it is necessary to perform a comprehensive evaluation regarding the efficiencies of newly manufactured instruments for different parameters. The current study was conducted to evaluate the abilities of RaceEvo, R-Motion, ProTaper Gold (PTG) systems in curved primary root canals with regard to the patterns of canal transportation and volumetric dentin removal by using cone-beam computed tomography (CBCT). Two experimental sets were designed following the determination of experimental groups by using pre- and post-operative CBCT data: canal transportation and volumetric dentin removal. The highest amount of canal transportation was significantly detected in the PTG group in comparison to RaceEvo and R-Motion groups. When the mean values of volumetric dentin removal data were analyzed across all groups, the PTG group again exhibited the significantly highest value of dentin removal volumetrically, compared to RaceEvo, R-Motion and manual instrumentation groups. It is possible to state that R-Motion and RaceEvo rotary systems could be used as reliable alternatives without causing adverse mechanical effects and maintaining the original root canal anatomy of curved primary root canal systems compared with PTG rotary systems and manual instrumentation, with a high diagnostic sensitivity of CBCT in pediatric endodontics when the alternative methods are not adequate.
CC(T) Specimen Load-Bearing Capacity Related to Yield Strength and Upper-Shelf Charpy-V Energy
Authors: Wallin Kim
Published: September 2021

The load-bearing capacity of a CC(T) specimen (Center-Cracked Tension) in the ductile fracture regime is usually controlled by plastic collapse. If the material’s tearing resistance is sufficiently low, the load-bearing capacity can drop below the plastic collapse value. Here, a recently developed simple fracture mechanics-based Charpy-V impact energy criterion for plastic collapse was used to provide a best estimate assessment of the CC(T) specimen load-bearing capacity.
Magnetic Angle Changer for Studies of Electronically Excited Long-Living Atomic States
Authors: Kłosowski Łukasz , Piwiński Mariusz
Published: September 2021

A new geometry of a magnetic angle changer (MAC) device is proposed, which allows experiments to be run on electron impact excitation of long-lived states of target atoms. The details of the device’s design are presented and discussed together with a numerical analysis of its magnetic field.
Can You Hear the Shape of a Market? Geometric Arbitrage and Spectral Theory
Authors: Farinelli Simone , Takada Hideyuki
Published: September 2021

Utilizing gauge symmetries, the Geometric Arbitrage Theory reformulates any asset model, allowing for arbitrage by means of a stochastic principal fibre bundle with a connection whose curvature measures the “instantaneous arbitrage capability”. The cash flow bundle is the associated vector bundle. The zero eigenspace of its connection Laplacian parameterizes all risk-neutral measures equivalent to the statistical one. A market satisfies the No-Free-Lunch-with-Vanishing-Risk (NFLVR) condition if and only if 0 is in the discrete spectrum of the Laplacian. The Jarrow–Protter–Shimbo theory of asset bubbles and their classification and decomposition extend to markets not satisfying the NFLVR. Euler’s characteristic of the asset nominal space and non-vanishing of the homology group of the cash flow bundle are both topological obstructions to NFLVR.
Natural Products as Protective Agents for Male Fertility
Authors: Martins Roberta V. L. , Silva Ana M. S. , Duarte Ana Paula , Socorro Sílvia , Correia Sara , Maia Cláudio J.
Published: September 2021

The male reproductive system is highly susceptible to noxious influences, such as oxidative stress, inflammation, drugs, and even diseases that can induce germ cell damage and alterations in spermatogenesis. All of these factors, which are caused by actions at the testicular level and/or at the excurrent ducts and accessory glands, significantly affect sperm parameters and male fertility. For this reason, it is of major importance to investigate possible ways to protect the male reproductive system since males are exposed to these toxic factors constantly. For centuries, natural products have been used by humans in folk medicine as therapeutic agents, and because of their beneficial properties for human health, plenty of them have been introduced to the pharmaceutical market as supplementary therapies. The present review aims to compile available information regarding different natural exogenous factors that demonstrate potential useful activity in the male reproductive system. The studies presented here reopen the perspective of using natural products as protective agents and eventually as new supplementary therapeutic options for the recovery of hampered spermatogenesis and/or male infertility.
Clitoria ternatea Flower Extract Attenuates Postprandial Lipemia and Increases Plasma Antioxidant Status Responses to a High-Fat Meal Challenge in Overweight and Obese Participants
Authors: Thilavech Thavaree , Adisakwattana Sirichai , Channuwong Pilailak , Radarit Korntima , Jantarapat Kanthida , Ngewlai Kittisak , Sonprasan Nantarat , Chusak Charoonsri
Published: September 2021

