bluuebunny/crossref_metadata_2025 huggingface dataset:
The Relationships of Watching Television, Computer Use, Physical Activity, and Food Preferences to Body Mass Index: Gender and Nativity Differences among Adolescents in Saudi Arabia
Authors: Alghadir Ahmad , Iqbal Zaheen , A. Gabr Sami
Published: September 2021

Background: Adolescents and ethnic subgroups have been identified at high risks of overweight and its associated complications. Although some studies have investigated overweight, obesity, nutritional status, physical activity, and associated factors among Saudi students, no studies have examined these characteristics among non-Saudi students or compared non-Saudi to Saudi adolescent students. The objective of this study was to compare differences between Saudi and non-Saudi adolescent students regarding time spent watching television, using computers, engaging in physical activity, and their food preferences. The relationships between these lifestyle behaviors and body mass index by Saudi nativity and gender were tested. Methods: Students aged 12 to 18 years (n = 214) from various schools in Riyadh, Saudi Arabia, completed a self-administered questionnaire that included questions about demographic and anthropometric characteristics, daily after-school routine, physical activity, watching television, using computers, and food preferences. Non-parametric (Mann–Whitney U) tests assessed the statistical differences between Saudi and non-Saudi respondents, and males and females were separately tested. Results: Saudi boys who reported physical activity two to five times per week, the most television time, the most computer time, and the highest frequency of eating fast food and drinking soft drinks had a significantly higher mean body mass index than the non-Saudi boys in their categories. However, there were no significant differences found between the Saudi and non-Saudi girls. Conclusions: High levels of sedentary and low levels of physical activities as well as high consumption of high-fat fast foods and high-sugar drinks threaten the health of Saudi adolescents. Cultural differences in lifestyle between Saudi and non-Saudi families should be considered when developing programs to improve knowledge, attitudes, and behaviors regarding diet quality and physical activity. The objective of this study is more important in the current situation where increased time spent on computers and mobile phones due to online teaching in schools or working from home, decreased physical activity due to precautionary lockdowns, and unchecked eating patterns while spending more time in sedentary activities in homes has become our COVID-19 pandemic lifestyle in all the age groups. A similar study should be replicated on a large scale to study the effect of this lifestyle on our lives in all the age groups.
Mercury Levels in Feathers of Penguins from the Antarctic Peninsula Area: Geographical and Inter-Specific Differences
Authors: Motas Miguel , Jerez Silvia , Esteban Marta , Valera Francisco , Cuervo José Javier , Barbosa Andrés
Published: September 2021

Polar regions, symbols of wilderness, have been identified as potential sinks of mercury coming from natural and anthropogenic sources at lower latitudes. Changes in ice coverage currently occurring in some areas such as the Antarctic Peninsula could enhance these phenomena and their impacts on local biota. As long-lived species at the top of food chains, seabirds are particularly sensitive to this highly toxic metal with the capacity to be biomagnified. Specifically, their feathers can be useful for Hg monitoring since they mainly accumulate its most toxic and persistent form, methyl-Hg. To that end, feathers of gentoo (Pygoscelis papua), chinstrap (P. antarcticus), and Adélie penguins (P. adeliae) (n = 108) were collected by passive sampling in seven different locations throughout the Antarctic Peninsula area and analyzed by ICP-MS after microwave-digestion. More than 93% of the samples showed detectable Hg levels (range: 6.3–12,529.8 ng g−1 dry weight), and the highest ones were found in the feathers of chinstrap penguins from King George Island. Hg bioconcentration and biomagnification seem to be occurring in the Antarctic food web, giving rise to high but non-toxic Hg levels in penguins, similar to those previously found in Arctic seabirds.
Suicide Risk Factors among Polish Adults Aged 65 or Older in 2000–2018 Compared with Selected Countries Worldwide
Authors: Śmigielski Witold , Małek Karolina , Jurczyk Tomasz , Korczak Karol , Gajda Robert , Cicha-Mikołajczyk Alicja , Piwoński Jerzy , Śmigielska-Kolańska Joanna , Śmigielski Janusz , Drygas Wojciech , Gałecki Piotr
Published: September 2021

The aim of this study was to determine the tendencies of change in suicide frequency among Polish adults aged 65 or older, recognize the importance of available socio-demographic data (age, sex, marital status, and education attainment level) and provide an in-depth psychological understanding of the obtained results. We analysed the influence of education and marital status on suicide risk in the Polish adult population aged 65 or older, which has not been previously presented in publications related to the Central Statistical Office or any other research. Our results indicated that male adults aged 65 or older that were single or divorced and with a lower education had a higher risk of death by suicide. In female adults aged 65 or older, those with higher education and who were divorced or married had a higher risk of fatal suicide behaviour meanwhile, single women and widows had a lower risk. The dominant method of suicide among Polish older adults was suicide by hanging, regardless of sex; female older adults were more likely to die by suicide by poisoning or jumping from a height, and male older adults were more likely to die by shooting with a firearm. Although data from recent years highlights a downward trend for suicide rates in Polish older adults, the problem cannot be considered solved.
Suicidology Post Graduate Curriculum: Priority Topics and Delivery Mechanisms for Suicide Prevention Education
Authors: Hawgood Jacinta , Krysinska Karolina , Mooney Maddeline , Ozols Ingrid , Andriessen Karl , Betterridge Carmen , De Leo Diego , Kõlves Kairi
Published: September 2021

