bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting AKT in ER-Positive HER2-Negative Metastatic Breast Cancer: From Molecular Promises to Real Life Pitfalls?
Authors: Mery Benoîte , Poulard Coralie , Le Romancer Muriel , Trédan Olivier
Published: December 2021

The AKT protein kinase plays a central role in several interconnected molecular pathways involved in growth, apoptosis, angiogenesis, and cell metabolism. It thereby represents a therapeutic target, especially in hormone receptor-positive (HR) breast cancers, where the PI3K/AKT signaling pathway is largely hyperactivated. Moreover, resistance to therapeutic classes, including endocrine therapy, is associated with the constitutive activation of the PI3K/AKT pathway. Improved knowledge on the molecular mechanisms underlying resistance to endocrine therapy has led to the diversification of the therapeutic arsenal, notably with the development of PI3K and mTOR inhibitors, which are currently approved for the treatment of advanced HR-positive breast cancer patients. AKT itself constitutes a novel pharmacological target for which AKT inhibitors have been developed and tested in clinical trials. However, despite its pivotal role in cell survival and anti-apoptotic mechanisms, as well as in endocrine therapy resistance, few drugs have been developed and are available for clinical practice. The scope of the present review is to focus on the pivotal role of AKT in metastatic breast cancer through the analysis of its molecular features and to discuss clinical implications and remaining challenges in the treatment of HR-positive metastatic breast cancer.
Organ-on-a-Chip for Studying Gut-Brain Interaction Mediated by Extracellular Vesicles in the Gut Microenvironment
Authors: Kim Min-Hyeok , van Noort Danny , Sung Jong Hwan , Park Sungsu
Published: December 2021

Extracellular vesicles (EVs) are a group of membrane vesicles that play important roles in cell-to-cell and interspecies/interkingdom communications by modulating the pathophysiological conditions of recipient cells. Recent evidence has implied their potential roles in the gut–brain axis (GBA), which is a complex bidirectional communication system between the gut environment and brain pathophysiology. Despite the evidence, the roles of EVs in the gut microenvironment in the GBA are less highlighted. Moreover, there are critical challenges in the current GBA models and analyzing techniques for EVs, which may hinder the research. Currently, advances in organ-on-a-chip (OOC) technologies have provided a promising solution. Here, we review the potential effects of EVs occurring in the gut environment on brain physiology and behavior and discuss how to apply OOCs to research the GBA mediated by EVs in the gut microenvironment.
Radiosensitizer Effect of β-Apopicropodophyllin against Colorectal Cancer via Induction of Reactive Oxygen Species and Apoptosis
Authors: Kwon Jin-Hee , Lee Na-Gyeong , Kang A-Ram , Song Jie-Young , Hwang Sang-Gu , Um Hong-Duck , Kim Joon , Park Jong Kuk
Published: December 2021

β-apopicropodophyllin (APP), a derivative of podophyllotoxin (PPT), has been identified as a potential anti-cancer drug. This study tested whether APP acts as an anti-cancer drug and can sensitize colorectal cancer (CRC) cells to radiation treatment. APP exerted an anti-cancer effect against the CRC cell lines HCT116, DLD-1, SW480, and COLO320DM, with IC50 values of 7.88 nM, 8.22 nM, 9.84 nM, and 7.757 nM, respectively, for the induction of DNA damage. Clonogenic and cell counting assays indicated that the combined treatment of APP and γ-ionizing radiation (IR) showed greater retardation of cell growth than either treatment alone, suggesting that APP sensitized CRC cells to IR. Annexin V–propidium iodide (PI) assays and immunoblot analysis showed that the combined treatment of APP and IR increased apoptosis in CRC cells compared with either APP or IR alone. Results obtained from the xenograft experiments also indicated that the combination of APP and IR enhanced apoptosis in the in vivo animal model. Apoptosis induction by the combined treatment of APP and IR resulted from reactive oxygen species (ROS). Inhibition of ROS by N-acetylcysteine (NAC) restored cell viability and decreased the induction of apoptosis by APP and IR in CRC cells. Taken together, these results indicate that a combined treatment of APP and IR might promote apoptosis by inducing ROS in CRC cells.
Toward Molecular Medicine in Female Infertility Management: Editorial to the Special Issue “Molecular Mechanisms of Human Oogenesis and Early Embryogenesis”
Authors: Tesarik Jan
Published: December 2021

Female infertility is the main reason for involuntary childlessness nowadays [...]
Human Glucose Transporters in Renal Glucose Homeostasis
Authors: Sędzikowska Aleksandra , Szablewski Leszek
Published: December 2021

The kidney plays an important role in glucose homeostasis by releasing glucose into the blood stream to prevent hypoglycemia. It is also responsible for the filtration and subsequent reabsorption or excretion of glucose. As glucose is hydrophilic and soluble in water, it is unable to pass through the lipid bilayer on its own; therefore, transport takes place using carrier proteins localized to the plasma membrane. Both sodium-independent glucose transporters (GLUT proteins) and sodium-dependent glucose transporters (SGLT proteins) are expressed in kidney tissue, and mutations of the genes coding for these glucose transporters lead to renal disorders and diseases, including renal cancers. In addition, several diseases may disturb the expression and/or function of renal glucose transporters. The aim of this review is to describe the role of the kidney in glucose homeostasis and the contribution of glucose transporters in renal physiology and renal diseases.
Aroylhydrazone Diorganotin Complexes Causes DNA Damage and Apoptotic Cell Death: From Chemical Synthesis to Biochemical Effects
Authors: Jiang Wujiu , Tan Yuxing , Peng Yiyuan
Published: December 2021

