bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolutionary Challenges to Humanity Caused by Uncontrolled Carbon Emissions: The Stockholm Paradigm
Authors: Boguslavsky Dmitry V. , Sharova Natalia P. , Sharov Konstantin S.
Published: December 2022

This review paper discusses the Stockholm Paradigm (SP) as a theoretical framework and practical computational instrument for studying and assessing the risk of emerging infectious diseases (EIDs) as a result of climate change. The SP resolves the long-standing parasite paradox and explains how carbon emissions in the atmosphere increase parasites’ generalization and intensify host switches from animals to humans. The SP argues that the growing rate of novel EID occurrence caused by mutated zoonotic pathogens is related to the following factors brought together as a unified issue of humanity: (a) carbon emissions and consequent climate change; (b) resettlement/migration of people with hyper-urbanization; (c) overpopulation; and (d) human-induced distortion of the biosphere. The SP demonstrates that, in an evolutionary way, humans now play a role migratory birds once played in spreading parasite pathogens between the three Earth megabiotopes (northern coniferous forest belt; tropical/equatorial rainforest areas; and hot/cold deserts), i.e., the role of “super-spreaders” of parasitic viruses, bacteria, fungi and protozoa. This makes humans extremely vulnerable to the EID threat. The SP sees the +1.0–+1.2 °C limit as the optimal target for the slow, yet feasible curbing of the EID hazard to public health (150–200 years). Reaching merely the +2.0 °C level will obviously be an EID catastrophe, as it may cause two or three pandemics each year. We think it useful and advisable to include the SP-based research in the scientific repository of the Intergovernmental Panel on Climate Change, since EID appearance and spread are indirect but extremely dangerous consequences of climate change.
Effects of Land Reclamation on Soil Bacterial Community and Potential Functions in Bauxite Mining Area
Authors: Li Xuesong , Jin Zhenjiang , Xiong Liyuan , Tong Lingchen , Zhu Hongying , Zhang Xiaowen , Qin Guangfa
Published: December 2022

Studying the characteristics of microorganisms in mine reclamation sites can provide a scientific reference basis for mine land reclamation. Soils in the plough layer (0–20 cm) of the bauxite mine plots in Pingguo city, Guangxi Zhuang Autonomous Region, China, with different reclamation years were used as the research objects. The community structure of soil bacteria was analyzed with high-throughput sequencing technology. The results show the following: (1) Reclamation significantly increased the contents of soil nutrients (p < 0.05). (2) The relative abundances of Proteobacteria were high (22.90~41.56%) in all plots, and reclamation significantly reduced the relative abundances of Firmicutes (3.42–10.77%) compared to that in the control plot (24.74%) (p < 0.05). The relative abundances of α-proteobacteria generally increased while the reclamation year increased. The relative abundances of α-proteobacteria and γ-proteobacteria showed significant positive correlations with soil carbon, nitrogen, and phosphorus nutrients (p < 0.01). The relative abundance of Acidobacteria Group 6 showed significant positive correlations with soil exchangeable Ca and Mg (p < 0.01). (3) Bacterial co-occurrence network showed more Copresence interactions in all plots (50.81–58.39%). The reclaimed plots had more nodes, higher modularity, and longer characteristic path length than the control plot, and the keystone taxa changed in different plots. (4) The chemoheterotrophy and aerobic chemoheterotrophy were the most abundant functional groups in all plots (35.66–48.26%), while reclamation reduced the relative abundance of fermentation groups (1.75–11.21%). The above findings indicated that reclamation improved soil nutrients, changed the bacterial community structure and potential functions, and accelerated the microbial stabilization of the reclaimed soil.
Rural Spatial Differentiation and Revitalization Approaches in China: A Case Study of Qingdao City
Authors: Cheng Xiaohua , Xu Difei , Sun Hui , Zheng Meiyi , Li Jintao
Published: December 2022

Rural revitalization, as a major strategy with the goal of realizing the overall development of strong agriculture industries, beautiful rural areas, and rich farmers, is an effective way of alleviating the loss of talent, land, capital, and other elements in rural areas and a possible cure for “rural diseases”. However, “rural diseases” faced by villages are very different, and thus exploring suitable strategies for rural revitalization is beneficial to the implementation of rural revitalization strategies and the promotion of urban–rural integration. Based on location theory, this paper constructs a point–axis–domain three-dimensional spatial location theory model that integrates market location, traffic location, and natural location and combines the coupling coordination model to comprehensively study the vitality and development directions of Qingdao’s rural areas. Results found that Qingdao’s high-level and medium–high-level coupling coordination areas are the main types of coupling coordination, accounting for 45.19% and 47.48%, respectively. Based on the development status of Qingdao, this study explores development directions for rural revitalization poles as well as high-level, medium–high-level, and medium-level coupling coordination areas and suggests the following: rural revitalization poles should play a demonstration role in rural revitalization in terms of industrial development, rural civilization, social governance, public service construction, etc.; high-level coupling coordination areas should focus on building modern hi-tech agriculture and rural marine tourism industries; medium–high-level coupling coordination areas should strengthen the building of satellite towns and promote industrial transformation and upgrading; medium-level coupling coordination areas should actively develop ecological environment conservation models and establish a characteristic mountainous eco-tourism industry. Thus, the findings provide important scientific reference for the implementation of rural revitalization.
Testing Small-Scale Vitality Measurement Based on 5D Model Assessment with Multi-Source Data: A Resettlement Community Case in Suzhou
Authors: Chen Jinliu , Tian Wenkang , Xu Kexin , Pellegrini Paola
Published: December 2022

