bluuebunny/crossref_metadata_2025 huggingface dataset:
A Multicentre, Randomised, Controlled Trial of a Combined Clinical Treatment for First-Episode Psychosis
Authors: González-Ortega Itxaso , Vega Patricia , Echeburúa Enrique , Alberich Susana , Fernández-Sevillano Jessica , Barbeito Sara , Balanzá-Martínez Vicent , Vieta Eduard , Lorente-Rovira Esther , Luengo Ana , Cerrillo Ester , Crespo José Manuel , Matute Carlos , González-Pinto Ana
Published: July 2021

Introduction: There is evidence that early intervention contributes to improving the prognosis and course of first-episode psychosis (FEP). However, further randomised treatment clinical trials are needed. Objectives: The aim of this study was to compare the efficacy of a combined clinical treatment involving Cognitive Behavioural Therapy (CBT) as an adjunctive to treatment-as-usual (TAU) (CBT+TAU) versus TAU alone for FEP. Patients and methods: In this multicentre, single-blind, randomised controlled trial, 177 participants were randomly allocated to either CBT+TAU or TAU. The primary outcome was post-treatment patient functioning. Results: The CBT+TAU group showed a greater improvement in functioning, which was measured using the Global Assessment Functioning (GAF) and Functioning Assessment Short Test (FAST), compared to the TAU group post-treatment. The CBT+TAU participants exhibited a greater decline in depressive, negative, and general psychotic symptoms; a better awareness of the disease and treatment adherence; and a greater increase in brain-derived neurotrophic factor levels than TAU participants. Conclusions: Early intervention based on a combined clinical treatment involving CBT as an adjunctive to standard treatment may improve clinical and functional outcomes in FEP.
Being Creative Makes You Happier: The Positive Effect of Creativity on Subjective Well-Being
Authors: Tan Cher-Yi , Chuah Chun-Qian , Lee Shwu-Ting , Tan Chee-Seng
Published: July 2021

The impact of happiness on creativity is well-established. However, little is known about the effect of creativity on well-being. Two studies were thus conducted to examine the impact of creativity on subjective well-being. In the first study, 256 undergraduate students (Study 1a) and 291 working adults (Study 1b) self-reported their creativity, stress, and subjective well-being. Hierarchical multiple regression analysis showed a positive relationship between creativity and subjective well-being after controlling the effect of self-perceived stress and demographics in both samples. Study 2 then employed an experimental design to examine the causal relationship between creativity and subjective well-being. Half of the 68 undergraduates underwent a creativity priming task followed by a divergent thinking test as well as self-reported stress and subjective well-being. The priming task was found to boost creative performance in the pilot study (Study 2a) and the actual study (Study 2b). Moreover, after controlling the effect of self-perceived stress, ANCOVA analysis showed that participants receiving the priming reported higher subjective well-being scores than their counterparts in the control group. The overall findings not only shed light on the facilitative effect of creativity on subjective well-being but also highlight the necessity of considering the reciprocal relationship of the two constructs in future research.
Mortality Associated with Idiopathic Pulmonary Fibrosis in Northeastern Italy, 2008–2020: A Multiple Cause of Death Analysis
Authors: Marcon Alessandro , Schievano Elena , Fedeli Ugo
Published: July 2021

Mortality from idiopathic pulmonary fibrosis (IPF) is increasing in most European countries, but there are no data for Italy. We analysed the registry data from a region in northeastern Italy to assess the trends in IPF-related mortality during 2008–2019, to compare results of underlying vs. multiple cause of death analyses, and to describe the impact of the COVID-19 epidemic in 2020. We identified IPF (ICD-10 code J84.1) among the causes of death registered in 557,932 certificates in the Veneto region. We assessed time trends in annual age-standardized mortality rates by gender and age (40–74, 75–84, and ≥85 years). IPF was the underlying cause of 1310 deaths in the 2251 certificates mentioning IPF. For all age groups combined, the age-standardized mortality rate from IPF identified as the underlying cause of death was close to the European median (males and females: 3.1 and 1.3 per 100,000/year, respectively). During 2008–2019, mortality rates increased in men aged ≥85 years (annual percent change of 6.5%, 95% CI: 2.0, 11.2%), but not among women or for the younger age groups. A 72% excess of IPF-related deaths was registered in March–April 2020 (mortality ratio 1.72, 95% CI: 1.29, 2.24). IPF mortality was increasing among older men in northeastern Italy. The burden of IPF was heavier than assessed by routine statistics, since less than two out of three IPF-related deaths were directly attributed to this condition. COVID-19 was accompanied by a remarkable increase in IPF-related mortality.
Using Machine Learning to Map Western Australian Landscapes for Mineral Exploration
Authors: Albrecht Thomas , González-Álvarez Ignacio , Klump Jens
Published: July 2021

