bluuebunny/crossref_metadata_2025 huggingface dataset:
Living Alone, Physical Health, and Mortality in Breast Cancer Survivors: A Prospective Observational Cohort Study
Authors: Doyle Cassie , Ko Eunjeong , Lemus Hector , Hsu Fang-Chi , Pierce John P. , Wu Tianying
Published: August 2023

Living alone, particularly for individuals with poor physical health, can increase the likelihood of mortality. This study aimed to explore the individual and joint associations of living alone and physical health with overall mortality among breast cancer survivors in the Women’s Healthy Eating and Living (WHEL). We collected baseline, 12-month and 48-month data among 2869 women enrolled in the WHEL cohort. Living alone was assessed as a binary variable (Yes, No), while scores of physical health were measured using the RAND Short Form–36 survey (SF-36), which include four domains (physical function, role limitation, bodily pain, and general health perceptions) and an overall summary score of physical health. Cox proportional hazard models were used to evaluate associations. No significant association between living alone and mortality was observed. However, several physical health measures showed significant associations with mortality (p-values < 0.05). For physical function, the multivariable model showed a hazard ratio (HR) of 2.1 (95% CI = 1.02–4.23). Furthermore, the study examined the joint impact of living alone and physical health measures on overall mortality. Among women with better physical function, those living alone had a 3.6-fold higher risk of death (95% CI = 1.01–12.89) compared to those not living alone. Similar trends were observed for pain. However, regarding role limitation, the pattern differed. Breast cancer survivors living alone with worse role limitations had the highest mortality compared to those not living alone but with better role limitations (HR = 2.6, 95% CI = 1.11–5.95). Similar trends were observed for general health perceptions. Our findings highlight that living alone amplifies the risk of mortality among breast cancer survivors within specific health groups.
Disruptions to and Innovations in HPV Vaccination Strategies within Safety-Net Healthcare Settings Resulting from the COVID-19 Pandemic
Authors: Garcia Samantha , Shin Michelle , Sloan Kylie , Dang Emily , Garcia Carlos Orellana , Baezconde-Garbanati Lourdes , Palinkas Lawrence A. , Crabtree Benjamin F. , Tsui Jennifer
Published: August 2023

The COVID-19 pandemic disrupted healthcare delivery within safety-net settings. Barriers to and facilitators of human papillomavirus (HPV) vaccination during the pandemic can inform future HPV vaccine strategies for underserved communities. Qualitative interviews (n = 52) between December 2020 and January 2022 in Los Angeles and New Jersey were conducted with providers, clinic leaders, clinic staff, advocates, payers, and policy-level representatives involved in the HPV vaccine process. Using the updated Consolidated Framework for Implementation Research we identified (1) outer setting barriers (i.e., vaccine hesitancy driven by social media, political views during the pandemic) and facilitators (e.g., partnerships); (2) inner setting clinic facilitators (i.e., motivation-driven clinic metrics, patient outreach, vaccine outreach events); (3) individual characteristics such as patient barriers (i.e., less likely to utilize clinic services during the pandemic and therefore, additional outreach to address missed vaccine doses are needed); (4) innovations in HPV vaccination strategies (i.e., clinic workflow changes to minimize exposure to COVID-19, leveraging new community partnerships (e.g., with local schools)); and (5) implementation strategies (i.e., multisectoral commitment to HPV goals). Pandemic setbacks forced safety-net settings to develop new vaccine approaches and partnerships that may translate to new implementation strategies for HPV vaccination within local contexts and communities.
Biological Control Mechanisms of Bacillus cabrialesii subsp. tritici TSO2T against Fusarium languescens, the Causal Agent of Wilt in Jalapeño Peppers
Authors: Montoya-Martínez Amelia C. , Figueroa-Brambila Karem M. , Escalante-Beltrán Alina , López-Montoya Naomi D. , Valenzuela-Ruíz Valeria , Parra-Cota Fannie I. , Estrada Alvarado María Isabel , de los Santos-Villalobos Sergio
Published: August 2023

Jalapeño peppers (Capsicum annuum var. Jalapeño) represent one of the most important crops in Mexico. However, many plant diseases, such as wilt caused by strains of the genus Fusarium, reduce its yield. A sustainable alternative to control diseases is the use of biological control agents (BCAs), for example, beneficial microorganisms such as strains of the genus Bacillus. This study aims to analyze the potential use of B. cabrialesii subsp. tritici TSO2T as a BCA and elucidate its potential modes of action against Fusarium strains causing wilt in Jalapeño peppers. For this, symptomatic samples were collected in a commercial field in the Yaqui Valley, Mexico. Six Fusarium isolates were morphologically and molecularly characterized. After pathogenicity tests, F. languescens CE2 was found to be pathogenic. In screening assays for biocontrol bacteria, strain TSO2T, which was isolated from soil in a wheat commercial field under an organic production system and preserved in the Culture Collection of Native Soil and Endophytic Microorganisms (COLMENA), had the best biocontrol effect against CE2, and its cell-free filtrate reduced mycelial growth by 30.95%. Genome mining (antiSMASH) of strain TSO2T allows us to identify gene clusters associated with biocontrol, such as fengycin, surfactin, bacillibactin, bacilysin, bacillaene, subtilosin A, and sporulation killing factor, which codify to antimicrobial metabolites and are associated with swarming motility of the studied beneficial strain. These results demonstrate the effectiveness of B. cabrialesii subsp. tritici TSO2T as a potential BCA for the control of Fusarium wilt, through competition and a complex of antifungal metabolites, which still need to be validated through metabolomic analysis. This study highlights the importance of the use of integrative genomic and bioactivity-guided methodologies in understanding biocontrol pathosystems.
Shoot Dieback in Thornless Blackberries in Northern Spain Caused by Diaporthe rudis and Gnomoniopsis idaeicola
Authors: González Ana J. , Ciordia Marta
Published: August 2023