Under microwave irradiation, eighteen new aroylhydrazone diorganotin complexes (1a–9b) were produced through the reaction of aroylhydrazine, 2-ketobutyric acid, and the corresponding diorganotin. Fourier transform infrared spectroscopy, 1H, 13C, and 119Sn nuclear magnetic resonance spectroscopies, high-resolution mass spectroscopy, X-ray crystallography, and thermogravimetric analysis (TGA) were performed to characterize the complexes. The in vitro anticancer activity for complexes were assessed using a CCK-8 assay on human cancer cells of HepG2, NCI-H460, and MCF-7. Complex 4b revealed more intensive anticancer activity against MCF-7 cells than the other complexes and cisplatin. Flow cytometry analysis and transmission electron microscope observation demonstrated that complex 4b mediated cell apoptosis of MCF-7 cells and arrested cell cycle in S phase. Western blotting analysis showed that 4b induced DNA damage in MCF-7 cells and led to apoptosis by the ATM-CHK2-p53 pathway. The single cell gel electrophoreses assay results showed that 4b induced DNA damage. The DNA binding activity of 4b was studied by UV–Visible absorption spectrometry, fluorescence competitive, viscosity measurements, gel electrophoresis, and molecular docking, and the results show that 4b can be well embedded in the groove and cleave DNA.
Genome Evolution from Random Ligation of RNAs of Autocatalytic Sets
Authors: Broecker Felix
Published: December 2021

The evolutionary origin of the genome remains elusive. Here, I hypothesize that its first iteration, the protogenome, was a multi-ribozyme RNA. It evolved, likely within liposomes (the protocells) forming in dry-wet cycling environments, through the random fusion of ribozymes by a ligase and was amplified by a polymerase. The protogenome thereby linked, in one molecule, the information required to seed the protometabolism (a combination of RNA-based autocatalytic sets) in newly forming protocells. If this combination of autocatalytic sets was evolutionarily advantageous, the protogenome would have amplified in a population of multiplying protocells. It likely was a quasispecies with redundant information, e.g., multiple copies of one ribozyme. As such, new functionalities could evolve, including a genetic code. Once one or more components of the protometabolism were templated by the protogenome (e.g., when a ribozyme was replaced by a protein enzyme), and/or addiction modules evolved, the protometabolism became dependent on the protogenome. Along with increasing fidelity of the RNA polymerase, the protogenome could grow, e.g., by incorporating additional ribozyme domains. Finally, the protogenome could have evolved into a DNA genome with increased stability and storage capacity. I will provide suggestions for experiments to test some aspects of this hypothesis, such as evaluating the ability of ribozyme RNA polymerases to generate random ligation products and testing the catalytic activity of linked ribozyme domains.
Regulation of p53 and Cancer Signaling by Heat Shock Protein 40/J-Domain Protein Family Members
Authors: Kaida Atsushi , Iwakuma Tomoo
Published: December 2021

Heat shock proteins (HSPs) are molecular chaperones that assist diverse cellular activities including protein folding, intracellular transportation, assembly or disassembly of protein complexes, and stabilization or degradation of misfolded or aggregated proteins. HSP40, also known as J-domain proteins (JDPs), is the largest family with over fifty members and contains highly conserved J domains responsible for binding to HSP70 and stimulation of the ATPase activity as a co-chaperone. Tumor suppressor p53 (p53), the most frequently mutated gene in human cancers, is one of the proteins that functionally interact with HSP40/JDPs. The majority of p53 mutations are missense mutations, resulting in acquirement of unexpected oncogenic activities, referred to as gain of function (GOF), in addition to loss of the tumor suppressive function. Moreover, stability and levels of wild-type p53 (wtp53) and mutant p53 (mutp53) are crucial for their tumor suppressive and oncogenic activities, respectively. However, the regulatory mechanisms of wtp53 and mutp53 are not fully understood. Accumulating reports demonstrate regulation of wtp53 and mutp53 levels and/or activities by HSP40/JDPs. Here, we summarize updated knowledge related to the link of HSP40/JDPs with p53 and cancer signaling to improve our understanding of the regulation of tumor suppressive wtp53 and oncogenic mutp53 GOF activities.
The Chemokine Systems at the Crossroads of Inflammation and Energy Metabolism in the Development of Obesity
Authors: Chan Pei-Chi , Hsieh Po-Shiuan
Published: December 2021

Obesity is characterized as a complex and multifactorial excess accretion of adipose tissue accompanied with alterations in the immune and metabolic responses. Although the chemokine systems have been documented to be involved in the control of tissue inflammation and metabolism, the dual role of chemokines and chemokine receptors in the pathogenesis of the inflammatory milieu and dysregulated energy metabolism in obesity remains elusive. The objective of this review is to present an update on the link between chemokines and obesity-related inflammation and metabolism dysregulation under the light of recent knowledge, which may present important therapeutic targets that could control obesity-associated immune and metabolic disorders and chronic complications in the near future. In addition, the cellular and molecular mechanisms of chemokines and chemokine receptors including the potential effect of post-translational modification of chemokines in the regulation of inflammation and energy metabolism will be discussed in this review.
Cell Fate Decisions in the Neural Crest, from Pigment Cell to Neural Development
Authors: Dawes Jonathan H. P. , Kelsh Robert N.
Published: December 2021