In China’s fourteenth five-year plan, urban regeneration has become one of the most crucial strategies for activating the existing cities. Since creating vibrant urban spaces is a critical component of urban regeneration, understanding the patterns of community vitality helps formulate reactive regeneration policies and design interventions. However, the lack of local-scale measurement criteria and data collection methods has posed significant constraints to assessing and rejuvenating community vitality. Taking Suzhou Nanhuan New Village as a study area, our research involved a comparative study approach to investigate the fundamental driving mechanism of urban vitality with the support of a theoretical model (5D theory), multi-source data input, real-time photography technologies, and statistical analysis tools (Analytic Hierarchy Process). The result shows at the community level, the original ‘3d’ dimensions (‘Density’, ‘Diversity’, ‘Design’) remain key elements for forming vibrant spatial quality and functionality, and density factors matter significantly. This study intends to provide a new paradigm for small-scale community vitality assessment, verification, and regeneration by combining urban morphology with people-oriented and environmental-oriented perspectives. This research could support quantitative research on creating vibrant high-density communities in the urban regeneration process and bring insights to academics and design practitioners.
Role of Oxidative Stress in Peyronie’s Disease: Biochemical Evidence and Experiences of Treatment with Antioxidants
Authors: Paulis Gianni , De Giorgio Giovanni , Paulis Luca
Published: December 2022

Background: Peyronie’s disease (PD) is a chronic inflammatory condition affecting adult males, involving the tunica albuginea of the corpora cavernosa of the penis. PD is frequently associated with penile pain, erectile dysfunction, and a secondary anxious–depressive state. The etiology of PD has not yet been completely elucidated, but local injury is generally recognized to be a triggering factor. It has also been widely proven that oxidative stress is an essential, decisive component in all inflammatory processes, whether acute or chronic. Current conservative medical treatment comprises oral substances, penile injections, and physical therapy. Aim: This article intends to show how antioxidant therapy is able to interfere with the pathogenetic mechanisms of the disease. Method: This article consists of a synthetic narrative review of the current scientific literature on antioxidant therapy for this disease. Results: The good results of the antioxidant treatment described above also prove that the doses used were adequate and the concentrations of the substances employed did not exceed the threshold at which they might have interacted negatively with the mechanisms of the redox regulation of tissue. Conclusions: We believe new, randomized, controlled studies are needed to confirm the efficacy of treatment with antioxidants. However, we consider the experiences of antioxidant treatment which can already be found in the literature useful for the clinical practice of urologists in the treatment of this chronic inflammatory disease.
The Mammalian Cysteine Protease Legumain in Health and Disease
Authors: Solberg Rigmor , Lunde Ngoc Nguyen , Forbord Karl Martin , Okla Meshail , Kassem Moustapha , Jafari Abbas
Published: December 2022

The cysteine protease legumain (also known as asparaginyl endopeptidase or δ-secretase) is the only known mammalian asparaginyl endopeptidase and is primarily localized to the endolysosomal system, although it is also found extracellularly as a secreted protein. Legumain is involved in the regulation of diverse biological processes and tissue homeostasis, and in the pathogenesis of various malignant and nonmalignant diseases. In addition to its proteolytic activity that leads to the degradation or activation of different substrates, legumain has also been shown to have a nonproteolytic ligase function. This review summarizes the current knowledge about legumain functions in health and disease, including kidney homeostasis, hematopoietic homeostasis, bone remodeling, cardiovascular and cerebrovascular diseases, fibrosis, aging and senescence, neurodegenerative diseases and cancer. In addition, this review addresses the effects of some marketed drugs on legumain. Expanding our knowledge on legumain will delineate the importance of this enzyme in regulating physiological processes and disease conditions.
A Novel Senescence-Specific Gene (ZmSAG39) Negatively Regulates Darkness and Drought Responses in Maize
Authors: Wang Chunlai , Gao Bai , Chen Nannan , Jiao Peng , Jiang Zhenzhong , Zhao Chunli , Ma Yiyong , Guan Shuyan , Liu Siyan
Published: December 2022

The papain-like cysteine proteases (PLCPs) is a subfamily of cysteine proteases that plays an important role in leaf senescence, and some of its members are involved in the regulation of plant growth and development under stress. In this study, we cloned a new gene, ZmSAG39, from maize. Expression profile analysis showed that ZmSAG39 was induced by darkness and drought treatments. In addition, the ZmSAG39 overexpression in maize accelerated the senescence of maize leaves under darkness and drought treatments. However, the knockout of ZmSAG39 in maize enhanced the resistance of maize to darkness and drought stresses and reduced the degree of senescence of maize leaves. Under drought stress, compared with WT plants, the knockout lines had a higher seed germination rate, seedling survival rate and chlorophyll content, and lower reactive oxygen species (ROS) level and malondialdehyde (MDA) content. In addition, quantitative real-time PCR (qRT-PCR) analysis showed that ZmSAG39 negatively regulated some stress-related genes but positively regulated senescence-related genes under darkness and drought stress conditions. To summarize, these results indicate that ZmSAG39 is a senescence-related gene and plays a negative role in response to darkness and drought stresses. This study laid a theoretical foundation for the innovation of maize germplasm resources with high quality, high yield and strong stress resistance.
The Impact of Taste Preference-Related Gene Polymorphisms on Alcohol Consumption Behavior: A Systematic Review
Authors: Kurshed Ali Abbas Mohammad , Ádány Róza , Diószegi Judit
Published: December 2022