High-fat (HF) meal-induced postprandial lipemia, oxidative stress and low-grade inflammation is exacerbated in overweight and obese individuals. This postprandial dysmetabolism contributes to an increased risk of cardiovascular disease and metabolic disorders. Clitoria ternatea flower extract (CTE) possesses antioxidant potential and carbohydrate and fat digestive enzyme inhibitory activity in vitro. However, no evidence supporting a favorable role of CTE in the modulation of postprandial lipemia, antioxidant status and inflammation in humans presently exists. In the present study, we determine the effect of CTE on changes in postprandial glycemic and lipemic response, antioxidant status and pro-inflammatory markers in overweight and obese men after consumption of an HF meal. Following a randomized design, sixteen participants (age, 23.5 ± 0.6 years, and BMI, 25.7 ± 0.7 kg/m2) were assigned to three groups that consumed the HF meal, or HF meal supplemented by 1 g and 2 g of CTE. Blood samples were collected at fasting state and then at 30, 60, 90, 120, 180, 240, 300 and 360 min after the meal consumption. No significant differences were observed in the incremental area under the curve (iAUC) for postprandial glucose among the three groups. Furthermore, 2 g of CTE decreased the iAUC for serum triglyceride and attenuated postprandial serum free fatty acids at 360 min after consuming the HF meal. In addition, 2 g of CTE significantly improved the iAUC for plasma antioxidant status, as characterized by increased postprandial plasma FRAP and thiol levels. Postprandial plasma glutathione peroxidase activity was significantly higher at 180 min after the consumption of HF meal with 2 g of CTE. No significant differences in the level of pro-inflammatory cytokines (interleukin-6, interleukin-1β and tumor necrosis factor-α) were observed at 360 min among the three groups. These findings suggest that CTE can be used as a natural ingredient for reducing postprandial lipemia and improving the antioxidant status in overweight and obese men after consuming HF meals.
Fetuin-A Deficiency but Not Pentraxin 3, FGF-21, or Irisin, Predisposes to More Serious COVID-19 Course
Authors: Kukla Michał , Menżyk Tomasz , Dembiński Marcin , Winiarski Marek , Garlicki Aleksander , Bociąga-Jasik Monika , Skonieczna Magdalena , Hudy Dorota , Maziarz Barbara , Kuśnierz-Cabala Beata , Kapusta Maria , Skladany Lubomir , Grgurevic Ivica , Mikolasevic Ivana , Filipec-Kanizaj Tajana , Wójcik-Bugajska Małgorzata , Grodzicki Tomasz , Rogula Tomasz , Stygar Dominika
Published: September 2021

Analysis of liver biopsy specimens showed that SARS-CoV-2 might have led to liver damage. This study aimed to evaluate the role of selected hepatokines and myokines in the development and progression of COVID-19. Seventy patients with laboratory-confirmed COVID-19 and 20 healthy volunteers were enrolled in the study. Irisin, pentraxin 3, fetuin-A, and FGF-21 serum concentrations and biochemical parameters were assessed using an immunoenzymatic method with commercially available enzyme immunoassay (EIA) or enzyme-linked immunosorbent assay (ELISA) kits. Serum fetuin-A concentrations were significantly decreased in COVID-19 patients compared to healthy volunteers. The serum concentration of FGF-21 was significantly increased in obese COVID-19 patients compared to overweight ones. Moreover, the FGF-21 level was higher in COVID-19 patients diagnosed with metabolic syndrome than in patients without metabolic syndrome. PTX3 concentration was higher in COVID-19 patients with higher HOMA-IR values than those with lower HOMA-IR values. COVID-19 patients with HOMA-IR ≤ 3 and >3 had significantly lower fetuin-A levels than the control group. Irisin concentration was significantly decreased in the HOMA-IR ≤ 3 COVID-19 subgroup when comparing with the control group. Lower levels of fetuin-A observed in COVID-19 patients despite higher HOMA-IR, CRP, and ferritin levels, pneumonia, patients requiring ICU care suggests that fetuin-A deficiency predisposes to more severe COVID-19 course. Upregulated pentraxin 3 may be used as a potential predictor of COVID-19 severity.
Airway Bacteria Quantification Using Polymerase Chain Reaction Combined with Neutrophil and Eosinophil Counts Identifies Distinct COPD Endotypes
Authors: Beech Augusta , Lea Simon , Li Jian , Jackson Natalie , Mulvanny Alex , Singh Dave
Published: September 2021