The neural crest shows an astonishing multipotency, generating multiple neural derivatives, but also pigment cells, skeletogenic and other cell types. The question of how this process is controlled has been the subject of an ongoing debate for more than 35 years. Based upon new observations of zebrafish pigment cell development, we have recently proposed a novel, dynamic model that we believe goes some way to resolving the controversy. Here, we will firstly summarize the traditional models and the conflicts between them, before outlining our novel model. We will also examine our recent dynamic modelling studies, looking at how these reveal behaviors compatible with the biology proposed. We will then outline some of the implications of our model, looking at how it might modify our views of the processes of fate specification, differentiation, and commitment.
Delineation of the Ancestral Tus-Dependent Replication Fork Trap
Authors: Toft Casey J. , Moreau Morgane J. J. , Perutka Jiri , Mandapati Savitri , Enyeart Peter , Sorenson Alanna E. , Ellington Andrew D. , Schaeffer Patrick M.
Published: December 2021

In Escherichia coli, DNA replication termination is orchestrated by two clusters of Ter sites forming a DNA replication fork trap when bound by Tus proteins. The formation of a ‘locked’ Tus–Ter complex is essential for halting incoming DNA replication forks. However, the absence of replication fork arrest at some Ter sites raised questions about their significance. In this study, we examined the genome-wide distribution of Tus and found that only the six innermost Ter sites (TerA–E and G) were significantly bound by Tus. We also found that a single ectopic insertion of TerB in its non-permissive orientation could not be achieved, advocating against a need for ‘back-up’ Ter sites. Finally, examination of the genomes of a variety of Enterobacterales revealed a new replication fork trap architecture mostly found outside the Enterobacteriaceae family. Taken together, our data enabled the delineation of a narrow ancestral Tus-dependent DNA replication fork trap consisting of only two Ter sites.
The Role of Prostaglandin E1 as a Pain Mediator through Facilitation of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel 2 via the EP2 Receptor in Trigeminal Ganglion Neurons of Mice
Authors: Kwon Jean , Choi Young In , Jo Hang Joon , Lee Sang Hoon , Lee Han Kyu , Kim Heesoo , Moon Jee Youn , Jung Sung Jun
Published: December 2021

Cyclooxygenase metabolizes dihomo-γ-linolenic acid and arachidonic acid to form prostaglandin (PG) E, including PGE1 and PGE2, respectively. Although PGE2 is well known to play an important role in the development and maintenance of hyperalgesia and allodynia, the role of PGE1 in pain is unknown. We confirm whether PGE1 induced pain using orofacial pain behavioral test in mice and determine the target molecule of PGE1 in TG neurons with whole-cell patch-clamp and immunohistochemistry. Intradermal injection of PGE1 to the whisker pads of mice induced a reduced threshold, enhancing the excitability of HCN channel-expressing trigeminal ganglion (TG) neurons. The HCN channel-generated inward current (Ih) was increased by 135.3 ± 4.8% at 100 nM of PGE1 in small- or medium-sized TG, and the action of PGE1 on Ih showed a concentration-dependent effect, with a median effective dose (ED50) of 29.3 nM. Adenylyl cyclase inhibitor (MDL12330A), 8-bromo-cAMP, and the EP2 receptor antagonist AH6809 inhibited PGE1-induced Ih. Additionally, PGE1-induced mechanical allodynia was blocked by CsCl and AH6809. PGE1 plays a role in mechanical allodynia through HCN2 channel facilitation via the EP2 receptor in nociceptive neurons, suggesting a potential therapeutic target in that PGE1 could be involved in pain as endogenous substances under inflammatory conditions.
Stability of Nuclear and Mitochondrial Reference Genes in Selected Tissues of the Ambrosia Beetle Xylosandrus germanus
Authors: Patwa Nisha , Ranger Christopher , Lehenberger Maximilian , Biedermann Peter , Reding Michael
Published: December 2021

The fungus-farming ambrosia beetle Xylosandrus germanus (Blandford) uses a pouch-like structure (i.e., mycangium) to transport spores of its nutritional fungal mutualist. Our current study sought to identify reference genes necessary for future transcriptome analyses aimed at characterizing gene expression within the mycangium. Complementary DNA was synthesized using selected tissue types from laboratory-reared and field-collected X. germanus consisting of the whole body, head + thorax, deflated or inflated mycangium + scutellum, inflated mycangium, and thorax + abdomen. Quantitative reverse-transcription PCR reactions were performed using primers for 28S ribosomal RNA (28S rRNA), arginine kinase (AK), carbamoyl-phosphate synthetase 2-aspartate transcarbamylase-dihydroorotase (CAD), mitochondrial cytochrome oxidase 1 (CO1), and elongation factor-1α (EF1α). Reference gene stability was analyzed using GeNorm, NormFinder, BestKeeper, ΔCt, and a comprehensive final ranking by RefFinder. The gene CO1 was identified as the primary reference gene since it was generally ranked in first or second position among the tissue types containing the mycangium. Reference gene AK was identified as a secondary reference gene. In contrast, EF1α was generally ranked in the last or penultimate place. Identification of two stable reference genes will aid in normalizing the expression of target genes for subsequent gene expression studies of X. germanus’ mycangium.
Modification of High-Density Lipoprotein Functions by Diet and Other Lifestyle Changes: A Systematic Review of Randomized Controlled Trials
Authors: Sanllorente Albert , Lassale Camille , Soria-Florido Maria Trinidad , Castañer Olga , Fitó Montserrat , Hernáez Álvaro
Published: December 2021