Unhealthy alcohol consumption is recognized as a leading contributory factor to mortality and disability. In addition to other factors, taste sensation also mediates alcohol intake. The orosensation provoked by alcoholic drinks may vary across individuals and may be responsible for differences in preference for alcoholic beverages. Thus, individual genetic variability of taste preference may have an impact on alcohol consumption practices. The present review aimed to explore the associations between different taste preference polymorphisms and alcohol consumption behavior. Based on the PRISMA statement, the three databases PubMed, Web of Science and ProQuest Central were searched to identify articles and the Q-Genie tool was used to assess the quality of the included studies. Among the 17 studies included in this review, 5 and 12 were of good and moderate quality, respectively. Most of the studies analyzed TAS2R38 (taste 2 receptor member 38) rs713598, rs1726866, rs10246939 polymorphisms. Due to the inconclusive findings on these variants and the very limited number of studies on other polymorphisms, additional extensive research is recommended to replicate the existing findings, to generate new knowledge to enhance our understanding of the complexity of alcohol consumption behavior and to aid the development of personalized recommendations on unhealthy alcohol use.
Shock-Driven Endotheliopathy in Trauma Patients Is Associated with Leucocyte Derived Extracellular Vesicles
Authors: Dujardin Romein W. G. , Kisters Jeske E. C. , Wirtz Mathijs R. , Hajji Najat , Tuip-de Boer Anita M. , Stensballe Jakob , Johansson Pär I. , Brohi Karim , Davenport Ross A. , Gaarder Christine , Stanworth Simon , Maegele Marc , Nieuwland Rienk , van der Pol Edwin , Juffermans Nicole P.
Published: December 2022

Endotheliopathy following trauma is associated with poor outcome, but the underlying mechanisms are unknown. This study hypothesized that an increased extracellular vesicle (EV) concentration is associated with endotheliopathy after trauma and that red blood cell (RBC) transfusion could further enhance endotheliopathy. In this post hoc sub study of a multicentre observational trial, 75 trauma patients were stratified into three groups based on injury severity score or shock. In patient plasma obtained at hospital admission and after transfusion of four RBC transfusions, markers for endotheliopathy were measured and EVs were labelled with anti CD41 (platelet EVs), anti CD235a (red blood cell EVs), anti CD45 (leucocyte EVs), anti CD144 (endothelial EVs) or anti CD62e (activated endothelial EVs) and EV concentrations were measured with flow cytometry. Statistical analysis was performed by a Kruskall Wallis test with Bonferroni correction or Wilcoxon rank test for paired data. In patients with shock, syndecan-1 and von Willebrand Factor (vWF) were increased compared to patients without shock. Additionally, patients with shock had increased red blood cell EV and leucocyte EV concentrations compared to patients without shock. Endotheliopathy markers correlated with leucocyte EVs (ρ = 0.263, p = 0.023), but not with EVs derived from other cells. Injury severity score had no relation with EV release. RBC transfusion increased circulating red blood cell EVs but did not impact endotheliopathy. In conclusion, shock is (weakly) associated with EVs from leucocytes, suggesting an immune driven pathway mediated (at least in part) by shock.
Novel Small Molecule Positive Allosteric Modulator SPAM1 Triggers the Nuclear Translocation of PAC1-R to Exert Neuroprotective Effects through Neuron-Restrictive Silencer Factor
Authors: Fan Guangchun , Chen Shang , Liang Lili , Zhang Huahua , Yu Rongjie
Published: December 2022

The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) exerts effective neuroprotective activity through its specific receptor, PAC1-R. We accidentally discovered that as a positive allosteric modulator (PAM) of PAC1-R, the small-molecule PAM (SPAM1) has a hydrazide-like structure, but different binding characteristics, from hydrazide for the N-terminal extracellular domain of PAC1-R (PAC1-R-EC1). SPAM1 had a significant neuroprotective effect against oxidative stress, both in a cell model treated with hydrogen peroxide (H2O2) and an aging mouse model induced by D-galactose (D-gal). SPAM1 was found to block the decrease in PACAP levels in brain tissues induced by D-gal and significantly induced the nuclear translocation of PAC1-R in PAC1R-CHO cells and mouse retinal ganglion cells. Nuclear PAC1-R was subjected to fragmentation and the nuclear 35 kDa, but not the 15 kDa fragments, of PAC1-R interacted with SP1 to upregulate the expression of Huntingtin (Htt), which then exerted a neuroprotective effect by attenuating the binding availability of the neuron-restrictive silencer factor (NRSF) to the neuron-restrictive silencer element (NRSE). This resulted in an upregulation of the expression of NRSF-related neuropeptides, including PACAP, the brain-derived neurotrophic factor (BDNF), tyrosine hydroxylase (TH), and synapsin-1 (SYN1). The novel mechanism reported in this study indicates that SPAM1 has potential use as a drug, as it exerts a neuroprotective effect by regulating NRSF.
Antiviral Activity and Crystal Structures of HIV-1 gp120 Antagonists
Authors: Curreli Francesca , Kwon Young D. , Nicolau Isabella , Burgos Giancarla , Altieri Andrea , Kurkin Alexander V. , Verardi Raffaello , Kwong Peter D. , Debnath Asim K.
Published: December 2022

