bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between First Sexual Intercourse and Sexual Violence Victimization, Symptoms of Depression, and Suicidal Behaviors among Adolescents in the United States: Findings from 2017 and 2019 National Youth Risk Behavior Survey
Authors: Baiden Philip , Panisch Lisa S. , Kim Yi Jin , LaBrenz Catherine A. , Kim Yeonwoo , Onyeaka Henry K.
Published: July 2021

The objective of this study was to investigate the association between first sexual intercourse and sexual violence victimization, symptoms of depression, and suicidal ideation among sexually active adolescents in the United States. Data for this study came from the U.S. 2017 and 2019 iterations of the National Youth Risk Behavior Survey. An analytic sample of 6252 adolescents aged 14–18 years old (49.5% female) who reported ever having sexual intercourse was analyzed using Poisson regression. The outcome variables investigated in this study were sexual violence victimization, symptoms of depression, suicidal ideation, a suicide plan, and suicide attempts, and the main explanatory variables were age at first sexual intercourse and forced sexual intercourse. We also analyzed differences by gender and race. Of the 6252 adolescents who reported ever having sexual intercourse, 7.1% had their first sexual intercourse before age 13, and 14.8% experienced forced sexual intercourse. About 16% of adolescents experienced sexual violence during the past year, 42.6% reported symptoms of depression, 23.9% experienced suicidal ideation, 19.3% made a suicide plan, and 11.1% attempted suicide during the past year. In the regression analysis, early sexual intercourse was significantly and positively associated with suicidal ideation (relative risk (RR) = 1.15, 95% Confidence Interval (CI) = 1.02–1.30), suicide plan (RR = 1.18, 95% CI = 1.00–1.38), and suicide attempts (RR = 1.36, 95% CI = 1.15–1.61). Controlling for the effects of covariates, history of forced sexual intercourse was positively associated with the five outcomes examined with the relative risk ranging between 1.59 and 6.01. Findings of this study suggest that history of early or forced sexual intercourse is associated with poor mental health outcomes among adolescents and underscores the importance of developing interventions that offer psychological support in reducing the adverse impact of early sexual intercourse and forced sexual intercourse on adolescent health.
Impact of Ed-LinQ: A Public Policy Strategy to Facilitate Engagement between Schools and the Mental Health Care System in Queensland, Australia
Authors: Salvador-Carulla Luis , Fernandez Ana , Sarma Haribondhu , Mendoza John , Wands Marion , Gandre Coralie , Chevreul Karine , Lukersmith Sue
Published: July 2021

Ed-LinQ is a mental health policy initiative to enhance the early detection and treatment of children with mental illness by improving the liaison between schools and health services in Queensland, Australia. We measured its impact from policy to practice to inform further program developments and public strategies. We followed a mixed quantitative/qualitative approach. The Adoption Impact Ladder (AIL) was used to analyse the adoption of this initiative by end-users (decision makers both in the health and education sectors) and the penetration of the initiative in the school sector. Survey respondents included representatives of schools (n = 186) and mental health providers (n = 78). In total, 63% of the school representative respondents were at least aware of the existence of the Ed-LinQ initiative, 74% were satisfied with the initiative and 28% of the respondent schools adopted the initiative to a significant extent. Adoption was higher in urban districts and in the health sector. The overall level of penetration in the school sector of Queensland was low (3%). The qualitative analysis indicated an improvement in the referral and communication processes between schools and the health sectors and the importance of funding in the implementation of the initiative. Mapping of existing programs is needed to assess the implementation of a new one as well as the design of different implementation strategies for urban and rural areas. Assessing the adoption of health policy strategies and their penetration in a target audience is critical to understand their proportional impacts across a defined ecosystem and constitutes a necessary preliminary step for the evaluation of their quality and efficiency.
Association of X-ray Absorptiometry Body Composition Measurements with Basic Anthropometrics and Mortality Hazard
Authors: Krakauer Nir Y. , Krakauer Jesse C.
Published: July 2021

Dual-energy X-ray absorptiometry (DEXA) is a non-invasive imaging modality that can estimate whole-body and regional composition in terms of fat, lean, and bone mass. We examined the ability of DEXA body composition measures (whole-body, trunk, and limb fat mass and fat-free mass) to predict mortality in conjunction with basic body measures (anthropometrics), expressed using body mass index (BMI) and a body shape index (ABSI). We used data from the 1999–2006 United States National Health and Nutrition Examination Survey (NHANES), with mortality follow-up to 2015. We found that all DEXA-measured masses were highly correlated with each other and with ABSI and that adjustment for BMI and ABSI reduced these dependencies. Whole-body composition did not substantially improve mortality prediction compared to basic anthropometrics alone, but regional composition did, with high trunk fat-free mass and low limb fat-free mass both associated with elevated mortality risk. These findings illustrate how DEXA body composition could guide health assessment in conjunction with the more widely employed simple anthropometrics.
“Don’t Know” Responses for Nicotine Vaping Product Features among Adult Vapers: Findings from the 2018 and 2020 ITC Four Country Smoking and Vaping Surveys
Authors: Felicione Nicholas J. , Cummings K. Michael , Gravely Shannon , Hammond David , McNeill Ann , Borland Ron , Fong Geoffrey T. , O’Connor Richard J.
Published: July 2021