High-density lipoprotein (HDL) functional traits have emerged as relevant elements that may explain HDL antiatherogenic capacity better than HDL cholesterol levels. These properties have been improved in several lifestyle intervention trials. The aim of this systematic review is to summarize the results of such trials of the most commonly used dietary modifications (fatty acids, cholesterol, antioxidants, alcohol, and calorie restriction) and physical activity. Articles were screened from the Medline database until March 2021, and 118 randomized controlled trials were selected. Results from HDL functions and associated functional components were extracted, including cholesterol efflux capacity, cholesteryl ester transfer protein, lecithin-cholesterol acyltransferase, HDL antioxidant capacity, HDL oxidation status, paraoxonase-1 activity, HDL anti-inflammatory and endothelial protection capacity, HDL-associated phospholipase A2, HDL-associated serum amyloid A, and HDL-alpha-1-antitrypsin. In mainly short-term clinical trials, the consumption of monounsaturated and polyunsaturated fatty acids (particularly omega-3 in fish), and dietary antioxidants showed benefits to HDL functionality, especially in subjects with cardiovascular risk factors. In this regard, antioxidant-rich dietary patterns were able to improve HDL function in both healthy individuals and subjects at high cardiovascular risk. In addition, in randomized trial assays performed mainly in healthy individuals, reverse cholesterol transport with ethanol in moderate quantities enhanced HDL function. Nevertheless, the evidence summarized was of unclear quality and short-term nature and presented heterogeneity in lifestyle modifications, trial designs, and biochemical techniques for the assessment of HDL functions. Such findings should therefore be interpreted with caution. Large-scale, long-term, randomized, controlled trials in different populations and individuals with diverse pathologies are warranted.
Effects of SARS-CoV-2 Pandemic on the Mental Health of Spanish Ob-Gyn Specialists—A Nationwide Study
Authors: González-Mesa Ernesto , Jiménez-López Jesus Salvador , Blasco-Alonso Marta , Anderica-Herrero Jose Ramon , Lubián-López Daniel
Published: December 2021

It has been reported that frontline health professionals have suffered from an increased rate of mental disorders as a consequence of the SARS-CoV-2 pandemic. Objective: This study aims to evaluate the impact of the pandemic on the mental health of Spanish specialists in the obstetrics and gynecology fields after the fifth Spanish COVID-19 wave. Methods: Psychometric screening of the professionals was performed using a nationwide online survey designed by the Psychosocial Obstetrics and Gynecology taskforce. Post-traumatic stress disorder (PTSD), depression, and general anxiety disorder were screened. Results: We found high scores for PTSD, depression, and generalized anxiety disorder. Up to 12.4% of specialists met the PTSD criteria, 12.8% showed complex PTSD, 37% showed depression, and up to 37% had a positive screening for generalized anxiety disorder. Our results showed that the pandemic has particularly affected the group of female Ob-Gyn specialists, with significant higher scores in depression and anxiety scales. Conclusions: As a lesson learned for the future in case of new health emergencies, it would be very important to provide professionals with adequate psychological support, ensuring enough human and material resources, flexible work shifts, and facilities to reconcile work and family-life, especially in the case of female specialists.
Myocardial Injury as a Prognostic Factor in Mid- and Long-Term Follow-Up of COVID-19 Survivors
Authors: Izquierdo Andrea , Mojón Diana , Bardají Alfredo , Carrasquer Anna , Calvo-Fernández Alicia , Carreras-Mora José , Giralt Teresa , Pérez-Fernández Sílvia , Farré Núria , Soler Cristina , Solà-Richarte Clàudia , Cabero Paula , Vaquerizo Beatriz , Marrugat Jaume , Ribas Núria
Published: December 2021

Myocardial injury, which is present in >20% of patients hospitalized for COVID-19, is associated with increased short-term mortality, but little is known about its mid- and long-term consequences. We evaluated the association between myocardial injury with one-year mortality and readmission in 172 COVID-19 patients discharged alive. Patients were grouped according to the presence or absence of myocardial injury (defined by hs-cTn levels) on admission and matched by age and sex. We report mortality and hospital readmission at one year after admission in all patients and echocardiographic, laboratory and clinical data at six months in a subset of 86 patients. Patients with myocardial injury had a higher prevalence of hypertension (73.3% vs. 50.0%, p = 0.003), chronic kidney disease (10.5% vs. 2.35%, p = 0.06) and chronic heart failure (9.3% vs. 1.16%, p = 0.03) on admission. They also had higher mortality or hospital readmissions at one year (11.6% vs. 1.16%, p = 0.01). Additionally, echocardiograms showed thicker walls in these patients (10 mm vs. 8 mm, p = 0.002) but without functional disorder. Myocardial injury in COVID-19 survivors is associated with poor clinical prognosis at one year, independent of age and sex, but not with echocardiographic functional abnormalities at six months.
Complicating Acute Myocardial Infarction. Current Status and Unresolved Targets for Subsequent Research
Authors: Zalewski Jaroslaw , Nowak Karol , Furczynska Patrycja , Zalewska Magdalena
Published: December 2021