Background: There has been limited attention to the development and delivery of tertiary suicide prevention curricula. The aim of this work was to describe the status of postgraduate suicide prevention education, with specific attention on examining the needs of the suicide prevention sector in Australia. Method: An online survey was completed by 76 stakeholders in Australia. Current curriculum learning outcomes from Griffith University’s postgraduate suicidology programs guided the development of the survey. Results: Four key learning domains were rated highest in importance by stakeholders. According to most stakeholders, skills-based qualifications were the most relevant type of qualification, and online modulized education was the most preferred delivery mode. Half of stakeholders supported suicide prevention professional development through a combination of financial support and study leave. Conclusions: The survey provided invaluable feedback regarding the priorities of Australia’s suicide prevention sector for content domains and delivery mechanisms for tertiary suicidology education. The findings showed the preferred type of organizational (employer) support that may be provided for employees to undertake such education. These findings will inform the future developments of Griffith University’s suicidology programs and may motivate other universities to consider offering same or a similar type of education to support the suicide prevention sector toward saving lives.
Application of Random Forest and SHAP Tree Explainer in Exploring Spatial (In)Justice to Aid Urban Planning
Authors: Deb Debzani , Smith Russell M.
Published: September 2021

In light of recent local, national, and global events, spatial justice provides a potentially powerful lens by which to explore a multitude of spatial inequalities. For more than two decades, scholars have been espousing the power of this concept to help develop more equitable and just communities. However, defining spatial justice and developing a methodology for quantitatively analyzing it is complicated and no agreed upon metric for examining spatial justice has been developed. Instead, individual measures of spatial injustices have been studied. One such individual measure is economic mobility. Recent research on economic mobility has revealed the importance of local geography on upward mobility and may serve as an important keystone in developing a metric for multiple place-based issues of spatial inequality. This paper seeks to explore place-based variables within individual census tracts in an effort to understand their impact on economic mobility and potentially spatial justice. The methodology relies on machine learning techniques and the results show that the best performing model is able to predict economic mobility of a census tract based on its spatial variables with 86% accuracy. The availability and density of jobs, compactness of the area, and the presence of medical facilities and underground storage tanks have the greatest influence, whereas some of the influential features are positively while the others are negatively associated. In the end, this research will allow for comparative analysis between differing geographies and also identify leading variables in the overall quest for spatial justice.
Diffuse Anthropization Impacts in Vulnerable Protected Areas: Comparative Analysis of the Spatial Correlation between Land Transformation and Ecological Deterioration of Three Wetlands in Spain
Authors: Garcia-Ayllon Salvador , Radke John
Published: September 2021

The management and conservation of wetlands and vulnerable protected areas of high ecological value dependent on the existence of water is complex and generally depends on the climate and rainfall in semi-arid territories such as southeastern Spain. However, one variable that is not usually considered sufficiently rigorously in this field of research is the environmental impact of the transformation of the surrounding territory due to anthropic diffuse issues. This phenomenon is not easy to appreciate, since it does not necessarily occur in the environment directly closest to protected areas and it is always difficult to measure and analyze. This study proposes an innovative spatiotemporal methodological framework to evaluate all these phenomena of diffuse anthropization whose indirect impacts on protected areas dependent on the existence of water are currently full of unknowns. Using GIS indicators, a geostatistical analysis based on the concept of the area of influence of diffuse anthropization (AIDA) is proposed to assess the spatial correlation between the anthropic transformation of the territory and the degradation of protected areas over time. The proposal has been applied with a comparative approach to three case studies located in Spain between 2000 and 2020, obtaining clarifying results on the existing spatial correlation patterns between both questions.
Profiling of Human Neural Crest Chemoattractant Activity as a Replacement of Fetal Bovine Serum for In Vitro Chemotaxis Assays
Authors: Dolde Xenia , Karreman Christiaan , Wiechers Marianne , Schildknecht Stefan , Leist Marcel
Published: September 2021

Fetal bovine serum (FBS) is the only known stimulus for the migration of human neural crest cells (NCCs). Non-animal chemoattractants are desirable for the optimization of chemotaxis as-says to be incorporated in a test battery for reproductive and developmental toxicity. We con-firmed here in an optimized transwell assay that FBS triggers directed migration along a con-centration gradient. The responsible factor was found to be a protein in the 30–100 kDa size range. In a targeted approach, we tested a large panel of serum constituents known to be chem-otactic for NCCs in animal models (e.g., VEGF, PDGF, FGF, SDF-1/CXCL12, ephrins, endothelin, Wnt, BMPs). None of the corresponding human proteins showed any effect in our chemotaxis assays based on human NCCs. We then examined, whether human cells would produce any fac-tor able to trigger NCC migration in a broad screening approach. We found that HepG2 hepa-toma cells produced chemotaxis-triggering activity (CTA). Using chromatographic methods and by employing the NCC chemotaxis test as bioassay, the responsible protein was enriched by up to 5000-fold. We also explored human serum and platelets as a direct source, independent of any cell culture manipulations. A CTA was enriched from platelet lysates several thousand-fold. Its temperature and protease sensitivity suggested also a protein component. The capacity of this factor to trigger chemotaxis was confirmed by single-cell video-tracking analysis of migrating NCCs. The human CTA characterized here may be employed in the future for the setup of assays testing for the disturbance of directed NCC migration by toxicants.
RETRACTED: Lakhani et al. Beneficial Role of HO-1-SIRT1 Axis in Attenuating Angiotensin II-Induced Adipocyte Dysfunction. Int. J. Mol. Sci. 2019, 20, 3205
Authors:   International Journal of Molecular Sciences Editorial Office
Published: September 2021