Nicotine vaping products (NVPs) have evolved rapidly, and some vapers have difficulty reporting about their NVP. NVP knowledge may be important for providing accurate survey data, understanding the potential risks of NVP use, and assessing legal and regulated products. This paper examines current vapers who responded “don’t know” (DK) regarding their NVP features. Data are from adult daily/weekly vapers in Waves Two (2018, n = 4192) and Three (2020, n = 3894) of the ITC Four Country Smoking and Vaping Survey. Analyses assessed DK responses for NVP features (e.g., type/appearance, nicotine) and consumption. A DK index score was computed based on the percent of all features with DK responses, which was tested for associations with demographics, smoking/vaping status, NVP features, purchase location, and knowledge of NVP relative risks. NVP description and appearance were easily identified, but DK was more common for features such as nicotine content (7.3–9.2%) and tank/cartridge volume capacity (26.6–30.0%). DK responses often differed by vaping/smoking status, NVP type/appearance, purchase location, and country. Vapers who are younger, use box-shaped NVPs, purchase online, and exclusive daily vapers were associated with lower DK index scores. Higher DK index scores were associated with poorer knowledge of relative health risks of NVP use. The diversity of the NVP market and wide variation in how products are used makes it challenging to capture information from users about device features, such as nicotine content and capacity, in population surveys.
A Novel Model for Generating Creative, Community-Responsive Interventions to Reduce Gender-Based Violence on College Campuses
Authors: Graham Sophia , Zha Caroline Cao , King Abby C. , Banchoff Ann W. , Sarnquist Clea , Dauber Michele , Baiocchi Michael
Published: July 2021

Currently, the most successful prevention interventions against sexual violence (SV) on United States college campuses target modifications at the individual and interpersonal levels. Community-level interventions have been under-developed for college campuses. To address this gap, we employ a citizen science model for understanding campus community factors affecting SV risk. The model, called Our Voice, starts by engaging groups of college students to collect data in their own communities, identifying factors they view as increasing the risk of SV. In facilitated meetings, participants then review and analyze their collective data and use it to generate actionable community-level solutions and advocate for them with local decision-makers. We share findings from a first-generation study of the Our Voice model applied to SV prevention on one college campus, and include recommendations for further research.
Self-Reported Modifiable Risk Factors of Cardiovascular Disease among Older Adults in Malaysia: A Cross-Sectional Study of Prevalence and Clustering
Authors: Chan Ying Ying , Sahril Norhafizah , Rezali Muhammad Solihin , Kuang Kuay Lim , Baharudin Azli , Abd Razak Mohamad Aznuddin , Azlan Kassim Mohd Shaiful , Mohd Yusoff Muhammad Fadhli , Omar Mohd Azahadi , Ahmad Noor Ani
Published: July 2021

The co-occurrence of multiple modifiable risk factors increases the risk of cardiovascular disease (CVD) morbidity or mortality. This study examines the prevalence and clustering of self-reported modifiable CVD risk factors among older adults in Malaysia. A total of 7117 adults aged ≥50 years participated in the National Health and Morbidity Survey (NHMS) 2018: Elderly Health, a community-based cross-sectional survey. Data were collected using a standardized structured questionnaire. Multivariable logistic regression was used to determine the factors associated with the clustering of self-reported modifiable CVD risk factors. The prevalence of self-reported diabetes, hypertension, hypercholesterolemia, overweight/obesity, and current smoking was 23.3%, 42.2%, 35.6%, 58.4%, and 17.5%, respectively. Overall, the prevalence of clustering of ≥1, ≥2, and ≥3 modifiable CVD risk factors was 83.3%, 75.4%, and 62.6%, respectively. Multivariable logistic regression analysis showed that men, 60–69 age group, urban dwellers, having no formal education, unemployed/retirees/homemakers, and being physically inactive were independently associated with self-reported modifiable CVD risk factors clustering. There are also ethnic differences in self-reported modifiable CVD risk factors clustering. Our findings underscore the necessity of targeted interventions and integrated strategies for early detection and treatment of modifiable CVD risk factors among older adults, considering age, sex, ethnicity, and socioeconomic status.
Frequency of Anti-SARS-CoV-2 Antibodies in Various Occupational Sectors in an Industrialized Area of Northern Italy from May to October 2020
Authors: Modenese Alberto , Mazzoli Tommaso , Berselli Nausicaa , Ferrari Davide , Bargellini Annalisa , Borella Paola , Filippini Tommaso , Marchesi Isabella , Paduano Stefania , Vinceti Marco , Gobba Fabriziomaria
Published: July 2021

The results of a voluntary screening campaign for the presence of anti-SARS-CoV-2 serum antibodies are presented, performed on workers in the highly industrialized province of Modena in northern Italy in the period 18 May–5 October 2020. The employment activities of the subjects that tested positive for anti-SARS-CoV-2 IgM and/or IgG antibodies were determined and classified using the International Standard Industrial Classification of All Economic Activities (ISIC). The distribution across different sectors was compared to the proportion of workers employed in the same sectors in the province of Modena as a whole. Workers with anti-SARS-CoV-2 serum antibodies were mainly employed in manufacturing (60%), trade (12%), transportation (9%), scientific and technical activities (5%), and arts, entertainment and recreation activities (4.5%). Within the manufacturing sector, a cluster of workers with positive serological tests was observed in the meat processing sector, confirming recent data showing a possible increased risk of SARS-CoV-2 infection in these workers.
Supramolecular Amphiphiles Based on Pillar[5]arene and Meroterpenoids: Synthesis, Self-Association and Interaction with Floxuridine
Authors: Akhmedov Alan A. , Shurpik Dmitriy N. , Padnya Pavel L. , Khadieva Alena I. , Gamirov Rustem R. , Panina Yulia V. , Gazizova Asiya F. , Grishaev Denis Yu. , Plemenkov Vitaliy V. , Stoikov Ivan I.
Published: July 2021