Background: Chronic obstructive pulmonary disease (COPD) inflammatory endotypes are associated with different airway microbiomes. We used quantitative polymerase chain reaction (qPCR) analysis of sputum samples to establish the bacterial load upper limit in healthy controls; these values determined the bacterial colonisation prevalence in a longitudinal COPD cohort. Bacteriology combined with sputum inflammatory cells counts were used to investigate COPD endotypes. Methods: Sixty COPD patients and 15 healthy non-smoking controls were recruited. Sputum was analysed by qPCR (for Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae and Psuedomonas aeruginosa) and sputum differential cell counts at baseline and 6 months. Results: At baseline and 6 months, 23.1% and 25.6% of COPD patients were colonised with H. influenzae, while colonisation with other bacterial species was less common, e.g., S. pneumoniae—1.9% and 5.1%, respectively. H. influenzae + ve patients had higher neutrophil counts at baseline (90.1% vs. 67.3%, p < 0.01), with similar results at 6 months. COPD patients with sputum eosinophil counts ≥3% at ≥1 visit rarely showed bacterial colonisation. Conclusions: The prevalence of H. influenzae colonisation was approximately 25%, with low colonisation for other bacterial species. H. influenzae colonisation was associated with sputum neutrophilia, while eosinophilic inflammation and H. influenzae colonisation rarely coexisted.
NK Cell-Mediated Eradication of Ovarian Cancer Cells with a Novel Chimeric Antigen Receptor Directed against CD44
Authors: Klapdor Rüdiger , Wang Shuo , Morgan Michael A. , Zimmermann Katharina , Hachenberg Jens , Büning Hildegard , Dörk Thilo , Hillemanns Peter , Schambach Axel
Published: September 2021

Ovarian cancer is the most common cause of gynecological cancer-related death in the developed world. Disease recurrence and chemoresistance are major causes of poor survival rates in ovarian cancer patients. Ovarian cancer stem cells (CSCs) were shown to represent a source of tumor recurrence owing to the high resistance to chemotherapy and enhanced tumorigenicity. Chimeric antigen receptor (CAR)-based adoptive immunotherapy represents a promising strategy to reduce the risk for recurrent disease. In this study, we developed a codon-optimized third-generation CAR to specifically target CD44, a marker widely expressed on ovarian cancer cells and associated with CSC-like properties and intraperitoneal tumor spread. We equipped NK-92 cells with the anti-CD44 CAR (CD44NK) and an anti-CD19 control CAR (CD19NK) using lentiviral SIN vectors. Compared to CD19NK and untransduced NK-92 cells, CD44NK showed potent and specific cytotoxic activity against CD44-positive ovarian cancer cell lines (SKOV3 and OVCAR3) and primary ovarian cancer cells harvested from ascites. In contrast, CD44NK had less cytotoxic activity against CD44-negative A2780 cells. Specific activation of engineered NK cells was also demonstrated by interferon-γ (IFNγ) secretion assays. Furthermore, CD44NK cells still demonstrated cytotoxic activity under cisplatin treatment. Most importantly, the simultaneous treatment with CD44NK and cisplatin showed higher anti-tumor activity than sequential treatment.
Astrocytes, a Promising Opportunity to Control the Progress of Parkinson’s Disease
Authors: Sanchez Alberto , Morales Ingrid , Rodriguez-Sabate Clara , Sole-Sabater Miguel , Rodriguez Manuel
Published: September 2021

