bluuebunny/crossref_metadata_2025 huggingface dataset:
RNF11 at the Crossroads of Protein Ubiquitination
Authors: Mattioni Anna , Castagnoli Luisa , Santonico Elena
Published: November 2020

RNF11 (Ring Finger Protein 11) is a 154 amino-acid long protein that contains a RING-H2 domain, whose sequence has remained substantially unchanged throughout vertebrate evolution. RNF11 has drawn attention as a modulator of protein degradation by HECT E3 ligases. Indeed, the large number of substrates that are regulated by HECT ligases, such as ITCH, SMURF1/2, WWP1/2, and NEDD4, and their role in turning off the signaling by ubiquitin-mediated degradation, candidates RNF11 as the master regulator of a plethora of signaling pathways. Starting from the analysis of the primary sequence motifs and from the list of RNF11 protein partners, we summarize the evidence implicating RNF11 as an important player in modulating ubiquitin-regulated processes that are involved in transforming growth factor beta (TGF-β), nuclear factor-κB (NF-κB), and Epidermal Growth Factor (EGF) signaling pathways. This connection appears to be particularly significant, since RNF11 is overexpressed in several tumors, even though its role as tumor growth inhibitor or promoter is still controversial. The review highlights the different facets and peculiarities of this unconventional small RING-E3 ligase and its implication in tumorigenesis, invasion, neuroinflammation, and cancer metastasis.
T Cells Subsets in the Immunopathology and Treatment of Sjogren’s Syndrome
Authors: Ríos-Ríos William de Jesús , Sosa-Luis Sorely Adelina , Torres-Aguilar Honorio
Published: November 2020

Sjogren’s syndrome (SS) is an autoimmune disease whose pathogenesis is characterized by an exacerbated T cell infiltration in exocrine glands, markedly associated to the inflammatory and detrimental features as well as the disease progression. Several helper T cell subsets sequentially converge at different stages of the ailment, becoming involved in specific pathologic roles. Initially, their activated phenotype endows them with high migratory properties and increased pro-inflammatory cytokine secretion in target tissues. Later, the accumulation of immunomodulatory T cells-derived factors, such as IL-17, IFN-γ, or IL-21, preserve the inflammatory environment. These effects favor strong B cell activation, instigating an extrafollicular antibody response in ectopic lymphoid structures mediated by T follicular helper cells (Tfh) and leading to disease progression. Additionally, the memory effector phenotype of CD8+ T cells present in SS patients suggests that the presence of auto-antigen restricted CD8+ T cells might trigger time-dependent and specific immune responses. Regarding the protective roles of traditional regulatory T cells (Treg), uncertain evidence shows decrease or invariable numbers of circulating and infiltrating cells. Nevertheless, an emerging Treg subset named follicular regulatory T cells (Tfr) seems to play a critical protective role owing to their deficiency that enhances SS development. In this review, the authors summarize the current knowledge of T cells subsets contribution to the SS immunopathology, focusing on the cellular and biomolecular properties allowing them to infiltrate and to harm target tissues, and that simultaneously make them key therapeutic targets for SS treatment.
Adenoviral E1A Exploits Flexibility and Disorder to Target Cellular Proteins
Authors: Murrali Maria Grazia , Felli Isabella C. , Pierattelli Roberta
Published: November 2020

Direct interaction between intrinsically disordered proteins (IDPs) is often difficult to characterize hampering the elucidation of their binding mechanism. Particularly challenging is the study of fuzzy complexes, in which the intrinsically disordered proteins or regions retain conformational freedom within the assembly. To date, nuclear magnetic resonance spectroscopy has proven to be one of the most powerful techniques to characterize at the atomic level intrinsically disordered proteins and their interactions, including those cases where the formed complexes are highly dynamic. Here, we present the characterization of the interaction between a viral protein, the Early region 1A protein from Adenovirus (E1A), and a disordered region of the human CREB-binding protein, namely the fourth intrinsically disordered linker CBP-ID4. E1A was widely studied as a prototypical viral oncogene. Its interaction with two folded domains of CBP was mapped, providing hints for understanding some functional aspects of the interaction with this transcriptional coactivator. However, the role of the flexible linker connecting these two globular domains of CBP in this interaction was never explored before.
Generation and Application of the Zebrafish heg1 Mutant as a Cardiovascular Disease Model
Authors: Lu Shuxian , Hu Mengyan , Wang Zhihao , Liu Hongkai , Kou Yao , Lyu Zhaojie , Tian Jing
Published: November 2020

Cardiovascular disease (CVD) is the leading cause of global mortality, which has caused a huge burden on the quality of human life. Therefore, experimental animal models of CVD have become essential tools for analyzing the pathogenesis, developing drug screening, and testing potential therapeutic strategies. In recent decades, zebrafish has entered the field of CVD as an important model organism. HEG1, a heart development protein with EGF like domains 1, plays important roles in the development of vertebrate cardiovascular system. Loss of HEG1 will affect the stabilization of vascular endothelial cell connection and eventually lead to dilated cardiomyopathy (DCM). Here, we generated a heg1-specific knockout zebrafish line using CRISPR/Cas9 technology. Zebrafish heg1 mutant demonstrated severe cardiovascular malformations, including atrial ventricular enlargement, heart rate slowing, venous thrombosis and slow blood flow, which were similar to human heart failure and thrombosis phenotype. In addition, the expression of zebrafish cardiac and vascular markers was abnormal in heg1 mutants. In order to apply zebrafish heg1 mutant in cardiovascular drug screening, four Traditional Chinese Medicine (TCM) herbs and three Chinese herbal monomers were used to treat heg1 mutant. The pericardial area, the distance between sinus venosus and bulbus arteriosus (SV-BA), heart rate, red blood cells (RBCs) accumulation in posterior cardinal vein (PCV), and blood circulation in the tail vein were measured to evaluate the therapeutic effects of those drugs on DCM and thrombosis. Here, a new zebrafish model of DCM and thrombosis was established, which was verified to be suitable for drug screening of cardiovascular diseases. It provided an alternative method for traditional in vitro screening, and produced potential clinical related drugs in a rapid and cost-effective way.
Mitochondrial Carriers Regulating Insulin Secretion Profiled in Human Islets upon Metabolic Stress
Authors: Jimenez-Sánchez Cecilia , Brun Thierry , Maechler Pierre
Published: November 2020