In recent years, meroterpenoids have found wide biomedical application due to their synthetic availability, low toxicity, and biocompatibility. However, these compounds are not used in targeted drug delivery systems due to their high affinity for cell membranes, both healthy and in cancer cells. Using the approach of creating supramolecular amphiphiles, we have developed self-assembling systems based on water-soluble pillar[5]arene and synthetic meroterpenoids containing geraniol, myrtenol, farnesol, and phytol fragments. The resulting systems can be used as universal drug delivery systems. It was shown by turbidimetry that the obtained pillar[5]arene/synthetic meroterpenoid systems do not interact with the model cell membrane at pH = 7.4, but the associates are destroyed at pH = 4.1. In this case, the synthetic meroterpenoid is incorporated into the lipid bilayer of the model membrane. The characteristics of supramolecular self-assembly, association constants and stoichiometry of the most stable pillar[5]arene/synthetic meroterpenoid complexes were established by UV-vis spectroscopy and dynamic light scattering (DLS). It was shown that supramolecular amphiphiles based on pillar[5]arene/synthetic meroterpenoid systems form monodisperse associates in a wide range of concentrations. The inclusion of the antitumor drug 5-fluoro-2′-deoxyuridine (floxuridine) into the structure of the supramolecular associate was demonstrated by DLS, 19F, 2D DOSY NMR spectroscopy.
Germline Whole-Gene Deletion of FH Diagnosed from Tumor Profiling
Authors: Ueki Arisa , Sugano Kokichi , Misu Kumiko , Aimono Eriko , Nakamura Kohei , Tanishima Shigeki , Tanaka Nobuyuki , Mikami Shuji , Hirasawa Akira , Ando Miho , Yoshida Teruhiko , Oya Mototsugu , Nishihara Hiroshi , Kosaki Kenjiro
Published: July 2021

Hereditary leiomyomatosis and renal cell carcinoma (HL (RCC)) entails cutaneous and uterine leiomyomatosis with aggressive type 2 papillary RCC-like histology. HLRCC is caused by pathogenic variants in the FH gene, which encodes fumarate hydratase (FH). Here, we describe an episode of young-onset RCC caused by a genomic FH deletion that was diagnosed via clinical sequencing. A 35-year-old woman was diagnosed with RCC and multiple metastases: histopathological analyses supported a diagnosis of FH-deficient RCC. Although the patient had neither skin tumors nor a family history of HLRCC, an aggressive clinical course at her age and pathological diagnosis of FH-deficient RCC suggested a germline FH variant. After counseling, the patient provided written informed consent for germline genetic testing. She was simultaneously subjected to paired tumor profiling tests targeting the exome to identify a therapeutic target. Although conventional germline sequencing did not detect FH variants, exome sequencing revealed a heterozygous germline FH deletion. As such, paired tumor profiling, not conventional sequencing, was required to identify this genetic deletion. RCC caused by a germline FH deletion has hitherto not been described in Japan, and the FH deletion detected in this patient was presumed to be of maternal European origin. Although the genotype-phenotype correlation in HLRCC-related tumors is unclear, the patient’s family was advised to undergo genetic counseling to consider additional RCC screening.
Mitochondrion as a Target of Astaxanthin Therapy in Heart Failure
Authors: Krestinina Olga , Baburina Yulia , Krestinin Roman
Published: July 2021

Mitochondria are considered to be important organelles in the cell and play a key role in the physiological function of the heart, as well as in the pathogenesis and development of various heart diseases. Under certain pathological conditions, such as cardiovascular diseases, stroke, traumatic brain injury, neurodegenerative diseases, muscular dystrophy, etc., mitochondrial permeability transition pore (mPTP) is formed and opened, which can lead to dysfunction of mitochondria and subsequently to cell death. This review summarizes the results of studies carried out by our group of the effect of astaxanthin (AST) on the functional state of rat heart mitochondria upon direct addition of AST to isolated mitochondria and upon chronic administration of AST under conditions of mPTP opening. It was shown that AST exerted a protective effect under all conditions. In addition, AST treatment was found to prevent isoproterenol-induced oxidative damage to mitochondria and increase mitochondrial efficiency. AST, a ketocarotenoid, may be a potential mitochondrial target in therapy for pathological conditions associated with oxidative damage and mitochondrial dysfunction, and may be a potential mitochondrial target in therapy for pathological conditions.
Kidney-Protector Lipidic Cilastatin Derivatives as Structure-Directing Agents for the Synthesis of Mesoporous Silica Nanoparticles for Drug Delivery
Authors: Martinez-Erro Samuel , Navas Francisco , Romaní-Cubells Eva , Fernández-García Paloma , Morales Victoria , Sanz Raul , García-Muñoz Rafael A.
Published: July 2021