As part of our effort to discover drugs that target HIV-1 entry, we report the antiviral activity and crystal structures of two novel inhibitors in a complex with a gp120 core. NBD-14204 showed similar antiviral activity against all the clinical isolates tested. The IC50 values were in the range of 0.24–0.9 µM with an overall mean of 0.47 ± 0.03 µM, showing slightly better activity against the clinical isolates than against the lab-adapted HIV-1HXB2 (IC50 = 0.96 ± 0.1 µM). Moreover, the antiviral activity of NBD-14208 was less consistent, showing a wider range of IC50 values (0.66–5.7 µM) with an overall mean of 3 ± 0.25 µM and better activity against subtypes B and D (Mean IC50 2.2–2.5 µM) than the A, C and Rec viruses (Mean IC50 2.9–3.9 µM). SI of NBD-14204 was about 10-fold higher than NBD-14208, making it a better lead compound for further optimization. In addition, we tested these compounds against S375Y and S375H mutants of gp120, which occurred in some clades and observed these to be sensitive to NBD-14204 and NBD-14208. These inhibitors also showed modest activity against HIV-1 reverse transcriptase. Furthermore, we determined the crystal structures of both inhibitors in complexes with gp120 cores. As expected, both NBD-14204 and NBD-14208 bind primarily within the Phe43 cavity. It is noteworthy that the electron density of the thiazole ring in both structures was poorly defined due to the flexibility of this scaffold, suggesting that these compounds maintain substantial entropy, even when bound to the Phe43 cavity.
Anti-Psoriatic Effect of Rheum palmatum L. and Its Underlying Molecular Mechanisms
Authors: Nguyen Ly Thi Huong , Ahn Sang-Hyun , Shin Heung-Mook , Yang In-Jun
Published: December 2022

Psoriasis is a chronic, immune-mediated inflammatory skin disorder. Rheum palmatum L. is a common traditional medicinal herb with anti-inflammatory and immunomodulatory activities. This study aimed to investigate the anti-psoriatic effects of the ethanolic extract from R. palmatum L. (RPE) and its chemical constituents, as well as the mechanisms underlying their therapeutic significance. An imiquimod (IMQ)-induced psoriasis-like mouse model was used to examine the anti-psoriatic effect of RPE in vivo. Network pharmacological analysis was performed to investigate the potential targets and related pathways of the RPE components, including rhein, emodin, chrysophanol, aloe-emodin, and physcion. The anti-inflammatory effects and underlying mechanisms of these components were examined using in vitro models. Topical application of RPE alleviated psoriasis-like symptoms and reduced levels of inflammatory cytokines and proliferation markers in the skin. Network pharmacological analysis revealed that RPE components target 20 genes that are linked to psoriasis-related pathways, such as IL-17, MAPK, and TNF signaling pathways. Among the five components of RPE, rhein and emodin showed inhibitory effects on TNF-α and IL-17 production in EL-4 cells, attenuated the production of CXCL8, CXCL10, CCL20, and MMP9, and reduced proliferation in HaCaT cells. Chrysophanol, aloe-emodin, and physcion were less effective than rhein and emodin in suppressing inflammatory responses and keratinocyte proliferation. The effects of these compounds might occur through the inhibition of the ERK, STAT3, and NF-κB signaling pathways. This study suggested the anti-psoriatic effect of RPE, with rhein and emodin as the main contributors that regulate multiple signaling pathways.
Olive Oil in the Mediterranean Diet and Its Biochemical and Molecular Effects on Cardiovascular Health through an Analysis of Genetics and Epigenetics
Authors: Riolo Renata , De Rosa Riccardo , Simonetta Irene , Tuttolomondo Antonino
Published: December 2022

Human nutrition is a relatively new science based on biochemistry and the effects of food constituents. Ancient medicine considered many foods as remedies for physical performance or the treatment of diseases and, since ancient times, especially Greek, Asian and pre-Christian cultures similarly thought that they had beneficial effects on health, while others believed some foods were capable of causing illness. Hippocrates described the food as a form of medicine and stated that a balanced diet could help individuals stay healthy. Understanding molecular nutrition, the interaction between nutrients and DNA, and obtaining specific biomarkers could help formulate a diet in which food is not only a food but also a drug. Therefore, this study aims to analyze the role of the Mediterranean diet and olive oil on cardiovascular risk and to identify their influence from the genetic and epigenetic point of view to understand their possible protective effects.
Photoluminescent Polymer Aerogels with R, G and B Emission
Authors: Stan Loredana , Malutan Teodor , Volf Irina , Popa Marcel , Tincu Camelia E. , Stan Corneliu S.
Published: December 2022

In this work, three new polymer aerogels based on 2-hydroxy ethyl methacrylate (HEMA) complexes with Eu(III), Tb(III) and La(III) are prepared and investigated. The polymer aerogels present strong photoluminescence with emissions located in the red, green and blue regions of the visible spectrum. Depending on the water content used during the preparation path, the consistency of the photoluminescent aerogels varies from rigid, regularly shaped monoliths to a flexible, fibrous material with very low density. The morpho-structural investigation was performed by FT-IR, XPS and SEM. Thermal behavior was also evaluated, while steady-state fluorescence spectroscopy, absolute PLQY and lifetime were used for the investigation of their luminescent properties. The impressive photoluminescent emission located in the red, green and blue areas of the visible spectrum is preserved irrespective of the selected porosity. Their photo-emissive properties, tunable porosity and the convenience of the preparation path could be some arguments for applications as photonic conversion mediums in special-purpose optoelectronic devices or sensors.
Molecular Pathology, Diagnostics, and Therapeutics of Nephropathy
Authors: Kronbichler Andreas , Tesar Vladimir
Published: December 2022