Mechanical reperfusion with primary angioplasty, as the treatment of choice in acute myocardial infarction (MI), is associated not only with a high percentage of full epicardial and tissue reperfusion but also with a very good immediate and long-term clinical outcome. However, the Achilles heel of MI treatment is its ensemble of complications, such as cardiogenic shock due to severe systolic and/or diastolic dysfunction or MI mechanical complications, including perforation of the left ventricular free wall, papillary muscle rupture with acute mitral regurgitation and ventricular septal rupture. They are associated with an increased or, sometimes, with an extremely high mortality rate, determining the overall mortality in an MI patient population. In this review we summarize the mechanisms of MI complications, current therapeutic management and alternative directions for overcoming their devastating consequences. Moreover, we have sought to indicate gaps in the evidence on current treatments as the potential targets for further clinical research. From the perspective of mortality trends that are not improving, the forthcoming therapeutic management of complicated MI will require an individualized and novel approach based on their thorough pathobiology.
Anterior Corpectomy and Plating with Carbon-PEEK Instrumentation for Cervical Spinal Metastases: Clinical and Radiological Outcomes
Authors: Trungu Sokol , Ricciardi Luca , Forcato Stefano , Scollato Antonio , Minniti Giuseppe , Miscusi Massimo , Raco Antonino
Published: December 2021

Background: Anterior cervical corpectomy and plating has been recognized as a valuable approach for the surgical treatment of cervical spinal metastases. This study aimed to report the surgical, clinical and radiological outcomes of anterior carbon-PEEK instrumentations for cervical spinal metastases. Methods: Demographical, clinical, surgical and radiological data were collected from 2017 to 2020. The Neck Disability Index (NDI) questionnaire for neck pain, EORTC QLQ-C30 questionnaire for quality of life, Nurick scale for myelopathy and radiological parameters (segmental Cobb angle and cervical lordosis) were collected before surgery, at 6 weeks postoperatively and follow-up. Results: Seventeen patients met inclusion criteria. Mean age was 60.9 ± 7.6 years and mean follow-up was 12.9 ± 4.0 months. The NDI (55.4 ± 11.7 to 25.1 ± 5.4, p < 0.001) scores and the EORTC QLQ-C30 global health/QoL significantly improved postoperatively and at the last follow-up. The segmental Cobb angle (10.7° ± 5.6 to 3.1° ± 2.2, p < 0.001) and cervical lordosis (0.9° ± 6.7 to −6.2 ± 7.8, p = 0.002) significantly improved postoperatively. Only one minor complication (5.9%) was recorded. Conclusions: Carbon/PEEK implants represent a safe alternative to commonly used titanium ones and should be considered in cervical spinal metastases management due to their lower artifacts in postoperative imaging and radiation planning. Further larger comparative and cost-effectiveness studies are needed to confirm these results.
Trueness of Intraoral Scanners in Implant-Supported Rehabilitations: An In Vitro Analysis on the Effect of Operators’ Experience and Implant Number
Authors: Pesce Paolo , Bagnasco Francesco , Pancini Nicolò , Colombo Marco , Canullo Luigi , Pera Francesco , Bressan Eriberto , Annunziata Marco , Menini Maria
Published: December 2021

(1) Background: Intraoral scanners (IOS) are widely used in prosthodontics. However, a good trueness is mandatory to achieve optimal clinical results. The aim of the present in vitro study was to compare two IOS considering the operator’s experience and different implant clinical scenarios. (2) Methods: Two IOS (IT—Itero, Align Technology; and OP—Opera MC, Opera System, Monaco) were compared simulating three different clinical scenarios: single implant, two implants, and full-arch rehabilitation. Ten scans were taken for each configuration by two different operators (one expert, one inexperienced); influence of operator experience and the type of scanner used was investigated. (3) Results: Trueness of the scans differed between the experienced and non-experienced operator and this difference was statistically significant in all the three scenarios (p = 0.000–0.001, 0.037). A significant difference was present between the scanners (p = 0.000), in the two-implant and full-arch scenarios (p = 0.00). (4) Conclusions: Experience of the operator significantly affect trueness of IT and OP scanners. A statistically significant difference was present among IOS in the two-implant and full-arch scenarios.
Additive Manufacturing of Carbon Fiber Reinforced Plastic Composites: The Effect of Fiber Content on Compressive Properties
Authors: Adeniran Olusanmi , Cong Weilong , Bediako Eric , Aladesanmi Victor
Published: December 2021

The additive manufacturing (AM) of carbon fiber reinforced plastic (CFRP) composites continue to grow due to the attractive strength-to-weight and modulus-to-weight ratios afforded by the composites combined with the ease of processibility achievable through the AM technique. Short fiber design factors such as fiber content effects have been shown to play determinant roles in the mechanical performance of AM fabricated CFRP composites. However, this has only been investigated for tensile and flexural properties, with no investigations to date on compressive properties effects of fiber content. This study examined the axial and transverse compressive properties of AM fabricated CFRP composites by testing CF-ABS with fiber contents from 0%, 10%, 20%, and 30% for samples printed in the axial and transverse build orientations, and for axial tensile in comparison to the axial compression properties. The results were that increasing carbon fiber content for the short-fiber thermoplastic CFRP composites slightly reduced compressive strength and modulus. However, it increased ductility and toughness. The 20% carbon fiber content provided the overall content with the most decent compressive properties for the 0–30% content studied. The AM fabricated composite demonstrates a generally higher compressive property than tensile property because of the higher plastic deformation ability which characterizes compression loaded parts, which were observed from the different failure modes.
The Potential of Hsp90 in Targeting Pathological Pathways in Cardiac Diseases
Authors: Roberts Richard J. , Hallee Logan , Lam Chi Keung
Published: December 2021