The journal retracts the article “Beneficial Role of HO-1-SIRT1 Axis in Attenuating Angiotensin II-Induced Adipocyte Dysfunction” [...]
Chronic Kidney Disease: Strategies to Retard Progression
Authors: Yan Ming-Tso , Chao Chia-Ter , Lin Shih-Hua
Published: September 2021

Chronic kidney disease (CKD), defined as the presence of irreversible structural or functional kidney damages, increases the risk of poor outcomes due to its association with multiple complications, including altered mineral metabolism, anemia, metabolic acidosis, and increased cardiovascular events. The mainstay of treatments for CKD lies in the prevention of the development and progression of CKD as well as its complications. Due to the heterogeneous origins and the uncertainty in the pathogenesis of CKD, efficacious therapies for CKD remain challenging. In this review, we focus on the following four themes: first, a summary of the known factors that contribute to CKD development and progression, with an emphasis on avoiding acute kidney injury (AKI); second, an etiology-based treatment strategy for retarding CKD, including the approaches for the common and under-recognized ones; and third, the recommended approaches for ameliorating CKD complications, and the final section discusses the novel agents for counteracting CKD progression.
Fusion with Promiscuous Gα16 Subunit Reveals Signaling Bias at Muscarinic Receptors
Authors: Randáková Alena , Nelic Dominik , Hochmalová Martina , Zimčík Pavel , Mulenga Mutale Jane , Boulos John , Jakubík Jan
Published: September 2021

A complex evaluation of agonist bias at G-protein coupled receptors at the level of G-protein classes and isoforms including non-preferential ones is essential for advanced agonist screening and drug development. Molecular crosstalk in downstream signaling and a lack of sufficiently sensitive and selective methods to study direct coupling with G-protein of interest complicates this analysis. We performed binding and functional analysis of 11 structurally different agonists on prepared fusion proteins of individual subtypes of muscarinic receptors and non-canonical promiscuous α-subunit of G16 protein to study agonist bias. We have demonstrated that fusion of muscarinic receptors with Gα16 limits access of other competitive Gα subunits to the receptor, and thus enables us to study activation of Gα16 mediated pathway more specifically. Our data demonstrated agonist-specific activation of G16 pathway among individual subtypes of muscarinic receptors and revealed signaling bias of oxotremorine towards Gα16 pathway at the M2 receptor and at the same time impaired Gα16 signaling of iperoxo at M5 receptors. Our data have shown that fusion proteins of muscarinic receptors with α-subunit of G-proteins can serve as a suitable tool for studying agonist bias, especially at non-preferential pathways.
Is Multiple System Atrophy a Prion-like Disorder?
Authors: Jellinger Kurt A. , Wenning Gregor K. , Stefanova Nadia
Published: September 2021

Multiple system atrophy (MSA) is a rapidly progressive, fatal neurodegenerative disease of uncertain aetiology that belongs to the family of α-synucleinopathies. It clinically presents with parkinsonism, cerebellar, autonomic, and motor impairment in variable combinations. Pathological hallmarks are fibrillary α-synuclein (αSyn)-rich glial cytoplasmic inclusions (GCIs) mainly involving oligodendroglia and to a lesser extent neurons, inducing a multisystem neurodegeneration, glial activation, and widespread demyelinization. The neuronal αSyn pathology of MSA has molecular properties different from Lewy bodies in Parkinson’s disease (PD), both of which could serve as a pool of αSyn (prion) seeds that could initiate and drive the pathogenesis of synucleinopathies. The molecular cascade leading to the “prion-like” transfer of “strains” of aggregated αSyn contributing to the progression of the disease is poorly understood, while some presented evidence that MSA is a prion disease. However, this hypothesis is difficult to reconcile with postmortem analysis of human brains and the fact that MSA-like pathology was induced by intracerebral inoculation of human MSA brain homogenates only in homozygous mutant 53T mice, without production of disease-specific GCIs, or with replication of MSA prions in primary astrocyte cultures from transgenic mice expressing human αSyn. Whereas recent intrastriatal injection of Lewy body-derived or synthetic human αSyn fibrils induced PD-like pathology including neuronal αSyn aggregates in macaques, no such transmission of αSyn pathology in non-human primates by MSA brain lysate has been reported until now. Given the similarities between αSyn and prions, there is a considerable debate whether they should be referred to as “prions”, “prion-like”, “prionoids”, or something else. Here, the findings supporting the proposed nature of αSyn as a prion and its self-propagation through seeding as well as the transmissibility of neurodegenerative disorders are discussed. The proof of disease causation rests on the concordance of scientific evidence, none of which has provided convincing evidence for the classification of MSA as a prion disease or its human transmission until now.
Hydrogen Peroxide Generation as an Underlying Response to High Extracellular Inorganic Phosphate (Pi) in Breast Cancer Cells
Authors: Lacerda-Abreu Marco Antonio , Russo-Abrahão Thais , Rocco-Machado Nathália , Cosentino-Gomes Daniela , Dick Claudia Fernanda , Carvalho-Kelly Luiz Fernando , Cunha Nascimento Michelle Tanny , Rocha-Vieira Thaís Cristino , Meyer-Fernandes José Roberto
Published: September 2021