Chronic exposure of β-cells to nutrient-rich metabolic stress impairs mitochondrial metabolism and its coupling to insulin secretion. We exposed isolated human islets to different metabolic stresses for 3 days: 0.4 mM oleate or 0.4 mM palmitate at physiological 5.5 mM glucose (lipotoxicity), high 25 mM glucose (glucotoxicity), and high 25 mM glucose combined with 0.4 mM oleate and/or palmitate (glucolipotoxicity). Then, we profiled the mitochondrial carriers and associated genes with RNA-Seq. Diabetogenic conditions, and in particular glucotoxicity, increased expression of several mitochondrial solute carriers in human islets, such as the malate carrier DIC, the α-ketoglutarate-malate exchanger OGC, and the glutamate carrier GC1. Glucotoxicity also induced a general upregulation of the electron transport chain machinery, while palmitate largely counteracted this effect. Expression of different components of the TOM/TIM mitochondrial protein import system was increased by glucotoxicity, whereas glucolipotoxicity strongly upregulated its receptor subunit TOM70. Expression of the mitochondrial calcium uniporter MCU was essentially preserved by metabolic stresses. However, glucotoxicity altered expression of regulatory elements of calcium influx as well as the Na+/Ca2+ exchanger NCLX, which mediates calcium efflux. Overall, the expression profile of mitochondrial carriers and associated genes was modified by the different metabolic stresses exhibiting nutrient-specific signatures.
Identification of Functional Single Nucleotide Polymorphisms in Porcine HSD17B14 Gene Associated with Estrus Behavior Difference between Large White and Mi Gilts
Authors: Gao Siyuan , Tao Ruixin , Tong Xian , Xu Qinglei , Zhao Jing , Guo Yanli , Schinckel Allan P. , Zhou Bo
Published: November 2020

Steroid hormone levels are associated with estrous behavior, which affects timely mating and reproductive efficiency in pigs. 17β-hydroxysteroid dehydrogenase type 14 (HSD17B14) modulates steroid synthesis and metabolism. To identify the functional single nucleotide polymorphisms (SNPs) in the porcine HSD17B14 gene, ear tissues from Large White and Mi gilts were collected to extract genomic DNA. Variable lengths of truncated promoter of HSD17B14 gene were used to determine the promoter activity by a dual luciferase reporter system. The vector HSD17B14Phe or HSD17B14Val was transfected into porcine granulosa cells (GCs). The core promoter region was identified between −72 bp and −218 bp. Six of seven SNPs had significant differences of allele frequency between Large White and Mi gilts. The plasmids with the wild genotype AA of rs329427898 maintained a smaller fraction of promoter activity compared with the plasmids with the mutant genotype GG, while the plasmids with wild the genotype TT of rs319864566 had a greater promoter activity than the plasmids with the mutant genotype CC. A missense mutation (Phe73Val) caused changes in the structural dynamics and function of the HSD17B14 protein. The highly expressed HSD17B14Val degraded less estradiol into estrone, while the relatively lowly expressed HSD17B14Phe degraded more estradiol into estrone, suggesting the protein activity of HSD17B14Phe was greater than that of HSD17B14Val. Moreover, the HSD17B14Phe group has a greater apoptosis rate of porcine GCs. The HSD17B14 gene could been used as a candidate molecular marker for estrus behavior in pigs.
Design and Engineering of Deimmunized Vaccinia Viral Vectors
Authors: Song Kevin , Viskovska Mariya
Published: November 2020

Vaccinia viral (VV) vectors are increasingly used in oncolytic virus therapy and vaccine development for cancer and infectious diseases. However, their effectiveness is hindered by the strong anti-viral immune response induced by the viral vector. In this review, we discuss the strategies to deimmunize vaccinia viral vector. One approach is to mask the virus from the neutralization antibody responses by mapping and eliminating of B-cell epitopes on the viral membrane proteins. The recombinant VVs contain one or more viral glycoproteins with mutations in the neutralizing antibody epitopes, resulting in viral escape from neutralization. In addition, a regulator of complement activation (e.g., CD55) can be expressed on the surface of the virus particle, leading to increased resistance to complement-mediated neutralization.
Current Evidence and Limitation of Biomarkers for Detecting Sepsis and Systemic Infection
Authors: Hung Shang-Kai , Lan Hao-Min , Han Shih-Tsung , Wu Chin-Chieh , Chen Kuan-Fu
Published: November 2020