Years of standing still have ended, and the field of nephrology has seen a plethora of clinical trials, changing the therapeutic landscape of chronic kidney disease (CKD) and immune-mediated kidney disease management [...]
Identification of Darunavir Derivatives for Inhibition of SARS-CoV-2 3CLpro
Authors: Ma Ling , Xie Yongli , Zhu Mei , Yi Dongrong , Zhao Jianyuan , Guo Saisai , Zhang Yongxin , Wang Jing , Li Quanjie , Wang Yucheng , Cen Shan
Published: December 2022

The effective antiviral agents that treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed around the world. The 3C-like protease (3CLpro) of SARS-CoV-2 plays a pivotal role in virus replication; it also has become an important therapeutic target for the infection of SARS-CoV-2. In this work, we have identified Darunavir derivatives that inhibit the 3CLpro through a high-throughput screening method based on a fluorescence resonance energy transfer (FRET) assay in vitro. We found that the compounds 29# and 50# containing polyphenol and caffeine derivatives as the P2 ligand, respectively, exhibited favorable anti-3CLpro potency with EC50 values of 6.3 μM and 3.5 μM and were shown to bind to SARS-CoV-2 3CLpro in vitro. Moreover, we analyzed the binding mode of the DRV in the 3CLpro through molecular docking. Importantly, 29# and 50# exhibited a similar activity against the protease in Omicron variants. The inhibitory effect of compounds 29# and 50# on the SARS-CoV-2 3CLpro warrants that they are worth being the template to design functionally improved inhibitors for the treatment of COVID-19.
Exposure to Endocrine Disruptors (Di(2-Ethylhexyl)phthalate (DEHP) and Bisphenol A (BPA)) in Women from Different Residing Areas in Italy: Data from the LIFE PERSUADED Project
Authors: Carli Fabrizia , Tait Sabrina , Busani Luca , Ciociaro Demetrio , Della Latta Veronica , Pala Anna Paola , Deodati Annalisa , Raffaelli Andrea , Pratesi Filippo , Conte Raffaele , Maranghi Francesca , Tassinari Roberta , Fabbrizi Enrica , Toffol Giacomo , Cianfarani Stefano , La Rocca Cinzia , Gastaldelli Amalia ,   LIFE PERSUADED Project Group
Published: December 2022

Phthalates and bisphenol A (BPA) are plasticizers used in many industrial products that can act as endocrine disruptors and lead to metabolic diseases. During the LIFE PERSUADED project, we measured the urinary concentrations of BPA and Di(2-ethylhexyl)phthalate (DEHP) metabolites in 900 Italian women representative of the Italian female adult population (living in the north, centre, and south of Italy in both rural and urban areas). The whole cohort was exposed to DEHP and BPA with measurable levels above limit of detection in more than 99% and 95% of the samples, respectively. The exposure patterns differed for the two chemicals in the three macro-areas with the highest urinary levels for DEHP in south compared to central and northern Italy and for BPA in northern compared to central and southern Italy. BPA levels were higher in women living in urban areas, whereas no difference between areas was observed for DEHP. The estimated daily intake of BPA was 0.11 μg/kg per day, about 36-fold below the current temporary tolerable daily intake of 4 μg/kg per day established by the EFSA in 2015. The analysis of cumulative exposure showed a positive correlation between DEHP and BPA. Further, the reduction of exposure to DEHP and BPA, through specific legislative measures, is necessary to limit the harmfulness of these substances.
Anti-SOD1 Nanobodies That Stabilize Misfolded SOD1 Proteins Also Promote Neurite Outgrowth in Mutant SOD1 Human Neurons
Authors: Kumar Meenakshi Sundaram , Fowler-Magaw Megan E. , Kulick Daniel , Boopathy Sivakumar , Gadd Del Hayden , Rotunno Melissa , Douthwright Catherine , Golebiowski Diane , Yusuf Issa , Xu Zuoshang , Brown Robert H. , Sena-Esteves Miguel , O'Neil Alison L. , Bosco Daryl A.
Published: December 2022

ALS-linked mutations induce aberrant conformations within the SOD1 protein that are thought to underlie the pathogenic mechanism of SOD1-mediated ALS. Although clinical trials are underway for gene silencing of SOD1, these approaches reduce both wild-type and mutated forms of SOD1. Here, we sought to develop anti-SOD1 nanobodies with selectivity for mutant and misfolded forms of human SOD1 over wild-type SOD1. Characterization of two anti-SOD1 nanobodies revealed that these biologics stabilize mutant SOD1 in vitro. Further, SOD1 expression levels were enhanced and the physiological subcellular localization of mutant SOD1 was restored upon co-expression of anti-SOD1 nanobodies in immortalized cells. In human motor neurons harboring the SOD1 A4V mutation, anti-SOD1 nanobody expression promoted neurite outgrowth, demonstrating a protective effect of anti-SOD1 nanobodies in otherwise unhealthy cells. In vitro assays revealed that an anti-SOD1 nanobody exhibited selectivity for human mutant SOD1 over endogenous murine SOD1, thus supporting the preclinical utility of anti-SOD1 nanobodies for testing in animal models of ALS. In sum, the anti-SOD1 nanobodies developed and presented herein represent viable biologics for further preclinical testing in human and mouse models of ALS.
Circulating Extracellular Vesicles: Their Role in Patients with Abdominal Aortic Aneurysm (AAA) Undergoing EndoVascular Aortic Repair (EVAR)
Authors: Serafini Francesco Lorenzo , Delli Pizzi Andrea , Simeone Pasquale , Giammarino Alberto , Mannetta Cristian , Villani Michela , Izzi Jacopo , Buca Davide , Catitti Giulia , Chiacchiaretta Piero , Trebeschi Stefano , Miscia Sebastiano , Caulo Massimo , Lanuti Paola
Published: December 2022