Mesoporous silica nanomaterials have emerged as promising vehicles in controlled drug delivery systems due to their ability to selectively transport, protect, and release pharmaceuticals in a controlled and sustained manner. One drawback of these drug delivery systems is their preparation procedure that usually requires several steps including the removal of the structure-directing agent (surfactant) and the later loading of the drug into the porous structure. Herein, we describe the preparation of mesoporous silica nanoparticles, as drug delivery systems from structure-directing agents based on the kidney-protector drug cilastatin in a simple, fast, and one-step process. The concept of drug-structure-directing agent (DSDA) allows the use of lipidic derivatives of cilastatin to direct the successful formation of mesoporous silica nanoparticles (MSNs). The inherent pharmacological activity of the surfactant DSDA cilastatin-based template permits that the MSNs can be directly employed as drug delivery nanocarriers, without the need of extra steps. MSNs thus synthesized have shown good sphericity and remarkable textural properties. The size of the nanoparticles can be adjusted by simply selecting the stirring speed, time, and aging temperature during the synthesis procedure. Moreover, the release experiments performed on these materials afforded a slow and sustained drug release over several days, which illustrates the MSNs potential utility as drug delivery system for the cilastatin cargo kidney protector. While most nanotechnology strategies focused on combating the different illnesses this methodology emphasizes on reducing the kidney toxicity associated to cancer chemotherapy.
Biomimetic Zirconia with Cactus-Inspired Meso-Scale Spikes and Nano-Trabeculae for Enhanced Bone Integration
Authors: Saruta Juri , Ozawa Ryotaro , Okubo Takahisa , Taleghani Samira R. , Ishijima Manabu , Kitajima Hiroaki , Hirota Makoto , Ogawa Takahiro
Published: July 2021

Biomimetic design provides novel opportunities for enhancing and functionalizing biomaterials. Here we created a zirconia surface with cactus-inspired meso-scale spikes and bone-inspired nano-scale trabecular architecture and examined its biological activity in bone generation and integration. Crisscrossing laser etching successfully engraved 60 μm wide, cactus-inspired spikes on yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) with 200–300 nm trabecular bone-inspired interwoven structures on the entire surface. The height of the spikes was varied from 20 to 80 μm for optimization. Average roughness (Sa) increased from 0.10 μm (polished smooth surface) to 18.14 μm (80 μm-high spikes), while the surface area increased by up to 4.43 times. The measured dimensions of the spikes almost perfectly correlated with their estimated dimensions (R2 = 0.998). The dimensional error of forming the architecture was 1% as a coefficient of variation. Bone marrow-derived osteoblasts were cultured on a polished surface and on meso- and nano-scale hybrid textured surfaces with different spike heights. The osteoblastic differentiation was significantly promoted on the hybrid-textured surfaces compared with the polished surface, and among them the hybrid-textured surface with 40 μm-high spikes showed unparalleled performance. In vivo bone-implant integration also peaked when the hybrid-textured surface had 40 μm-high spikes. The relationships between the spike height and measures of osteoblast differentiation and the strength of bone and implant integration were non-linear. The controllable creation of meso- and nano-scale hybrid biomimetic surfaces established in this study may provide a novel technological platform and design strategy for future development of biomaterial surfaces to improve bone integration and regeneration.
Regulatory Macrophages and Tolerogenic Dendritic Cells in Myeloid Regulatory Cell-Based Therapies
Authors: Suuring Maaike , Moreau Aurélie
Published: July 2021

Myeloid regulatory cell-based therapy has been shown to be a promising cell-based medicinal approach in organ transplantation and for the treatment of autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, Crohn’s disease and multiple sclerosis. Dendritic cells (DCs) are the most efficient antigen-presenting cells and can naturally acquire tolerogenic properties through a variety of differentiation signals and stimuli. Several subtypes of DCs have been generated using additional agents, including vitamin D3, rapamycin and dexamethasone, or immunosuppressive cytokines, such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β). These cells have been extensively studied in animals and humans to develop clinical-grade tolerogenic (tol)DCs. Regulatory macrophages (Mregs) are another type of protective myeloid cell that provide a tolerogenic environment, and have mainly been studied within the context of research on organ transplantation. This review aims to thoroughly describe the ex vivo generation of tolDCs and Mregs, their mechanism of action, as well as their therapeutic application and assessment in human clinical trials.
S100A9 Alters the Pathway of Alpha-Synuclein Amyloid Aggregation
Authors: Toleikis Zigmantas , Ziaunys Mantas , Baranauskiene Lina , Petrauskas Vytautas , Jaudzems Kristaps , Smirnovas Vytautas
Published: July 2021

The formation of amyloid fibril plaques in the brain creates inflammation and neuron death. This process is observed in neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Alpha-synuclein is the main protein found in neuronal inclusions of patients who have suffered from Parkinson’s disease. S100A9 is a calcium-binding, pro-inflammation protein, which is also found in such amyloid plaques. To understand the influence of S100A9 on the aggregation of α-synuclein, we analyzed their co-aggregation kinetics and the resulting amyloid fibril structure by Fourier-transform infrared spectroscopy and atomic force microscopy. We found that the presence of S100A9 alters the aggregation kinetics of α-synuclein and stabilizes the formation of a particular amyloid fibril structure. We also show that the solution’s ionic strength influences the interplay between S100A9 and α-synuclein, stabilizing a different structure of α-synuclein fibrils.
Ligand-Tuning of the Stability of Pd(II) Conjugates with Cyanocobalamin
Authors: Porębska Dominika , Orzeł Łukasz , Rutkowska-Zbik Dorota , Stochel Grażyna , van Eldik Rudi
Published: July 2021

