bluuebunny/crossref_metadata_2025 huggingface dataset:
The Relationship between City Size and Carbon Monoxide (CO) Concentration and Their Effect on Heart Rate Variability (HRV)
Authors: Saadi Diana , Tirosh Emanuel , Schnell Izhak
Published: January 2021

Generally, larger cities are characterized by traffic congestion, which is associated with higher concentrations of pollution, including Carbon Monoxide (CO) pollution. However, this convention requires empirical support on the basis of accurate and reliable measurements. In addition, the assessment of the effect of CO on the autonomic nervous system (ANS), as measured by heart rate variability (HRV), has yielded conflicting results. A majority of the (few) studies on the topic have shown that increases in CO concentration of up to about 10 parts per million (ppm) are associated with a decrease in stress and risk to health in subjects. Beyond the hypothesis postulating city size as a determinant of increased CO concentration, the hypothesis proposing a causal link between CO concentration and HRV balance also requires empirical support. This article compares CO concentrations in a large metropolis with those in a small town, analyzing the relationship between CO and the HRV responses of young women in terms of city size. Four different types of environments were compared, taking into account mediating variables. The study participants spent 35 min in selected environments (a city center, a residential environment, a park, and a home) wearing Polar devices to measure HRV, and portable devices to measure noise thermal load and CO. The average concentrations of CO in each environment were calculated, along with the time distribution of the CO concentration, and the regression slopes between the concentrations of CO and the ANS balance, as measured by the low frequency power/high frequency power ratio (LF/HF) expressed as an HRV index. The results show that, regardless of size, the cities measured were all characterized by low levels of CO, far below the maximal accepted threshold standards, and that urban residents were exposed to these concentrations for less than half of the daytime hours. Furthermore, in contrast to the common view, larger cities do not necessarily accumulate higher concentrations of CO compared to small cities, regardless of the level of transport congestion. This study confirms the findings of the majority of the other studies on the subject, which showed a decrease in stress (as measured by HRV) as a result of an increase in CO concentrations below 7 ppm. Finally, following the assessment of the differential contribution attributed to the different environmental factors, it appears that noise, thermal load, and congestion all contribute more to a higher level of HRV balance than CO. This finding highlights the importance of a multivariable approach to the study, and a remediation of the effect of environmental factors on stress in urban environments.
An Experimental Evidence on Eco-Friendly Advertisement Appeals and Intention to Use Bio-Nanomaterial Plastics: Institutional Collectivism and Performance Orientation as Moderators
Authors: Raza Syed Hassan , Zaman Umer , Iftikhar Moneeba , Shafique Owais
Published: January 2021

Plastic waste management has become a serious environmental and health concern owing to large amounts of plastic deposits globally. Recently, innovative and sustainable solutions have been introduced (e.g., bio-nanomaterial plastics) to overcome the growing environmental threats. Hence, green marketers need to develop effective advertising campaigns to enhance the usage of bio-nanomaterial plastics. Past literature has suggested that cultural value-laden advertising appeals can give sustainable behavioral cues to consumers. Hence, this research unfolds the underlying cultural dimensions between the value-laden eco-friendly advertising appeals and intention to use bio-nanomaterial plastics (henceforth IBP). The present study proposes a moderating model in which two dimensions presented in the Global Leadership and Organizational Behavior Effectiveness (henceforth GLOBE) framework interact with the individuals’ perception of eco-friendly advertising appeals (henceforth IPEA) to drive bio-nanomaterial plastics usage. The model was tested by conducting an experimental study on a sample of 364 Pakistani consumers. Findings of structural equation modeling show a significant difference in the relationship between IPEA and IBP, which is moderated by the performance orientation (henceforth PO) and institutional collectivism (henceforth IC) dimensions with diverse intensity. These findings validate the effectiveness of PO and IC (as cultural dimensions) and eco-friendly advertisements that can potentially promote the consumption of bio-nanomaterials plastic.
The Association between Social Determinants of Health and Self-Reported Diabetic Retinopathy: An Exploratory Analysis
Authors: Silverberg Emily L. , Sterling Trevor W. , Williams Tyler H. , Castro Grettel , Rodriguez de la Vega Pura , Barengo Noël C.
Published: January 2021

