bluuebunny/crossref_metadata_2025 huggingface dataset:
Environmental Protection or Development? Multiple Policy Effects Evaluation of the Resource Tax Collection Reform for Iron Ore Enterprises in China
Authors: Yin Yanhui , Yang Bowen
Published: February 2023

The change from quantity-based taxation to price-based taxation of iron ore resources is an important measure for China to implement the goal of carbon peaking and carbon neutralization, and to achieve green economic recovery. To explore the policy’s effectiveness in playing its tax function, and improving the environment and production efficiency, this paper takes the reform of the method of resource tax collection as the “quasi natural experiment” object, and selects the balanced panel data of 16 provinces in China from 2011 to 2021. The double difference method is used to evaluate the policy effect of the reform of resource tax collection. The research shows that: (1) Changing the resource tax from a “volume-based tax” to an “ad valorem tax” can effectively increase the government’s resource tax revenue, and promote the upgrading of enterprise production technology. (2) The reform of resource tax collection will eliminate some small and medium-sized enterprises that are backward in production technology and bring more pollution to the environment. (3) The reform of resource tax collection mode will increase the number of large and medium-sized iron ore enterprises and promote the standardization of the whole iron ore industry.
Consensus on Prioritisation of Actions for Reducing the Environmental Impact of a Large Tertiary Hospital: Application of the Nominal Group Technique
Authors: Davies Jessica F. , McGain Forbes , Francis Jillian J.
Published: February 2023

Hospitals are the largest greenhouse gas producers within the Australian healthcare sector due to the large amounts of energy, resource utilization, equipment and pharmaceuticals required to deliver care. In order to reduce healthcare emissions, healthcare services must take multiple actions to address the broad range of emissions produced when delivering patient care. The goal of this study was to seek consensus on the priority actions needed to reduce the environmental impact of a tertiary Australian hospital. A nominal group technique was utilized within a multidisciplinary, executive-led environmental sustainability committee to find consensus on the 62 proposed actions to reduce the environmental impact of a tertiary Australian hospital. Thirteen participants joined an online workshop during which an educational presentation was delivered, 62 potential actions were privately ranked according to two domains of ‘amenability to change’ and ‘scale of climate impact’ and a moderated group discussion ensued. The group achieved verbal consensus on 16 actions that span staff education, procurement, pharmaceuticals, waste, transport and advocacy on all-electric capital works upgrades. In addition, the individual ratings of potential actions according to each domain were ranked and shared with the group. Despite a large number of actions and varied perspectives within the group, the nominal group technique can be used to focus a hospital leadership group on priority actions to improve environmental sustainability.
Polychlorinated Diphenyl Ethers in the Environment: A Review and Future Perspectives
Authors: Wu Qiuxuan , Wu Qiong , Wang Xiaoxiang , Zhang Xuesheng , Zhang Rui
Published: February 2023

Polychlorinated diphenyl ethers (PCDEs) are a class of synthetic halogenated aromatic compounds, which have gradually attracted widespread attention due to potential environmental risks to humans and ecosystems. This paper presents a literature review of research on PCDEs using PubMed, Web of Science and Google Scholar as search engines/databases with no constraints on publishing year or number. A total of 98 publications on the sources, environmental levels, environmental behavior and fate, synthesis and analysis and toxicology of PCDEs were retrieved. Existing studies have shown that PCDEs widely exist in the environment with the ability of long-range transport, bioaccumulation and biomagnification, which are almost comparable to polychlorinated biphenyls. They can elicit adverse effects including hepatic oxidative stress, immunosuppression, endocrine disorders, growth retardation, malformations, reduced fertility and increased mortality in organisms, among which some seem to be related to the activation of the aryl hydrocarbon receptor. PCDEs can be metabolized into other organic pollutants, such as hydroxylated and methoxylated PCDEs and even polychlorinated dibenzo-p-dioxins and furans through biotransformation, photolysis and pyrolysis reactions in the environment. Compared with reviews on PCDEs published previously, some new information and findings are summarized in this review, such as new sources, current environmental exposure levels, main metabolism pathways in aquatic organisms, acute toxicity data for more species and relationships between structural parameters and toxicity and bioaccumulation potentials of PCDE congeners. Finally, current research deficiencies and future research perspectives are proposed to facilitate the assessment of health and ecological risks of PCDEs.
Evaluating Community Capability to Prevent and Control COVID-19 Pandemic in Shenyang, China: An Empirical Study Based on a Modified Framework of Community Readiness Model
Authors: Zhang Xiaojie , Liu Xiaoyu , Wang Lili
Published: February 2023