A cane disease of a non-commercial thornless blackberry cultivar (genus Rubus, subgenus Rubus Watson) obtained in a breeding program was observed in May 2021 in northern Spain during a field evaluation. Symptoms of the disease appeared in spring and firstly consisted of dark-brown lesions in the petioles, tips, and intermediate zones of the canes, finally causing the leaves, canes, and lateral shoots to die. Two strains were recovered from infected canes and identified by morphological characteristics and multigene analysis as Gnomoniopsis idaeicola (LPPAF-977) and Diaporthe rudis (LPPAF-981). Pathogenicity tests showed that both fungi caused shoot dieback when artificially inoculated, reproducing the symptoms originally observed. Moreover, tissue necrosis was enhanced when Diaporthe rudis and Gnomoniopsis idaeicola were co-inoculated. This is the first report of Diaporthe rudis and Gnomoniopsis idaeicola causing a potentially serious disease to blackberries in Spain.
Modeling Hydrodynamic Behavior of the Ottawa River: Harnessing the Power of Numerical Simulation and Machine Learning for Enhanced Predictability
Authors: Cardi Jean , Dussel Antony , Letessier Clara , Ebtehaj Isa , Gumiere Silvio Jose , Bonakdari Hossein
Published: August 2023

The Ottawa River Watershed is a vast area that stretches across Ontario and Quebec and holds great importance for Canada’s people, economy, and collective history, both in the present and the future. The river has faced numerous floods in recent years due to climate change. The most significant flood occurred in 2019, surpassing a 100-year flood event, and serves as a stark reminder of how climate change impacts our environment. Considering the limitations of machine learning (ML) models, which heavily rely on historical data used during training, they may struggle to accurately predict such “non-experienced” or “unseen” floods that were not encountered during the training process. To tackle this challenge, our study has utilized a combination of numerical modeling and ML to create an integrated methodology. Indeed, a comprehensive dataset of river flow discharge was generated using a numerical model, encompassing a wide range of potential future floods. This significantly improved the ML training process to generalize the accuracy of results. Utilizing this dataset, a novel ML model called the Expanded Framework of Group Method of Data Handling (EFGMDH) has been developed. Its purpose is to provide decision-makers with explicit equations for estimating three crucial hydrodynamic characteristics of the Ottawa River: floodplain width, flow velocity, and river flow depth. These predictions rely on various inputs, including the location of the desired cross-section, river slope, Manning roughness coefficient at different river sections (right, left, and middle), and river flow discharge. To establish practical models for each of the aforementioned hydrodynamic characteristics of the Ottawa River, different input combinations were tested to identify the most optimal ones. The EFGMDH model demonstrated high accuracy throughout the training and testing stages, achieving an R2 value exceeding 0.99. The proposed model’s exceptional performance demonstrates its reliability and practical applications for the study area.
Geostatistics on Real-Time Geodata Streams—High-Frequent Dynamic Autocorrelation with an Extended Spatiotemporal Moran’s I Index
Authors: Lemmerz Thomas , Herlé Stefan , Blankenbach Jörg
Published: August 2023

The availability of spatial and spatiotemporal big data is increasing rapidly. Spatially and temporally high resolved data are especially gathered via the Internet of Things. This data can often be accessed as data streams that push new data tuples continuously and make the data available in real time. Such real-time spatiotemporal data have great potential for new analysis approaches based on modern data processing technologies. The ability to retrieve spatial big data in real time, as well as process it in real time, demands new analysis methodologies that catch up with the instantaneous and continuous character of today’s spatiotemporal data. In this work, we present an evaluation of a high-frequent dynamic spatiotemporal autocorrelation approach. This approach allows for geostatistical analysis of streaming spatiotemporal data in real time and can provide insights into spatiotemporal processes while they are still ongoing. To evaluate this new approach, it was applied to mobility data from New York City. The results show that a high-frequent dynamic spatiotemporal autocorrelation approach provides comparable and meaningful results. In this way, high-frequent geostatistical analyses in real time can become an addition to retrospective analyses based on historical data.
Unraveling DNA Repair Processes In Vivo: Insights from Zebrafish Studies
Authors: Shin Unbeom , Lee Yoonsung
Published: August 2023

The critical role of the DNA repair system in preserving the health and survival of living organisms is widely recognized as dysfunction within this system can result in a broad range of severe conditions, including neurodegenerative diseases, blood disorders, infertility, and cancer. Despite comprehensive research on the molecular and cellular mechanisms of DNA repair pathways, there remains a significant knowledge gap concerning these processes at an organismal level. The teleost zebrafish has emerged as a powerful model organism for investigating these intricate DNA repair mechanisms. Their utility arises from a combination of their well-characterized genomic information, the ability to visualize specific phenotype outcomes in distinct cells and tissues, and the availability of diverse genetic experimental approaches. In this review, we provide an in-depth overview of recent advancements in our understanding of the in vivo roles of DNA repair pathways. We cover a variety of critical biological processes including neurogenesis, hematopoiesis, germ cell development, tumorigenesis, and aging, with a specific emphasis on findings obtained from the use of zebrafish as a model system. Our comprehensive review highlights the importance of zebrafish in enhancing our understanding of the functions of DNA repair systems at the organismal level and paves the way for future investigations in this field.
Sympathetic Nervous System and Atherosclerosis
Authors: Wang Yutang , Anesi Jack , Maier Michelle C. , Myers Mark A. , Oqueli Ernesto , Sobey Christopher G. , Drummond Grant R. , Denton Kate M.
Published: August 2023