Sepsis was recently redefined as a life-threatening disease involving organ dysfunction caused by a dysregulated host response to infection. Biomarkers play an important role in early detection, diagnosis, and prognostication. We reviewed six promising biomarkers for detecting sepsis and systemic infection, including C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), CD64, presepsin, and sTREM-1. Among the recent studies, we found the following risks of bias: only a few studies adopted the random or consecutive sampling strategy; extensive case-control analysis, which worsened the over-estimated performance; most of the studies used post hoc cutoff values; and heterogeneity with respect to the inclusion criteria, small sample sizes, and different quantitative synthesis methods applied in meta-analyses. We recommend that CD64 and presepsin should be considered as the most promising biomarkers for diagnosing sepsis. Future studies should enroll a larger sample size with a cohort rather than a case-control study design. A random or consecutive study design with a pre-specified laboratory threshold, consistent sampling timing, and an updated definition of sepsis will also increase the reliability of the studies. Further investigations of appropriate specimens, testing assays, and cutoff levels for specific biomarkers are also warranted.
Cardiomyopathies and Arrhythmias Induced by Cancer Therapies
Authors: Romitan Dragoș-Mihai , Rădulescu Dan , Berindan-Neagoe Ioana , Stoicescu Laurențiu , Grosu Alin , Rădulescu Liliana , Gulei Diana , Ciuleanu Tudor-Eliade
Published: November 2020

Cardiology and oncology are two fields dedicated to the study of various types of oncological and cardiac diseases, but when they collide, a new specialty is born, i.e., cardio-oncology. Continuous research on cancer therapy has brought into the clinic novel therapeutics that have significantly improved patient survival. However, these therapies have also been associated with adverse effects that can impede the proper management of oncological patients through the necessity of drug discontinuation due to life-threatening or long-term morbidity risks. Cardiovascular toxicity from oncological therapies is the main issue that needs to be solved. Proper knowledge, interpretation, and management of new drugs are key elements for developing the best therapeutic strategies for oncological patients. Upon continuous investigations, the profile of cardiotoxicity events has been enlarged with the inclusion of myocarditis upon administration of immune checkpoint inhibitors and cardiac dysfunction in the context of cytokine release syndrome with chimeric antigen receptor T cell therapy. Affinity enhanced and chimeric antigen receptor T cells have both been associated with hypotension, arrhythmia, and left ventricular dysfunction, typically in the setting of cytokine release syndrome. Therefore, the cardiologist must adhere to the progressing field of cancer therapy and become familiar with the adverse effects of novel drugs, and not only the ones of standard care, such as anthracycline, trastuzumab, and radiation therapy. The present review provides essential information summarized from the latest studies from cardiology, oncology, and hematology to bring together the three specialties and offers proper management options for oncological patients.
Memory Traces Formed in Utero—Newborns’ Autonomic and Neuronal Responses to Prenatal Stimuli and the Maternal Voice
Authors: Lang Adelheid , Ott Peter , del Giudice Renata , Schabus Manuel
Published: November 2020

In our pilot study, we exposed third-trimester fetuses, from week 34 of gestation onwards, twice daily to a maternal spoken nursery rhyme. Two and five weeks after birth, 34 newborns, who were either familiarized with rhyme stimulation in utero or stimulation naïve, were (re-)exposed to the familiar, as well as to a novel and unfamiliar, rhyme, both spoken with the maternal and an unfamiliar female voice. For the stimulation-naïve group, both rhymes were unfamiliar. During stimulus presentation, heart rate activity and high-density electroencephalography were collected and newborns’ responses during familiar and unfamiliar stimulation were analyzed. All newborns demonstrated stronger speech–brain coupling at 1 Hz during the presentation of the maternal voice vs. the unfamiliar female voice. Rhyme familiarity originating from prenatal exposure had no effect on speech–brain coupling in experimentally stimulated newborns. Furthermore, only stimulation-naïve newborns demonstrated an increase in heart rate during the presentation of the unfamiliar female voice. The results indicate prenatal familiarization to auditory speech and point to the specific significance of the maternal voice already in two- to five-week-old newborns.
Caenorhabditis elegans Models to Investigate the Mechanisms Underlying Tau Toxicity in Tauopathies
Authors: Natale Carmina , Barzago Maria Monica , Diomede Luisa
Published: November 2020

The understanding of the genetic, biochemical, and structural determinants underlying tau aggregation is pivotal in the elucidation of the pathogenic process driving tauopathies and the design of effective therapies. Relevant information on the molecular basis of human neurodegeneration in vivo can be obtained using the nematode Caenorhabditis elegans (C. elegans). To this end, two main approaches can be applied: the overexpression of genes/proteins leading to neuronal dysfunction and death, and studies in which proteins prone to misfolding are exogenously administered to induce a neurotoxic phenotype. Thanks to the easy generation of transgenic strains expressing human disease genes, C. elegans allows the identification of genes and/or proteins specifically associated with pathology and the specific disruptions of cellular processes involved in disease. Several transgenic strains expressing human wild-type or mutated tau have been developed and offer significant information concerning whether transgene expression regulates protein production and aggregation in soluble or insoluble form, onset of the disease, and the degenerative process. C. elegans is able to specifically react to the toxic assemblies of tau, thus developing a neurodegenerative phenotype that, even when exogenously administered, opens up the use of this assay to investigate in vivo the relationship between the tau sequence, its folding, and its proteotoxicity. These approaches can be employed to screen drugs and small molecules that can interact with the biogenesis and dynamics of formation of tau aggregates and to analyze their interactions with other cellular proteins.
Clozapine: An Updated Overview of Pharmacogenetic Biomarkers, Risks, and Safety—Particularities in the Context of COVID-19
Authors: Dragoi Ana , Radulescu Ioana , Năsui Bogdana , Pop Anca , Varlas Valentin , Trifu Simona
Published: November 2020