Community plays a crucial role in the successful prevention and control of the COVID-19 pandemic in China. However, evaluation of community capability to fight against COVID-19 is rarely reported. The present study provides a first attempt to assess community capability to combat COVID-19 in Shenyang, the capital city of Liaoning province in Northeast China, based on a modified framework of a community readiness model. We conducted semi-structured interviews with ninety key informants from fifteen randomly selected urban communities to collect the data. The empirical results indicate that the overall level of community capability for epidemic prevention and control in Shenyang was at the stage of preparation. The specific levels of the fifteen communities ranged from the stages of preplanning to preparation to initiation. Concerning the level of each dimension, community knowledge about the issue, leadership, and community attachment exhibited significant disparities between communities, while there were slight differences among communities on community efforts, community knowledge of efforts, and community resources. In addition, leadership demonstrated the highest overall level among all the six dimensions, followed by community attachment and community knowledge of efforts. Community resources displayed the lowest level, followed by community efforts. This study not only extends the application of the modified community readiness model to evaluate community capability of epidemic prevention in the Chinese community context, but also offers practical implications for enhancing Chinese communities’ capabilities to deal with various future public health emergencies.
Using Large-Scale Truck Trajectory Data to Explore the Location of Sustainable Urban Logistics Centres—The Case of Wuhan
Authors: Jiao Hongzan , Yang Faxing , Xu Shasha , Huang Shibiao
Published: February 2023

Urban logistics is important to a city’s sustainable growth and development. With the increase in population and the economic growth in urban areas, the issue of congestion and the negative influence of transport of goods on people and the environment is one of the most important factors in the development of urban logistics. By determining the optimal location of urban logistics centres, total transport costs of logistics, the flow of goods in urban areas and the greenhouse gas emissions will be reduced. However, the traditional methods are easily influenced by the ambiguity of objective data, which makes it difficult to accurately describe the logistics demand in the urban area. To address this issue, the improved location–allocation model for urban logistics centres based on truck trajectory data is proposed. After extracting the origin–destination points, the logistics service demand can be estimated by the DBSCAN (density-based spatial clustering of applications with noise) clustering method. Then, the location–allocation of logistics centres is determined by an improved P-median method with the supply capacity limitation for simultaneous delivery of goods in the logistics centres. To validate the model, taking Wuhan, a central logistics city in China, as an example, the model can effectively ensure the equitable distribution of logistics facilities, minimize freight expenses, achieve more uniformity in logistics center services, and foster sustainable development of the city’s logistics sector.
Purification of PaTx-II from the Venom of the Australian King Brown Snake and Characterization of Its Antimicrobial and Wound Healing Activities
Authors: Samy Ramar Perumal , Mackessy Stephen P. , Jeyasankar Alagarmalai , Ponraj Mano Ranjana , Franco Octavio Luiz , Cooper Matthew A. , Kandasamy Matheswaran , Mohanta Tapan Kumar , Bhagavathsingh Jebasingh , Vaiyapuri Sakthivel
Published: February 2023

Infections caused by multi-drug-resistant (MDR) bacteria are a global threat to human health. As venoms are the source of biochemically diverse bioactive proteins and peptides, we investigated the antimicrobial activity and murine skin infection model-based wound healing efficacy of a 13 kDa protein. The active component PaTx-II was isolated from the venom of Pseudechis australis (Australian King Brown or Mulga Snake). PaTx-II inhibited the growth of Gram-positive bacteria in vitro, with moderate potency (MICs of 25 µM) observed against S. aureus, E. aerogenes, and P. vulgaris. The antibiotic activity of PaTx-II was associated with the disruption of membrane integrity, pore formation, and lysis of bacterial cells, as evidenced by scanning and transmission microscopy. However, these effects were not observed with mammalian cells, and PaTx-II exhibited minimal cytotoxicity (CC50 > 1000 µM) toward skin/lung cells. Antimicrobial efficacy was then determined using a murine model of S. aureus skin infection. Topical application of PaTx-II (0.5 mg/kg) cleared S. aureus with concomitant increased vascularization and re-epithelialization, promoting wound healing. As small proteins and peptides can possess immunomodulatory effects to enhance microbial clearance, cytokines and collagen from the wound tissue samples were analyzed by immunoblots and immunoassays. The amounts of type I collagen in PaTx-II-treated sites were elevated compared to the vehicle controls, suggesting a potential role for collagen in facilitating the maturation of the dermal matrix during wound healing. Levels of the proinflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2) and interleukin-10 (IL-10), factors known to promote neovascularization, were substantially reduced by PaTx-II treatment. Further studies that characterize the contributions towards efficacy imparted by in vitro antimicrobial and immunomodulatory activity with PaTx-II are warranted.
Can T Cells Abort SARS-CoV-2 and Other Viral Infections?
Authors: Swadling Leo , Maini Mala K.
Published: February 2023

Despite the highly infectious nature of the SARS-CoV-2 virus, it is clear that some individuals with potential exposure, or even experimental challenge with the virus, resist developing a detectable infection. While a proportion of seronegative individuals will have completely avoided exposure to the virus, a growing body of evidence suggests a subset of individuals are exposed, but mediate rapid viral clearance before the infection is detected by PCR or seroconversion. This type of “abortive” infection likely represents a dead-end in transmission and precludes the possibility for development of disease. It is, therefore, a desirable outcome on exposure and a setting in which highly effective immunity can be studied. Here, we describe how early sampling of a new pandemic virus using sensitive immunoassays and a novel transcriptomic signature can identify abortive infections. Despite the challenges in identifying abortive infections, we highlight diverse lines of evidence supporting their occurrence. In particular, expansion of virus-specific T cells in seronegative individuals suggests abortive infections occur not only after exposure to SARS-CoV-2, but for other coronaviridae, and diverse viral infections of global health importance (e.g., HIV, HCV, HBV). We discuss unanswered questions related to abortive infection, such as: ‘Are we just missing antibodies? Are T cells an epiphenomenon? What is the influence of the dose of viral inoculum?’ Finally, we argue for a refinement of the current paradigm that T cells are only involved in clearing established infection; instead, we emphasise the importance of considering their role in terminating early viral replication by studying abortive infections.
A Postsynaptic Density Immediate Early Gene-Based Connectome Analysis of Acute NMDAR Blockade and Reversal Effect of Antipsychotic Administration
Authors: Barone Annarita , De Simone Giuseppe , Ciccarelli Mariateresa , Buonaguro Elisabetta Filomena , Tomasetti Carmine , Eramo Anna , Vellucci Licia , de Bartolomeis Andrea
Published: February 2023