Besides the well-known functions performed by vitamin B12 (CblCN) in biochemical processes of the human body, an increasing interest has been raised by the possibility of its use as a transmembrane drug carrier, capable, among others, of enhancing the accumulation of inorganic cytostatics in cancer cells. The present study was aimed at determining the possibility of the formation of CblCN conjugates with Pd(II) complexes. A key aspect was their stability, which we attempted to tune by appropriate choice of ligands. Syntheses, spectroscopic analysis of postreaction systems and kinetic investigations of conjugate formation reactions, have been complemented by DFT modelling. The obtained results showed that ligand charge, geometry and electron affinity may have a significant impact on carrier binding and release leading to the activation of the Pd(II) complex. This provides a rationale to expect that with appropriate composition of the coordination sphere, it will be possible to extend the spectrum of less toxic inorganic chemotherapeutics.
Bidentatide, a Novel Plant Peptide Derived from Achyranthes bidentata Blume: Isolation, Characterization, and Neuroprotection through Inhibition of NR2B-Containing NMDA Receptors
Authors: Ding Fei , Bai Yunpeng , Cheng Qiong , Yu Shu , Cheng Mengchun , Wu Yulin , Zhang Xiaozhe , Liang Xinmiao , Gu Xiaosong
Published: July 2021

Increasing attention is being focused on the use of polypeptide-based N-methyl-d-aspartate (NMDA) receptor antagonists for the treatment of nervous system disorders. In our study on Achyranthes bidentata Blume, we identified an NMDA receptor subtype 2B (NR2B) antagonist that exerts distinct neuroprotective actions. This antagonist is a 33 amino acid peptide, named bidentatide, which contains three disulfide bridges that form a cysteine knot motif. We determined the neuroactive potential of bidentatide by evaluating its in vitro effects against NMDA-mediated excitotoxicity. The results showed that pretreating primary cultured hippocampal neurons with bidentatide prevented NMDA-induced cell death and apoptosis via multiple mechanisms that involved intracellular Ca2+ inhibition, NMDA current inhibition, and apoptosis-related protein expression regulation. These mechanisms were all dependent on bidentatide-induced inhibitory regulation of NR2B-containing NMDA receptors; thus, bidentatide may contribute to the development of neuroprotective agents that would likely possess the high selectivity and safety profiles inherent in peptide drugs.
Sex Steroids and the Shaping of the Peripubertal Brain: The Sexual-Dimorphic Set-Up of Adult Neurogenesis
Authors: Trova Sara , Bovetti Serena , Bonzano Sara , De Marchis Silvia , Peretto Paolo
Published: July 2021

Steroid hormones represent an amazing class of molecules that play pleiotropic roles in vertebrates. In mammals, during postnatal development, sex steroids significantly influence the organization of sexually dimorphic neural circuits underlying behaviors critical for survival, such as the reproductive one. During the last decades, multiple studies have shown that many cortical and subcortical brain regions undergo sex steroid-dependent structural organization around puberty, a critical stage of life characterized by high sensitivity to external stimuli and a profound structural and functional remodeling of the organism. Here, we first give an overview of current data on how sex steroids shape the peripubertal brain by regulating neuroplasticity mechanisms. Then, we focus on adult neurogenesis, a striking form of persistent structural plasticity involved in the control of social behaviors and regulated by a fine-tuned integration of external and internal cues. We discuss recent data supporting that the sex steroid-dependent peripubertal organization of neural circuits involves a sexually dimorphic set-up of adult neurogenesis that in turn could be relevant for sex-specific reproductive behaviors.
Altered Root Growth, Auxin Metabolism and Distribution in Arabidopsis thaliana Exposed to Salt and Osmotic Stress
Authors: Smolko Ana , Bauer Nataša , Pavlović Iva , Pěnčík Aleš , Novák Ondřej , Salopek-Sondi Branka
Published: July 2021

Salt and osmotic stress are the main abiotic stress factors affecting plant root growth and architecture. We investigated the effect of salt (100 mM NaCl) and osmotic (200 mM mannitol) stress on the auxin metabolome by UHPLC-MS/MS, auxin distribution by confocal microscopy, and transcript levels of selected genes by qRT-PCR in Arabidopsis thaliana ecotype Columbia-0 (Col-0) and DR5rev::GFP (DR5) line. During long-term stress (13 days), a stability of the auxin metabolome and a tendency to increase indole-3-acetic acid (IAA) were observed, especially during salt stress. Short-term stress (3 h) caused significant changes in the auxin metabolome, especially NaCl treatment resulted in a significant reduction of IAA. The data derived from auxin profiling were consistent with gene expressions showing the most striking changes in the transcripts of YUC, GH3, and UGT transcripts, suggesting disruption of auxin biosynthesis, but especially in the processes of amide and ester conjugation. These data were consistent with the auxin distribution observed in the DR5 line. Moreover, NaCl treatment caused a redistribution of auxin signals from the quiescent center and the inner layers of the root cap to the epidermal and cortical cells of the root elongation zone. The distribution of PIN proteins was also disrupted by salt stress; in particular, PIN2 was suppressed, even after 5 min of treatment. Based on our results, the DR5 line was more sensitive to the applied stresses than Col-0, although both lines showed similar trends in root morphology, as well as transcriptome and metabolome parameters under stress conditions.
The Essential Role of PRAK in Preserving Cardiac Function and Insulin Resistance in High-Fat Diet-Induced Diabetes
Authors: Du Jianfeng , Zhao Yu Tina , Wang Hao , Zhang Ling X. , Qin Gangjian , Zhuang Shougang , Kadin Marshall , Chin Y. Eugene , Liu Paul Y. , Zhao Ting C.
Published: July 2021