Background: clozapine (CLZ) use is precarious due to its neurological, cardiovascular, and hematological side effects; however, it is the gold standard in therapy-resistant schizophrenia (TRS) in adults and is underused. Objective: to examine the most recent CLZ data on (a) side effects concerning (b) recent pharmacological mechanisms, (c) therapy benefits, and (d) the particularities of the COVID-19 pandemic. Data sources: a search was performed in two databases (PubMed and Web of Science) using the specific keywords “clozapine” and “schizophrenia”, “side effects”, “agranulocytosis”, “TRS”, or “bipolar affective disorder (BAF)” for the last ten years. Study eligibility criteria: clinical trials on adults with acute symptoms of schizophrenia or related disorders. Results: we selected 37 studies, randomized controlled trials (RCTs), and clinical case series (CCS), centered on six main topics in the search area: (a) CLZ in schizophrenia, (b) CLZ in bipolar disorder, (c) side effects during the clozapine therapy, (d) CLZ in pregnancy, (e) CLZ in early-onset schizophrenia, and (f) CLZ therapy and COVID-19 infection. Limitations: we considered RCTs and CCS from two databases, limited to the search topics. Conclusions and implications of key findings: (a) clozapine doses should be personalized for each patient based on pharmacogenetics testing when available; the genetic vulnerability postulates predictors of adverse reactions’ severity; patients with a lower genetic risk could have less frequent hematological monitoring; (b) a CLZ-associated risk of pulmonary embolism imposes prophylactic measures for venous thromboembolism; (c) convulsive episodes are not an indication for stopping treatment; the plasma concentration of clozapine is a better side effect predictor than the dosage; (d) COVID-19 infection may enhance clozapine toxicity, generating an increased risk of pneumonia. Therapy must be continued with the proper monitoring of the white blood count, and the clozapine dose decreased by half until three days after the fever breaks; psychiatrists and healthcare providers must act together.
Effects of tDCS on Tactile Perception Depend on Tactile Expertise in Both Musicians and Non-Musicians
Authors: Godde Ben , Dadashev Lev , Karim Ahmed A.
Published: November 2020

Brain plasticity in the somatosensory cortex and tactile performance can be facilitated by brain stimulation. Here, we investigated the effects of transcranial direct current stimulation (tDCS) on tactile perception in musicians and non-musicians to elucidate how tDCS-effects might depend on tactile expertise. On three separate days, 17 semi-professional musicians (e.g., piano or violin players) and 16 non-musicians aged 18–27 years received 15 min of 1 mA anodal (a-tDCS), cathodal (c-tDCS) or sham tDCS in a pseudorandomized design. Pre and post tDCS, tactile sensitivity (Touch Detection Task; TDT) and discrimination performance (Grating Orientation Task; GOT) were assessed. For further analysis, the weekly hours of instrument-playing and computer-typing were combined into a “tactile experience” variable. For GOT, but not TDT, a significant group effect at baseline was revealed with musicians performing better than non-musicians. TDT thresholds were significantly reduced after a-tDCS but not c-tDCS or sham stimulation. While both musicians’ and non-musicians’ performance improved after anodal stimulation, neither musical nor tactile expertise was directly associated with the magnitude of this improvement. Low performers in TDT with high tactile experience profited most from a-tDCS. We conclude that tactile expertise may facilitate somatosensory cortical plasticity and tactile learning in low performers.
Neuroprognostication of Consciousness Recovery in a Patient with COVID-19 Related Encephalitis: Preliminary Findings from a Multimodal Approach
Authors: Sangare Aude , Dong Anceline , Valente Melanie , Pyatigorskaya Nadya , Cao Albert , Altmayer Victor , Zyss Julie , Lambrecq Virginie , Roux Damien , Morlon Quentin , Perez Pauline , Ben Salah Amina , Virolle Sara , Puybasset Louis , Sitt Jacobo D , Rohaut Benjamin , Naccache Lionel
Published: November 2020

Predicting the functional recovery of patients with severe neurological condition due to coronavirus disease 2019 (COVID-19) is a challenging task. Only limited outcome data are available, the pathophysiology is poorly understood, and the time-course of recovery is still largely unknown. Here, we report the case of a patient with COVID-19 associated encephalitis presenting as a prolonged state of unresponsiveness for two months, who finally fully recovered consciousness, functional communication, and autonomy after immunotherapy. In a multimodal approach, a high-density resting state EEG revealed a rich brain activity in spite of a severe clinical presentation. Using our previously validated algorithms, we could predict a possible improvement of consciousness in this patient. This case report illustrates the value of a multimodal approach capitalizing on advanced brain-imaging and bedside electrophysiology techniques to improve prognosis accuracy in this complex and new aetiology.
Anxiety Regulation: From Affective Neuroscience to Clinical Practice
Authors: Grecucci Alessandro , Sığırcı Hüseyin , Lapomarda Gaia , Amodeo Letizia , Messina Irene , Frederickson Jon
Published: November 2020