Although antipsychotics’ mechanisms of action have been thoroughly investigated, they have not been fully elucidated at the network level. We tested the hypothesis that acute pre-treatment with ketamine (KET) and administration of asenapine (ASE) would modulate the functional connectivity of brain areas relevant to the pathophysiology of schizophrenia, based on transcript levels of Homer1a, an immediate early gene encoding a key molecule of the dendritic spine. Sprague–Dawley rats (n = 20) were assigned to KET (30 mg/kg) or vehicle (VEH). Each pre-treatment group (n = 10) was randomly split into two arms, receiving ASE (0.3 mg/kg), or VEH. Homer1a mRNA levels were evaluated by in situ hybridization in 33 regions of interest (ROIs). We computed all possible pairwise Pearson correlations and generated a network for each treatment group. Acute KET challenge was associated with negative correlations between the medial portion of cingulate cortex/indusium griseum and other ROIs, not detectable in other treatment groups. KET/ASE group showed significantly higher inter-correlations between medial cingulate cortex/indusium griseum and lateral putamen, the upper lip of the primary somatosensory cortex, septal area nuclei, and claustrum, in comparison to the KET/VEH network. ASE exposure was associated with changes in subcortical-cortical connectivity and an increase in centrality measures of the cingulate cortex and lateral septal nuclei. In conclusion, ASE was found to finely regulate brain connectivity by modelling the synaptic architecture and restoring a functional pattern of interregional co-activation.
Recent Progress in the Identification of Early Transition Biomarkers from Relapsing-Remitting to Progressive Multiple Sclerosis
Authors: Maier Smaranda , Barcutean Laura , Andone Sebastian , Manu Doina , Sarmasan Emanuela , Bajko Zoltan , Balasa Rodica
Published: February 2023

Despite extensive research into the pathophysiology of multiple sclerosis (MS) and recent developments in potent disease-modifying therapies (DMTs), two-thirds of relapsing-remitting MS patients transition to progressive MS (PMS). The main pathogenic mechanism in PMS is represented not by inflammation but by neurodegeneration, which leads to irreversible neurological disability. For this reason, this transition represents a critical factor for the long-term prognosis. Currently, the diagnosis of PMS can only be established retrospectively based on the progressive worsening of the disability over a period of at least 6 months. In some cases, the diagnosis of PMS is delayed for up to 3 years. With the approval of highly effective DMTs, some with proven effects on neurodegeneration, there is an urgent need for reliable biomarkers to identify this transition phase early and to select patients at a high risk of conversion to PMS. The purpose of this review is to discuss the progress made in the last decade in an attempt to find such a biomarker in the molecular field (serum and cerebrospinal fluid) between the magnetic resonance imaging parameters and optical coherence tomography measures.
Transcriptional Regulatory Network of Plant Cadmium Stress Response
Authors: Li Yakun , Ding Lihong , Zhou Mei , Chen Zhixiang , Ding Yanfei , Zhu Cheng
Published: February 2023

Cadmium (Cd) is a non-essential heavy metal with high toxicity to plants. Plants have acquired specialized mechanisms to sense, transport, and detoxify Cd. Recent studies have identified many transporters involved in Cd uptake, transport, and detoxification. However, the complex transcriptional regulatory networks involved in Cd response remain to be elucidated. Here, we provide an overview of current knowledge regarding transcriptional regulatory networks and post-translational regulation of the transcription factors involved in Cd response. An increasing number of reports indicate that epigenetic regulation and long non-coding and small RNAs are important in Cd-induced transcriptional responses. Several kinases play important roles in Cd signaling that activate transcriptional cascades. We also discuss the perspectives to reduce grain Cd content and improve crop tolerance to Cd stress, which provides a theoretical reference for food safety and the future research of plant varieties with low Cd accumulation.
Exosomes in Colorectal Cancer: From Physiology to Clinical Applications
Authors: Titu Stefan , Gata Vlad Alexandru , Decea Roxana Maria , Mocan Teodora , Dina Constantin , Irimie Alexandru , Lisencu Cosmin Ioan
Published: February 2023