Landscapes evolve due to climatic conditions, tectonic activity, geological features, biological activity, and sedimentary dynamics. Geological processes at depth ultimately control and are linked to the resulting surface features. Large regions in Australia, West Africa, India, and China are blanketed by cover (intensely weathered surface material and/or later sediment deposition, both up to hundreds of metres thick). Mineral exploration through cover poses a significant technological challenge worldwide. Classifying and understanding landscape types and their variability is of key importance for mineral exploration in covered regions. Landscape variability expresses how near-surface geochemistry is linked to underlying lithologies. Therefore, landscape variability mapping should inform surface geochemical sampling strategies for mineral exploration. Advances in satellite imaging and computing power have enabled the creation of large geospatial data sets, the sheer size of which necessitates automated processing. In this study, we describe a methodology to enable the automated mapping of landscape pattern domains using machine learning (ML) algorithms. From a freely available digital elevation model, derived data, and sample landclass boundaries provided by domain experts, our algorithm produces a dense map of the model region in Western Australia. Both random forest and support vector machine classification achieve approximately 98% classification accuracy with a reasonable runtime of 48 minutes on a single Intel® Core™ i7-8550U CPU core. We discuss computational resources and study the effect of grid resolution. Larger tiles result in a more contiguous map, whereas smaller tiles result in a more detailed and, at some point, noisy map. Diversity and distribution of landscapes mapped in this study support previous results. In addition, our results are consistent with the geological trends and main basement features in the region. Mapping landscape variability at a large scale can be used globally as a fundamental tool for guiding more efficient mineral exploration programs in regions under cover.
The OsERF115/AP2EREBP110 Transcription Factor Is Involved in the Multiple Stress Tolerance to Heat and Drought in Rice Plants
Authors: Park Seong-Im , Kwon Hyeok Jin , Cho Mi Hyeon , Song Ji Sun , Kim Beom-Gi , Baek JeongHo , Kim Song Lim , Ji HyeonSo , Kwon Taek-Ryoun , Kim Kyung-Hwan , Yoon In Sun
Published: July 2021

The AP2/EREBP family transcription factors play important roles in a wide range of stress tolerance and hormone signaling. In this study, a heat-inducible rice ERF gene was isolated and functionally characterized. The OsERF115/AP2EREBP110 was categorized to Group-IIIc of the rice AP2/EREBP family and strongly induced by heat and drought treatment. The OsERF115/AP2EREBP110 protein targeted to nuclei and suppressed the ABA-induced transcriptional activation of Rab16A promoter in rice protoplasts. Overexpression of OsERF115/AP2EREBP110 enhanced thermotolerance of seeds and vegetative growth stage plants. The OsERF115/AP2EREBP110 overexpressing (OE) plants exhibited higher proline level and increased expression of a proline biosynthesis P5CS1 gene. Phenotyping of water use dynamics of the individual plant indicates that the OsERF115/AP2EREBP110-OE plant exhibited better water saving traits under heat and drought combined stress. Our combined results suggest the potential use of OsERF115/AP2EREBP110 as a candidate gene for genetic engineering approaches to develop heat and drought stress-tolerant crops.
Hops/Tmub1 Heterozygous Mouse Shows Haploinsufficiency Effect in Influencing p53-Mediated Apoptosis
Authors: Ferracchiato Simona , Di-Iacovo Nicola , Scopetti Damiano , Piobbico Danilo , Castelli Marilena , Pieroni Stefania , Gargaro Marco , Manni Giorgia , Brancorsini Stefano , Della-Fazia Maria Agnese , Servillo Giuseppe
Published: July 2021

HOPS is a ubiquitin-like protein implicated in many aspects of cellular function including the regulation of mitotic activity, proliferation, and cellular stress responses. In this study, we focused on the complex relationship between HOPS and the tumor suppressor p53, investigating both transcriptional and non-transcriptional p53 responses. Here, we demonstrated that Hops heterozygous mice and mouse embryonic fibroblasts exhibit an impaired DNA-damage response to etoposide-induced double-strand breaks when compared to wild-type genes. Specifically, alterations in HOPS levels caused significant defects in the induction of apoptosis, including a reduction in p53 protein level and percentage of apoptotic cells. We also analyzed the effect of reduced HOPS levels on the DNA-damage response by examining the transcript profiles of p53-dependent genes, showing a suggestive deregulation of the mRNA levels for a number of p53-dependent genes. Taken together, these results show an interesting haploinsufficiency effect mediated by Hops monoallelic deletion, which appears to be enough to destabilize the p53 protein and its functions. Finally, these data indicate a novel role for Hops as a tumor-suppressor gene in DNA damage repair in mammalian cells.
Biomarkers for Comorbidities Modulate the Activity of T-Cells in COPD
Authors: Jamal Jameel Kaschin , Gallert Willem-Jakob , Yanik Sarah D. , Panek Susanne , Kronsbein Juliane , Jungck David , Koch Andrea , Knobloch Jürgen
Published: July 2021