According to psychoanalysis, anxiety signals a threat whenever a forbidden feeling emerges. Anxiety triggers defenses and maladaptive behaviors, thus leading to clinical problems. For these reasons, anxiety regulation is a core aspect of psychodynamic-oriented treatments to help clients. In the present theoretical paper, we review and discuss anxiety generation and dysregulation, first from a neural point of view, presenting findings from neuroimaging and psychophysiological studies. The aim is to trace parallels with psychodynamic theories of anxiety. Then, we discuss the psychological mechanisms and neural bases of emotion regulation in the laboratory, and possible neurobiological mechanisms of anxiety regulation in psychotherapy. We describe two different approaches to emotion/anxiety regulation, one based on the standard cognitive model of emotion regulation, the other based on psychodynamic principles and affective neuroscience. We then illustrate in detail a dynamic experiential approach to regulation. This model claims that emotions arise before cognition and are not inherently dysregulated. Dysregulation emerges from co-occurrences of emotions and associated anxiety. Technical consequences of this model are discussed and include strategies to regulate anxiety.
Efficacy of Deep Brain Stimulation on the Improvement of the Bladder Functions in Traumatic Brain Injured Rats
Authors: Praveen Rajneesh Chellappan , Liou Jian-Chiun , Hsieh Tsung-Hsun , Chin Hung-Yen , Peng Chih-Wei
Published: November 2020

Objective: Traumatic brain injuries (TBIs) are a prime public health challenge with a high incidence of mortality, and also reflect severe economic impacts. One of their severe symptoms is bladder dysfunction. Conventional therapeutic methods are not effective in managing bladder dysfunction. Henceforth, a research endeavor was attempted to explore a new therapeutic approach for bladder dysfunction through deep brain stimulation (DBS) procedures in a TBI animal model. Methods: TBI in this animal model was induced by the weight-drop method. All rats with an induced TBI were housed for 4 weeks to allow severe bladder dysfunction to develop. Subsequently, an initial urodynamic measurement, the simultaneous recording of cystometric (CMG) and external urethral sphincter electromyography (EUS-EMG) activity was conducted to evaluate bladder function. Further, standard DBS procedures with varying electrical stimulation parameters were executed in the target area of the pedunculopontine tegmental nucleus (PPTg). Simultaneously, urodynamic measurements were re-established to compare the effects of DBS interventions on bladder functions. Results: From the variable combinations of electrical stimulation, DBS at 50 Hz and 2.0 V, significantly reverted the voiding efficiency from 39% to 69% in TBI rats. Furthermore, MRI studies revealed the precise localization of the DBS electrode in the target area. Conclusions: The results we obtained showed an insightful understanding of PPTg-DBS and its therapeutic applications in alleviating bladder dysfunction in rats with a TBI. Hence, the present study suggests that PPTg-DBS is an effective therapeutic strategy for treating bladder dysfunction.
Proximal Protein Interaction Landscape of RAS Paralogs
Authors: Béganton Benoît , Coyaud Etienne , Laurent Estelle M. N. , Mangé Alain , Jacquemetton Julien , Le Romancer Muriel , Raught Brian , Solassol Jérôme
Published: November 2020

RAS proteins (KRAS, NRAS and HRAS) are frequently activated in different cancer types (e.g., non-small cell lung cancer, colorectal cancer, melanoma and bladder cancer). For many years, their activities were considered redundant due to their high degree of sequence homology (80% identity) and their shared upstream and downstream protein partners. However, the high conservation of the Hyper-Variable-Region across mammalian species, the preferential activation of different RAS proteins in specific tumor types and the specific post-translational modifications and plasma membrane-localization of each paralog suggest they could ensure discrete functions. To gain insights into RAS proteins specificities, we explored their proximal protein–protein interaction landscapes using the proximity-dependent biotin identification technology (BioID) in Flp-In T-REx 293 cell lines stably transfected and inducibly expressing wild type KRAS4B, NRAS or HRAS. We identified more than 800 high-confidence proximal interactors, allowing us to propose an unprecedented comparative analysis of wild type RAS paralogs protein networks. These data bring novel information on poorly characterized RAS functions, e.g., its putative involvement in metabolic pathways, and on shared as well as paralog-specific protein networks that could partially explain the complexity of RAS functions. These networks of protein interactions open numerous avenues to better understand RAS paralogs biological activities.
Hitting the Target but Missing the Point: Recent Progress towards Adenovirus-Based Precision Virotherapies
Authors: Cunliffe Tabitha G. , Bates Emily A. , Parker Alan L.
Published: November 2020

More people are surviving longer with cancer. Whilst this can be partially attributed to advances in early detection of cancers, there is little doubt that the improvement in survival statistics is also due to the expansion in the spectrum of treatments available for efficacious treatment. Transformative amongst those are immunotherapies, which have proven effective agents for treating immunogenic forms of cancer, although immunologically “cold” tumour types remain refractive. Oncolytic viruses, such as those based on adenovirus, have great potential as anti-cancer agents and have seen a resurgence of interest in recent years. Amongst their many advantages is their ability to induce immunogenic cell death (ICD) of infected tumour cells, thus providing the alluring potential to synergise with immunotherapies by turning immunologically “cold” tumours “hot”. Additionally, enhanced immune mediated cell killing can be promoted through the local overexpression of immunological transgenes, encoded from within the engineered viral genome. To achieve this full potential requires the development of refined, tumour selective “precision virotherapies” that are extensively engineered to prevent off-target up take via native routes of infection and targeted to infect and replicate uniquely within malignantly transformed cells. Here, we review the latest advances towards this holy grail within the adenoviral field.
Prognostic Factors Involved in the Epithelial–Mesenchymal Transition Process in Colorectal Cancer Have a Preponderant Role in Oxidative Stress: A Systematic Review and Meta-Analysis
Authors: Parisi Eva , Sorolla Anabel , Montal Robert , González-Resina Rita , Novell Anna , Salud Antonieta , Sorolla Maria
Published: November 2020