Exosomes are nanosized vesicles that have been found to be involved in many diseases. Exosomes can mediate communication between cells in a variety of ways. Certain types of mediators derived from cancer cells can play a crucial role in the development of this pathology, promoting tumor growth, invasion, metastasis, angiogenesis, and immunomodulation. Exosomes in the bloodstream show promise as a future tool for detecting cancer at an early stage. The sensitivity and specificity of clinical exosome biomarkers need to be enhanced. Knowledge of exosomes is not only important for understanding the significance of cancer progression but also for providing clinicians with useful information for the diagnosis, treatment, and discovery of methods to prevent cancer from recurring. The widespread adoption of diagnostic tools based on exosomes may revolutionize cancer diagnosis and treatment. Tumor metastasis, chemoresistance, and immunity are all aided by exosomes. A potential new approach to cancer therapy involves preventing metastasis by inhibiting miRNA intracellular signaling and blocking the formation of pre-metastatic niches. For colorectal patients, exosomes represent a promising area of investigation for improving the diagnosis, treatment, and management. Reported data demonstrate that the serum expression level of certain exosomal miRNA is significantly higher in primary colorectal cancer patients. The present review discusses mechanisms and clinical implications of exosomes in colorectal cancer.
Cationic Pullulan Derivatives Based Flocculants for Removal of Some Metal Oxides from Simulated Wastewater
Authors: Ghimici Luminita , Nafureanu Maria Magdalena , Constantin Marieta
Published: February 2023

Modified polysaccharides have been increasingly used as flocculants in wastewater treatment due to their non-toxicity, low price, biodegradability, etc. However, the pullulan derivatives are less used in wastewater purification processes. Therefore, this article presents some data regarding FeO and TiO2 particle removal from model suspensions by some pullulan derivatives with pendant quaternary ammonium salt groups, trimethylammonium propyl carbamate chloride (TMAPx–P). The influence of the polymer ionic content, dose, and initial solution concentration as well as of the dispersion pH and composition (metal oxide content, salts, and kaolin) on the separation efficacy were considered. UV-Vis spectroscopy measurements have shown a very good removal efficacy of TMAPx–P for the FeO particles (around 95% and more), irrespective of the polymer and suspension characteristics; a lower clarification of the TiO2 particles suspension (removal efficiency between 68% and 75%) was noticed. Both the zeta potential and the particle aggregates size measurements revealed the charge patch as the main mechanism which governs the metal oxide removal process. The surface morphology analysis/EDX data provided supplementary evidence regarding the separation process. A good removal efficiency (90%) of the pullulan derivatives/FeO flocs for the Bordeaux mixture particles from simulated wastewater was found.
A Competition between Relative Stability and Binding Energy in Caffeine Phenyl-Glucose Aggregates: Implications in Biological Mechanisms
Authors: Calabrese Camilla , Camiruaga Ander , Parra-Santamaria Maider , Evangelisti Luca , Melandri Sonia , Maris Assimo , Usabiaga Imanol , Fernandez José A.
Published: February 2023

Hydrogen bonds and stacking interactions are pivotal in biological mechanisms, although their proper characterisation within a molecular complex remains a difficult task. We used quantum mechanical calculations to characterise the complex between caffeine and phenyl-β-D-glucopyranoside, in which several functional groups of the sugar derivative compete with each other to attract caffeine. Calculations at different levels of theory (M06-2X/6-311++G(d,p) and B3LYP-ED=GD3BJ/def2TZVP) agree to predict several structures similar in stability (relative energy) but with different affinity (binding energy). These computational results were experimentally verified by laser infrared spectroscopy, through which the caffeine·phenyl-β-D-glucopyranoside complex was identified in an isolated environment, produced under supersonic expansion conditions. The experimental observations correlate with the computational results. Caffeine shows intermolecular interaction preferences that combine both hydrogen bonding and stacking interactions. This dual behaviour had already been observed with phenol, and now with phenyl-β-D-glucopyranoside, it is confirmed and maximised. In fact, the size of the complex’s counterparts affects the maximisation of the intermolecular bond strength because of the conformational adaptability given by the stacking interaction. Comparison with the binding of caffeine within the orthosteric site of the A2A adenosine receptor shows that the more strongly bound caffeine·phenyl-β-D-glucopyranoside conformer mimics the interactions occurring within the receptor.
The Role of Alpha-Synuclein Deposits in Parkinson’s Disease: A Focus on the Human Retina
Authors: Di Pippo Mariachiara , Fragiotta Serena , Di Staso Federico , Scuderi Luca , Abdolrahimzadeh Solmaz
Published: February 2023

Parkinson’s disease (PD) is a neurodegenerative condition characterized by the progressive deterioration of dopaminergic neurons in the central and peripheral autonomous system and the intraneuronal cytoplasmic accumulation of misfolded α-synuclein. The clinical features are the classic triad of tremor, rigidity, and bradykinesia and a set of non-motor symptoms, including visual deficits. The latter seems to arise years before the onset of motor symptoms and reflects the course of brain disease. The retina, by virtue of its similarity to brain tissue, is an excellent site for the analysis of the known histopathological changes of PD that occur in the brain. Numerous studies conducted on animal and human models of PD have shown the presence of α-synuclein in retinal tissue. Spectral-domain optical coherence tomography (SD-OCT) could be a technique that enables the study of these retinal alterations in vivo. The objective of this review is to describe recent evidence on the accumulation of native or modified α-synuclein in the human retina of patients with PD and its effects on the retinal tissue evaluated through SD-OCT.
Anti-Spike Antibodies Present in the Milk of SARS-CoV-2 Vaccinated Mothers Are Complement-Activating
Authors: Agostinis Chiara , Toffoli Miriam , Balduit Andrea , Mangogna Alessandro , Yasmin Hadida , Ragazzon Chiara , Pegoraro Silvia , Campisciano Giuseppina , Stabile Guglielmo , Zito Gabriella , Kishore Uday , Comar Manola , Scrimin Federica , Bulla Roberta , Ricci Giuseppe
Published: February 2023