According to the growth rate hypothesis (GRH), tumour cells have high inorganic phosphate (Pi) demands due to accelerated proliferation. Compared to healthy individuals, cancer patients present with a nearly 2.5-fold higher Pi serum concentration. In this work, we show that an increasing concentration of Pi had the opposite effect on Pi-transporters only in MDA-MB-231 when compared to other breast cell lines: MCF-7 or MCF10-A (non-tumoural breast cell line). Here, we show for the first time that high extracellular Pi concentration mediates ROS production in TNBC (MDA-MB-231). After a short-time exposure (1 h), Pi hyperpolarizes the mitochondrial membrane, increases mitochondrial ROS generation, impairs oxygen (O2) consumption and increases PKC activity. However, after 24 h Pi-exposure, the source of H2O2 seems to shift from mitochondria to an NADPH oxidase enzyme (NOX), through activation of PKC by H2O2. Exogenous-added H2O2 modulated Pi-transporters the same way as extracellular high Pi, which could be reversed by the addition of the antioxidant N-acetylcysteine (NAC). NAC was also able to abolish Pi-induced Epithelial-mesenchymal transition (EMT), migration and adhesion of MDA-MB-231. We believe that Pi transporters support part of the energy required for the metastatic processes stimulated by Pi and trigger Pi-induced H2O2 production as a signalling response to promote cell migration and adhesion.
Lipid Droplet Biosynthesis Impairment through DGAT2 Inhibition Sensitizes MCF7 Breast Cancer Cells to Radiation
Authors: Nisticò Clelia , Pagliari Francesca , Chiarella Emanuela , Fernandes Guerreiro Joana , Marafioti Maria Grazia , Aversa Ilenia , Genard Geraldine , Hanley Rachel , Garcia-Calderón Daniel , Bond Heather Mandy , Mesuraca Maria , Tirinato Luca , Spadea Maria Francesca , Seco Joao Carlos
Published: September 2021

Breast cancer is the most frequent cancer in women worldwide and late diagnosis often adversely affects the prognosis of the disease. Radiotherapy is commonly used to treat breast cancer, reducing the risk of recurrence after surgery. However, the eradication of radioresistant cancer cells, including cancer stem cells, remains the main challenge of radiotherapy. Recently, lipid droplets (LDs) have been proposed as functional markers of cancer stem cells, also being involved in increased cell tumorigenicity. LD biogenesis is a multistep process requiring various enzymes, including Diacylglycerol acyltransferase 2 (DGAT2). In this context, we evaluated the effect of PF-06424439, a selective DGAT2 inhibitor, on MCF7 breast cancer cells exposed to X-rays. Our results demonstrated that 72 h of PF-06424439 treatment reduced LD content and inhibited cell migration, without affecting cell proliferation. Interestingly, PF-06424439 pre-treatment followed by radiation was able to enhance radiosensitivity of MCF7 cells. In addition, the combined treatment negatively interfered with lipid metabolism-related genes, as well as with EMT gene expression, and modulated the expression of typical markers associated with the CSC-like phenotype. These findings suggest that PF-06424439 pre-treatment coupled to X-ray exposure might potentiate breast cancer cell radiosensitivity and potentially improve the radiotherapy effectiveness.
Striking Back against Fungal Infections: The Utilization of Nanosystems for Antifungal Strategies
Authors: Du Wei , Gao Yiru , Liu Li , Sai Sixiang , Ding Chen
Published: September 2021

Fungal infections have become a major health concern, given that invasive infections by Candida, Cryptococcus, and Aspergillus species have led to millions of mortalities. Conventional antifungal drugs including polyenes, echinocandins, azoles, allylamins, and antimetabolites have been used for decades, but their limitations include off-target toxicity, drug-resistance, poor water solubility, low bioavailability, and weak tissue penetration, which cannot be ignored. These drawbacks have led to the emergence of novel antifungal therapies. In this review, we discuss the nanosystems that are currently utilized for drug delivery and the application of antifungal therapies.
Personalized Medicine for TP53 Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia
Authors: Cluzeau Thomas , Loschi Michael , Fenaux Pierre , Komrokji Rami , Sallman David A.
Published: September 2021

Targeting TP53 mutated myelodysplastic syndromes and acute myeloid leukemia remains a significant unmet need. Recently, new drugs have attempted to improve the outcomes of this poor molecular subgroup. The aim of this article is to review all the current knowledge using active agents including hypomethylating agents with venetoclax, eprenetapopt or magrolimab. We include comprehensive analysis of clinical trials to date evaluating these drugs in TP53 myeloid neoplasms as well as discuss future novel combinations for consideration. Additionally, further understanding of the unique clinicopathologic components of TP53 mutant myeloid neoplasms versus wild-type is critical to guide future study. Importantly, the clinical trajectory of patients is uniquely tied with the clonal burden of TP53, which enables serial TP53 variant allele frequency analysis to be a critical early biomarker in investigational studies. Together, significant optimism is now possible for improving outcomes in this patient population.
Efficient Neutrophil Activation Requires Two Simultaneous Activating Stimuli
Authors: Mol Sanne , Hafkamp Florianne M. J. , Varela Laura , Simkhada Neena , Taanman-Kueter Esther W. , Tas Sander W. , Wauben Marca H. M. , Groot Kormelink Tom , de Jong Esther C.
Published: September 2021