In smoking-induced chronic obstructive pulmonary disease (COPD), various comorbidities are linked to systemic inflammation and infection-induced exacerbations. The underlying mechanisms are unclear but might provide therapeutic targets. T-cell activity is central in systemic inflammation and for infection-defense mechanisms and might be influenced by comorbidities. Hypothesis: Circulating biomarkers of comorbidities modulate the activity of T-cells of the T-helper type 1 (Th1) and/or T-cytotoxic type 1 (Tc1). T-cells in peripheral blood mononuclear cells (PBMCs) from non-smokers (NS), current smokers without COPD (S), and COPD subjects (total n = 34) were ex vivo activated towards Th1/Tc1 and were then stimulated with biomarkers for metabolic and/or cardiovascular comorbidities (Brain Natriuretic Peptide, BNP; chemokine (C-C motif) ligand 18, CCL18; C-X3-C motif chemokine ligand 1, CX3CL1; interleukin-18, IL-18) or for asthma- and/or cancer-related comorbidities (CCL22; epidermal growth factor, EGF; IL-17; periostin) each at 10 or 50 ng/mL. The Th1/Tc1 activation markers interferon-γ (IFNγ), tumor necrosis factor-α (TNFα), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were analyzed in culture supernatants by Enzyme-Linked Immunosorbent Assay (ELISA). Ex-vivo activation induced IFNγ and TNFα without differences between the groups but GM-CSF more in S vs. NS. At 10 ng/mL, the different biomarkers increased or reduced the T-cell activation markers without a clear trend for one direction in the different categories of comorbidities or for the different T-cell activation markers. At 50 ng/mL, there was a clear shift towards suppressive effects, particularly for the asthma— and cancer-related biomarkers and in cells of S and COPD. Comorbidities might suppress T-cell immunity in COPD. This could explain the association of comorbidities with frequent exacerbations.
Genetic Dissection of Seedling Root System Architectural Traits in a Diverse Panel of Hexaploid Wheat through Multi-Locus Genome-Wide Association Mapping for Improving Drought Tolerance
Authors: Danakumara Thippeswamy , Kumari Jyoti , Singh Amit Kumar , Sinha Subodh Kumar , Pradhan Anjan Kumar , Sharma Shivani , Jha Shailendra Kumar , Bansal Ruchi , Kumar Sundeep , Jha Girish Kumar , Yadav Mahesh C. , Prasad P.V. Vara
Published: July 2021

Cultivars with efficient root systems play a major role in enhancing resource use efficiency, particularly water absorption, and thus in drought tolerance. In this study, a diverse wheat association panel of 136 wheat accessions including mini core subset was genotyped using Axiom 35k Breeders’ Array to identify genomic regions associated with seedling stage root architecture and shoot traits using multi-locus genome-wide association studies (ML-GWAS). The association panel revealed a wide variation of 1.5- to 50-fold and were grouped into six clusters based on 15 traits. Six different ML-GWAS models revealed 456 significant quantitative trait nucleotides (QTNs) for various traits with phenotypic variance in the range of 0.12–38.60%. Of these, 87 QTNs were repeatedly detected by two or more models and were considered reliable genomic regions for the respective traits. Among these QTNs, eleven were associated with average diameter and nine each for second order lateral root number (SOLRN), root volume (RV) and root length density (RLD). A total of eleven genomic regions were pleiotropic and each controlled two or three traits. Some important candidate genes such as Formin homology 1, Ubiquitin-like domain superfamily and ATP-dependent 6-phosphofructokinase were identified from the associated genomic regions. The genomic regions/genes identified in this study could potentially be targeted for improving root traits and drought tolerance in wheat.
Connecting Cholesterol Efflux Factors to Lung Cancer Biology and Therapeutics
Authors: Maslyanko Maria , Harris Ryan D. , Mu David
Published: July 2021

Cholesterol is a foundational molecule of biology. There is a long-standing interest in understanding how cholesterol metabolism is intertwined with cancer biology. In this review, we focus on the known connections between lung cancer and molecules mediating cholesterol efflux. A major take-home lesson is that the roles of many cholesterol efflux factors remain underexplored. It is our hope that this article would motivate others to investigate how cholesterol efflux factors contribute to lung cancer biology.
A Systematic Review of Parkinson’s Disease Pharmacogenomics: Is There Time for Translation into the Clinics?
Authors: Vuletić Vladimira , Rački Valentino , Papić Eliša , Peterlin Borut
Published: July 2021

Background: Parkinson’s disease (PD) is the second most frequent neurodegenerative disease, which creates a significant public health burden. There is a challenge for the optimization of therapies since patients not only respond differently to current treatment options but also develop different side effects to the treatment. Genetic variability in the human genome can serve as a biomarker for the metabolism, availability of drugs and stratification of patients for suitable therapies. The goal of this systematic review is to assess the current evidence for the clinical translation of pharmacogenomics in the personalization of treatment for Parkinson’s disease. Methods: We performed a systematic search of Medline database for publications covering the topic of pharmacogenomics and genotype specific mutations in Parkinson’s disease treatment, along with a manual search, and finally included a total of 116 publications in the review. Results: We analyzed 75 studies and 41 reviews published up to December of 2020. Most research is focused on levodopa pharmacogenomic properties and catechol-O-methyltransferase (COMT) enzymatic pathway polymorphisms, which have potential for clinical implementation due to changes in treatment response and side-effects. Likewise, there is some consistent evidence in the heritability of impulse control disorder via Opioid Receptor Kappa 1 (OPRK1), 5-Hydroxytryptamine Receptor 2A (HTR2a) and Dopa decarboxylase (DDC) genotypes, and hyperhomocysteinemia via the Methylenetetrahydrofolate reductase (MTHFR) gene. On the other hand, many available studies vary in design and methodology and lack in sample size, leading to inconsistent findings. Conclusions: This systematic review demonstrated that the evidence for implementation of pharmacogenomics in clinical practice is still lacking and that further research needs to be done to enable a more personalized approach to therapy for each patient.
Extracellular Vesicles in the Fungi Kingdom
Authors: Liebana-Jordan Marc , Brotons Bruno , Falcon-Perez Juan Manuel , Gonzalez Esperanza
Published: July 2021