Although only 0.8–1% of SARS-CoV-2 infections are in the 0–9 age-group, pneumonia is still the leading cause of infant mortality globally. Antibodies specifically directed against SARS-CoV-2 spike protein (S) are produced during severe COVID-19 manifestations. Following vaccination, specific antibodies are also detected in the milk of breastfeeding mothers. Since antibody binding to viral antigens can trigger activation of the complement classical - pathway, we investigated antibody-dependent complement activation by anti-S immunoglobulins (Igs) present in breast milk following SARS-CoV-2 vaccination. This was in view of the fact that complement could play a fundamentally protective role against SARS-CoV-2 infection in newborns. Thus, 22 vaccinated, lactating healthcare and school workers were enrolled, and a sample of serum and milk was collected from each woman. We first tested for the presence of anti-S IgG and IgA in serum and milk of breastfeeding women by ELISA. We then measured the concentration of the first subcomponents of the three complement pathways (i.e., C1q, MBL, and C3) and the ability of anti-S Igs detected in milk to activate the complement in vitro. The current study demonstrated that vaccinated mothers have anti-S IgG in serum as well as in breast milk, which is capable of activating complement and may confer a protective benefit to breastfed newborns.
Virus-like Particles of Nodavirus Displaying the Receptor Binding Domain of SARS-CoV-2 Spike Protein: A Potential VLP-Based COVID-19 Vaccine
Authors: Kumar Kiven , Tan Wen Siang , Arshad Siti Suri , Ho Kok Lian
Published: February 2023

Since the outbreak of the coronavirus disease 2019 (COVID-19), various vaccines have been developed for emergency use. The efficacy of the initial vaccines based on the ancestral strain of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has become a point of contention due to the emergence of new variants of concern (VOCs). Therefore, continuous innovation of new vaccines is required to target upcoming VOCs. The receptor binding domain (RBD) of the virus spike (S) glycoprotein has been extensively used in vaccine development due to its role in host cell attachment and penetration. In this study, the RBDs of the Beta (β) and Delta (δ) variants were fused to the truncated Macrobrachium rosenbergii nodavirus capsid protein without the protruding domain (CΔ116-MrNV-CP). Immunization of BALB/c mice with the virus-like particles (VLPs) self-assembled from the recombinant CP showed that, with AddaVax as an adjuvant, a significantly high level of humoral response was elicited. Specifically, mice injected with equimolar of adjuvanted CΔ116-MrNV-CP fused with the RBD of the β- and δ-variants increased T helper (Th) cell production with a CD8+/CD4+ ratio of 0.42. This formulation also induced proliferation of macrophages and lymphocytes. Overall, this study demonstrated that the nodavirus truncated CP fused with the SARS-CoV-2 RBD has potential to be developed as a VLP-based COVID-19 vaccine.
Natural Alkaloids as Multi-Target Compounds towards Factors Implicated in Alzheimer’s Disease
Authors: Vrabec Rudolf , Blunden Gerald , Cahlíková Lucie
Published: February 2023

Alzheimer’s disease (AD) is the most common cause of dementia in elderly people; currently, there is no efficient treatment. Considering the increase in life expectancy worldwide AD rates are predicted to increase enormously, and thus the search for new AD drugs is urgently needed. A great amount of experimental and clinical evidence indicated that AD is a complex disorder characterized by widespread neurodegeneration of the CNS, with major involvement of the cholinergic system, causing progressive cognitive decline and dementia. The current treatment, based on the cholinergic hypothesis, is only symptomatic and mainly involves the restoration of acetylcholine (ACh) levels through the inhibition of acetylcholinesterase (AChE). Since the introduction of the Amaryllidaceae alkaloid galanthamine as an antidementia drug in 2001, alkaloids have been one of the most attractive groups for searching for new AD drugs. The present review aims to comprehensively summarize alkaloids of various origins as multi-target compounds for AD. From this point of view, the most promising compounds seem to be the β-carboline alkaloid harmine and several isoquinoline alkaloids since they can simultaneously inhibit several key enzymes of AD’s pathophysiology. However, this topic remains open for further research on detailed mechanisms of action and the synthesis of potentially better semi-synthetic analogues.
Lessons Learnt from COVID-19: Computational Strategies for Facing Present and Future Pandemics
Authors: Pavan Matteo , Moro Stefano
Published: February 2023