Regulated/activated protein kinase (PRAK) plays a crucial role in modulating biological function. However, the role of PRAK in mediating cardiac dysfunction and metabolic disorders remains unclear. We examined the effects of deletion of PRAK on modulating cardiac function and insulin resistance in mice exposed to a high-fat diet (HFD). Wild-type and PRAK−/− mice at 8 weeks old were exposed to either chow food or HFD for a consecutive 16 weeks. Glucose tolerance tests and insulin tolerance tests were employed to assess insulin resistance. Echocardiography was employed to assess myocardial function. Western blot was used to determine the molecular signaling involved in phosphorylation of IRS-1, AMPKα, ERK-44/42, and irisin. Real time-PCR was used to assess the hypertrophic genes of the myocardium. Histological analysis was employed to assess the hypertrophic response, interstitial myocardial fibrosis, and apoptosis in the heart. Western blot was employed to determine cellular signaling pathway. HFD-induced metabolic stress is indicated by glucose intolerance and insulin intolerance. PRAK knockout aggravated insulin resistance, as indicated by glucose intolerance and insulin intolerance testing as compared with wild-type littermates. As compared with wild-type mice, hyperglycemia and hypercholesterolemia were manifested in PRAK-knockout mice following high-fat diet intervention. High-fat diet intervention displayed a decline in fractional shortening and ejection fraction. However, deletion of PRAK exacerbated the decline in cardiac function as compared with wild-type mice following HFD treatment. In addition, PRAK knockout mice enhanced the expression of myocardial hypertrophic genes including ANP, BNP, and βMHC in HFD treatment, which was also associated with an increase in cardiomyocyte size and interstitial fibrosis. Western blot indicated that deletion of PRAK induces decreases in phosphorylation of IRS-1, AMPKα, and ERK44/42 as compared with wild-type controls. Our finding indicates that deletion of PRAK promoted myocardial dysfunction, cardiac remodeling, and metabolic disorders in response to HFD.
Human Mitochondrial RNA Processing and Modifications: Overview
Authors: Jedynak-Slyvka Marta , Jabczynska Agata , Szczesny Roman J.
Published: July 2021

Mitochondria, often referred to as the powerhouses of cells, are vital organelles that are present in almost all eukaryotic organisms, including humans. They are the key energy suppliers as the site of adenosine triphosphate production, and are involved in apoptosis, calcium homeostasis, and regulation of the innate immune response. Abnormalities occurring in mitochondria, such as mitochondrial DNA (mtDNA) mutations and disturbances at any stage of mitochondrial RNA (mtRNA) processing and translation, usually lead to severe mitochondrial diseases. A fundamental line of investigation is to understand the processes that occur in these organelles and their physiological consequences. Despite substantial progress that has been made in the field of mtRNA processing and its regulation, many unknowns and controversies remain. The present review discusses the current state of knowledge of RNA processing in human mitochondria and sheds some light on the unresolved issues.
Istradefylline Mitigates Age-Related Hearing Loss in C57BL/6J Mice
Authors: Shin Min , Pandya Madhavi , Espinosa Kristan , Telang Ravindra , Boix Jordi , Thorne Peter R. , Vlajkovic Srdjan M.
Published: July 2021

Age-related hearing loss (ARHL) is the most common sensory disorder among older people, and yet, the treatment options are limited to medical devices such as hearing aids and cochlear implants. The high prevalence of ARHL mandates the development of treatment strategies that can prevent or rescue age-related cochlear degeneration. In this study, we investigated a novel pharmacological strategy based on inhibition of the adenosine A2A receptor (A2AR) in middle aged C57BL/6 mice prone to early onset ARHL. C57BL/6J mice were treated with weekly istradefylline (A2AR antagonist; 1 mg/kg) injections from 6 to 12 months of age. Auditory function was assessed using auditory brainstem responses (ABR) to tone pips (4–32 kHz). ABR thresholds and suprathreshold responses (wave I amplitudes and latencies) were evaluated at 6, 9, and 12 months of age. Functional outcomes were correlated with quantitative histological assessments of sensory hair cells. Cognitive function was assessed using the Morris water maze and the novel object recognition test, and the zero maze test was used to assess anxiety-like behaviour. Weekly injections of istradefylline attenuated ABR threshold shifts by approximately 20 dB at mid to high frequencies (16–32 kHz) but did not improve ABR suprathreshold responses. Istradefylline treatment improved hair cell survival in a turn-dependent manner, whilst the cognitive function was unaffected by istradefylline treatment. This study presents the first evidence for the rescue potential of istradefylline in ARHL and highlights the role of A2AR in development of age-related cochlear degeneration.
HTLV-1 Infection and Pathogenesis: New Insights from Cellular and Animal Models
Authors: Forlani Greta , Shallak Mariam , Accolla Roberto Sergio , Romanelli Maria Grazia
Published: July 2021

Since the discovery of the human T-cell leukemia virus-1 (HTLV-1), cellular and animal models have provided invaluable contributions in the knowledge of viral infection, transmission and progression of HTLV-associated diseases. HTLV-1 is the causative agent of the aggressive adult T-cell leukemia/lymphoma and inflammatory diseases such as the HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Cell models contribute to defining the role of HTLV proteins, as well as the mechanisms of cell-to-cell transmission of the virus. Otherwise, selected and engineered animal models are currently applied to recapitulate in vivo the HTLV-1 associated pathogenesis and to verify the effectiveness of viral therapy and host immune response. Here we review the current cell models for studying virus–host interaction, cellular restriction factors and cell pathway deregulation mediated by HTLV products. We recapitulate the most effective animal models applied to investigate the pathogenesis of HTLV-1-associated diseases such as transgenic and humanized mice, rabbit and monkey models. Finally, we summarize the studies on STLV and BLV, two closely related HTLV-1 viruses in animals. The most recent anticancer and HAM/TSP therapies are also discussed in view of the most reliable experimental models that may accelerate the translation from the experimental findings to effective therapies in infected patients.
Daytime Dependence of the Activity of the Rat Brain Pyruvate Dehydrogenase Corresponds to the Mitochondrial Sirtuin 3 Level and Acetylation of Brain Proteins, All Regulated by Thiamine Administration Decreasing Phosphorylation of PDHA Ser293
Authors: Aleshin Vasily A. , Artiukhov Artem V. , Kaehne Thilo , Graf Anastasia V. , Bunik Victoria I.
Published: July 2021