Epithelial-to-mesenchymal transition (EMT) is one of the most accepted mechanisms leading to metastasis, which is responsible for most of the cancer-related deaths. In order to identify EMT-related biomarkers able to predict clinical outcomes in colorectal cancer (CRC), a systematic review and meta-analysis of prognostic factors associated to overall survival (OS) and progression free survival (PFS) was conducted. The systematic literature search included studies from June 2014 to June 2019 available at PubMed and Scopus databases. Meta-analysis was performed for those markers appearing in minimum three works with a total number of 8656 participants. The rest were enlisted and subjected to functional enrichment. We identified nine clinical biomarkers and 73 EMT-related molecular biomarkers associated to OS and/or PFS in CRC. The significant enrichment of biomarkers found involved in cellular oxidoreductase activity suggests that ROS generation plays an active role in the EMT process. Clinical practice needs new biomarkers with a reliable prognostic value able to predict clinical outcomes in CRC. Our integrative work supports the role of oxidative stress in tumorigenesis and EMT progress highlighting the importance of deciphering this specific mechanism to get a better understanding of metastasis.
The Potential of Lonidamine in Combination with Chemotherapy and Physical Therapy in Cancer Treatment
Authors: Huang Yaxin , Sun Guohui , Sun Xiaodong , Li Feifan , Zhao Lijiao , Zhong Rugang , Peng Yongzhen
Published: November 2020

Lonidamine (LND) has the ability to resist spermatogenesis and was first used as an anti-spermatogenic agent. Later, it was found that LND has a degree of anticancer activity. Currently, LND is known to target energy metabolism, mainly involving the inhibition of monocarboxylate transporter (MCT), mitochondrial pyruvate carrier (MPC), respiratory chain complex I/II, mitochondrial permeability transition (PT) pore, and hexokinase II (HK-II). However, phase II clinical studies showed that LND alone had a weak therapeutic effect, and the effect was short and reversible. Interestingly, LND does not have the common side effects of traditional chemotherapeutic drugs, such as alopecia and myelosuppression. In addition, LND has selective activity toward various tumors, and its toxic and side effects do not overlap when combined with other chemotherapeutic drugs. Therefore, LND is commonly used as a chemosensitizer to enhance the antitumor effects of chemotherapeutic drugs based on its disruption of energy metabolism relating to chemo- or radioresistance. In this review, we summarized the combination treatments of LND with several typical chemotherapeutic drugs and several common physical therapies, such as radiotherapy (RT), hyperthermia (HT), and photodynamic therapy (PDT), and discussed the underlying mechanisms of action. Meanwhile, the development of novel formulations of LND in recent years and the research progress of LND derivative adjudin (ADD) as an anticancer drug were also discussed.
A Comparative Oncology Drug Discovery Pipeline to Identify and Validate New Treatments for Osteosarcoma
Authors: Somarelli Jason A. , Rupprecht Gabrielle , Altunel Erdem , Flamant Etienne M. , Rao Sneha , Sivaraj Dharshan , Lazarides Alexander L. , Hoskinson Sarah M. , Sheth Maya U. , Cheng Serene , Kim So Young , Ware Kathryn E. , Agarwal Anika , Cullen Mark M. , Selmic Laura E. , Everitt Jeffrey I. , McCall Shannon J. , Eward Cindy , Eward William C. , Hsu David S.
Published: November 2020

Background: Osteosarcoma is a rare but aggressive bone cancer that occurs primarily in children. Like other rare cancers, treatment advances for osteosarcoma have stagnated, with little improvement in survival for the past several decades. Developing new treatments has been hampered by extensive genomic heterogeneity and limited access to patient samples to study the biology of this complex disease. Methods: To overcome these barriers, we combined the power of comparative oncology with patient-derived models of cancer and high-throughput chemical screens in a cross-species drug discovery pipeline. Results: Coupling in vitro high-throughput drug screens on low-passage and established cell lines with in vivo validation in patient-derived xenografts we identify the proteasome and CRM1 nuclear export pathways as therapeutic sensitivities in osteosarcoma, with dual inhibition of these pathways inducing synergistic cytotoxicity. Conclusions: These collective efforts provide an experimental framework and set of new tools for osteosarcoma and other rare cancers to identify and study new therapeutic vulnerabilities.
Experimental Assessment of Color Deconvolution and Color Normalization for Automated Classification of Histology Images Stained with Hematoxylin and Eosin
Authors: Bianconi Francesco , Kather Jakob N. , Reyes-Aldasoro Constantino Carlos
Published: November 2020