Since its outbreak in December 2019, the COVID-19 pandemic has caused the death of more than 6.5 million people around the world. The high transmissibility of its causative agent, the SARS-CoV-2 virus, coupled with its potentially lethal outcome, provoked a profound global economic and social crisis. The urgency of finding suitable pharmacological tools to tame the pandemic shed light on the ever-increasing importance of computer simulations in rationalizing and speeding up the design of new drugs, further stressing the need for developing quick and reliable methods to identify novel active molecules and characterize their mechanism of action. In the present work, we aim at providing the reader with a general overview of the COVID-19 pandemic, discussing the hallmarks in its management, from the initial attempts at drug repurposing to the commercialization of Paxlovid, the first orally available COVID-19 drug. Furthermore, we analyze and discuss the role of computer-aided drug discovery (CADD) techniques, especially those that fall in the structure-based drug design (SBDD) category, in facing present and future pandemics, by showcasing several successful examples of drug discovery campaigns where commonly used methods such as docking and molecular dynamics have been employed in the rational design of effective therapeutic entities against COVID-19.
Revisiting Cryptocyanine Dye, NK-4, as an Old and New Drug: Review and Future Perspectives
Authors: Liu Shihui , Matsuo Toshihiko , Abe Takumi
Published: February 2023

NK-4 plays a key role in the treatment of various diseases, such as in hay fever to expect anti-allergic effects, in bacterial infections and gum abscesses to expect anti-inflammatory effects, in scratches, cuts, and mouth sores from bites inside the mouth for enhanced wound healing, in herpes simplex virus (HSV)-1 infections for antiviral effects, and in peripheral nerve disease that causes tingling pain and numbness in hands and feet, while NK-4 is used also to expect antioxidative and neuroprotective effects. We review all therapeutic directions for the cyanine dye NK-4, as well as the pharmacological mechanism of NK-4 in animal models of related diseases. Currently, NK-4, which is sold as an over-the-counter drug in drugstores, is approved for treating allergic diseases, loss of appetite, sleepiness, anemia, peripheral neuropathy, acute suppurative diseases, wounds, heat injuries, frostbite, and tinea pedis in Japan. The therapeutic effects of NK-4’s antioxidative and neuroprotective properties in animal models are now under development, and we hope to apply these pharmacological effects of NK-4 to the treatment of more diseases. All experimental data suggest that different kinds of utility of NK-4 in the treatment of diseases can be developed based on the various pharmacological properties of NK-4. It is expected that NK-4 could be developed in more therapeutic strategies to treat many types of diseases, such as neurodegenerative and retinal degenerative diseases.
A2B Adenosine Receptor in Idiopathic Pulmonary Fibrosis: Pursuing Proper Pit Stop to Interfere with Disease Progression
Authors: Effendi Wiwin Is , Nagano Tatsuya
Published: February 2023

Purine nucleotides and nucleosides are involved in various human physiological and pathological mechanisms. The pathological deregulation of purinergic signaling contributes to various chronic respiratory diseases. Among the adenosine receptors, A2B has the lowest affinity such that it was long considered to have little pathophysiological significance. Many studies suggest that A2BAR plays protective roles during the early stage of acute inflammation. However, increased adenosine levels during chronic epithelial injury and inflammation might activate A2BAR, resulting in cellular effects relevant to the progression of pulmonary fibrosis.
Influence of Genetic Variations in miRNA and Genes Encoding Proteins in the miRNA Synthesis Complex on Toxicity of the Treatment of Pediatric B-Cell ALL in the Brazilian Amazon
Authors: da Silva Menezes Elisa , de Moraes Francisco Cezar Aquino , de Nazaré Cohen-Paes Amanda , Wanderley Alayde Vieira , Pereira Esdras Edgar Batista , Pastana Lucas Favacho , Modesto Antônio André Conde , de Assumpção Paulo Pimentel , Burbano Rommel Mario Rodríguez , dos Santos Sidney Emanuel Batista , dos Santos Ney Pereira Carneiro , Fernandes Marianne Rodrigues
Published: February 2023

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer in the world. Single nucleotide variants (SNVs) in miRNA and genes encoding proteins of the miRNA synthesis complex (SC) may affect the processing of drugs used in the treatment of ALL, resulting in treatment-related toxicities (TRTs). We investigated the role of 25 SNVs in microRNA genes and genes encoding proteins of the miRNA SC, in 77 patients treated for ALL-B from the Brazilian Amazon. The 25 SNVs were investigated using the TaqMan® OpenArray™ Genotyping System. SNVs rs2292832 (MIR149), rs2043556 (MIR605), and rs10505168 (MIR2053) were associated with an increased risk of developing Neurological Toxicity, while rs2505901 (MIR938) was associated with protection from this toxicity. MIR2053 (rs10505168) and MIR323B (rs56103835) were associated with protection from gastrointestinal toxicity, while DROSHA (rs639174) increased the risk of development. The rs2043556 (MIR605) variant was related to protection from infectious toxicity. SNVs rs12904 (MIR200C), rs3746444 (MIR499A), and rs10739971 (MIRLET7A1) were associated with a lower risk for severe hematologic toxicity during ALL treatment. These findings reveal the potential for the use of these genetic variants to understand the development of toxicities related to the treatment of ALL in patients from the Brazilian Amazon region.
Vertical Integration Dynamics to Innovate in Technology Business
Authors: Nogueira Pedro , Pereira Leandro , Simões Ana , Dias Alvaro , Lopes da Costa Renato
Published: February 2023