Neutrophils are abundantly present in the synovium and synovial fluid of patients suffering from arthritis. Neutrophils can be activated by a multitude of stimuli and the current dogma states that this is a two-step process, consisting of a priming step followed by an activation step. Considering that neutrophil activation occurs in an inflammatory environment, where multiple stimuli are present, we argue that a two-step process is highly unlikely. Here, we indeed demonstrate that neutrophils require simultaneous ligation of two different receptors for efficient activation. We isolated human peripheral blood neutrophils and cultured them with various combinations of stimuli (GM-CSF, fMLF, TNF, and LPS). Next, we evaluated essential neutrophil functions, including degranulation and ROS production using flow cytometry, mediator release using ELISA, NETosis by a live cell imaging method, phagocytosis by imaging flow cytometry, and extracellular vesicle (EV) release quantified by high-resolution flow cytometry. Exposure of neutrophils to any combination of stimuli, but not to single stimuli, resulted in significant degranulation, and mediator and EV release. Furthermore, ROS production increased substantially by dual stimulation, yet appeared to be more dependent on the type of stimulation than on dual stimulation. Phagocytosis was induced to its maximum capacity by a single stimulus, while NETosis was not induced by any of the used physiological stimuli. Our data indicate that neutrophil activation is tightly regulated and requires activation by two simultaneous stimuli, which is largely independent of the combination of stimuli.
Inhibition of BMI-1 Induces Apoptosis through Downregulation of DUB3-Mediated Mcl-1 Stabilization
Authors: Wu Kaixin , Woo Seon-Min , Seo Seung-Un , Kwon Taeg-Kyu
Published: September 2021

BMI-1, a polycomb ring finger oncogene, is highly expressed in multiple cancer cells and is involved in cancer cell proliferation, invasion, and apoptosis. BMI-1 represents a cancer stemness marker that is associated with the regulation of stem cell self-renewal. In this study, pharmacological inhibition (PTC596) or knockdown (siRNA) of BMI-1 reduced cancer stem-like cells and enhanced cancer cell death. Mechanistically, the inhibition of BMI-1 induced the downregulation of Mcl-1 protein, but not Mcl-1 mRNA. PTC596 downregulated Mcl-1 protein expression at the post-translational level through the proteasome-ubiquitin system. PTC596 and BMI-1 siRNA induced downregulation of DUB3 deubiquitinase, which was strongly linked to Mcl-1 destabilization. Furthermore, overexpression of Mcl-1 or DUB3 inhibited apoptosis by PTC596. Taken together, our findings reveal that the inhibition of BMI-1 induces Mcl-1 destabilization through downregulation of DUB3, resulting in the induction of cancer cell death.
Metabolic and Lipidomic Assessment of Kidney Cells Exposed to Nephrotoxic Vancomycin Dosages
Authors: Lagies Simon , Pichler Roman , Vladimirov Georg , Gawron Jana , Bäzner Fabian , Schreiner Annabell , Kadena Dajana , Plattner Dietmar A. , Lienkamp Soeren S. , Kammerer Bernd
Published: September 2021

Vancomycin is a glycopeptide antibiotic used against multi-drug resistant gram-positive bacteria such as Staphylococcus aureus (MRSA). Although invaluable against resistant bacteria, vancomycin harbors adverse drug reactions including cytopenia, ototoxicity, as well as nephrotoxicity. Since nephrotoxicity is a rarely occurring side effect, its mechanism is incompletely understood. Only recently, the actual clinically relevant concentration the in kidneys of patients receiving vancomycin was investigated and were found to exceed plasma concentrations by far. We applied these clinically relevant vancomycin concentrations to murine and canine renal epithelial cell lines and assessed metabolic and lipidomic alterations by untargeted and targeted gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry analyses. Despite marked differences in the lipidome, both cell lines increased anabolic glucose reactions, resulting in higher sorbitol and lactate levels. To the best of our knowledge, this is the first endometabolic profiling of kidney cells exposed to clinically relevant vancomycin concentrations. The presented study will provide a valuable dataset to nephrotoxicity researchers and might add to unveiling the nephrotoxic mechanism of vancomycin.
The Catastrophic HPV/HIV Dual Viral Oncogenomics in Concert with Dysregulated Alternative Splicing in Cervical Cancer
Authors: Marima Rahaba , Hull Rodney , Lolas Georgios , Syrigos Konstantinos N. , Kgoebane-Maseko Minah , Kaufmann Andreas Martin , Dlamini Zodwa
Published: September 2021