Atherosclerosis is characterized by the narrowing of the arterial lumen due to subendothelial lipid accumulation, with hypercholesterolemia being a major risk factor. Despite the recent advances in effective lipid-lowering therapies, atherosclerosis remains the leading cause of mortality globally, highlighting the need for additional therapeutic strategies. Accumulating evidence suggests that the sympathetic nervous system plays an important role in atherosclerosis. In this article, we reviewed the sympathetic innervation in the vasculature, norepinephrine synthesis and metabolism, sympathetic activity measurement, and common signaling pathways of sympathetic activation. The focus of this paper was to review the effectiveness of pharmacological antagonists or agonists of adrenoceptors (α1, α2, β1, β2, and β3) and renal denervation on atherosclerosis. All five types of adrenoceptors are present in arterial blood vessels. α1 blockers inhibit atherosclerosis but increase the risk of heart failure while α2 agonism may protect against atherosclerosis and newer generations of β blockers and β3 agonists are promising therapies against atherosclerosis; however, new randomized controlled trials are warranted to investigate the effectiveness of these therapies in atherosclerosis inhibition and cardiovascular risk reduction in the future. The role of renal denervation in atherosclerosis inhibition in humans is yet to be established.
Present and Future of IgA Nephropathy and Membranous Nephropathy Immune Monitoring: Insights from Molecular Studies
Authors: Zanoni Francesca , Abinti Matteo , Belingheri Mirco , Castellano Giuseppe
Published: August 2023

IgA Nephropathy (IgAN) and Membranous Nephropathy (MN) are primary immune-mediated glomerular diseases with highly variable prognosis. Current guidelines recommend that greater immunologic activity and worse prognosis should guide towards the best treatment in an individualized approach. Nevertheless, proteinuria and glomerular filtration rate, the current gold standards for prognosis assessment and treatment guidance in primary glomerular diseases, may be altered with chronic damage and nephron scarring, conditions that are not related to immune activity. In recent years, thanks to the development of new molecular technologies, among them genome-wide genotyping, RNA sequencing techniques, and mass spectrometry, we have witnessed an outstanding improvement in understanding the pathogenesis of IgAN and MN. In addition, recent genome-wide association studies have suggested potential targets for immunomodulating agents, stressing the need for the identification of specific biomarkers of immune activity. In this work, we aim to review current evidence and recent progress, including the more recent use of omics techniques, in the identification of potential biomarkers for immune monitoring in IgAN and MN.
Changes in Adenosine Deaminase Activity and Endothelial Dysfunction after Mild Coronavirus Disease-2019
Authors: Jedrzejewska Agata , Kawecka Ada , Braczko Alicja , Romanowska-Kocejko Marzena , Stawarska Klaudia , Deptuła Milena , Zawrzykraj Małgorzata , Franczak Marika , Krol Oliwia , Harasim Gabriela , Walczak Iga , Pikuła Michał , Hellmann Marcin , Kutryb-Zając Barbara
Published: August 2023

Endothelial cells are a preferential target for SARS-CoV-2 infection. Previously, we have reported that vascular adenosine deaminase 1 (ADA1) may serve as a biomarker of endothelial activation and vascular inflammation, while ADA2 plays a critical role in monocyte and macrophage function. In this study, we investigated the activities of circulating ADA isoenzymes in patients 8 weeks after mild COVID-19 and related them to the parameters of inflammation and microvascular/endothelial function. Post-COVID patients revealed microvascular dysfunction associated with the changes in circulating parameters of endothelial dysfunction and inflammatory activation. Interestingly, serum total ADA and ADA2 activities were diminished in post-COVID patients, while ADA1 remained unchanged in comparison to healthy controls without a prior diagnosis of SARS-CoV-2 infection. While serum ADA1 activity tended to positively correspond with the parameters of endothelial activation and inflammation, sICAM-1 and TNFα, serum ADA2 activity correlated with IL-10. Simultaneously, post-COVID patients had lower circulating levels of ADA1-anchoring protein, CD26, that may serve as an alternative receptor for virus binding. This suggests that after the infection CD26 is rather maintained in cell-attached form, enabling ADA1 complexing. This study points to the possible role of ADA isoenzymes in cardiovascular complications after mild COVID-19.
Identification of New Antiseizure Medication Candidates in Preclinical Animal Studies
Authors: Yang Chih-Sheng , Wu Man-Chun , Lai Ming-Chi , Wu Sheng-Nan , Huang Chin-Wei
Published: August 2023