One-third of Americans with diabetes will develop diabetic retinopathy (DR), the leading cause of blindness in working-age Americans. Social determinants of health (SDOHs) are conditions in a person’s environment that may impact health. The objective of this study was to determine whether there is an association between SDOHs and DR in patients with type II diabetes. This cross-section study used data from the 2018 Behavioral Risk Factor Surveillance System (BRFSS). This study included people with self-reported diabetes in the US in 2018 (n = 60,703). Exposure variables included homeownership, marital status, income, health care coverage, completed level of education, and urban vs. rural environment. The outcome variable was DR. Logistic regression analysis were applied to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Alaskan Native/Native American (OR 2.11; 95% CI: 1.14–3.90), out of work (OR 2.82; 95% CI: 1.62–4.92), unable to work (OR 2.14; 95% CI: 1.57–2.91), did not graduate high school (OR 1.91; 95% CI: 1.30–2.79), only graduated high school (OR 1.43; 95% CI 1.08–1.97), or only attended college or technical school without graduating (OR 1.42; 95% CI: 1.09–1.86) were SDOHs associated with DR in patients with diabetes. Health care providers should identify these possible SDOHs affecting their diabetic patients.
Improving Global Healthcare and Reducing Costs Using Second-Generation Artificial Intelligence-Based Digital Pills: A Market Disruptor
Authors: Ilan Yaron
Published: January 2021

Background and Aims: Improving global health requires making current and future drugs more effective and affordable. While healthcare systems around the world are faced with increasing costs, branded and generic drug companies are facing the challenge of creating market differentiators. Two of the problems associated with the partial or complete loss of response to chronic medications are a lack of adherence and compensatory responses to chronic drug administration, which leads to tolerance and loss of effectiveness. Approach and Results: First-generation artificial intelligence (AI) systems do not address these needs and suffer from a low adoption rate by patients and clinicians. Second-generation AI systems are focused on a single subject and on improving patients’ clinical outcomes. The digital pill, which combines a personalized second-generation AI system with a branded or generic drug, improves the patient response to drugs by increasing adherence and overcoming the loss of response to chronic medications. By improving the effectiveness of drugs, the digital pill reduces healthcare costs and increases end-user adoption. The digital pill also provides a market differentiator for branded and generic drug companies. Conclusions: Implementing the use of a digital pill is expected to reduce healthcare costs, providing advantages for all the players in the healthcare system including patients, clinicians, healthcare authorities, insurance companies, and drug manufacturers. The described business model for the digital pill is based on distributing the savings across all stakeholders, thereby enabling improved global health.
The Alexafication of Adult Social Care: Virtual Assistants and the Changing Role of Local Government in England
Authors: Wright James
Published: January 2021

Voice controlled virtual assistants, delivered via consumer devices such as smart speakers and tablets, are being trialled by local authorities across England as a convenient and low-cost supplement or potential alternative to “traditional” telecare. Few papers have explored this increasingly widespread phenomenon, despite its growing importance. This article looks at choices by some local authorities to trial Alexa, within the context of the ongoing care crisis in England, with councils facing depleted funds, a lack of expert guidance on care technologies, and an increasingly complex and fragmented care technology marketplace. It draws on interviews with managers from eight English local authorities involved in the commissioning and trialling of technologies for adult social care to examine how and why virtual assistants are being implemented, and what implications their use might hold for care. Scaling up the application of such technologies could shift the role of local authorities towards one of an app developer and data broker, while generating considerable risks of reliance on the precarious technological infrastructure of global corporations that may have little interest in or sensitivity towards local care concerns. The findings suggest an urgent need for a national social care technology strategy and increased support for local authorities.
The Role of Coping in the Wellbeing and Work-Related Quality of Life of UK Health and Social Care Workers during COVID-19
Authors: McFadden Paula , Ross Jana , Moriarty John , Mallett John , Schroder Heike , Ravalier Jermaine , Manthorpe Jill , Currie Denise , Harron Jaclyn , Gillen Patricia
Published: January 2021