Extracellular vesicles (EVs) are membranous, rounded vesicles released by prokaryotic and eukaryotic cells in their normal and pathophysiological states. These vesicles form a network of intercellular communication as they can transfer cell- and function-specific information (lipids, proteins and nucleic acids) to different cells and thus alter their function. Fungi are not an exception; they also release EVs to the extracellular space. The vesicles can also be retained in the periplasm as periplasmic vesicles (PVs) and the cell wall. Such fungal vesicles play various specific roles in the lives of these organisms. They are involved in creating wall architecture and maintaining its integrity, supporting cell isolation and defence against the environment. In the case of pathogenic strains, they might take part in the interactions with the host and affect the infection outcomes. The economic importance of fungi in manufacturing high-quality nutritional and pharmaceutical products and in remediation is considerable. The analysis of fungal EVs opens new horizons for diagnosing fungal infections and developing vaccines against mycoses and novel applications of nanotherapy and sensors in industrial processes.
Low-Dose Acrolein, an Endogenous and Exogenous Toxic Molecule, Inhibits Glucose Transport via an Inhibition of Akt-Regulated GLUT4 Signaling in Skeletal Muscle Cells
Authors: Wang Ching-Chia , Chen Huang-Jen , Chan Ding-Cheng , Chiu Chen-Yuan , Liu Shing-Hwa , Lan Kuo-Cheng
Published: July 2021

Urinary acrolein adduct levels have been reported to be increased in both habitual smokers and type-2 diabetic patients. The impairment of glucose transport in skeletal muscles is a major factor responsible for glucose uptake reduction in type-2 diabetic patients. The effect of acrolein on glucose metabolism in skeletal muscle remains unclear. Here, we investigated whether acrolein affects muscular glucose metabolism in vitro and glucose tolerance in vivo. Exposure of mice to acrolein (2.5 and 5 mg/kg/day) for 4 weeks substantially increased fasting blood glucose and impaired glucose tolerance. The glucose transporter-4 (GLUT4) protein expression was significantly decreased in soleus muscles of acrolein-treated mice. The glucose uptake was significantly decreased in differentiated C2C12 myotubes treated with a non-cytotoxic dose of acrolein (1 μM) for 24 and 72 h. Acrolein (0.5–2 μM) also significantly decreased the GLUT4 expression in myotubes. Acrolein suppressed the phosphorylation of glucose metabolic signals IRS1, Akt, mTOR, p70S6K, and GSK3α/β. Over-expression of constitutive activation of Akt reversed the inhibitory effects of acrolein on GLUT4 protein expression and glucose uptake in myotubes. These results suggest that acrolein at doses relevant to human exposure dysregulates glucose metabolism in skeletal muscle cells and impairs glucose tolerance in mice.
Identification of 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine Derivatives as Novel Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase
Authors: Hartuti Endah Dwi , Sakura Takaya , Tagod Mohammed S. O. , Yoshida Eri , Wang Xinying , Mochizuki Kota , Acharjee Rajib , Matsuo Yuichi , Tokumasu Fuyuki , Mori Mihoko , Waluyo Danang , Shiomi Kazuro , Nozaki Tomoyoshi , Hamano Shinjiro , Shiba Tomoo , Kita Kiyoshi , Inaoka Daniel Ken
Published: July 2021

Plasmodium falciparum’s resistance to available antimalarial drugs highlights the need for the development of novel drugs. Pyrimidine de novo biosynthesis is a validated drug target for the prevention and treatment of malaria infection. P. falciparum dihydroorotate dehydrogenase (PfDHODH) catalyzes the oxidation of dihydroorotate to orotate and utilize ubiquinone as an electron acceptor in the fourth step of pyrimidine de novo biosynthesis. PfDHODH is targeted by the inhibitor DSM265, which binds to a hydrophobic pocket located at the N-terminus where ubiquinone binds, which is known to be structurally divergent from the mammalian orthologue. In this study, we screened 40,400 compounds from the Kyoto University chemical library against recombinant PfDHODH. These studies led to the identification of 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine and its derivatives as a new class of PfDHODH inhibitor. Moreover, the hit compounds identified in this study are selective for PfDHODH without inhibition of the human enzymes. Finally, this new scaffold of PfDHODH inhibitors showed growth inhibition activity against P. falciparum 3D7 with low toxicity to three human cell lines, providing a new starting point for antimalarial drug development.
Drugs and Epigenetic Molecular Functions. A Pharmacological Data Scientometric Analysis
Authors: Kringel Dario , Malkusch Sebastian , Lötsch Jörn
Published: July 2021

Interactions of drugs with the classical epigenetic mechanism of DNA methylation or histone modification are increasingly being elucidated mechanistically and used to develop novel classes of epigenetic therapeutics. A data science approach is used to synthesize current knowledge on the pharmacological implications of epigenetic regulation of gene expression. Computer-aided knowledge discovery for epigenetic implications of current approved or investigational drugs was performed by querying information from multiple publicly available gold-standard sources to (i) identify enzymes involved in classical epigenetic processes, (ii) screen original biomedical scientific publications including bibliometric analyses, (iii) identify drugs that interact with epigenetic enzymes, including their additional non-epigenetic targets, and (iv) analyze computational functional genomics of drugs with epigenetic interactions. PubMed database search yielded 3051 hits on epigenetics and drugs, starting in 1992 and peaking in 2016. Annual citations increased to a plateau in 2000 and show a downward trend since 2008. Approved and investigational drugs in the DrugBank database included 122 compounds that interacted with 68 unique epigenetic enzymes. Additional molecular functions modulated by these drugs included other enzyme interactions, whereas modulation of ion channels or G-protein-coupled receptors were underrepresented. Epigenetic interactions included (i) drug-induced modulation of DNA methylation, (ii) drug-induced modulation of histone conformations, and (iii) epigenetic modulation of drug effects by interference with pharmacokinetics or pharmacodynamics. Interactions of epigenetic molecular functions and drugs are mutual. Recent research activities on the discovery and development of novel epigenetic therapeutics have passed successfully, whereas epigenetic effects of non-epigenetic drugs or epigenetically induced changes in the targets of common drugs have not yet received the necessary systematic attention in the context of pharmacological plasticity.
Key Regulators of Sucrose Metabolism Identified through Comprehensive Comparative Transcriptome Analysis in Peanuts
Authors: Li Weitao , Huang Li , Liu Nian , Pandey Manish K. , Chen Yuning , Cheng Liangqiang , Guo Jianbin , Yu Bolun , Luo Huaiyong , Zhou Xiaojing , Huai Dongxin , Chen Weigang , Yan Liying , Wang Xin , Lei Yong , Varshney Rajeev K. , Liao Boshou , Jiang Huifang
Published: July 2021