At present, there is no efficient treatment to prevent the evolution of Parkinson’s disease (PD). PD is generated by the concurrent activity of multiple factors, which is a serious obstacle for the development of etio-pathogenic treatments. Astrocytes may act on most factors involved in PD and the promotion of their neuroprotection activity may be particularly suitable to prevent the onset and progression of this basal ganglia (BG) disorder. The main causes proposed for PD, the ability of astrocytes to control these causes, and the procedures that can be used to promote the neuroprotective action of astrocytes will be commented upon, here.
HCC and Molecular Targeting Therapies: Back to the Future
Authors: Rinaldi Luca , Vetrano Erica , Rinaldi Barbara , Galiero Raffaele , Caturano Alfredo , Salvatore Teresa , Sasso Ferdinando Carlo
Published: September 2021

Hepatocellular carcinoma (HCC) is one of the leading causes of death from cancer in the world. Recently, the effectiveness of new antiviral therapies and the HBV vaccine have reduced HCC’s incidence, while non-alcoholic steato-hepatitis is an emerging risk factor. This review focuses on antiangiogenic molecules and immune checkpoint inhibitors approved for HCC treatment and possible future approaches. Sorafenib was the first drug approved for the treatment of advanced HCC (aHCC) and it has been shown to increase survival by a few months. Lenvatinib, a multikinase inhibitor, has shown non-inferiority in survival compared with sorafenib and an improvement in progression-free survival (PFS). The combination of atezolizumab (an anti-PDL1 antibody) and bevacizumab (an anti-VEGF antibody) was the first drug combination approved for HCC, demonstrating improved survival compared with sorafenib (19.2 vs. 13.4 months). As a second line of therapy, three regimens (regorafenib, cabozantinib, and ramucirumab) have been approved for the treatment of aHCC after progression on sorafenib according to guidelines. Furthermore, nivolumab, pembrolizumab, and nivolumab plus ipilimumab have been approved by the FDA (2017, 2018, and 2020, respectively). Finally, immune target therapy, cancer vaccines, and epigenetic drugs represent three new possible weapons for the treatment of HCC.
Non-Alcoholic Fatty Liver Disease in Lean and Non-Obese Individuals: Current and Future Challenges
Authors: Kuchay Mohammad Shafi , Martínez-Montoro José Ignacio , Choudhary Narendra Singh , Fernández-García José Carlos , Ramos-Molina Bruno
Published: September 2021

Non-alcoholic fatty liver disease (NAFLD), which approximately affects a quarter of the world’s population, has become a major public health concern. Although usually associated with excess body weight, it may also affect normal-weight individuals, a condition termed as lean/non-obese NAFLD. The prevalence of lean/non-obese NAFLD is around 20% within the NAFLD population, and 5% within the general population. Recent data suggest that individuals with lean NAFLD, despite the absence of obesity, exhibit similar cardiovascular- and cancer-related mortality compared to obese NAFLD individuals and increased all-cause mortality risk. Lean and obese NAFLD individuals share several metabolic abnormalities, but present dissimilarities in genetic predisposition, body composition, gut microbiota, and susceptibility to environmental factors. Current treatment of lean NAFLD is aimed at improving overall fitness and decreasing visceral adiposity, with weight loss strategies being the cornerstone of treatment. Moreover, several drugs including PPAR agonists, SGLT2 inhibitors, or GLP-1 receptor agonists could also be useful in the management of lean NAFLD. Although there has been an increase in research regarding lean NAFLD, there are still more questions than answers. There are several potential drugs for NAFLD therapy, but clinical trials are needed to evaluate their efficacy in lean individuals.
Mechanistic Insights into the Inhibition of SARS-CoV-2 Main Protease by Clovamide and Its Derivatives: In Silico Studies
Authors: Ye Naike , Caruso Francesco , Rossi Miriam
Published: September 2021