Heat shock protein 90 (Hsp90) is a molecular chaperone that interacts with up to 10% of the proteome. The extensive involvement in protein folding and regulation of protein stability within cells makes Hsp90 an attractive therapeutic target to correct multiple dysfunctions. Many of the clients of Hsp90 are found in pathways known to be pathogenic in the heart, ranging from transforming growth factor β (TGF-β) and mitogen activated kinase (MAPK) signaling to tumor necrosis factor α (TNFα), Gs and Gq g-protein coupled receptor (GPCR) and calcium (Ca2+) signaling. These pathways can therefore be targeted through modulation of Hsp90 activity. The activity of Hsp90 can be targeted through small-molecule inhibition. Small-molecule inhibitors of Hsp90 have been found to be cardiotoxic in some cases however. In this regard, specific targeting of Hsp90 by modulation of post-translational modifications (PTMs) emerges as an attractive strategy. In this review, we aim to address how Hsp90 functions, where Hsp90 interacts within pathological pathways, and current knowledge of small molecules and PTMs known to modulate Hsp90 activity and their potential as therapeutics in cardiac diseases.
Unraveling the Relationship of Asthma and COVID-19
Authors: Bakakos Agamemnon , Bakakos Petros , Rovina Nikoletta
Published: December 2021

Viral infections are one of the main causes of asthma exacerbations. During the COVID-19 era, concerns regarding the relationship of SARS-CoV2 with asthma have been raised. The concerns are both for COVID severity and asthma exacerbations. Many studies on COVID-19 epidemiology and comorbidities have assessed whether asthma represents a risk factor for SARS-CoV2 infection and/or more severe course of the disease. This review covers the current evidence on the prevalence of asthma in COVID-19 and its association with susceptibility to and severity of SARS-CoV2 infection. It will examine the possible role of underlying asthma severity in COVID-19 related outcomes as well as the molecular mechanisms involved in the co-existence of these entities. The possible role of asthma inflammatory phenotypes will also be evaluated. Finally, the impact of asthma comorbidities and the implications of asthma medication on COVID-19 will be addressed.
Vertical Root Fracture in Non-Endodontically and Endodontically Treated Teeth: Current Understanding and Future Challenge
Authors: Liao Wan-Chuen , Chen Chi-Hung , Pan Yu-Hwa , Chang Mei-Chi , Jeng Jiiang-Huei
Published: December 2021

A vertical root fracture (VRF) is a complex complication that usually leads to tooth extraction. The aim of this article is to review the prevalence, demography, distribution, diagnostic methods, etiology and predisposing factors, clinical features, radiographic characteristics and treatment strategies of VRFs in non-endodontically treated teeth (VRFNETT) and endodontically treated teeth (VRFETT). Search terms for each subject related to VRFNETT and VRFETT were entered into MEDLINE, PubMed and Google Scholar. Systematic reviews, retrospective cohort studies, demographic research, clinical studies, case reports and case series were reviewed. Most of the VRFs were found in patients older than 40 years old. Older populations were discovered in the non-endodontically treated VRF group when compared to the endodontically treated VRF group. Male patients were found at a greater prevalence than females in the non-endodontically treated VRF group. The initial occurrence of a VRF may accompany radiolucent lines within the root canal, unusual space between the canal wall and intracanal material, a widening of the PDL space along the periradicular surfaces, angular bony destruction, step-like bone defects, V-shaped diffuse bone defects, or root resorptions corresponding to the fracture line before the clear separation of the fractured fragment. The indicative clinical and radiographic signs of VRF included a coronally positioned sinus tract, deep-narrow periodontal defects, the displacement of a fractured fragment, periradicular radiolucent halos and the widening of the root canal space. Interestingly, VRFNETT are more often observed in the Chinese population. Some patients with multiple VRFs were observed, suggesting possible predisposing factors in genetics and tooth development. The management of a VRF usually involves a multidisciplinary approach. The common distribution and features of VRFNETT and VRFETT were elucidated to facilitate recognition and diagnosis. Besides extraction, variable therapeutic schemes, such as the repair of the VRF, root amputation and others reported in earlier literature, are available. A long-term prognosis study of the various therapeutic strategies is needed.
Prediction of Real-World Long-Term Outcomes of People with CF Homozygous for the F508del Mutation Treated with CFTR Modulators
Authors: Muilwijk Danya , Bierlaagh Marlou , van Mourik Peter , Kraaijkamp Jasmijn , van der Meer Renske , van den Bor Rutger , Heijerman Harry , Eijkemans René , Beekman Jeffrey , van der Ent Kors
Published: December 2021