Sucrose content is a crucial indicator of quality and flavor in peanut seed, and there is a lack of clarity on the molecular basis of sucrose metabolism in peanut seed. In this context, we performed a comprehensive comparative transcriptome study on the samples collected at seven seed development stages between a high-sucrose content variety (ICG 12625) and a low-sucrose content variety (Zhonghua 10). The transcriptome analysis identified a total of 8334 genes exhibiting significantly different abundances between the high- and low-sucrose varieties. We identified 28 differentially expressed genes (DEGs) involved in sucrose metabolism in peanut and 12 of these encoded sugars will eventually be exported transporters (SWEETs). The remaining 16 genes encoded enzymes, such as cell wall invertase (CWIN), vacuolar invertase (VIN), cytoplasmic invertase (CIN), cytosolic fructose-bisphosphate aldolase (FBA), cytosolic fructose-1,6-bisphosphate phosphatase (FBP), sucrose synthase (SUS), cytosolic phosphoglucose isomerase (PGI), hexokinase (HK), and sucrose-phosphate phosphatase (SPP). The weighted gene co-expression network analysis (WGCNA) identified seven genes encoding key enzymes (CIN, FBA, FBP, HK, and SPP), three SWEET genes, and 90 transcription factors (TFs) showing a high correlation with sucrose content. Furthermore, upon validation, six of these genes were successfully verified as exhibiting higher expression in high-sucrose recombinant inbred lines (RILs). Our study suggested the key roles of the high expression of SWEETs and enzymes in sucrose synthesis making the genotype ICG 12625 sucrose-rich. This study also provided insights into the molecular basis of sucrose metabolism during seed development and facilitated exploring key candidate genes and molecular breeding for sucrose content in peanuts.
Smoking and Neuropsychiatric Disease—Associations and Underlying Mechanisms
Authors: Hahad Omar , Daiber Andreas , Michal Matthias , Kuntic Marin , Lieb Klaus , Beutel Manfred , Münzel Thomas
Published: July 2021

Despite extensive efforts to combat cigarette smoking/tobacco use, it still remains a leading cause of global morbidity and mortality, killing more than eight million people each year. While tobacco smoking is a major risk factor for non-communicable diseases related to the four main groups—cardiovascular disease, cancer, chronic lung disease, and diabetes—its impact on neuropsychiatric risk is rather elusive. The aim of this review article is to emphasize the importance of smoking as a potential risk factor for neuropsychiatric disease and to identify central pathophysiological mechanisms that may contribute to this relationship. There is strong evidence from epidemiological and experimental studies indicating that smoking may increase the risk of various neuropsychiatric diseases, such as dementia/cognitive decline, schizophrenia/psychosis, depression, anxiety disorder, and suicidal behavior induced by structural and functional alterations of the central nervous system, mainly centered on inflammatory and oxidative stress pathways. From a public health perspective, preventive measures and policies designed to counteract the global epidemic of smoking should necessarily include warnings and actions that address the risk of neuropsychiatric disease.
Bactericidal Activity of a Self-Biodegradable Lysine-Containing Dendrimer against Clinical Isolates of Acinetobacter Genus
Authors: Alfei Silvana , Caviglia Debora , Piatti Gabriella , Zuccari Guendalina , Schito Anna Maria
Published: July 2021

The genus Acinetobacter consists of Gram-negative obligate aerobic pathogens, including clinically relevant species, such as A. baumannii, which frequently cause hospital infections, affecting debilitated patients. The growing resistance to antimicrobial therapies shown by A. baumannii is reaching unacceptable levels in clinical practice, and there is growing concern that the serious conditions it causes may soon become incurable. New therapeutic possibilities are, therefore, urgently needed to circumvent this important problem. Synthetic cationic macromolecules, such as cationic antimicrobial peptides (AMPs), which act as membrane disrupters, could find application in these conditions. A lysine-modified cationic polyester-based dendrimer (G5-PDK), capable of electrostatically interacting with bacterial surfaces as AMPs do, has been synthesized and characterized here. Given its chemical structure, similar to that of a fifth-generation lysine containing dendrimer (G5K) with a different core, and previously found inactive against Gram-positive bacterial species and Enterobacteriaceae, the new G5-PDK was also ineffective on the species mentioned above. In contrast, it showed minimum inhibitory concentration values (MICs) lower than reported for several AMPs and other synthetic cationic compounds on Acinetobacter genus (3.2–12.7 µM). Time-kill experiments on A. baumannii, A. pittii, and A. ursingii ascertained the rapid bactericidal effects of G5-PDK, while subsequent bacterial regrowth supported its self-biodegradability.
Preconditioning-Activated AKT Controls Neuronal Tolerance to Ischemia through the MDM2–p53 Pathway
Authors: Barrio Emilia , Vecino Rebeca , Sánchez-Morán Irene , Rodríguez Cristina , Suárez-Pindado Alberto , Bolaños Juan P. , Almeida Angeles , Delgado-Esteban Maria
Published: July 2021