Companies try to acquire the finest advantages and techniques in a technologically advanced and end-to-end market to have a stronger foothold there. Although empirical research on this topic links IT to a decline in vertical integration, corporations are increasingly using this corporate strategy. The goal of this study is to show how over the past 22 years, scientific literature has changed with regard to how information technology (IT) affects vertical integration, one of the main types of corporate strategies. The findings demonstrated that vertical integration has been evolving in a balanced manner in a technological environment. Three categories—information technology, innovation, and processes—help explain this association and were discovered through cluster analysis. The direction of operational integration, the degree of industry concentration, demand unpredictability, and innovation should all be considered while making integration decisions.
Selectivity of Insecticides to a Pupal Parasitoid, Trichospilus diatraeae (Hymenoptera: Eulophidae), of Soybean Caterpillars
Authors: Pereira Helter Carlos , Pereira Fabricio Fagundes , Insabrald Vitor Bortolanza , Rodrigues Augusto , Lucchetta Jéssica Terilli , Silva Farley William Souza , Fernandes Winnie Cezario , Carneiro Zenilda de Fatima , Périgo Pedro Henrique Breda , Zanuncio José Cola
Published: February 2023

Selectivity is an important aspect of modern insecticides to be able to target pests whilst maintaining beneficial entomofauna in the crop. The present objective was to assess the selectivity of different insecticides for the pupal parasitoid of soybean caterpillars, i.e., Trichospilus diatraeae Cherian & Margabandhu, 1942 (Hymenoptera: Eulophidae). Acephate, azadirachtin, Bacillus thuringiensis (Bt), deltamethrin, lufenuron, teflubenzuron and thiamethoxam + lambda-cyhalothrin at the highest recommended concentrations for the soybean looper Chrysodeixis includens (Walker, [1858]) (Lepidoptera: Noctuidae), as well as water in the control, were used against the pupal parasitoid T. diatraeae. The insecticides and the control were sprayed on the soybean leaves, which were left to dry naturally and placed in cages with T. diatraeae females in each one. Survival data were submitted to analysis of variance (ANOVA) and the means were compared using Tukey’s HSD test (α = 0.05). Survival curves were plotted according to the Kaplan–Meier method, and the pairs of curves were compared using the log-rank test at 5% probability. The insecticides azadirachtin, Bt, lufenuron and teflubenzuron did not affect T. diatraeae survival, while deltamethrin and thiamethoxam + lambda-cyhalothrin presented low toxicity and acephate was highly toxic, causing 100% mortality in the parasitoid. Azadirachtin, Bt, lufenuron and teflubenzuron are selective for T. diatraeae and could be used in IPM programs.
Commissioning Results of the New Compact ECR Ion Source for Electrostatic Storage Ring at KACST
Authors: Alshammari Suliman , Jabr Abdullh , Jaddua Saad , Alabadusalam Abdulhakim
Published: February 2023

A compact microwave ECR ion source with low operating power was tested and commissioned for the ion injector line in the multipurpose low-energy ELASR storage ring facility at King Abdulaziz City for Science and Technology (KACST) in Riyadh. The compact ECR ion source can deliver singly charged ions with an energy of up to 50 keV and a beam current of up to 50 μA or up to 500 µA with a larger extraction aperture. The plasma in the ECR chamber is driven by a simple transmitter antenna, making the overall size of the ion source only 6 cm in diameter, which is relatively small when compared with other ECR systems. Additionally, the source operates without a high-voltage platform, which significantly reduces the overall footprint and simplifies the system operation. In this paper, the mechanical design and modeling of the ECR ion source are introduced, and the layout of the first part of the beam line is presented along with the numerical simulation results. In addition, the experimental results obtained for the first generated ion beam and commissioning of the ECR ion source are introduced and discussed.
CPVT and Complete Atrio-Ventricular Block: The Flipside of the Same Coin
Authors: Petrungaro Mattia , Scarà Antonio , Borrelli Alessio , Sciarra Luigi
Published: February 2023

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a rare electrical genetic disease characterized by ventricular polymorphic tachycardia and/or bidirectional ventricular tachycardia induced by the release of catecholamines caused by intense physical or emotional stress in structurally normal hearts. Mostly, it is caused by mutations in genes that are involved in calcium homeostasis, in particular in the gene encoding for cardiac ryanodine receptor (RyR2). Our observation is the first description of familial CPVT caused by mutation of the RyR2 gene, linked to the complete AV block.
A Pilot Trial to Compare the Long-Term Efficacy of Pulmonary Vein Isolation with High-Power Short-Duration Radiofrequency Versus Laser Energy with Rapid Ablation Mode
Authors: Schildt Sönke , Fredersdorf Sabine , Jungbauer Carsten G. , Hauck Christian , Tarnowski Daniel , Debl Kurt , Neef Stefan , Schach Christian , Sossalla Samuel , Maier Lars S. , Üçer Ekrem
Published: February 2023