The clinical response to cystic fibrosis transmembrane conductance regulator (CFTR) modulators is variable within people with cystic fibrosis (pwCF) homozygous for the F508del mutation. The prediction of clinical effect in individual patients would be useful to target therapy to those who would benefit from it. A multicenter observational cohort study was conducted including 97 pwCF (F508del/F508del), who started lumacaftor/ivacaftor (LUM/IVA) treatment before June 2018. In order to assess the associations of individual in vivo and in vitro biomarkers with clinical outcomes, we collected clinical data regarding sex, age, and sweat chloride concentration (SwCl) at baseline and after six months of LUM/IVA; the percent predicted forced expiratory volume in 1 s (ppFEV1) and the number of pulmonary exacerbations (PEx) during the three years before up to three years after modulator initiation; and the forskolin-induced swelling (FIS) responses to LUM/IVA, quantified in intestinal organoids. On a group level, the results showed an acute change in ppFEV1 after LUM/IVA initiation (2.34%, 95% CI 0.85–3.82, p = 0.003), but no significant change in annual ppFEV1 decline in the three years after LUM/IVA compared to the three years before (change: 0.11% per year, 95%CI: −1.94–2.19, p = 0.913). Neither of these two outcomes was associated with any of the candidate predictors on an individual level. The median number of pulmonary exacerbations (PEx) per patient year did not significantly change in the three years after LUM/IVA compared to the years before (median: 0.33/patient year, IQR: 0–0.67 before vs. median: 0/patient year, IQR: 0–0.67 after p = 0. 268). The PEx rate after modulator initiation was associated with the PEx rate before (IRR: 2.26, 95%CI: 1.67–3.08, p < 0.001), with sex (males vs. females IRR: 0.36, 95%CI: 0.21–0.63, p = 0.001) and with sweat chloride concentration (SwCl) at baseline (IRR: 0.96, 95%CI: 0.94–0.98, p = 0.001). The change in SwCl was also significant (−22.9 mmol/L (95%CI: −27.1–−18.8, p < 0.001) and was associated with SwCl at baseline (−0.64, 95%CI: −0.90–−0.37, p < 0.001) and with sex (males vs. females 8.32, 95%CI: 1.82–14.82, p = 0.013). In conclusion, ppFEV1 decline after CFTR modulator initiation remains difficult to predict in individual patients in a real-world setting, with limited effectiveness for double CFTR modulator therapies. The PEx rate prior to CFTR modulator treatment initiation, sex and SwCl at baseline could be potential predictors of long-term PEx rate and of changes in SwCl after modulator initiation.
Association of Polymorphisms in Plasminogen Activator Inhibitor-1 (PAI-1), Tissue Plasminogen Activator (tPA), and Renin (REN) with Recurrent Pregnancy Loss in Korean Women
Authors: Cho Hee Young , Park Han Sung , Ahn Eun Hee , Ko Eun Ju , Park Hyeon Woo , Kim Young Ran , Kim Ji Hyang , Lee Woo Sik , Kim Nam Keun
Published: December 2021

Recurrent pregnancy loss (RPL) is defined as two or more consecutive pregnancy losses prior to 20 weeks of gestational age. Various factors, including immune dysfunction, endocrine disorders, coagulation abnormality, and genetic disorders influence RPL. In particular, plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), and renin (REN) have important roles in the thrombotic and thrombolytic systems, and abnormal expression of these genes have a reported negative correlation with pregnancy maintenance. Moreover, some polymorphisms of the three genes are related to expression levels and thrombotic disorder. Therefore, we investigated whether polymorphisms of PAI-1, tPA, and REN are linked to RPL. Genotyping of the six polymorphisms (PAI-1 rs11178, rs1050955, tPA rs4646972, rs2020918, REN rs1464816, and rs5707) was performed using polymerase chain reaction (PCR)-restriction fragment length polymorphism and associations of the polymorphisms with RPL were evaluated by statistical analysis. The polymorphism PAI-1 rs1050955 GA+AA was associated with decreased RPL risk (AOR, 0.528; 95% CI 0.356–0.781; p = 0.001) as was the REN 10795 rs5707 GG genotype (AOR, 0.487; 95% CI 0.301–0.787; p = 0.003). In contrast, the tPA rs4646972 II genotype correlated with increased RPL risk (AOR, 1.606; 95% CI, 1.047–2.463; p = 0.030). This study provides evidence that tPA Alu rs4646972 may contribute to the risk of idiopathic RPL, but PAI-1 12068 rs1050955 and REN 10795 rs5707 are associated with a decreased risk of RPL. Therefore, these alleles may be useful as biomarkers to evaluate the risk of RPL.
Investigating the Effect of Disturbance on Prey Consumption in Captive Congo Caecilians Herpele squalostoma
Authors: Carter Kimberley C. , Fieschi-Méric Léa , Servini Francesca , Wilkinson Mark , Gower David J. , Tapley Benjamin , Michaels Christopher J.
Published: December 2021

Maintaining Gymnophiona in captivity provides opportunities to study the behaviour and life-history of this poorly known Order, and to investigate and provide species-appropriate welfare guidelines, which are currently lacking. This study focuses on the terrestrial caecilian Herpele squalostoma to investigate its sensitivity to disturbances associated with routine husbandry needed for monitoring and maintaining adequate wellbeing in captivity. Fossorial caecilians gradually pollute their environment in captivity with waste products, and substrate must be replaced at intervals; doing so disturbs the animals directly and via destruction of burrow networks. As inappetence is frequently associated with stress in amphibians, the percentage consumption of offered food types, river shrimp (Palaemon varians) and brown crickets (Gryllus assimilis), was measured as an indicator of putative stress following three routine substrate changes up to 297 days post-substrate change. Mean daily variation in substrate temperatures were also recorded in order to account for environmental influences on food consumption, along with nitrogenous waste in tank substrate prior to a substrate change and fresh top soil in order to understand the trade-off between dealing with waste accumulation and disturbing animals. We found a significant negative effect of substrate disturbance on food intake, but no significant effect of prey type. Variations in daily soil temperatures did not have a significant effect on food intake, but mean substrate temperature did. Additionally, substrate nitrogenous waste testing indicated little difference between fresh and tank substrate. In conclusion, this study provides a basis from which to develop further welfare assessment for this and other rarely kept and rarely observed terrestrial caecilian species.
Identification of Regional Drought Processes in North China Using MCI Analysis
Authors: Cai Xiuhua , Zhang Wenqian , Fang Xiaoyi , Zhang Qiang , Zhang Cunjie , Chen Dong , Cheng Chen , Fan Wenjie , Yu Ying
Published: December 2021