Coupling glycolysis and mitochondrial tricarboxylic acid cycle, pyruvate dehydrogenase (PDH) complex (PDHC) is highly responsive to cellular demands through multiple mechanisms, including PDH phosphorylation. PDHC also produces acetyl-CoA for protein acetylation involved in circadian regulation of metabolism. Thiamine (vitamin B1) diphosphate (ThDP) is known to activate PDH as both coenzyme and inhibitor of the PDH inactivating kinases. Molecular mechanisms integrating the function of thiamine-dependent PDHC into general redox metabolism, underlie physiological fitness of a cell or an organism. Here, we characterize the daytime- and thiamine-dependent changes in the rat brain PDHC function, expression and phosphorylation, assessing their impact on protein acetylation and metabolic regulation. Morning administration of thiamine significantly downregulates both the PDH phosphorylation at Ser293 and SIRT3 protein level, the effects not observed upon the evening administration. This action of thiamine nullifies the daytime-dependent changes in the brain PDHC activity and mitochondrial acetylation, inducing diurnal difference in the cytosolic acetylation and acetylation of total brain proteins. Screening the daytime dependence of central metabolic enzymes and proteins of thiol/disulfide metabolism reveals that thiamine also cancels daily changes in the malate dehydrogenase activity, opposite to those of the PDHC activity. Correlation analysis indicates that thiamine abrogates the strong positive correlation between the total acetylation of the brain proteins and PDHC function. Simultaneously, thiamine heightens interplay between the expression of PDHC components and total acetylation or SIRT2 protein level. These thiamine effects on the brain acetylation system change metabolic impact of acetylation. The changes are exemplified by the thiamine enhancement of the SIRT2 correlations with metabolic enzymes and proteins of thiol-disulfide metabolism. Thus, we show the daytime- and thiamine-dependent changes in the function and phosphorylation of brain PDHC, contributing to regulation of the brain acetylation system and redox metabolism. The daytime-dependent action of thiamine on PDHC and SIRT3 may be of therapeutic significance in correcting perturbed diurnal regulation.
Cell Signaling in Model Plants 2.0
Authors: Chen Jen-Tsung , Heidari Parviz
Published: July 2021

Plant cell signaling is an intensive research topic in which reductionist can be achieved when we investigate the systems of model plants [...]
Effect of Microbiome on Non-Alcoholic Fatty Liver Disease and the Role of Probiotics, Prebiotics, and Biogenics
Authors: Nagashimada Mayumi , Honda Masao
Published: July 2021

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of liver cirrhosis and hepatocellular carcinoma. NAFLD is associated with metabolic disorders such as obesity, insulin resistance, dyslipidemia, steatohepatitis, and liver fibrosis. Liver-resident (Kupffer cells) and recruited macrophages contribute to low-grade chronic inflammation in various tissues by modulating macrophage polarization, which is implicated in the pathogenesis of metabolic diseases. Abnormalities in the intestinal environment, such as the gut microbiota, metabolites, and immune system, are also involved in the pathogenesis and development of NAFLD. Hepatic macrophage activation is induced by the permeation of antigens, endotoxins, and other proinflammatory substances into the bloodstream as a result of increased intestinal permeability. Therefore, it is important to understand the role of the gut–liver axis in influencing macrophage activity, which is central to the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH). Not only probiotics but also biogenics (heat-killed lactic acid bacteria) are effective in ameliorating the progression of NASH. Here we review the effect of hepatic macrophages/Kupffer cells, other immune cells, intestinal permeability, and immunity on NAFLD and NASH and the impact of probiotics, prebiotics, and biogenesis on those diseases.
Assessing the Use of the sGC Stimulator BAY-747, as a Potential Treatment for Duchenne Muscular Dystrophy
Authors: Krishnan Shalini Murali , Nordlohne Johannes , Dietz Lisa , Vakalopoulos Alexandros , Haning Petra , Hartmann Elke , Seifert Roland , Hüser Jörg , Mathar Ilka , Sandner Peter
Published: July 2021

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder, affecting one in 3500 to 5000 boys worldwide. The NO-sGC-cGMP pathway plays an important role in skeletal muscle function, primarily by improving blood flow and oxygen supply to the muscles during exercise. In fact, PDE5 inhibitors have previously been investigated as a potential therapy for DMD, however, a large-scale Phase III clinical trial did not meet its primary endpoint. Since the efficacy of PDE5i is dependent on sufficient endogenous NO production, which might be impaired in DMD, we investigated if NO-independent sGC stimulators, could have therapeutic benefits in a mouse model of DMD. Male mdx/mTRG2 mice aged six weeks were given food supplemented with the sGC stimulator, BAY-747 (150 mg/kg of food) or food alone (untreated) ad libitum for 16 weeks. Untreated C57BL6/J mice were used as wild type (WT) controls. Assessments of the four-limb hang, grip strength, running wheel and serum creatine kinase (CK) levels showed that mdx/mTRG2 mice had significantly reduced skeletal muscle function and severe muscle damage compared to WT mice. Treatment with BAY-747 improved grip strength and running speed, and these mice also had reduced CK levels compared to untreated mdx/mTRG2 mice. We also observed increased inflammation and fibrosis in the skeletal muscle of mdx/mTRG2 mice compared to WT. While gene expression of pro-inflammatory cytokines and some pro-fibrotic markers in the skeletal muscle was reduced following BAY-747 treatment, there was no reduction in infiltration of myeloid immune cells nor collagen deposition. In conclusion, treatment with BAY-747 significantly improves several functional and pathological parameters of the skeletal muscle in mdx/mTRG2 mice. However, the effect size was moderate and therefore, more studies are needed to fully understand the potential treatment benefit of sGC stimulators in DMD.
Clinical Proteomics of Biofluids in Haematological Malignancies
Authors: Dunphy Katie , O’Mahoney Kelly , Dowling Paul , O’Gorman Peter , Bazou Despina
Published: July 2021