The novel coronavirus SARS-CoV-2 Main Protease (Mpro) is an internally encoded enzyme that hydrolyzes the translated polyproteins at designated sites. The protease directly mediates viral replication processes; hence, a promising target for drug design. Plant-based natural products, especially polyphenols and phenolic compounds, provide the scaffold for many effective antiviral medications, and have recently been shown to be able to inhibit Mpro of SARS-CoV-2. Specifically, polyphenolic compounds found in cacao and chocolate products have been shown by recent experimental studies to have strong inhibitory effects against Mpro activities. This work aims to uncover the inhibition processes of Mpro by a natural phenolic compound found in cacao and chocolate products, clovamide. Clovamide (caffeoyl-DOPA) is a naturally occurring caffeoyl conjugate that is found in the phenolic fraction of Theobroma Cacao L. and a potent radical-scavenging antioxidant as suggested by previous studies of our group. Here, we propose inhibitory mechanisms by which clovamide may act as a Mpro inhibitor as it becomes oxidized by scavenging reactive oxygen species (ROS) in the body, or becomes oxidized as a result of enzymatic browning. We use molecular docking, annealing-based molecular dynamics, and Density Functional Theory (DFT) calculations to study the interactions between clovamide with its derivatives and Mpro catalytic and allosteric sites. Our molecular modelling studies provide mechanistic insights of clovamide inhibition of Mpro, and indicate that clovamide may be a promising candidate as a drug lead molecule for COVID-19 treatments.
The Effect of Sand Type on the Rheological Properties of Self-Compacting Mortar
Authors: Yang Song , Zhang Jingbin , An Xuehui , Qi Bing , Li Wenqiang , Shen Dejian , Li Pengfei , Lv Miao
Published: September 2021

In order to understand the effect of sand type on the rheological properties of self-compacting mortar, four varieties of sand, namely, quartz sand (QS), river sand (RS), and two kinds of manufactured sand, marked as MS-A and MS-B, were studied. As part of this study, the sands’ particle shape parameters, such as their length:width ratio and roundness, were determined. Mortars containing the four varieties of sand were tested using the slump flow test and the V-funnel test in oven-dried (OD) and saturated surface-dried (SSD) conditions in order to identify the water absorption, shape-related differences, and specific gravity in their rheological performance. The changing trends of the slump flows and the V-funnel times of the different mortars in OD and SSD were similar. By eliminating the influence of water absorption on mortar rheology, shape–weight parameters, such as the ratio between the length:width ratio and specific gravity (LWS) and the product of roundness and specific gravity (ROS), were defined in order to quantify the compound effects of sand type on mortar rheology. The regression analysis showed an excellent linear correlation between slump flow and both LWS and ROS, and a very good linear correlation was also demonstrated between the V-funnel time and both LWS and ROS. Based on the particle shape–weight parameters, the rheological properties of mortars can be predicted. Based on the mortar rheological threshold theory, the self-compacting mortar (SCM) zone can be drawn. The predicted SCM zone overlaps considerably with the experimental SCM zone for MS-A.
A Numerical Study of the Stiffness and Strength of Cross-Laminated Timber Wall-to-Floor Connections under Compression Perpendicular to the Grain
Authors: Akter Shaheda T. , Schweigler Michael , Serrano Erik , Bader Thomas K.
Published: September 2021

The use of cross-laminated timber (CLT) in multi-story buildings is increasing due to the potential of wood to reduce green house gas emissions and the high load-bearing capacity of CLT. Compression perpendicular to the grain (CPG) in CLT is an important design aspect, especially in multi-storied platform-type CLT buildings, where CPG stress develops in CLT floors due to loads from the roof or from upper floors. Here, CPG of CLT wall-to-floor connections are studied by means of finite element modeling with elasto-plastic material behavior based on a previously validated Quadratic multi-surface (QMS) failure criterion. Model predictions were first compared with experiments on CLT connections, before the model was used in a parameter study, to investigate the influence of wall and floor thicknesses, the annual ring pattern of the boards and the number of layers in the CLT elements. The finite element model agreed well with experimental findings. Connection stiffness was overestimated, while the strength was only slightly underestimated. The parameter study revealed that the wall thickness effect on the stiffness and strength of the connection was strongest for the practically most relevant wall thicknesses between 80 and about 160 mm. It also showed that an increasing floor thickness leads to higher stiffness and strength, due to the load dispersion effect. The increase was found to be stronger for smaller wall thicknesses. The influence of the annual ring orientation, or the pith location, was assessed as well and showed that boards cut closer to the pith yielded lower stiffness and strength. The findings of the parameter study were fitted with regression equations. Finally, a dimensionless ratio of the wall-to-floor thickness was used for deriving regression equations for stiffness and strength, as well as for load and stiffness increase factors, which could be used for the engineering design of CLT connections.
Mechanisms of Cancer Cell Death: Therapeutic Implications for Pancreatic Ductal Adenocarcinoma
Authors: Pook Hannah , Pauklin Siim
Published: September 2021