Epilepsy is a multifactorial neurologic disease that often leads to many devastating disabilities and an enormous burden on the healthcare system. Until now, drug-resistant epilepsy has presented a major challenge for approximately 30% of the epileptic population. The present article summarizes the validated rodent models of seizures employed in pharmacological researches and comprehensively reviews updated advances of novel antiseizure candidates in the preclinical phase. Newly discovered compounds that demonstrate antiseizure efficacy in preclinical trials will be discussed in the review. It is inspiring that several candidates exert promising antiseizure activities in drug-resistant seizure models. The representative compounds consist of derivatives of hybrid compounds that integrate multiple approved antiseizure medications, novel positive allosteric modulators targeting subtype-selective γ-Aminobutyric acid type A receptors, and a derivative of cinnamamide. Although the precise molecular mechanism, pharmacokinetic properties, and safety are not yet fully clear in every novel antiseizure candidate, the adapted approaches to design novel antiseizure medications provide new insights to overcome drug-resistant epilepsy.
Exploring the Feasibility of Circulating miRNAs as Diagnostic and Prognostic Biomarkers in Osteoarthritis: Challenges and Opportunities
Authors: Felekkis Kyriacos , Pieri Myrtani , Papaneophytou Christos
Published: August 2023

Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by progressive cartilage degradation and joint inflammation. As the most common aging-related joint disease, OA is marked by inadequate extracellular matrix synthesis and the breakdown of articular cartilage. However, traditional diagnostic methods for OA, relying on clinical assessments and radiographic imaging, often need to catch up in detecting early-stage disease or i accurately predicting its progression. Consequently, there is a growing interest in identifying reliable biomarkers that can facilitate early diagnosis and prognosis of OA. MicroRNAs (miRNAs) have emerged as potential candidates due to their involvement in various cellular processes, including cartilage homeostasis and inflammation. This review explores the feasibility of circulating miRNAs as diagnostic and prognostic biomarkers in OA, focusing on knee OA while shedding light on the challenges and opportunities associated with their implementation in clinical practice.
Differential Type-I Interferon Response in Buffy Coat Transcriptome of Individuals Infected with SARS-CoV-2 Gamma and Delta Variants
Authors: da Fonseca Guilherme C. , Cavalcante Liliane T. F. , Brustolini Otávio J. , Luz Paula M. , Pires Debora C. , Jalil Emilia M. , Peixoto Eduardo M. , Grinsztejn Beatriz , Veloso Valdilea G. , Nazer Sandro , Costa Carlos A. M. , Villela Daniel A. M. , Goedert Guilherme T. , Santos Cleber V. B. D. , Rodrigues Nadia C. P. , do Couto Motta Fernando , Siqueira Marilda Mendonça , Coelho Lara E. , Struchiner Claudio J. , Vasconcelos Ana Tereza R.
Published: August 2023

The innate immune system is the first line of defense against pathogens such as the acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The type I-interferon (IFN) response activation during the initial steps of infection is essential to prevent viral replication and tissue damage. SARS-CoV and SARS-CoV-2 can inhibit this activation, and individuals with a dysregulated IFN-I response are more likely to develop severe disease. Several mutations in different variants of SARS-CoV-2 have shown the potential to interfere with the immune system. Here, we evaluated the buffy coat transcriptome of individuals infected with Gamma or Delta variants of SARS-CoV-2. The Delta transcriptome presents more genes enriched in the innate immune response and Gamma in the adaptive immune response. Interactome and enriched promoter analysis showed that Delta could activate the INF-I response more effectively than Gamma. Two mutations in the N protein and one in the nsp6 protein found exclusively in Gamma have already been described as inhibitors of the interferon response pathway. This indicates that the Gamma variant evolved to evade the IFN-I response. Accordingly, in this work, we showed one of the mechanisms that variants of SARS-CoV-2 can use to avoid or interfere with the host Immune system.
Bioaccumulation of Non-Essential Trace Elements Detected in Women’s Follicular Fluid, Urine, and Plasma Is Associated with Poor Reproductive Outcomes following Single Euploid Embryo Transfer: A Pilot Study
Authors: Palomar Andrea , Gonzalez-Martin Roberto , Quiñonero Alicia , Pellicer Nuria , Fernandez-Saavedra Rocio , Rucandio Isabel , Fernandez-Martinez Rodolfo , Conde-Vilda Estefania , Quejido Alberto J. , Zuckerman Caroline , Whitehead Christine , Scott Richard T. , Dominguez Francisco
Published: August 2023

This study aims to determine the association of non-essential trace elements present in follicular fluid, plasma, and urine with reproductive outcomes of women undergoing intracytoplasmic sperm injection (ICSI), preimplantation genetic testing for aneuploidies (PGT-A) and single frozen euploid embryo transfer (SET/FET). This single-center, prospective cohort study included sixty women undergoing ICSI with PGT-A and SET/FET between 2018 and 2019. Urine, plasma and follicular fluid samples were collected on the vaginal oocyte retrieval day to simultaneously quantify ten non-essential trace elements (i.e., Ba, Sr, Rb, Sn, Ti, Pb, Cd, Hg, Sb, and As). We found several associations between the levels of these non-essential trace elements and clinical IVF parameters. Specifically, the increased levels of barium in follicular fluid were negatively associated with ovarian function, pre-implantation development and embryo euploidy, while elevated strontium concentrations in this biofluid were negatively associated with impaired blastulation and embryo euploidy. Elevated plasma strontium levels were negatively associated with ovarian function, fertilization and blastulation. Enhanced presence of other trace elements in plasma (i.e., rubidium and arsenic) were associated with a diminished ovarian function and limited the number of recovered oocytes, mature oocytes and zygotes, respectively. Fully adjusted models suggested significantly lower odds of achieving a live birth when increased concentrations of barium and tin were found in urine.
Dual Modulator of ASIC Channels and GABAA Receptors from Thyme Alters Fear-Related Hippocampal Activity
Authors: Kalinovskii Aleksandr P. , Pushkarev Anton P. , Mikhailenko Anastasia D. , Kudryavtsev Denis S. , Belozerova Olga A. , Shmygarev Vladimir I. , Yatskin Oleg N. , Korolkova Yuliya V. , Kozlov Sergey A. , Osmakov Dmitry I. , Popov Alexander , Andreev Yaroslav A.
Published: August 2023