Since the emergence of high-throughput proteomic techniques and advances in clinical technologies, there has been a steady rise in the number of cancer-associated diagnostic, prognostic, and predictive biomarkers being identified and translated into clinical use. The characterisation of biofluids has become a core objective for many proteomic researchers in order to detect disease-associated protein biomarkers in a minimally invasive manner. The proteomes of biofluids, including serum, saliva, cerebrospinal fluid, and urine, are highly dynamic with protein abundance fluctuating depending on the physiological and/or pathophysiological context. Improvements in mass-spectrometric technologies have facilitated the in-depth characterisation of biofluid proteomes which are now considered hosts of a wide array of clinically relevant biomarkers. Promising efforts are being made in the field of biomarker diagnostics for haematologic malignancies. Several serum and urine-based biomarkers such as free light chains, β-microglobulin, and lactate dehydrogenase are quantified as part of the clinical assessment of haematological malignancies. However, novel, minimally invasive proteomic markers are required to aid diagnosis and prognosis and to monitor therapeutic response and minimal residual disease. This review focuses on biofluids as a promising source of proteomic biomarkers in haematologic malignancies and a key component of future diagnostic, prognostic, and disease-monitoring applications.
Vitamin D Deficiency and Gender Alter Vasoconstrictor and Vasodilator Reactivity in Rat Carotid Artery
Authors: Sipos Miklós , Gerszi Dóra , Dalloul Hicham , Bányai Bálint , Sziva Réka Eszter , Kollarics Réka , Magyar Péter , Török Marianna , Ács Nándor , Szekeres Mária , Nádasy György L. , Hadjadj Leila , Horváth Eszter Mária , Várbíró Szabolcs
Published: July 2021

The vitamin-D-sensitivity of the cardiovascular system may show gender differences. The prevalence of vitamin D (VD) deficiency (VDD) is high, and it alters cardiovascular function and increases the risk of stroke. Our aim was to investigate the vascular reactivity and histological changes of isolated carotid artery of female and male rats in response to different VD supplies. A total of 48 male and female Wistar rats were divided into four groups: female VD supplemented, female VDD, male VD supplemented, male VDD. The vascular function of isolated carotid artery segments was examined by wire myography. Both vitamin D deficiency and male gender resulted in increased phenylephrine-induced contraction. Acetylcholine-induced relaxation decreased in male rats independently from VD status. Inhibition of prostanoid signaling by indomethacin reduced contraction in females, but increased relaxation ability in male rats. Functional changes were accompanied by VDD and gender-specific histological alterations. Elastic fiber density was significantly decreased by VDD in female rats, but not in males. Smooth muscle actin and endothelial nitric oxide synthase levels were significantly lowered, but the thromboxane receptor was elevated in VDD males. Decreased nitrative stress was detected in both male groups independently from VD supply. The observed interactions between vitamin D deficiency and sex may play a role in the gender difference of cardiovascular risk.
The Course of AαVal541 as a Proteinase 3 Specific Neo-Epitope after Alpha-1-Antitrypsin Augmentation in Severe Deficient Patients
Authors: Schouten Iris G. M. , Mumford Richard A. , Moes Dirk Jan A. R. , Hiemstra Pieter S. , Stolk Jan
Published: July 2021

In alpha-1-antitrypsin deficiency (AATD), neutrophil serine proteases such as elastase and proteinase 3 (PR3) are insufficiently inhibited. A previous study in AATD patients showed a higher plasma level of the specific PR3-generated fibrinogen-derived peptide AαVal541, compared with healthy controls. Here, we analyzed the course of AαVal541 plasma levels during 4 weeks after a single iv dose of 240 mg/kg AAT in ten patients with genotype Z/Rare or Rare/Rare. To this end, we developed an immunoassay to measure AαVal541 in plasma and applied population pharmacokinetic modeling for AAT. The median AαVal541 plasma level before treatment was 140.2 nM (IQR 51.5–234.8 nM)). In five patients who received AAT for the first time, AαVal541 levels decreased to 20.6 nM (IQR 5.8–88.9 nM), and in five patients who already had received multiple infusions before, it decreased to 26.2 nM (IQR 22.31–35.0 nM). In 9 of 10 patients, AαVal541 levels were reduced to the median level of healthy controls (21.4 nM; IQR 16.7–30.1 nM). At 7–14 days after treatment, AαVal541 levels started to increase again in all patients. Our results show that fibrinopeptide AαVal541 may serve as a biochemical footprint to assess the efficacy of in vivo inhibition of PR3 activity in patients receiving intravenous AAT augmentation therapy.