Background: Pulmonary vein (PV) reconnection is the major cause of atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI). The probability of reconnection is higher if the primary lesion is not sufficiently effective, which can be unmasked with an adenosine provocation test (APT). High-power short-duration radiofrequency energy (HPSD) guided with ablation index (AI) and the third generation of the visually guided laser balloon (VGLB) are new methods for PVI. Methods: A total of 70 participants (35 in each group) who underwent a PVI with either AI-guided HPSD (50 W; AI 500 for the anterior and 400 for the posterior wall, respectively) or VGLB ablation were included in this observational pilot trial. Twenty minutes after each PVI, an APT was performed. The primary endpoint was the event-free survival from AF after three years. Results: A total of 137 (100%) PVs in the HPSD arm and 131 PVs (98.5%) in the VGLB arm were initially successfully isolated (p = 0.24). The overall procedure duration was similar in both arms (155 ± 39 in HPSD vs. 175 ± 58 min in VGLB, p = 0.191). Fluoroscopy time, left atrial dwelling time and duration from the first to the last ablation were longer in the VGLB arm (23 ± 8 vs. 12 ± 3 min, p < 0.001; 157 (111–185) vs. 134 (104–154) min, p = 0.049; 92(59–108) vs. 72 (43–85) min, p = 0.010). A total of 127 (93%) in the HPSD arm and 126 (95%) PVs in the VGLB arm remained isolated after APT (p = 0.34). The primary endpoint was met 1107 ± 68 days after ablation in 71% vs. 66% in the VGLB and HPSD arms, respectively (p = 0.65). Conclusions: HPSD and VGLB did not differ with respect to long-term outcome of PVI. A large, randomized study should be conducted to compare clinical outcomes with respect to these new ablation techniques.
Hybrid-Total Ankle Arthroplasty (H-TAA) for Failed Talar Component in Mobile-Bearing Total Ankle Arthroplasty
Authors: Santini Simone , Alharbi Waheeb , Teoh Kar Hao , Herrera-Perez Mario , Valderrabano Victor
Published: February 2023

Introduction: Revision Total Ankle Arthroplasty (TAA) surgery due to TAA aseptic loosening is increasing. It is possible to exchange the talar component and inlay to another system for isolated talar component loosening in a primary mobile-bearing TAA: Hybrid-Total Ankle Arthroplasty (H-TAA). The purpose of this study was to analyze the results of the revision surgery of an isolated aseptic talar component loosening in a mobile-bearing three-component TAA with a H-TAA solution. Methods: In this prospective case study, nine patients (six women, three men; mean age 59.8 years; range 41–80 years) with symptomatic isolated aseptic loosening of the talar component of a mobile-bearing TAA were treated with an isolated talar component and inlay substitution. In all nine cases, a hybrid TAA revision surgery was performed by implanting a VANTAGE TAA talar and insert component (Flatcut talar component: six cases, standard talar component: three cases). The patients were reviewed with the pain score (VAS Pain Score 0–10), Dorsiflexion/Plantarflexion (DF/PF) Range of Motion (ROM; degrees), the American Orthopaedic Foot and Ankle Society (AOFAS) Ankle/Hindfoot Score (0–100 points), Sports Frequency Score (Level 0–4), and subjective Patients’ Satisfaction Score (0–10 points). Results: The average Pain score improved significantly from preoperative 6.7 points to postoperative 1.1 points (p < 0.001). Average Dorsiflexion/Plantarflexion ROM values increased significantly post-surgery: 21.7° preoperative to 45.6° postoperative (p < 0.001). The postoperative AOFAS scores were significantly greater than the preoperative values: 47.7 points preoperative, 92.3 points postoperative (p < 0.001). The sports activity improved from preoperative to postoperative where, preoperative, none of the patients were able to perform sports. Postoperative, eight patients were able to be sports-active again. The overall average postoperative level of sports activity was 1.4. The postoperative average patient’s satisfaction was 9.3 points. Conclusions: In painful talar component aseptic loosening of a three-component mobile-bearing TAA, H-TAA is a good surgical solution for reducing pain, restoring ankle function, and improving patients’ life quality.
Provocation and Localization of Arrhythmogenic Triggers from Persistent Left Superior Vena Cava in Patients with Atrial Fibrillation
Authors: Minami Kentaro , Nakamura Kohki , Maeno Eiko , Iida Keitaro , Saito Ikuta , Masuyama Taiki , Kitagawa Yoshiyuki , Nakajima Toshiaki , Nakatani Yosuke , Naito Shigeto , Toyoda Shigeru , Chovanec Milan , Petrů Jan , Škoda Jan , Kumagai Koji , Neužil Petr
Published: February 2023

Background: Although pulmonary vein isolation (PVI) is an established procedure for atrial fibrillation (AF), non-PV foci play a crucial role in AF recurrence. Persistent left superior vena cava (PLSVC) has been reported as critical non-PV foci. However, the effectiveness of provocation of AF triggers from PLSVC remains unclear. This study was designed to validate the usefulness of provoking AF triggers from PLSVC. Methods: This multicenter retrospective study included 37 patients with AF and PLSVC. To provoke triggers, AF was cardioverted, and re-initiation of AF was monitored under high-dose isoproterenol infusion. The patients were divided into two groups: those whose PLSVC had arrhythmogenic triggers initiating AF (Group A) and those whose PLSVC did not have triggers (Group B). Group A underwent isolation of PLSVC after PVI. Group B received PVI only. Results: Group A had 14 patients, whereas Group B had 23 patients. After a 3-year follow-up, no difference in the success rate for maintaining sinus rhythm was observed between the two groups. Group A was significantly younger and had lower CHADS2-VASc scores than Group B. Conclusions: The provocation of arrhythmogenic triggers from PLSVC was effective for the ablation strategy. PLSVC electrical isolation would not be necessary if arrhythmogenic triggers are not provoked.