Acid-sensing ion channels (ASICs) are proton-gated ion channels that mediate nociception in the peripheral nervous system and contribute to fear and learning in the central nervous system. Sevanol was reported previously as a naturally-occurring ASIC inhibitor from thyme with favorable analgesic and anti-inflammatory activity. Using electrophysiological methods, we found that in the high micromolar range, the compound effectively inhibited homomeric ASIC1a and, in sub- and low-micromolar ranges, positively modulated the currents of α1β2γ2 GABAA receptors. Next, we tested the compound in anxiety-related behavior models using a targeted delivery into the hippocampus with parallel electroencephalographic measurements. In the open field, 6 µM sevanol reduced both locomotor and θ-rhythmic activity similar to GABA, suggesting a primary action on the GABAergic system. At 300 μM, sevanol markedly suppressed passive avoidance behavior, implying alterations in conditioned fear memory. The observed effects could be linked to distinct mechanisms involving GABAAR and ASIC1a. These results elaborate the preclinical profile of sevanol as a candidate for drug development and support the role of ASIC channels in fear-related functions of the hippocampus.
Targeting AHR Increases Pancreatic Cancer Cell Sensitivity to Gemcitabine through the ELAVL1-DCK Pathway
Authors: Stukas Darius , Jasukaitiene Aldona , Bartkeviciene Arenida , Matthews Jason , Maimets Toivo , Teino Indrek , Jaudzems Kristaps , Gulbinas Antanas , Dambrauskas Zilvinas
Published: August 2023

The aryl hydrocarbon receptor (AHR) is a transcription factor that is commonly upregulated in pancreatic ductal adenocarcinoma (PDAC). AHR hinders the shuttling of human antigen R (ELAVL1) from the nucleus to the cytoplasm, where it stabilises its target messenger RNAs (mRNAs) and enhances protein expression. Among these target mRNAs are those induced by gemcitabine. Increased AHR expression leads to the sequestration of ELAVL1 in the nucleus, resulting in chemoresistance. This study aimed to investigate the interaction between AHR and ELAVL1 in the pathogenesis of PDAC in vitro. AHR and ELAVL1 genes were silenced by siRNA transfection. The RNA and protein were extracted for quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot (WB) analysis. Direct binding between the ELAVL1 protein and AHR mRNA was examined through immunoprecipitation (IP) assay. Cell viability, clonogenicity, and migration assays were performed. Our study revealed that both AHR and ELAVL1 inter-regulate each other, while also having a role in cell proliferation, migration, and chemoresistance in PDAC cell lines. Notably, both proteins function through distinct mechanisms. The silencing of ELAVL1 disrupts the stability of its target mRNAs, resulting in the decreased expression of numerous cytoprotective proteins. In contrast, the silencing of AHR diminishes cell migration and proliferation and enhances cell sensitivity to gemcitabine through the AHR-ELAVL1-deoxycytidine kinase (DCK) molecular pathway. In conclusion, AHR and ELAVL1 interaction can form a negative feedback loop. By inhibiting AHR expression, PDAC cells become more susceptible to gemcitabine through the ELAVL1-DCK pathway.
Targeting NKG2DL with Bispecific NKG2D–CD16 and NKG2D–CD3 Fusion Proteins on Triple–Negative Breast Cancer
Authors: Kaidun Polina , Holzmayer Samuel J. , Greiner Sarah M. , Seller Anna , Tegeler Christian M. , Hagelstein Ilona , Mauermann Jonas , Engler Tobias , Koch André , Hartkopf Andreas D. , Salih Helmut R. , Märklin Melanie
Published: August 2023

Triple–negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with a poor response rate to conventional systemic treatment and high relapse rates. Members of the natural killer group 2D ligand (NKG2DL) family are expressed on cancer cells but are typically absent from healthy tissues; thus, they are promising tumor antigens for novel immunotherapeutic approaches. We developed bispecific fusion proteins (BFPs) consisting of the NKG2D receptor domain targeting multiple NKG2DLs, fused to either anti–CD3 (NKG2D–CD3) or anti–CD16 (NKG2D–CD16) Fab fragments. First, we characterized the expression of the NKG2DLs (MICA, MICB, ULBP1–4) on TNBC cell lines and observed the highest surface expression for MICA and ULBP2. Targeting TNBC cells with NKG2D–CD3/CD16 efficiently activated both NK and T cells, leading to their degranulation and cytokine release and lysis of TNBC cells. Furthermore, PBMCs from TNBC patients currently undergoing chemotherapy showed significantly higher NK and T cell activation and tumor cell lysis when stimulated with NKG2D–CD3/CD16. In conclusions, BFPs activate and direct the NK and T cells of healthy and TNBC patients against TNBC cells, leading to efficient eradication of tumor cells. Therefore, NKG2D–based NK and T cell engagers could be a valuable addition to the treatment options for TNBC patients.
Latest Research of Doped Hydroxyapatite for Bone Tissue Engineering
Authors: Radulescu Diana-Elena , Vasile Otilia Ruxandra , Andronescu Ecaterina , Ficai Anton
Published: August 2023