Pancreatic ductal adenocarcinoma (PDAC) is a type of cancer that is strongly associated with poor prognosis and short median survival times. In stark contrast to the progress seen in other cancer types in recent decades, discoveries of new treatments in PDAC have been few and far between and there has been little improvement in overall survival (OS). The difficulty in treating this disease is multifactorial, contributed to by late presentation, difficult access to primary tumour sites, an ‘immunologically cold’ phenotype, and a strong tendency of recurrence likely driven by cancer stem cell (CSC) populations. Furthermore, apparently contrasting roles of tumour components (such as fibrotic stroma) and intracellular pathways (such as autophagy and TGFβ) have made it difficult to distinguish beneficial from detrimental drug targets. Despite this, progress has been made in the field, including the determination of mFOLFIRINOX as the standard-of-care adjuvant therapy and the discovery of KRASG12C mutant inhibitors. Moreover, new research, as outlined in this review, has highlighted promising new approaches including the targeting of the tumour microenvironment, enhancement of immunotherapies, epigenetic modulation, and destruction of CSCs.
Using Breast Cancer Gene Expression Signatures in Clinical Practice: Unsolved Issues, Ongoing Trials and Future Perspectives
Authors: Varnier Romain , Sajous Christophe , de Talhouet Solène , Smentek Colette , Péron Julien , You Benoît , Reverdy Thibaut , Freyer Gilles
Published: September 2021

The development of gene expression signatures since the early 2000′s has offered standardized assays to evaluate the prognosis of early breast cancer. Five signatures are currently commercially available and recommended by several international guidelines to individualize adjuvant chemotherapy decisions in hormone receptors-positive/HER2-negative early breast cancer. However, many questions remain unanswered about their predictive ability, reproducibility and external validity in specific populations. They also represent a new hope to tailor (neo)adjuvant systemic treatment, adjuvant radiation therapy, hormone therapy duration and to identify a subset of patients who might benefit from CDK4/6 inhibitor adjuvant treatment. This review will highlight these particular issues, address the remaining questions and discuss the ongoing and future trials.
Prognosis Parameters of Oral Carcinomas Developed in Proliferative Verrucous Leukoplakia: A Systematic Review and Meta-Analysis
Authors: González-Moles Miguel Ángel , Warnakulasuriya Saman , Ramos-García Pablo
Published: September 2021

Proliferative verrucous leukoplakia (PVL) is contemplated by the World Health Organization (WHO) as an oral potentially malignant disorder (OPMD) with a high the highest malignant transformation ratio among all OPMD (approximately 50%). Our aim was to evaluate the current evidence in relation to the prognosis of oral carcinoma developed in patients with proliferative verrucous leukoplakia (PVL-OC). We searched PubMed, Embase, Web of Science and Scopus for published studies (upper date limit = June 2021). We evaluated the quality of studies (QUIPS tool). We carried out meta-analyses, examined inter-study heterogeneity through subgroup and meta-regression analyses, and performed sensitivity and small-study effects analyses to test the stability and reliability of results. 23 studies met inclusion criteria (505 patients with PVL, of which 288 developed a total of 504 carcinomas). The meta-analyzed overall mortality rate was 21.29% (pooled proportions [PP] = 95% confidence intervals [CI] = 8.77–36.36) for PVL-OC, clearly lower than the 34.7–50% mortality rate for conventional oral cancer reported in previous studies. In comparison with a single study reporting on conventional oral cancers, mortality was significantly lower for PVL-OC (hazard ratio = 0.29 [95%CI = 0.10–0.89], p = 0.03). Univariable meta-regression verified that case series that presented higher proportions of verrucous carcinomas showed a better survival of PVL-OC (p = 0.05), but not with higher proportion of oral squamous cell carcinomas (p = 0.74). Significant differences were not found for other relevant variables such as follow up period (p = 0.44) or multiple tumor development (p = 0.74). In conclusion, PVL-OC show favorable prognostic parameters, especially with regard to the mortality rate.
Heat Shock Protein 27, a Novel Downstream Target of Collagen Type XI alpha 1, Synergizes with Fatty Acid Oxidation to Confer Cisplatin Resistance in Ovarian Cancer Cells
Authors: Heiserman James Patrick , Nallanthighal Sameera , Gifford Cody C. , Graham Kayla , Samarakoon Rohan , Gao Chao , Sage Jessica J. , Zhang Wenzheng , Higgins Paul J. , Cheon Dong-Joo
Published: September 2021