Cervical cancer is a public health problem and has devastating effects in low-to-middle-income countries (LTMICs) such as the sub-Saharan African (SSA) countries. Infection by the human papillomavirus (HPV) is the main cause of cervical cancer. HIV positive women have higher HPV prevalence and cervical cancer incidence than their HIV negative counterparts do. Concurrent HPV/HIV infection is catastrophic, particularly to African women due to the high prevalence of HIV infections. Although various studies show a relationship between HPV, HIV and cervical cancer, there is still a gap in the knowledge concerning the precise nature of this tripartite association. Firstly, most studies show the relationship between HPV and cervical cancer at genomic and epigenetic levels, while the transcriptomic landscape of this relationship remains to be elucidated. Even though many studies have shown HPV/HIV dual viral pathogenesis, the dual molecular oncoviral effects on the development of cervical cancer remains largely uncertain. Furthermore, the effect of highly active antiretroviral therapy (HAART) on the cellular splicing machinery is unclear. Emerging evidence indicates the vital role played by host splicing events in both HPV and HIV infection in the development and progression to cervical cancer. Therefore, decoding the transcriptome landscape of this tripartite relationship holds promising therapeutic potential. This review will focus on the link between cellular splicing machinery, HPV, HIV infection and the aberrant alternative splicing events that take place in HIV/HPV-associated cervical cancer. Finally, we will investigate how these aberrant splicing events can be targeted for the development of new therapeutic strategies against HPV/HIV-associated cervical cancer.
Synthesis and Application of Silica-Coated Quantum Dots in Biomedicine
Authors: Pham Xuan-Hung , Park Seung-Min , Ham Kyeong-Min , Kyeong San , Son Byung Sung , Kim Jaehi , Hahm Eunil , Kim Yoon-Hee , Bock Sungje , Kim Wooyeon , Jung Seunho , Oh Sangtaek , Lee Sang Hun , Hwang Do Won , Jun Bong-Hyun
Published: September 2021

Quantum dots (QDs) are semiconductor nanoparticles with outstanding optoelectronic properties. More specifically, QDs are highly bright and exhibit wide absorption spectra, narrow light bands, and excellent photovoltaic stability, which make them useful in bioscience and medicine, particularly for sensing, optical imaging, cell separation, and diagnosis. In general, QDs are stabilized using a hydrophobic ligand during synthesis, and thus their hydrophobic surfaces must undergo hydrophilic modification if the QDs are to be used in bioapplications. Silica-coating is one of the most effective methods for overcoming the disadvantages of QDs, owing to silica’s physicochemical stability, nontoxicity, and excellent bioavailability. This review highlights recent progress in the design, preparation, and application of silica-coated QDs and presents an overview of the major challenges and prospects of their application.
Design and Development of Nanomaterial-Based Drug Carriers to Overcome the Blood–Brain Barrier by Using Different Transport Mechanisms
Authors: Song Jisu , Lu Chao , Leszek Jerzy , Zhang Jin
Published: September 2021

Central nervous system (CNS) diseases are the leading causes of death and disabilities in the world. It is quite challenging to treat CNS diseases efficiently because of the blood–brain barrier (BBB). It is a physical barrier with tight junction proteins and high selectivity to limit the substance transportation between the blood and neural tissues. Thus, it is important to understand BBB transport mechanisms for developing novel drug carriers to overcome the BBB. This paper introduces the structure of the BBB and its physiological transport mechanisms. Meanwhile, different strategies for crossing the BBB by using nanomaterial-based drug carriers are reviewed, including carrier-mediated, adsorptive-mediated, and receptor-mediated transcytosis. Since the viral-induced CNS diseases are associated with BBB breakdown, various neurotropic viruses and their mechanisms on BBB disruption are reviewed and discussed, which are considered as an alternative solution to overcome the BBB. Therefore, most recent studies on virus-mimicking nanocarriers for drug delivery to cross the BBB are also reviewed and discussed. On the other hand, the routes of administration of drug-loaded nanocarriers to the CNS have been reviewed. In sum, this paper reviews and discusses various strategies and routes of nano-formulated drug delivery systems across the BBB to the brain, which will contribute to the advanced diagnosis and treatment of CNS diseases.
Accumulation of Uroporphyrin I in Necrotic Tissues of Squamous Cell Carcinoma after Administration of 5-Aminolevulinic Acid
Authors: Beika Masatomo , Harada Yoshinori , Minamikawa Takeo , Yamaoka Yoshihisa , Koizumi Noriaki , Murayama Yasutoshi , Konishi Hirotaka , Shiozaki Atsushi , Fujiwara Hitoshi , Otsuji Eigo , Takamatsu Tetsuro , Tanaka Hideo
Published: September 2021

5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) fluorescence is widely used for the intraoperative detection of malignant tumors. However, the fluorescence emission profiles of the accompanying necrotic regions of these tumors have yet to be determined. To address this, we performed fluorescence and high-performance liquid chromatography (HPLC) analyses of necrotic tissues of squamous cancer after 5-ALA administration. In resected human lymph nodes of metastatic squamous cell carcinoma, we found a fluorescence peak at approximately 620 nm in necrotic lesions, which was distinct from the PpIX fluorescence peak at 635 nm for viable cancer lesions. Necrotic lesions obtained from a subcutaneous xenograft model of human B88 oral squamous cancer also emitted the characteristic fluorescence peak at 620 nm after light irradiation: the fluorescence intensity ratio (620 nm/635 nm) increased with the energy of the irradiation light. HPLC analysis revealed a high content ratio of uroporphyrin I (UPI)/total porphyrins in the necrotic cores of murine tumors, indicating that UPI is responsible for the 620 nm peak. UPI accumulation in necrotic tissues after 5-ALA administration was possibly due to the failure of the heme biosynthetic pathway. Taken together, fluorescence imaging of UPI after 5-ALA administration may be applicable for the evaluation of tumor necrosis.
Effect of Endogenic and Exogenic Oxidative Stress Triggers on Adverse Pregnancy Outcomes: Preeclampsia, Fetal Growth Restriction, Gestational Diabetes Mellitus and Preterm Birth
Authors: Joo Eun Hui , Kim Young Ran , Kim Nari , Jung Jae Eun , Han Seon Ha , Cho Hee Young
Published: September 2021