One of the most important mechanisms of preconditioning-mediated neuroprotection is the attenuation of cell apoptosis, inducing brain tolerance after a subsequent injurious ischemia. In this context, the antiapoptotic PI3K/AKT signaling pathway plays a key role by regulating cell differentiation and survival. Active AKT is known to increase the expression of murine double minute-2 (MDM2), an E3-ubiquitin ligase that destabilizes p53 to promote the survival of cancer cells. In neurons, we recently showed that the MDM2–p53 interaction is potentiated by pharmacological preconditioning, based on subtoxic stimulation of NMDA glutamate receptor, which prevents ischemia-induced neuronal apoptosis. However, whether this mechanism contributes to the neuronal tolerance during ischemic preconditioning (IPC) is unknown. Here, we show that IPC induced PI3K-mediated phosphorylation of AKT at Ser473, which in turn phosphorylated MDM2 at Ser166. This phosphorylation triggered the nuclear stabilization of MDM2, leading to p53 destabilization, thus preventing neuronal apoptosis upon an ischemic insult. Inhibition of the PI3K/AKT pathway with wortmannin or by AKT silencing induced the accumulation of cytosolic MDM2, abrogating IPC-induced neuroprotection. Thus, IPC enhances the activation of PI3K/AKT signaling pathway and promotes neuronal tolerance by controlling the MDM2–p53 interaction. Our findings provide a new mechanistic pathway involved in IPC-induced neuroprotection via modulation of AKT signaling, suggesting that AKT is a potential therapeutic target against ischemic injury.
Prolonged Chronic Consumption of a High Fat with Sucrose Diet Alters the Morphology of the Small Intestine
Authors: Sferra Roberta , Pompili Simona , Cappariello Alfredo , Gaudio Eugenio , Latella Giovanni , Vetuschi Antonella
Published: July 2021

(1) The high-fat diet (HFD) of western countries has dramatic effect on the health of several organs, including the digestive tract, leading to the accumulation of fats that can also trigger a chronic inflammatory process, such as that which occurs in non-alcohol steatohepatitis. The effects of a HFD on the small intestine, the organ involved in the absorption of this class of nutrients, are still poorly investigated. (2) To address this aspect, we administered a combined HFD with sucrose (HFD w/Suc, fat: 58% Kcal) regimen (18 months) to mice and investigated the morphological and molecular changes that occurred in the wall of proximal tract of the small intestine compared to the intestine of mice fed with a standard diet (SD) (fat: 18% Kcal). (3) We found an accumulation of lipid droplets in the mucosa of HFD w/Suc-fed mice that led to a disarrangement of mucosa architecture. Furthermore, we assessed the expression of several key players involved in lipid metabolism and inflammation, such as perilipin, leptin, leptin receptor, PI3K, p-mTOR, p-Akt, and TNF-α. All these molecules were increased in HFD mice compared to the SD group. We also evaluated anti-inflammatory molecules like adiponectin, adiponectin receptor, and PPAR-γ, and observed their significant reduction in the HFD w/Suc group compared to the control. Our data are in line with the knowledge that improper eating habits present a primary harmful assault on the bowel and the entire body’s health. (4) These results represent a promising starting point for future studies, helping to better understand the complex and not fully elucidated spectrum of intestinal alterations induced by the overconsumption of fat.
A Simple Approach to Relating the Optimal Learning and the Meaningful Learning Experience in Students Age 14–16
Authors: Díaz de León-López Ma. Guadalupe , Velázquez-Sánchez María de Lourdes , Sánchez-Madrid Silvia , Olais-Govea José Manuel
Published: July 2021

Using a questionnaire applied in real time to students in stages 14–16 during a distance class, the authors appraise whether they experience feelings that lead to a central experience of flow, according to the flow theory of positive psychology. Students are exposed to a planned session that considers the moments of the training sequence and consciously integrates technological tools to support learning. A formal evaluation system, which includes formative and summative evaluations, determines if students build meaningful learning. This research contributes to understanding that an optimal learning experience characterized by the pedagogical principles of curiosity, concentration, challenge, and enjoyment, favor the construction of meaningful learning. Furthermore, the simplicity of the proposed experimental design suggests a direct way to replicate the study in later learning stages and assess the efficiency of new technology-based pedagogies within the distance education paradigm imposed by the 2020 pandemic crisis.
Formalizing the Blockchain-Based BlockVoke Protocol for Fast Certificate Revocation Using Colored Petri Nets
Authors: Sujatanagarjuna Anant , Bochem Arne , Leiding Benjamin
Published: July 2021