Abdominal aortic aneurysm (AAA) is a frequent aortic disease. If the diameter of the aorta is larger than 5 cm, an open surgical repair (OSR) or an endovascular aortic repair (EVAR) are recommended. To prevent possible complications (i.e., endoleaks), EVAR-treated patients need to be monitored for 5 years following the intervention, using computed tomography angiography (CTA). However, this radiological method involves high radiation exposure in terms of CTA/year. In such a context, the study of peripheral-blood-circulating extracellular vesicles (pbcEVs) has great potential to identify biomarkers for EVAR complications. We analyzed several phenotypes of pbcEVs using polychromatic flow cytometry in 22 patients with AAA eligible for EVAR. From each enrolled patient, peripheral blood samples were collected at AAA diagnosis, and after 1, 6, and 12 months following EVAR implantation, i.e. during the diagnostic follow-up protocol. Patients developing an endoleak displayed a significant decrease in activated-platelet-derived EVs between the baseline condition and 6 months after EVAR intervention. Furthermore, we also observed, that 1 month after EVAR implantation, patients developing an endoleak showed higher concentrations of activated-endothelial-derived EVs than patients who did not develop one, suggesting their great potential as a noninvasive and specific biomarker for early identification of EVAR complications.
Markers of Oxidative Stress, Inflammation and Endothelial Function following High-Dose Intravenous Iron in Patients with Non-Dialysis-Dependent Chronic Kidney Disease—A Pooled Analysis
Authors: Kassianides Xenophon , White Steven , Bhandari Sunil
Published: December 2022

Chronic kidney disease (CKD) represents a state of oxidative stress imbalance, which is potentially amplified by iron deficiency. Intravenous iron is considered safe and efficacious in the treatment of iron deficiency anemia, however, concerns remain regarding its potential pro-oxidant effect, leading to inflammatory and endothelial consequences. This pooled analysis of two pilot randomized controlled trials aimed to group and analyze the potential effect of high-dose intravenous iron (ferric derisomaltose, 1000 mg) on markers of oxidative stress (thiobarbituric acid reactive substance), inflammation (C-reactive protein, interleukins 6 and 10) and endothelial response (E-selectin, P-selectin) in patients with non-dialysis-dependent CKD and iron deficiency with/without anemia. Pulse wave velocity as a surrogate measure of arterial stiffness was measured. Thirty-six patients were included. No statistically significant trend was identified for any of the aforementioned markers. Stratification and comparison of data based on CKD stage did not yield statistically significant trajectories with the exception of the C-reactive protein in CKD stage 3b. These results suggest that high-dose intravenous iron does not impact measures of oxidative stress or inflammation; however, the results are not conclusive. Further research in a larger cohort is necessary to characterize the effect of intravenous iron on oxidative status and inflammation and its potential sequela in CKD.
Differential Regulation of Two Arms of mTORC1 Pathway Fine-Tunes Global Protein Synthesis in Resting B Lymphocytes
Authors: Dev Gagan , Chawla Amanpreet Singh , Gupta Suman , Bal Vineeta , George Anna , Rath Satyajit , Arimbasseri G. Aneeshkumar
Published: December 2022

Protein synthesis is tightly regulated by both gene-specific and global mechanisms to match the metabolic and proliferative demands of the cell. While the regulation of global protein synthesis in response to mitogen or stress signals is relatively well understood in multiple experimental systems, how different cell types fine-tune their basal protein synthesis rate is not known. In a previous study, we showed that resting B and T lymphocytes exhibit dramatic differences in their metabolic profile, with implications for their post-activation function. Here, we show that resting B cells, despite being quiescent, exhibit increased protein synthesis in vivo as well as ex vivo. The increased protein synthesis in B cells is driven by mTORC1, which exhibits an intermediate level of activation in these cells when compared with resting T cells and activated B cells. A comparative analysis of the transcriptome and translatome of these cells indicates that the genes encoding the MHC Class II molecules and their chaperone CD74 are highly translated in B cells. These data suggest that the translatome of B cells shows enrichment for genes associated with antigen processing and presentation. Even though the B cells exhibit higher mTORC1 levels, they prevent the translational activation of TOP mRNAs, which are mostly constituted by ribosomal proteins and other translation factors, by upregulating 4EBP1 levels. This mechanism may keep the protein synthesis machinery under check while enabling higher levels of translation in B cells.
Functional Characterization of Novel Bony Fish Lipoxygenase Isoforms and Their Possible Involvement in Inflammation
Authors: Roigas Sophie , Heydeck Dagmar , Kuhn Hartmut
Published: December 2022