Histological evaluation plays a major role in cancer diagnosis and treatment. The appearance of H&E-stained images can vary significantly as a consequence of differences in several factors, such as reagents, staining conditions, preparation procedure and image acquisition system. Such potential sources of noise can all have negative effects on computer-assisted classification. To minimize such artefacts and their potentially negative effects several color pre-processing methods have been proposed in the literature—for instance, color augmentation, color constancy, color deconvolution and color transfer. Still, little work has been done to investigate the efficacy of these methods on a quantitative basis. In this paper, we evaluated the effects of color constancy, deconvolution and transfer on automated classification of H&E-stained images representing different types of cancers—specifically breast, prostate, colorectal cancer and malignant lymphoma. Our results indicate that in most cases color pre-processing does not improve the classification accuracy, especially when coupled with color-based image descriptors. Some pre-processing methods, however, can be beneficial when used with some texture-based methods like Gabor filters and Local Binary Patterns.
Reactivity and Mechanism of Photo- and Electrocatalytic Hydrogen Evolution by a Diimine Copper(I) Complex
Authors: Drosou Maria , Kamatsos Fotios , Ioannidis George , Zarkadoulas Athanasios , Mitsopoulou Christiana A. , Papatriantafyllopoulou Constantina , Tzeli Demeter
Published: November 2020

The tetrahedral copper(I) diimine complex [Cu(pq)2]BF4 displays high photocatalytic activity for the H2 evolution reaction with a turnover number of 3564, thus representing the first type of a Cu(I) quinoxaline complex capable of catalyzing proton reduction. Electrochemical experiments indicate that molecular mechanisms prevail and DFT calculations provide in-depth insight into the catalytic pathway, suggesting that the coordinating nitrogens play crucial roles in proton exchange and hydrogen formation.
Biocatalytic Process Optimization
Authors: Kuo Chia-Hung , Shieh Chwen-Jen
Published: November 2020

Biocatalysis refers to the use of microorganisms and enzymes in chemical reactions, has become increasingly popular and is frequently used in industrial applications due to the high efficiency and selectivity of biocatalysts [...]
Rational Design of Binary Alloys for Catalytic Growth of Graphene via Chemical Vapor Deposition
Authors: Li Yanglizhi , Sun Luzhao , Liu Haiyang , Wang Yuechen , Liu Zhongfan
Published: November 2020

Chemical vapor deposition is the most promising technique for the mass production of high-quality graphene, in which the metal substrate plays a crucial role in the catalytic decomposition of the carbon source, assisting the attachment of the active carbon species, and regulating the structure of the graphene film. Due to some drawbacks of single metal substrates, alloy substrates have gradually attracted attention owing to their complementarity in the catalytic growth of graphene. In this review, we focus on the rational design of binary alloys, such as Cu/Ni, Ni/Mo, and Cu/Si, to control the layer numbers and growth rate of graphene. By analyzing the elementary steps of graphene growth, general principles are summarized in terms of the catalytic activity, metal–carbon interactions, carbon solubility, and mutual miscibility. Several challenges in this field are also put forward to inspire the novel design of alloy catalysts and the synthesis of graphene films bearing desirable properties.
The Issue of Soot-Catalyst Contact in Regeneration of Catalytic Diesel Particulate Filters: A Critical Review
Authors: Lisi Luciana , Landi Gianluca , Di Sarli Valeria
Published: November 2020

Soot-catalyst contact represents the main critical issue for an effective regeneration of catalytic (i.e., catalyst-coated) diesel particulate filters (DPFs). Most of the literature reviews on this topic have mainly been focused on studies dealing with powdered soot-catalyst mixtures. Although the results obtained on powders surely provide significant indications, especially in terms of intrinsic activity of materials towards soot oxidation, they cannot be directly extended to DPFs due to completely different soot-catalyst contact conditions generated during filtration and subsequent regeneration. In this work, attention is devoted to catalytic DPFs and, more specifically, studies on both catalyst dispersion and soot distribution inside the filter are critically reviewed from the perspective of soot-catalyst contact optimization. The main conclusion drawn from the literature analysis is that, in order to fully exploit the potential of catalytic DPFs in soot abatement, both a widespread and homogeneous presence of catalyst in the macro-pores of the filter walls and a suitably low soot load are needed. Under optimal soot-catalyst contact conditions, the consequent decrease in the temperature required for soot oxidation to values within the temperature range of diesel exhausts suggests the passage to a continuous functioning mode for catalytic filters with simultaneous filtration and regeneration, thus overcoming the drawbacks of periodic regeneration performed in current applications.
Oxidative Condensation of Furfural with Ethanol Using Pd-Based Catalysts: Influence of the Support
Authors: Cecilia Juan Antonio , Jiménez-Gómez Carmen Pilar , Torres-Bujalance Virginia , García-Sancho Cristina , Moreno-Tost Ramón , Maireles-Torres Pedro
Published: November 2020

PdO nanoparticles were deposited on several supports (β-zeolite, Al2O3, Fe2O3, MgO, and SiO2), which displayed different crystallinity, textural properties, and amount of acid and basic sites. These catalysts were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), N2 adsorption–desorption isotherms at −196 °C, NH3 and CO2 thermoprogrammed desorption analyses (NH3- and CO2-TPD, and X-ray photoelectron spectroscopy (XPS). Pd-based catalysts were tested in the oxidative condensation of furfural with ethanol to obtain value-added chemicals. The catalytic results revealed high conversion values, although the presence of a high proportion of carbonaceous deposits, mainly in the case of the PdO supported on β-zeolite and Al2O3, is also noteworthy. The presence of basic sites led to a beneficial effect on the catalytic behavior, since the formation of carbonaceous deposits was minimized. Thus, the 2Pd-MgO (2 wt.% Pd) catalyst reached the highest yield of furan-2-acrolein (70%) after 3 h of reaction at 170 °C. This better catalytic performance can be explained by the high basicity of MgO, used as support, together with the large amount of available PdO, as inferred from XPS.
Pt-Co3O4 Superstructures by One-Pot Reduction/Precipitation in Bicontinuous Microemulsion for Electrocatalytic Oxygen Evolution Reaction
Authors: Adesuji Elijah T. , Guardado-Villegas Esther , Fuentes Keyla M. , Sánchez-Domínguez Margarita , Videa Marcelo
Published: November 2020