Protocol flaws such as the well-known Heartbleed bug, security and privacy issues or incomplete specifications, in general, pose risks to the direct users of a protocol and further stakeholders. Formal methods, such as Colored Petri Nets (CPNs), facilitate the design, development, analysis and verification of new protocols; the detection of flaws; and the mitigation of identified security risks. BlockVoke is a blockchain-based scheme that decentralizes certificate revocations, allows certificate owners and certificate authorities to revoke certificates and rapidly distributes revocation information. CPNs in particular are well-suited to formalize blockchain-based protocols—thus, in this work, we formalize the BlockVoke protocol using CPNs, resulting in a verifiable CPN model and a formal specification of the protocol. We utilize an agent-oriented modeling (AOM) methodology to create goal models and corresponding behavior interface models of BlockVoke. Subsequently, protocols semantics are defined, and the CPN models are derived and implemented using CPN Tools. Moreover, a full state-space analysis of the resulting CPN model is performed to derive relevant model properties of the protocol. The result is a complete and correct formal BlockVoke specification used to guide future implementations and security assessments.
Different Population Phenologies of Grapholita molesta (Busck) in Two Hosts and Two Nearby Regions in the NE of Spain
Authors: Amat Carles , Bosch-Serra Dolors , Avilla Jesús , Escudero Colomar Lucía Adriana
Published: July 2021

Grapholita molesta is an important pest of stone and pome fruits. In commercial orchards, integrated pest management programs use pheromone traps to monitor the population dynamics of G. molesta and adjust treatments. Phenology models can be used to forecast the population phenology of pests and to help optimise the time point at which to spray the orchards with insecticides. In the present study, the adult population phenologies of G. molesta in two provinces of north-east Spain were studied, as well as their fit to the phenology model most used in both provinces. Weekly captures of adults in pheromone traps through the season were recorded over 5 y in a large number of commercial orchards, and these data were used to determine the number of generations of G. molesta in each province. The results show significant differences between provinces in the generation time, being 97 degree days (DD) shorter in the Lleida province than in the Girona province. In Girona province, four generations were registered, while five were detected in Lleida. As a result of the differences found, the phenology model was not able to predict precisely the population dynamics in the Girona province.
Fight or Flight? Alternative Defense of the Pea Aphids, Acyrthosiphon pisum on Different Host Plants
Authors: Martin Martin John , Li Yueming , Ma Li , Feng Yi , Lu Zhiqiang
Published: July 2021

Non-immunological responses are important alternative strategies for animals to deal with pathogens. It has long been recognized that fecundity compensation and production of winged offspring are two common non-immunological responses used by aphids when confronted with predators or pathogens. However, the effects of host plant on these responses have received little attention. This study investigated the effects of host plant on non-immunological defense in the pea aphids, Acyrthosiphon pisum, after bacterial and fungal infections. The aphids were raised in two groups, with one group being raised on broad beans and the other group being raised on alfalfa. The secondary symbiont background was examined, and the aphids were then infected with bacteria and fungus to assess fecundity and winged offspring production. We found that aphids that had been fed alfalfa had fewer offspring than those fed broad beans. Alfalfa-fed aphids produced more winged offspring in response to S. aureus and B. bassiana infections. Our findings suggest that the host plant plays a key role in fecundity and winged offspring production in pea aphid colony.
An Active Plasma Beam Dump for EuPRAXIA Beams
Authors: Bonatto Alexandre , Nunes Roger Pizzato , Nunes Bruno Silveira , Kumar Sanjeev , Liang Linbo , Xia Guoxing
Published: July 2021

Plasma wakefields driven by high power lasers or relativistic particle beams can be orders of magnitude larger than the fields produced in conventional accelerating structures. Since the plasma wakefield is composed not only of accelerating but also of decelerating phases, this paper proposes to utilize the strong decelerating field induced by a laser pulse in the plasma to absorb the beam energy, in a scheme known as the active plasma beam dump. The design of this active plasma beam dump has considered the beam output by the EuPRAXIA facility. Analytical estimates were obtained, and compared with particle-in-cell simulations. The obtained results indicate that this active plasma beam dump can contribute for more compact, safer, and greener accelerators in the near future.
Independent Predicting Factors for Subcutaneous Emphysema Associated with Robotic-Assisted Laparoscopic Radical Prostatectomy: A Retrospective Single-Center Study
Authors: Yamamoto Waichi , Nishihara Tasuku , Hamada Taisuke , Takeuchi Mikiko , Nandate Hideyuki , Kitamura Sakiko , Takasaki Yasushi , Yorozuya Toshihiro
Published: July 2021

Objectives: Subcutaneous emphysema (SCE) is a complication associated with laparoscopic surgery. Severe SCE complicated by excessive hypercarbia may afford detrimental effects in surgical patients with cardiac dysfunction. Robotic-assisted laparoscopic radical prostatectomy (RALP) has several predisposing factors that contribute to SCE. The main purpose of our single-center retrospective study was to determine the preoperative and intraoperative predicting factors for SCE associated with RALP and to determine the actual incidence of SCE. Methods: In total, 229 adult male patients underwent standardized RALP for prostate cancer over the period of 1 May 2016 to 31 October 2018 at the Ehime University Hospital. We reviewed electronic clinical records for individual characteristics including age, body weight, height, coexisting disorders, preoperative ASA physical status, and the length of postoperative hospital stay. We also reviewed surgical and anesthetic records for the operation time, anesthetic method, and the partial pressure of end-tidal CO2 (PetCO2) during RALP. To determine the presence of SCE, we examined supine chest X-rays obtained after the completion of surgery. Results: We found 55 cases (24.0%) of SCE. Multiple logistic regression analysis showed that a BMI < 25 kg/m2 (OR: 3.0, 95% CI: 1.25–7.26) and a maximum value of PetCO2 of 46 mmHg or greater (OR: 23.3, 95% CI: 8.22–66.1) were independent predicting factors for SCE. Conclusion: These two predicting factors may be helpful to recognize the occurrence of SCE. Anesthesiologists should protect against SCE progression with the earlier detection of SCE for safe anesthetic management in patients undergoing RALP.
A Kinesio Taping Method Applied in the Treatment of Postsurgical Knee Swelling after Primary Total Knee Arthroplasty
Authors: Jarecki Jaromir , Sobiech Magdalena , Turżańska Karolina , Tomczyk-Warunek Agnieszka , Jabłoński Mirosław
Published: July 2021