Bone tissue engineering has attracted great interest in the last few years, as the frequency of tissue-damaging or degenerative diseases has increased exponentially. To obtain an ideal treatment solution, researchers have focused on the development of optimum biomaterials to be applied for the enhancement of bioactivity and the regeneration process, which are necessary to support the proper healing process of osseous tissues. In this regard, hydroxyapatite (HA) has been the most widely used material in the biomedical field due to its great biocompatibility and similarity with the native apatite from the human bone. However, HA still presents some deficiencies related to its mechanical properties, which are essential for HA to be applied in load-bearing applications. Bioactivity is another vital property of HA and is necessary to further improve regeneration and antibacterial activity. These drawbacks can be solved by doping the material with trace elements, adapting the properties of the material, and, finally, sustaining bone regeneration without the occurrence of implant failure. Considering these aspects, in this review, we have presented some general information about HA properties, synthesis methods, applications, and the necessity for the addition of doping ions into its structure. Also, we have presented their influence on the properties of HA, as well as the latest applications of doped materials in the biomedical field.
Extracellular Vesicles in Neurodegenerative Diseases: An Update
Authors: Sigdel Smara , Swenson Sabrina , Wang Jinju
Published: August 2023

Neurodegenerative diseases affect millions of people worldwide. The likelihood of developing a neurodegenerative disease rises dramatically as life expectancy increases. Although it has drawn significant attention, there is still a lack of proper effective treatments for neurodegenerative disease because the mechanisms of its development and progression are largely unknown. Extracellular vesicles (EVs) are small bi-lipid layer-enclosed nanosized particles in tissues and biological fluids. EVs are emerging as novel intercellular messengers and regulate a series of biological responses. Increasing evidence suggests that EVs are involved in the pathogenesis of neurodegenerative disorders. In this review, we summarize the recent findings of EVs in neurodegenerative diseases and bring up the limitations in the field.
Effect of Antioxidant Supplementation on NET Formation Induced by LPS In Vitro; the Roles of Vitamins E and C, Glutathione, and N-acetyl Cysteine
Authors: Muñoz-Sánchez Germán , Godínez-Méndez Lucila A. , Fafutis-Morris Mary , Delgado-Rizo Vidal
Published: August 2023

Neutrophil extracellular traps (NETs) require reactive oxygen species (ROS) to eliminate pathogens by inducing oxidative stress. However, this process can also cause tissue damage to the host. Neutrophils contain high concentrations of vitamin C (1.5 mM) compared to the bloodstream (0.1 mM), and this antioxidant can interact with vitamin E and glutathione (GSH) inside the cell to maintain the redox balance. Previous studies have investigated the effect of vitamins E or C and N-acetyl cysteine (NAC) on NET formation, but the interactions of these molecules in neutrophils remain unknown. In this study, we investigated the effect of antioxidants alone and two combinations on NET formation and oxidative stress. Neutrophils were pre-loaded with GSH + NAC or vitamin E + vitamin C + GSH + NAC (termed ALL), and LPS-induced NET formation was assessed using fluorometry and immunofluorescence. Antioxidant effects were evaluated by measuring the total antioxidant capacity (TAC), GSH/GSSG ratio, ROS production, nitrite + nitrate levels, and lipid peroxidation. Our results showed that even low doses of antioxidants are capable of decreasing NETs. Furthermore, the combinations augmented TAC and GSH/GSSG ratio and decreased ROS, nitrites + nitrates, and malondialdehyde (MDA) levels in supplemented neutrophils in vitro.
C-H Groups as Donors in Hydrogen Bonds: A Historical Overview and Occurrence in Proteins and Nucleic Acids
Authors: Derewenda Zygmunt Stanislaw
Published: August 2023

Hydrogen bonds constitute a unique type of non-covalent interaction, with a critical role in biology. Until fairly recently, the canonical view held that these bonds occur between electronegative atoms, typically O and N, and that they are mostly electrostatic in nature. However, it is now understood that polarized C-H groups may also act as hydrogen bond donors in many systems, including biological macromolecules. First recognized from physical chemistry studies, C-H…X bonds were visualized with X-ray crystallography sixty years ago, although their true significance has only been recognized in the last few decades. This review traces the origins of the field and describes the occurrence and significance of the most important C-H…O bonds in proteins and nucleic acids.
Abandoning the Isochore Theory Can Help Explain Genome Compositional Organization in Fish
Authors: Vohnoutová Marta , Sedláková Anastázie , Symonová Radka
Published: August 2023