Bicontinuous microemulsions (BCME) were used to synthesize hierarchical superstructures (HSs) of Pt-Co3O4 by reduction/precipitation. BCMEs possess water and oil nanochannels, and therefore, both hydrophilic and lipophilic precursors can be used. Thus, PtAq-CoAq, PtAq-CoOi, PtOi-CoAq and PtOi-CoOi were prepared (where Aq and Oi stand for the precursor present in aqueous or oily phase, respectively). The characterization of the Pt-Co3O4-HS confirmed the formation of metallic Pt and Co3O4 whose composition and morphology are controlled by the initial pH and precursor combination, determining the presence of the reducing/precipitant species in the reaction media. The electrocatalytic activity of the Pt-Co3O4-HSs for oxygen evolution reaction (OER) was investigated using linear sweep voltammetry in 0.1 M KOH and compared with Pt-HS. The lowest onset overpotentials for Pt-Co3O4-Hs were achieved with PtOi-CoOi (1.46 V vs. RHE), while the lowest overpotential at a current density of 10 mA cm−2 (η10) was obtained for the PtAq-CoAq (381 mV). Tafel slopes were 102, 89, 157 and 92 mV dec−1, for PtAq-CoAq, PtAq-CoOi, PtOi-CoAq and PtOi-CoOi, respectively. The Pt-Co3O4-HSs showed a better performance than Pt-HS. Our work shows that the properties and performance of metal–metal oxide HSs obtained in BCMEs depend on the phases in which the precursors are present.
Biocomputing and Synthetic Biology in Cells: Cells Special Issue
Authors: Cui Feifei , Zou Quan
Published: November 2020

Biocomputing and synthetic biology have been two of the most exciting emerging fields in recent years [...]
Special Issue: “Inflammation, Oxidative Stress and Protein Aggregation; Any Links?”
Authors: Žerovnik Eva , Ventura Salvador , Jerala Nataša Kopitar
Published: November 2020

Inflammation is a complex immune response that enables survival during infection and maintains tissue homeostasis [...]
Fundamental Movement Skills and Accelerometer-Measured Physical Activity Levels during Early Childhood: A Systematic Review
Authors: Dobell Alexandra , Pringle Andy , Faghy Mark A. , Roscoe Clare M. P.
Published: November 2020

Early childhood is a key period for children to begin developing and practicing fundamental movement skills (FMS), while aiming to perform sufficient physical activity (PA). This study reviews the current evidence for the levels of achievement in FMS and PA measured using accelerometers among 4–5-year-old children and examines differences by gender. This review was conducted using the PRISMA framework. Keyword searches were conducted in Pubmed, Medline, Google Scholar and SPORTDiscus. Inclusion criteria included age: 4–5 years old; FMS measurement: Test of Gross Motor Development 2 and 3; PA measurement: objective methods; balance measurement: static single limb; study design: cross-sectional observational/descriptive, randomised control trials, intervention studies; language: English. Twenty-eight articles from twenty-one countries met the inclusion criteria and were split into either FMS and PA articles (n = 10) or balance articles (n = 18). Three articles showed children achieving 60 min of moderate to vigorous PA per day, two articles demonstrated significant differences between girls’ and boys’ performance of locomotor skills and five reported locomotor skills to be more proficient than object control skills at this age for both genders. Balance was measured in time (n = 12), points score (n = 3) or biomechanical variables (n = 3), displaying heterogeneity of not only measurement but also outcomes within these data, with static single limb balance held between 6.67 to 87.6 s within the articles. Four articles reported girls to have better balance than boys. There is little conclusive evidence of the current levels for FMS, PA and balance achievement in young children 4–5 years of age. The academic literature consistently reports low levels of FMS competence and mixed evidence for PA levels. Inconsistencies lie in balance measurement methodology, with broad-ranging outcomes of both low and high achievement at 4–5 years old. Further research is required to focus on increasing practice opportunities for children to improve their FMS, increase PA levels and establish sufficient balance ability. Consistent and comparable outcomes during early childhood through more homogenous methodologies are warranted.
Detection of Spin Polarized Band in VO2/TiO2(001) Strained Films via Orbital Selective Constant Initial State Spectroscopy
Authors: D’Elia Alessandro , Grazioli Cesare , Cossaro Albano , Li Bowen , Zou Chongwen , Rezvani Seyed Javad , Marcelli Augusto , Coreno Marcello
Published: November 2020

The VO2 is a 3d1 electron system that undergoes a reversible metal–insulator transition (MIT) triggered by temperature and characterized by an interplay between orbital, charge and lattice degrees of freedom. The characterization of the MIT features are therefore extremely challenging and powerful investigation tools are required. In this work, we demonstrate how a combination of resonant photoemission and constant initial state (CIS) spectroscopy can be used as an orbital selective probe of the MIT studying three different VO2/TiO2(001) strained films. The CIS spectra of the V 3d and V 3p photo-electrons shows sensitivity to different orbital contribution and the presence of a spin polarized band close to the Fermi level.