Background The knee is one of the joints in the human body that is most susceptible of osteoarthritis (OA). In the case of advanced-stage OA, total knee arthroplasty (TKA) is a treatment of choice. One modern physiotherapeutic method to support the treatment in the early postsurgical period is Kinesio Taping (KT). The aim of this study is to evaluate the efficacy of KT on swollen subcutaneous tissue after TKA. Materials and methods. The studied group consisted of 23 patients who had received TKA. The mean BMI was 30.60 ± 4.91, and KT was applied between the 3rd and 8th day of the early postoperative period. The control group was constituted by 22 patients who had received TKA. The mean BMI was 30.41 ± 6.00, and KT was not applied. On the 3rd and 8th day after TKA, in all patients, the swelling of the shin, range of motions (ROM), and pain were measured using ultrasound, a goniometer, and a VAS scale, respectively. Results. In the KT group, the lateral measurement at the top of the head of the fibula significantly decreased between the 3rd and 8th day (11.47 ± 0.76 vs. 9.76 ± 0.77; p = 0.0004). The knee flexion angle on day 3 was statistically significantly different from that on day 8 (48.61 ± 3.08 vs. 72.74 ± 3.92; p = 0.00004). The evaluation results for severity of pain using the VAS scale on day 3 were statistically significantly higher than those on day 8 (5.74 ± 0.25 vs. 4.30 ± 0.25; p = 0.00006). In the group of patients to whom KT was not applied, the lateral measurement at the top of the head of the fibula on day 3 was not statistically significantly different from that on day 8 (10.323 ± 0.828 vs. 10.273 ± 0.995; p = 0.9227). The knee flexion angle in the group that did not receive KT on day 3 was statistically significantly different from that on day 8 (45.182 ± 3.654 vs. 59.909 ± 4.817; p = 0.0006). The severity of pain evaluated using the VAS scale on day 3 was statistically significantly different from that on day 8 (6.227 ± 0.146 vs. 4.864 ± 0.190; p = 0.0001). Conclusions. KT is an effective method for improving subcutaneous drainage and decreasing subcutaneous tissue. However, KT does not affect postoperative pain and ROM.
Predictive Factors of Pulmonary Embolism in Older Patients with SARS-CoV-2: The OCTA-COVID-19 Study
Authors: Quezada-Feijoo Maribel , Ramos Mónica , Lozano-Montoya Isabel , Toro Rocío , Jaramillo-Hídalgo Javier , Fernández de la Puente Eva , Garmendia Blanca , Carrillo Pamela , Cristofori Giovanna , Goñi Rosón Saleta , Ayala Rocío , Sarro Mónica , Gómez-Pavón Francisco J.
Published: July 2021

Background: The risk of pulmonary embolism (PE) has not been studied in older patients affected by COVID-19. We aimed to assess PE incidence and risk factors in a population of older patients infected with SARS-CoV-2. Methods: An ambispective, observational cohort study. A total of 305 patients ≥ 75 years old had the SARS-CoV-2 infection from March to May 2020. The incidence rate of PE was estimated as the proportion of new cases within the whole sample. Youden’s index was used to assess the cutoff point of D-dimer. To select factors associated with the risk of PE, time-to-event analyses were performed using cause-specific hazard models. Results: In total, 305 patients with a median age of 87 years (62.3% female) were studied; 67.9% were referred from nursing homes and 90.4% received any type of anticoagulation. A total of 64.9% showed frailty and 44% presented with dementia. The PE incidence was 5.6%. The cutoff value of a D-dimer level over 2.59 mg/L showed a sensitivity of 82.4% and specificity of 73.8% in discriminating a PE diagnosis. In the multivariate analysis, the factors associated with PE were previous oncological events and D-dimer levels. Conclusions: The PE incidence was 5.6%, and major risk factors for PE were oncological antecedents and increased plasma D-dimer levels.
Sex Differences Are Here to Stay: Relevance to Prenatal Care
Authors: Inkster Amy M. , Fernández-Boyano Icíar , Robinson Wendy P.
Published: July 2021

Sex differences exist in the incidence and presentation of many pregnancy complications, including but not limited to pregnancy loss, spontaneous preterm birth, and fetal growth restriction. Sex differences arise very early in development due to differential gene expression from the X and Y chromosomes, and later may also be influenced by the action of gonadal steroid hormones. Though offspring sex is not considered in most prenatal diagnostic or therapeutic strategies currently in use, it may be beneficial to consider sex differences and the associated mechanisms underlying pregnancy complications. This review will cover (i) the prevalence and presentation of sex differences that occur in perinatal complications, particularly with a focus on the placenta; (ii) possible mechanisms underlying the development of sex differences in placental function and pregnancy phenotypes; and (iii) knowledge gaps that should be addressed in the development of diagnostic or risk prediction tools for such complications, with an emphasis on those for which it would be important to consider sex.