The organization of the genome nucleotide (AT/GC) composition in vertebrates remains poorly understood despite the numerous genome assemblies available. Particularly, the origin of the AT/GC heterogeneity in amniotes, in comparison to the homogeneity in anamniotes, is controversial. Recently, several exceptions to this dichotomy were confirmed in an ancient fish lineage with mammalian AT/GC heterogeneity. Hence, our current knowledge necessitates a reevaluation considering this fact and utilizing newly available data and tools. We analyzed fish genomes in silico with as low user input as possible to compare previous approaches to assessing genome composition. Our results revealed a disparity between previously used plots of GC% and histograms representing the authentic distribution of GC% values in genomes. Previous plots heavily reduced the range of GC% values in fish to comply with the alleged AT/GC homogeneity and AT-richness of their genomes. We illustrate how the selected sequence size influences the clustering of GC% values. Previous approaches that disregarded chromosome and genome sizes, which are about three times smaller in fish than in mammals, distorted their results and contributed to the persisting confusion about fish genome composition. Chromosome size and their transposons may drive the AT/GC heterogeneity apparent on mammalian chromosomes, whereas far less in fishes.
Structural Insights into Neonicotinoids and N-Unsubstituted Metabolites on Human nAChRs by Molecular Docking, Dynamics Simulations, and Calcium Imaging
Authors: Grillberger Karin , Cöllen Eike , Trivisani Claudia Immacolata , Blum Jonathan , Leist Marcel , Ecker Gerhard F.
Published: August 2023

Neonicotinoid pesticides were initially designed in order to achieve species selectivity on insect nicotinic acetylcholine receptors (nAChRs). However, concerns arose when agonistic effects were also detected in human cells expressing nAChRs. In the context of next-generation risk assessments (NGRAs), new approach methods (NAMs) should replace animal testing where appropriate. Herein, we present a combination of in silico and in vitro methodologies that are used to investigate the potentially toxic effects of neonicotinoids and nicotinoid metabolites on human neurons. First, an ensemble docking study was conducted on the nAChR isoforms α7 and α3β4 to assess potential crucial molecular initiating event (MIE) interactions. Representative docking poses were further refined using molecular dynamics (MD) simulations and binding energy calculations using implicit solvent models. Finally, calcium imaging on LUHMES neurons confirmed a key event (KE) downstream of the MIE. This method was also used to confirm the predicted agonistic effect of the metabolite descyano-thiacloprid (DCNT).
Identification of Male Sex-Related Genes Regulated by SDHB in Macrobrachium nipponense Based on Transcriptome Analysis after an RNAi Knockdown
Authors: Gao Zijian , Zhang Wenyi , Jiang Sufei , Yuan Huwei , Cai Pengfei , Jin Shubo , Fu Hongtuo
Published: August 2023

The oriental river prawn (Macrobrachium nipponense) is a commercially important species in Asia. A previous study showed that the succinate dehydrogenase complex iron sulfur subunit B (SDHB) gene participates in testes development in this species through its effect on the expression of the insulin-like androgenic gland hormone gene. This study knocked-down the Mn-SDHB genes in M. nipponense using RNAi. A transcriptome analysis of the androgenic gland and testes was then performed to discover the male sex-related genes regulated by SDHB and investigate the mechanism of male sexual development in this species. More than 16,623 unigenes were discovered in each sample generated. In the androgenic gland, most of the differentially expressed genes were enriched in the hypertrophic cardiomyopathy pathway, while in the testes, they were enriched in the citrate cycle pathway. In addition, after Mn-SDHB knockdown, five genes were found to be downregulated in the androgenic gland in a series of biological processes associated with phosphorylated carbohydrate synthesis and transformations in the glycolysis/gluconeogenesis pathway. Moreover, a total of nine male sex-related genes were identified including Pro-resilin, insulin-like androgenic gland hormone, Protein mono-ADP-ribosyltransferase PAPR11, DNAJC2, C-type Lectin-1, Tyrosine-protein kinase Yes, Vigilin, and Sperm motility kinase Y-like, demonstrating the regulatory effects of Mn-SDHB, and providing a reference for the further study of the mechanisms of male development in M. nipponense.
Cancer Stem Cells in Renal Cell Carcinoma: Origins and Biomarkers
Authors: Lasorsa Francesco , Rutigliano Monica , Milella Martina , Ferro Matteo , Pandolfo Savio Domenico , Crocetto Felice , Autorino Riccardo , Battaglia Michele , Ditonno Pasquale , Lucarelli Giuseppe
Published: August 2023

The term “cancer stem cell” (CSC) refers to a cancer cell with the following features: clonogenic ability, the expression of stem cell markers, differentiation into cells of different lineages, growth in nonadhesive spheroids, and the in vivo ability to generate serially transplantable tumors that reflect the heterogeneity of primary cancers (tumorigenicity). According to this model, CSCs may arise from normal stem cells, progenitor cells, and/or differentiated cells because of striking genetic/epigenetic mutations or from the fusion of tissue-specific stem cells with circulating bone marrow stem cells (BMSCs). CSCs use signaling pathways similar to those controlling cell fate during early embryogenesis (Notch, Wnt, Hedgehog, bone morphogenetic proteins (BMPs), fibroblast growth factors, leukemia inhibitory factor, and transforming growth factor-β). Recent studies identified a subpopulation of CD133+/CD24+ cells from ccRCC specimens that displayed self-renewal ability and clonogenic multipotency. The development of agents targeting CSC signaling-specific pathways and not only surface proteins may ultimately become of utmost importance for patients with RCC.
The Ins and Outs of Clusterin: Its Role in Cancer, Eye Diseases and Wound Healing
Authors: Gross Christelle , Guérin Louis-Philippe , Socol Bianca G. , Germain Lucie , Guérin Sylvain L.
Published: August 2023