Collagen type XI alpha 1 (COL11A1) is a novel biomarker associated with cisplatin resistance in ovarian cancer. We have previously reported that COL11A1 activates Src-Akt signaling through the collagen receptors discoidin domain receptor 2 (DDR2) and integrin α1β1 to confer cisplatin resistance to ovarian cancer cells. To identify the potential signaling molecules downstream of COL11A1 signaling, we performed protein kinase arrays and identified heat shock protein 27 (HSP27) as a potential mediator of COL11A1-induced cisplatin resistance. Through receptor knockdown and inhibitor experiments, we demonstrated that COL11A1 significantly upregulates HSP27 phosphorylation and expression via DDR2/integrin α1β1 and Src/Akt signaling in ovarian cancer cells. Furthermore, genetic knockdown and pharmacological inhibition of HSP27, via ivermectin treatment, significantly sensitizes ovarian cancer cells cultured on COL11A1 to cisplatin treatment. HSP27 knockdown or inhibition also decreases NFκB activity as well as the expression of inhibitors of apoptosis proteins (IAPs), which are known downstream effector molecules of COL11A1 that promote cisplatin resistance. Interestingly, HSP27 knockdown or inhibition stimulates ovarian cancer cells to upregulate fatty acid oxidation (FAO) for survival and cisplatin resistance, and dual inhibition of HSP27 and FAO synergistically kills ovarian cancer cells that are cultured on COL11A1. Collectively, this study identifies HSP27 as a novel and druggable COL11A1 downstream effector molecule that may be targeted to overcome cisplatin resistance in recurrent ovarian cancer, which often overexpress COL11A1.
Halloysite Nanoclay with High Content of Sulfonic Acid-Based Ionic Liquid: A Novel Catalyst for the Synthesis of Tetrahydrobenzo[b]pyrans
Authors: Sadjadi Samahe , Koohestani Fatemeh , Abedian-Dehaghani Neda , Heravi Majid M.
Published: September 2021

One of the main drawbacks of supported ionic liquids is their low loading and consequently, low activity of the resultant catalysts. To furnish a solution to this issue, a novel heterocyclic ligand with multi imine sites was introduced on the surface of amino-functionalized halloysite support via successive reactions with 2,4,6-trichloro-1,3,5-triazine and 2-aminopyrimidine. Subsequently, the imine sites were transformed to sulfonic acid-based ionic liquids via reaction with 1,4-butanesultone. Using this strategy, high loading of ionic liquid was loaded on halloysite nanoclay. The supported ionic liquid was then characterized with XRD, SEM, TEM, EDS, FTIR, BET, TGA and elemental mapping analysis and utilized as a metal-free Brønsted acid catalyst for promoting one-pot reaction of aldehydes, dimedone and malononitrile to furnish tetrahydrobenzo[b]pyrans. The catalytic tests confirmed high performance of the catalyst. Moreover, the catalyst was stable upon recycling.
Covalently Bonded Ir(IV) on Conducted Blue TiO2 for Efficient Electrocatalytic Oxygen Evolution Reaction in Acid Media
Authors: Nguyen Chau T. K. , Tran Ngoc Quang , Le Thi Anh , Lee Hyoyoung
Published: September 2021