Comprehensive identification of drought events is of great significance for monitoring and evaluating drought processes. Based on the date of daily precipitation, temperature and drought-affected area of 403 meteorological stations in North China from 1960 to 2019, the Comprehensive Drought Process Intensity Index (CDPII) has been developed by using the Meteorological-drought Composite Index (MCI) and regional drought process identification method, as well as the EIDR theory method. The regional drought processes in the past 60 years in North China, including Beijing, Tianjin, Hebei, Shanxi and Middle Inner Mongolia, were analyzed and identified. The result shows that the distribution characteristic of droughts with different intensities is as follows: The number of days of all annual-average mild droughts, moderate droughts and severe droughts was highest in Tianjin and that of extreme droughts was highest in Shanxi. The number of days of mild droughts was highest in May and lowest in January. The number of days of moderate droughts was highest in June. The number of days with mild and moderate drought showed an overall increasing trend, while the number of days with severe drought and above showed an overall decreasing trend (through a 95% significance test). The number of drought days was the highest in the 1990s. The annual frequency of drought is between 66.7% and 86.7%; the drought frequency in Hebei is the highest at 86.7%, followed by Beijing at 80%. There were 75 regional drought processes in North China from 1960 to 2019, and the correlation coefficient between process intensity and the drought-affected area was 0.55, which passed the 99% significance test. The comprehensive intensity of drought process from 27 April to 1 September 1972 was the strongest. From 18 May to 31 October 1965, the drought lasted 167 days. The overall drought intensity had a slight weakening trend in the past 60 years. A total of 75 regional drought processes occurred in North China, and the process intensity showed a trend of wavy decline with a determination coefficient (R2) of 0.079 (95% significance test). Overall, the regional drought process identification method and strength assessment result tally with the drought disaster, which can better identify the regional drought process. Furthermore, including the last days, the average intensity, average scope comprehensive strength, there are many angles to monitor and evaluate the drought and drought process. These provide a reference for drought control and decision-making.
A Robotic Milling System Based on 3D Point Cloud
Authors: Gao Yongzhuo , Gao Haibo , Bai Kunpeng , Li Mingyang , Dong Wei
Published: December 2021

Industrial robots have advantages in the processing of large-scale components in the aerospace industry. Compared to CNC machine tools, robot arms are cheaper and easier to deploy. However, due to the poor consistency of incoming materials, large-scale and lightweight components make it difficult to automate robotic machining. In addition, the stiffness of the tandem structure is quite low. Therefore, the stability of the milling process is always a concern. In this paper, the robotic milling research is carried out for the welding pre-processing technology of large-scale components. In order to realize the automatic production of low-conformity parts, the on-site measurement–planning–processing method is adopted with the laser profiler. On the one hand, the laser profiler hand–eye calibration method is optimized to improve the measurement accuracy. On the other hand, the stiffness of the robot’s processing posture is optimized, combined with the angle of the fixture turntable. Finally, the experiment shows the feasibility of the on-site measurement–planning–processing method and verifies the correctness of the stiffness model.
Physical and Mechanical Properties Evolution of Coal Subjected to Salty Solution and a Damage Constitutive Model under Uniaxial Compression
Authors: Wang Min , Guo Qifeng , Tian Yakun , Dai Bing
Published: December 2021

Many underground reservoirs for storing water have been constructed in China’s western coal mines to protect water resources. Coal pillars which work as dams are subjected to a long-term soaking environment of concentrated salty water. Deterioration of the coal dam under the attack of the salty solution poses challenges for the long-term stability and serviceability of underground reservoirs. The evolution of the physical and mechanical properties of coal subjected to salty solutions are investigated in this paper. Coal from a western China mine is made to standard cylinder samples. The salty solution is prepared according to chemical tests of water in the mine. The coal samples soaked in the salty solution for different periods are tested by scanning electron microscope, nuclear magnetic resonance, and ultrasonic detector techniques. Further, uniaxial compression tests are carried out on the coal specimens. The evolutions of porosity, mass, microstructures of coal, solution pH values, and stress–strain curves are obtained for different soaking times. Moreover, a damage constitutive model for the coal samples is developed by introducing a chemical-stress coupling damage variable. The result shows that the corrosion effect of salty solution on coal samples becomes stronger with increasing immersion time. The degree of deterioration of the longitudinal wave velocity (vp) is positively correlated with the immersion time. With the increase in soaking times, the porosity of coal gradually increases. The relative mass firstly displays an increasing trend and then decreases with time. The peak strength and elastic modulus of coal decreases exponentially with soaking times. The developed damage constitutive model can well describe the stress–strain behavior of coal subjected to salty solution under the uniaxial compression.