Clusterin (CLU) is a glycoprotein originally discovered in 1983 in ram testis fluid. Rapidly observed in other tissues, it was initially given various names based on its function in different tissues. In 1992, it was finally named CLU by consensus. Nearly omnipresent in human tissues, CLU is strongly expressed at fluid–tissue interfaces, including in the eye and in particular the cornea. Recent research has identified different forms of CLU, with the most prominent being a 75–80 kDa heterodimeric protein that is secreted. Another truncated version of CLU (55 kDa) is localized to the nucleus and exerts pro-apoptotic activities. CLU has been reported to be involved in various physiological processes such as sperm maturation, lipid transportation, complement inhibition and chaperone activity. CLU was also reported to exert important functions in tissue remodeling, cell–cell adhesion, cell–substratum interaction, cytoprotection, apoptotic cell death, cell proliferation and migration. Hence, this protein is sparking interest in tissue wound healing. Moreover, CLU gene expression is finely regulated by cytokines, growth factors and stress-inducing agents, leading to abnormally elevated levels of CLU in many states of cellular disturbance, including cancer and neurodegenerative conditions. In the eye, CLU expression has been reported as being severely increased in several pathologies, such as age-related macular degeneration and Fuch’s corneal dystrophy, while it is depleted in others, such as pathologic keratinization. Nevertheless, the precise role of CLU in the development of ocular pathologies has yet to be deciphered. The question of whether CLU expression is influenced by these disorders or contributes to them remains open. In this article, we review the actual knowledge about CLU at both the protein and gene expression level in wound healing, and explore the possibility that CLU is a key factor in cancer and eye diseases. Understanding the expression and regulation of CLU could lead to the development of novel therapeutics for promoting wound healing.
Hormonal Regulation and Stimulation Response of Jatropha curcas L. Homolog Overexpression on Tobacco Leaf Growth by Transcriptome Analysis
Authors: Wu Qiuhong , Zheng Dongchao , Lian Na , Zhu Xuli , Wu Jun
Published: August 2023

The Flowering locus T (FT) gene encodes the florigen protein, which primarily regulates the flowering time in plants. Recent studies have shown that FT genes also significantly affect plant growth and development. The FT gene overexpression in plants promotes flowering and suppresses leaf and stem development. This study aimed to conduct a transcriptome analysis to investigate the multiple effects of Jatropha curcas L. homolog (JcFT) overexpression on leaf growth in tobacco plants. The findings revealed that JcFT overexpression affected various biological processes during leaf development, including plant hormone levels and signal transduction, lipid oxidation metabolism, terpenoid metabolism, and the jasmonic-acid-mediated signaling pathway. These results suggested that the effects of FT overexpression in plants were complex and multifaceted, and the combination of these factors might contribute to a reduction in the leaf size. This study comprehensively analyzed the effects of JcFT on leaf development at the transcriptome level and provided new insights into the function of FT and its homologous genes.
Efficacy of the Continuous Resuscitation Training with the Gap Period Due to the COVID-19 Pandemic
Authors: Tran Que N. N. , Moriguchi Takeshi , Harii Norikazu , Goto Junko , Harada Daiki , Sugawara Hisanori , Takamino Junichi , Ueno Masateru , Ise Hirobumi , Watanabe Akino , Sakata Hiroki , Kondo Kengo , Myose Natsuhiko , Sakurabayashi Fuki
Published: August 2023

(1) Objective: This study evaluates the effects of simulation education at our institute on cardiac arrest resuscitation regarding knowledge, attitude, and practice (KAP) over a five-year period (2016–2020). (2) Subjects: Staff responded to the annual survey questionnaires followed by monthly training in Basic Life Support/Advanced Cardiovascular Life Support (BLS/ACLS) and Immediate Cardiac Life Support (ICLS) of the Japanese Association for Acute Medicine (JAAM) in 2016, 2017, and 2018. Additionally, in-house training was implemented in 2019 without post-assessment followed by training suspension in 2020 due to the COVID-19 pandemic. The last delivery of the survey questionnaires was in late 2020 for KAP retention measurement. (3) Measurements and Results: The self-efficacy level of BLS/ACLS/ICLS KAP of the survey respondents was analyzed using a five-point Likert scale. The mean self-efficacy level of BLS/ACLS/ICLS KAP increased over time, and that of the trained people was three-fold that of the untrained people. Trainees that had no cardiopulmonary resuscitation (CPR) experience gained the BLS/ACLS/ICLS key-point self-efficacy level, which we call the “Grip 14” in this study, as high as their untrained counterparts who had three-time CPR experience. Training suspension lessened the BLS/ACLS/ICLS KAP in both groups. (4) Conclusions: Continuous training enhances not only the BLS/ACLS/ICLS KAP of trainees but also of their untrained colleagues. The training likely had the same efficacy as the CPR experience.
Myocardial Functional Imaging in Pediatric Nuclear Cardiology
Authors: Perrone Marco Alfonso , Cimini Andrea , Ricci Maria , Pizzoferro Milena , Garganese Maria Carmen , Raponi Massimiliano , Schillaci Orazio
Published: August 2023

The role of nuclear medicine in pediatric cardiology has grown rapidly over the years, providing useful functional and prognostic information and playing a complementary role to morphological imaging in the evaluation of myocardial perfusion, cardiovascular inflammation and infections, and cardiac sympathetic innervation. The aim of this narrative review is to summarize and highlight the most important evidence on pediatric nuclear cardiology, describing clinical applications and the possibilities, advantages, and limitations of nuclear medicine techniques. Moreover, a special focus will be given to the minimization of radiation exposure in pediatric nuclear cardiology imaging, a critical topic in children.