The stability of anode electrode has been a primary obstacle for the oxygen evolution reaction (OER) in acid media. We design Ir-oxygen of hydroxyl-rich blue TiO2 through covalent bonds (Ir–O2–2Ti) and investigate the outcome of favored exposure of different amounts of covalent Ir–oxygen linked to the conductive blue TiO2 in the acidic OER. The Ir-oxygen-blue TiO2 nanoclusters show a strong synergy in terms of improved conductivity and tiny amount usage of Ir by using blue TiO2 supporter, and enhanced stability using covalent Ir-oxygen-linking (i.e., Ir oxide) in acid media, leading to high acidic OER performance with a current density of 10 mA cm−2 at an overpotential of 342 mV, which is much higher than that of IrO2 at 438 mV in 0.1 M HClO4 electrolyte. Notably, the Ir–O2–2Ti has a great mass activity of 1.38 A/mgIr at an overpotential 350 mV, which is almost 27 times higher than the mass activity of IrO2 at the same overpotential. Therefore, our work provides some insight into non-costly, highly enhanced, and stable electrocatalysts for the OER in acid media.
The N-Terminal Region of the Polo Kinase Cdc5 Is Required for Downregulation of the Meiotic Recombination Checkpoint
Authors: González-Arranz Sara , Acosta Isabel , Carballo Jesús A. , Santos Beatriz , San-Segundo Pedro A.
Published: September 2021

During meiosis, the budding yeast polo-like kinase Cdc5 is a crucial driver of the prophase I to meiosis I (G2/M) transition. The meiotic recombination checkpoint restrains cell cycle progression in response to defective recombination to ensure proper distribution of intact chromosomes to the gametes. This checkpoint detects unrepaired DSBs and initiates a signaling cascade that ultimately inhibits Ndt80, a transcription factor required for CDC5 gene expression. Previous work revealed that overexpression of CDC5 partially alleviates the checkpoint-imposed meiotic delay in the synaptonemal complex-defective zip1Δ mutant. Here, we show that overproduction of a Cdc5 version (Cdc5-ΔN70), lacking the N-terminal region required for targeted degradation of the protein by the APC/C complex, fails to relieve the zip1Δ-induced meiotic delay, despite being more stable and reaching increased protein levels. However, precise mutation of the consensus motifs for APC/C recognition (D-boxes and KEN) has no effect on Cdc5 stability or function during meiosis. Compared to the zip1Δ single mutant, the zip1Δ cdc5-ΔN70 double mutant exhibits an exacerbated meiotic block and reduced levels of Ndt80 consistent with persistent checkpoint activity. Finally, using a CDC5-inducible system, we demonstrate that the N-terminal region of Cdc5 is essential for its checkpoint erasing function. Thus, our results unveil an additional layer of regulation of polo-like kinase function in meiotic cell cycle control.
Circulating miR-185-5p as a Potential Biomarker for Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Sacchetto Claudia , Mohseni Zenab , Colpaert Robin M. W. , Vitiello Libero , De Bortoli Marzia , Vonhögen Indira G. C. , Xiao Ke , Poloni Giulia , Lorenzon Alessandra , Romualdi Chiara , Bariani Riccardo , Mazzotti Elisa , Daliento Luciano , Bauce Barbara , Corrado Domenico , Thum Thomas , Rampazzo Alessandra , de Windt Leon J. , Calore Martina
Published: September 2021

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiac disease characterized by progressive myocardial fibro-fatty replacement, arrhythmias and risk of sudden death. Its diagnosis is challenging and often it is achieved after disease onset or postmortem. In this study, we sought to identify circulating microRNAs (miRNAs) differentially expressed in ARVC patients compared to healthy controls. In the pilot study, we screened the expression of 754 miRNAs from 21 ARVC patients and 20 healthy controls. After filtering the miRNAs considering a log fold-change cut-off of ±1, p-value < 0.05, we selected five candidate miRNAs for a subsequent validation study in which we used TaqMan-based real-time PCR to analyse samples from 37 ARVC patients and 30 healthy controls. We found miR-185-5p significantly upregulated in ARVC patients. Receiver operating characteristic analysis indicated an area under the curve of 0.854, corroborating the link of this miRNA and ARVC pathophysiology.