Oxidative stress is caused by an imbalance between the production of reactive oxygen species (ROS) in cells and tissues and the ability of a biological system to detoxify them. During a normal pregnancy, oxidative stress increases the normal systemic inflammatory response and is usually well-controlled by the balanced body mechanism of the detoxification of anti-oxidative products. However, pregnancy is also a condition in which this adaptation and balance can be easily disrupted. Excessive ROS is detrimental and associated with many pregnancy complications, such as preeclampsia (PE), fetal growth restriction (FGR), gestational diabetes mellitus (GDM), and preterm birth (PTB), by damaging placentation. The placenta is a tissue rich in mitochondria that produces the majority of ROS, so it is important to maintain normal placental function and properly develop its vascular network to ensure a safe and healthy pregnancy. Antioxidants may ameliorate these diseases, and related research is progressing. This review aimed to determine the association between oxidative stress and adverse pregnancy outcomes, especially PE, FGR, GDM, and PTB, and explore how to overcome this oxidative stress in these unfavorable conditions.
Functional and Structural Changes in the Corticospinal Tract of Streptozotocin-Induced Diabetic Rats
Authors: Muramatsu Ken , Shimo Satoshi , Tamaki Toru , Ikutomo Masako , Niwa Masatoshi
Published: September 2021

This study aimed to reveal functional and morphological changes in the corticospinal tract, a pathway shown to be susceptible to diabetes. Type 1 diabetes was induced in 13-week-old male Wistar rats administered streptozotocin. Twenty-three weeks after streptozotocin injection, diabetic animals and age-matched control animals were used to demonstrate the conduction velocity of the corticospinal tract. Other animals were used for morphometric analyses of the base of the dorsal funiculus of the corticospinal tract in the spinal cord using both optical and electron microscopy. The conduction velocity of the corticospinal tract decreased in the lumbar spinal cord in the diabetic animal, although it did not decrease in the cervical spinal cord. Furthermore, atrophy of the fibers of the base of the dorsal funiculus was observed along their entire length, with an increase in the g-ratio in the lumbar spinal cord in the diabetic animal. This study indicates that the corticospinal tract fibers projecting to the lumbar spinal cord experience a decrease in conduction velocity at the lumbar spinal cord of these axons in diabetic animals, likely caused by a combination of axonal atrophy and an increased g-ratio due to thinning of the myelin sheath.
Intermittent Hypoxia Upregulates the Renin and Cd38 mRNAs in Renin-Producing Cells via the Downregulation of miR-203
Authors: Takeda Yoshinori , Itaya-Hironaka Asako , Yamauchi Akiyo , Makino Mai , Sakuramoto-Tsuchida Sumiyo , Ota Hiroyo , Kawaguchi Ryuji , Takasawa Shin
Published: September 2021

Sleep apnea syndrome is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]), and it is a known risk factor for hypertension. The upregulation of the renin-angiotensin system has been reported in IH, and the correlation between renin and CD38 has been noted. We exposed human HEK293 and mouse As4.1 renal cells to experimental IH or normoxia for 24 h and then measured the mRNA levels using a real-time reverse transcription polymerase chain reaction. The mRNA levels of Renin (Ren) and Cd38 were significantly increased by IH, indicating that they could be involved in the CD38-cyclic ADP-ribose signaling pathway. We next investigated the promotor activities of both genes, which were not increased by IH. Yet, a target mRNA search of the microRNA (miRNA) revealed both mRNAs to have a potential target sequence for miR-203. The miR-203 level of the IH-treated cells was significantly decreased when compared with the normoxia-treated cells. The IH-induced upregulation of the genes was abolished by the introduction of the miR-203 mimic, but not the miR-203 mimic NC negative control. These results indicate that IH stress downregulates the miR-203 in renin-producing cells, thereby resulting in increased mRNA levels of Ren and Cd38, which leads to hypertension.
Conformational Insights into the Control of CNF1 Toxin Activity by Peptidyl-Prolyl Isomerization: A Molecular Dynamics Perspective
Authors: Paillares Eléa , Marechal Maud , Swistak Léa , Tsoumtsa Meda Landry , Lemichez Emmanuel , Malliavin Thérèse E.
Published: September 2021