Eicosanoids and related compounds are pleiotropic lipid mediators, which are biosynthesized in mammals via three distinct metabolic pathways (cyclooxygenase pathway, lipoxygenase pathway, epoxygenase pathway). These mediators have been implicated in the pathogenesis of inflammatory diseases and drugs interfering with eicosanoid signaling are currently available as antiphlogistics. Eicosanoid biosynthesis has well been explored in mammals including men, but much less detailed information is currently available on eicosanoid biosynthesis in other vertebrates including bony fish. There are a few reports in the literature describing the expression of arachidonic acid lipoxygenases (ALOX isoforms) in several bony fish species but except for two zebrafish ALOX-isoforms (zfALOX1 and zfALOX2) bony fish eicosanoid biosynthesizing enzymes have not been characterized. To fill this gap and to explore the possible roles of ALOX15 orthologs in bony fish inflammation we cloned and expressed putative ALOX15 orthologs from three different bony fish species (N. furzeri, P. nyererei, S. formosus) as recombinant N-terminal his-tag fusion proteins and characterized the corresponding enzymes with respect to their catalytic properties (temperature-dependence, activation energy, pH-dependence, substrate affinity and substrate specificity with different polyenoic fatty acids). Furthermore, we identified the chemical structure of the dominant oxygenation products formed by the recombinant enzymes from different free fatty acids and from more complex lipid substrates. Taken together, our data indicate that functional ALOX isoforms occur in bony fish but that their catalytic properties are different from those of mammalian enzymes. The possible roles of these ALOX-isoforms in bony fish inflammation are discussed.
Antiplatelet Therapy Aims and Strategies in Asian Patients with Acute Coronary Syndrome or Stable Coronary Artery Disease
Authors: Tam Chor-Cheung , Tse Hung-Fat
Published: December 2022

Dual antiplatelet therapy (DAPT) has been the mainstay treatment to reduce ischemic events, such as myocardial infarction or stroke, in patients with coronary artery disease (CAD). The development of potent P2Y12 inhibitors (ticagrelor and prasugrel) has helped to further reduce ischemic events, particularly among high-risk patients. Meanwhile, the evolution of newer generations of drug-eluting stents are also improving outcomes of percutaneous coronary intervention. Research studies on antiplatelet therapy in recent years have focused on balancing ischemic and bleeding risks through different strategies, which include P2Y12 inhibitor monotherapy, escalation and de-escalation, and extended DAPT. Because results from the large number of clinical studies may sometimes appear conflicting, this review aims to summarize recent advances, and demonstrate that they are aligned by a general principle, namely, strategies may be adopted based on treatment aims for specific patients at several time points. Another aim of this review is to outline the important considerations for using antiplatelet therapy in Asian patients, in whom there is a greater prevalence of CYP2C19 loss-of-function mutations, and a common increased risk of bleeding, despite high platelet reactivity (the so-called “East Asian Paradox”).
Spontaneous Breathing and Pendelluft in Patients with Acute Lung Injury: A Narrative Review
Authors: Su Po-Lan , Zhao Zhanqi , Ko Yen-Fen , Chen Chang-Wen , Cheng Kuo-Sheng
Published: December 2022

Acute respiratory distress syndrome (ARDS) is characterized by acute-onset rapid-deteriorating inflammatory lung injury. Although the preservation of spontaneous breathing may have physiological benefits in oxygenation, increasing evidence shows that vigorous spontaneous breathing may aggravate lung injury (i.e., patient self-inflicted lung injury). Increased lung stress and pendelluft, which is defined as intrapulmonary gas redistribution without a significant change in tidal volume, are important mechanisms of patient self-inflicted lung injury. The presence of pendelluft may be considered a surrogate marker of vigorous inspiratory effort, which can cause the dependent lung to overstretch. In this review, we summarized three major methods for electrical impedance tomography–based pendelluft monitoring. Future studies are warranted to compare and validate the different methods of pendelluft estimation in patients with ARDS.
Associations of Circulating Irisin and Fibroblast Growth Factor-21 Levels with Measures of Energy Homeostasis in Highly Trained Adolescent Rhythmic Gymnasts
Authors: Jürimäe Jaak , Remmel Liina , Tamm Anna-Liisa , Purge Priit , Maasalu Katre , Tillmann Vallo
Published: December 2022

The aim of this investigation was to determine the associations of serum irisin and fibroblast growth factor-21 (FGF-21) with the measures of energy homeostasis, training stress and other energy homeostasis hormones in highly trained adolescent rhythmic gymnasts (RG). Thirty-three RG and 20 untrained controls (UC) aged 14–18 years participated in this study. Body composition, resting energy expenditure (REE), peak oxygen consumption, and different energy homeostasis hormones in serum, including irisin, FGF-21, leptin, and resistin, were measured. Irisin and FGF-21 were not significantly different (p > 0.05) between RG and UC groups. In RG, serum irisin was positively associated with REE (r = 0.40; p = 0.021) and leptin (r = 0.60; p = 0.013), while serum FGF-21 was related to body fat mass (r = 0.46; p = 0.007) and leptin (r = 0.45; p = 0.009). Irisin was related to FGF-21, independent of age, body fat, and lean masses (r = 0.36; p = 0.049) in RG. In conclusion, serum irisin concentration was associated with energy expenditure and serum FGF-21 level with energy availability measures in lean adolescent athletes, while no relationships of irisin and FGF-21 with energy status measures were observed in lean nonathletic adolescents.
New Perspectives on the Adverse Effects of NSAIDs in Cancer Pain: An Italian Delphi Study from the Rational Use of Analgesics (RUA) Group
Authors: Varrassi Giustino , Coluzzi Flaminia , Fornasari Diego , Fusco Flavio , Gianni Walter , Guardamagna Vittorio Andrea , Puntillo Filomena , Sotgiu Giovanni
Published: December 2022

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed drugs for cancer pain. We used the Delphi methodology to evaluate the opinions of clinicians on NSAIDs and paracetamol, with a specific focus on their safety profile. Consensus was reached on seven statements. A high level of consensus was reached regarding the use of NSAIDs and gastrointestinal, cardiovascular, and renal risk in patients taking low-dose aspirin and assessment of liver function during long-term treatment with paracetamol. Consensus was also reached that assessment and monitoring of eGFR are important in the elderly being administered NSAIDs. It was further agreed that NSAIDs can often play a key role in association with opioids in the treatment of cancer pain and that paracetamol is the analgesic of first choice for patients with mild chronic pain. When NSAIDs are administered in combination with steroids, it was agreed that the risk of gastrointestinal damage is increased since steroids delay the healing of ulcers and that paracetamol can be used during pregnancy and does not affect the health of the fetus. This Delphi study highlights that there is poor agreement on how these drugs are routinely prescribed. However, a consensus was reached for seven key statements and may represent a valid contribution to daily practice.
Assessing the Efficacy of Early Therapies against SARS-CoV-2 in Hematological Patients: A Real-Life Study from a COVID-19 Referral Centre in Northern Italy
Authors: Colaneri Marta , Pieri Teresa Chiara , Roda Silvia , Ricciardi Alessandra , Gotti Manuel , Ferrari Jacqueline , Arcaini Luca , Rattotti Sara , Piralla Antonio , Giardina Federica , Ferrari Guglielmo , Sacchi Paolo , Zuccaro Valentina , Baldanti Fausto , Bruno Raffaele
Published: December 2022

Early therapies to prevent severe COVID-19 have an unclear impact on patients with hematological malignancies. The aim of this study was to assess their efficacy in this group of high-risk patients with COVID-19 in preventing hospitalizations and reducing the SARS-CoV-2 shedding. This was a single-center, retrospective, observational study conducted in the Fondazione IRCSS Policlinico San Matteo of Pavia, Northern Italy. We extracted the data of patients with hematologic malignancies and COVID-19 who received and did not receive early COVID-19 treatment between 23 December 2021, and May 2022. We used a Cox proportional hazard model to assess whether receiving any early treatment was associated with lower rates of hospitalization and reduced viral shedding. Data from 88 patients with hematologic malignancies were extracted. Among the patients, 55 (62%) received any early treatment, whereas 33 (38%) did not. Receiving any early therapy did not significantly reduce the hospitalization rate in patients with hematologic malignancies (HR 0.51; SE 0.63; p-value = 0.28), except in the vaccinated non-responders subgroup of patients with negative anti SARS-CoV-2 antibodies at the time of infection, who benefited from early therapies against SARS-CoV-2 (HR 0.07; SE 1.04; p-value = 0.001). Moreover, no difference on viral load decay was observed. In our cohort of patients with hematologic malignancies infected with SARS-CoV-2, early treatment were not effective in reducing the hospitalization rate due to COVID-19, neither in reducing its viral shedding.
A Review of Ophthalmic Complications in Inflammatory Bowel Diseases
Authors: Pytrus Wiktoria , Akutko Katarzyna , Pytrus Tomasz , Turno-Kręcicka Anna
Published: December 2022

Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic immune-mediated conditions caused by various polygenic and environmental factors. Clinical manifestations of IBD primarily occur in the gastrointestinal tract, but many patients are affected by extraintestinal complications, including eye diseases. Ocular disorders are the third most common extraintestinal manifestation (EIM), following musculoskeletal and mucocutaneous involvement. Episcleritis, frequently occurring in IBD patients, may be associated with exacerbation of the intestinal disease. Uveitis does not correlate with IBD activity but may be related to the presence of other EIMs, particularly erythema nodosum and peripheral arthritis. Early detection and specific therapy of ocular manifestations of IBD are fundamental to avoiding sight-threatening complications. Therefore, ophthalmic evaluation should be performed in all IBD patients. Systemic corticosteroids or immunosuppressants may be inevitable in severe cases to control ocular inflammation. Persistent and relapsing conditions usually respond well to TNF-α-inhibitors. Interdisciplinary cooperation between gastroenterologists and ophthalmologists is fundamental in initiating the appropriate treatment for patients.
Evidence for Local Antibiotics in the Prevention of Infection in Orthopaedic Trauma
Authors: Flores Michael J. , Brown Kelsey E. , Morshed Saam , Shearer David W.
Published: December 2022

Prevention of fracture-related infection (FRI) remains a substantial challenge in orthopaedic trauma care. There is evolving evidence to support the use of local antibiotics for both the prevention and treatment of musculoskeletal infection. Local antibiotics can achieve higher local tissue concentrations with a lower risk of systemic complications compared to intravenously administered antibiotics. These antibiotics may be administered in powder or liquid form without carrier, or if sustained release is desired, using a carrier. Polymethylmethacrylate (PMMA), ceramics, and hydrogels are examples of antibiotic carriers. Unlike PMMA, ceramics and hydrogels have the advantage of not requiring a second surgery for removal. The VANCO trial supported the use of powdered vancomycin in high-risk fracture cases for the reduction of Gram-positive infections; although, data is limited. Future studies will evaluate the use of aminoglycoside antibiotics to address Gram-negative infection prevention. While theoretical concerns exist with the use of local antibiotics, available studies suggest local antibiotics are safe with a low-risk of adverse effects.