The cytotoxic necrotizing factor 1 (CNF1) toxin from uropathogenic Escherichia coli constitutively activates Rho GTPases by catalyzing the deamidation of a critical glutamine residue located in the switch II (SWII). In crystallographic structures of the CNF1 catalytic domain (CNF1CD), surface-exposed P768 and P968 peptidyl-prolyl imide bonds (X-Pro) adopt an unusual cis conformation. Here, we show that mutation of each proline residue into glycine abrogates CNF1CD in vitro deamidase activity, while mutant forms of CNF1 remain functional on RhoA in cells. Using molecular dynamics simulations coupled to protein-peptide docking, we highlight the long-distance impact of peptidyl-prolyl cis-trans isomerization on the network of interactions between the loops bordering the entrance of the catalytic cleft. The energetically favorable isomerization of P768 compared with P968, induces an enlargement of loop L1 that fosters the invasion of CNF1CD catalytic cleft by a peptide encompassing SWII of RhoA. The connection of the P968 cis isomer to the catalytic cysteine C866 via a ladder of stacking interactions is alleviated along the cis-trans isomerization. Finally, the cis-trans conversion of P768 favors a switch of the thiol side chain of C866 from a resting to an active orientation. The long-distance impact of peptidyl-prolyl cis-trans isomerizations is expected to have implications for target modification.
Advances in the Genetically Engineered KillerRed for Photodynamic Therapy Applications
Authors: Liu Jiexi , Wang Fei , Qin Yang , Feng Xiaolan
Published: September 2021

Photodynamic therapy (PDT) is a clinical treatment for cancer or non-neoplastic diseases, and the photosensitizers (PSs) are crucial for PDT efficiency. The commonly used chemical PSs, generally produce ROS through the type II reaction that highly relies on the local oxygen concentration. However, the hypoxic tumor microenvironment and unavoidable dark toxicity of PSs greatly restrain the wide application of PDT. The genetically encoded PSs, unlike chemical PSs, can be modified using genetic engineering techniques and targeted to unique cellular compartments, even within a single cell. KillerRed, as a dimeric red fluorescent protein, can be activated by visible light or upconversion luminescence to execute the Type I reaction of PDT, which does not need too much oxygen and surely attract the researchers’ focus. In particular, nanotechnology provides new opportunities for various modifications of KillerRed and versatile delivery strategies. This review more comprehensively outlines the applications of KillerRed, highlighting the fascinating features of KillerRed genes and proteins in the photodynamic systems. Furthermore, the advantages and defects of KillerRed are also discussed, either alone or in combination with other therapies. These overviews may facilitate understanding KillerRed progress in PDT and suggest some emerging potentials to circumvent challenges to improve the efficiency and accuracy of PDT.
Brain Renin–Angiotensin System as Novel and Potential Therapeutic Target for Alzheimer’s Disease
Authors: Loera-Valencia Raúl , Eroli Francesca , Garcia-Ptacek Sara , Maioli Silvia
Published: September 2021

The activation of the brain renin-angiotensin system (RAS) plays a pivotal role in the pathophysiology of cognition. While the brain RAS has been studied before in the context of hypertension, little is known about its role and regulation in relation to neuronal function and its modulation. Adequate blood flow to the brain as well as proper clearing of metabolic byproducts become crucial in the presence of neurodegenerative disorders such as Alzheimer’s disease (AD). RAS inhibition (RASi) drugs that can cross into the central nervous system have yielded unclear results in improving cognition in AD patients. Consequently, only one RASi therapy is under consideration in clinical trials to modify AD. Moreover, the role of non-genetic factors such as hypercholesterolemia in the pathophysiology of AD remains largely uncharacterized, even when evidence exists that it can lead to alteration of the RAS and cognition in animal models. Here we revise the evidence for the function of the brain RAS in cognition and AD pathogenesis and summarize the evidence that links it to hypercholesterolemia and other risk factors. We review existent medications for RASi therapy and show research on novel drugs, including small molecules and nanodelivery strategies that can target the brain RAS with potential high specificity. We hope that further research into the brain RAS function and modulation will lead to innovative therapies that can finally improve AD neurodegeneration.
Neuropeptide Y Reduces Social Fear in Male Mice: Involvement of Y1 and Y2 Receptors in the Dorsolateral Septum and Central Amygdala
Authors: Kornhuber Johannes , Zoicas Iulia
Published: September 2021

Neuropeptide Y (NPY) has anxiolytic-like effects and facilitates the extinction of cued and contextual fear in rodents. We previously showed that intracerebroventricular administration of NPY reduces the expression of social fear in a mouse model of social fear conditioning (SFC) and localized these effects to the dorsolateral septum (DLS) and central amygdala (CeA). In the present study, we aimed to identify the receptor subtypes that mediate these local effects of NPY. We show that NPY (0.1 nmol/0.2 µL/side) reduced the expression of SFC-induced social fear in a brain region- and receptor-specific manner in male mice. In the DLS, NPY reduced the expression of social fear by acting on Y2 receptors but not on Y1 receptors. As such, prior administration of the Y2 receptor antagonist BIIE0246 (0.2 nmol/0.2 μL/side) but not the Y1 receptor antagonist BIBO3304 trifluoroacetate (0.2 nmol/0.2 μL/side) blocked the effects of NPY in the DLS. In the CeA, however, BIBO3304 trifluoroacetate but not BIIE0246 blocked the effects of NPY, suggesting that NPY reduced the expression of social fear by acting on Y1 receptors but not Y2 receptors within the CeA. This study suggests that at least two distinct receptor subtypes are differentially recruited in the DLS and CeA to mediate the effects of NPY on the expression of social fear.