The coronavirus disease 2019 (COVID-19) was declared a global pandemic in early 2020. Due to the rapid spread of the virus and limited availability of effective treatments, health and social care systems worldwide quickly became overwhelmed. Such stressful circumstances are likely to have negative impacts on health and social care workers’ wellbeing. The current study examined the relationship between coping strategies and wellbeing and quality of working life in nurses, midwives, allied health professionals, social care workers and social workers who worked in health and social care in the UK during its first wave of COVID-19. Data were collected using an anonymous online survey (N = 3425), and regression analyses were used to examine the associations of coping strategies and demographic characteristics with staff wellbeing and quality of working life. The results showed that positive coping strategies, particularly active coping and help-seeking, were associated with higher wellbeing and better quality of working life. Negative coping strategies, such as avoidance, were risk factors for low wellbeing and worse quality of working life. The results point to the importance of organizational and management support during stressful times, which could include psycho-education and training about active coping and might take the form of workshops designed to equip staff with better coping skills.
Safe Healthcare Facilities: A Systematic Review on the Costs of Establishing and Maintaining Environmental Health in Facilities in Low- and Middle-Income Countries
Authors: Anderson Darcy M. , Cronk Ryan , Fejfar Donald , Pak Emily , Cawley Michelle , Bartram Jamie
Published: January 2021

A hygienic environment is essential to provide quality patient care and prevent healthcare-acquired infections. Understanding costs is important to budget for service delivery, but costs evidence for environmental health services (EHS) in healthcare facilities (HCFs) is lacking. We present the first systematic review to evaluate the costs of establishing, operating, and maintaining EHS in HCFs in low- and middle-income countries (LMICs). We systematically searched for studies costing water, sanitation, hygiene, cleaning, waste management, personal protective equipment, vector control, laundry, and lighting in LMICs. Our search yielded 36 studies that reported costs for 51 EHS. There were 3 studies that reported costs for water, 3 for sanitation, 4 for hygiene, 13 for waste management, 16 for cleaning, 2 for personal protective equipment, 10 for laundry, and none for lighting or vector control. Quality of evidence was low. Reported costs were rarely representative of the total costs of EHS provision. Unit costs were infrequently reported. This review identifies opportunities to improve costing research through efforts to categorize and disaggregate EHS costs, greater dissemination of existing unpublished data, improvements to indicators to monitor EHS demand and quality necessary to contextualize costs, and development of frameworks to define EHS needs and essential inputs to guide future costing.
Customized Human Milk Fortification Based on Measured Human Milk Composition to Improve the Quality of Growth in Very Preterm Infants: A Mixed-Cohort Study Protocol
Authors: Cardoso Manuela , Virella Daniel , Macedo Israel , Silva Diana , Pereira-da-Silva Luís
Published: January 2021

Adequate nutrition of very preterm infants comprises fortification of human milk (HM), which helps to improve their nutrition and health. Standard HM fortification involves a fixed dose of a multi-nutrient HM fortifier, regardless of the composition of HM. This fortification method requires regular measurements of HM composition and has been suggested to be a more accurate fortification method. This observational study protocol is designed to assess whether the target HM fortification method (contemporary cohort) improves the energy and macronutrient intakes and the quality of growth of very preterm infants, compared with the previously used standard HM fortification (historical cohorts). In the contemporary cohort, a HM multi-nutrient fortifier and modular supplements of protein and fat are used for HM fortification, and the enteral nutrition recommendations of the European Society for Paediatric Gastroenterology Hepatology and Nutrition for preterm infants will be considered. For both cohorts, the composition of HM is assessed using the Miris Human Milk analyzer (Uppsala, Sweden). The quality of growth will be assessed by in-hospital weight, length, and head circumference growth velocities and a single measurement of adiposity (fat mass percentage and fat mass index) performed just after discharge, using the air displacement plethysmography method (Pea Pod, Cosmed, Italy). ClinicalTrials.gov registration number: NCT04400396.
The Politics of LGBT+ Health Inequality: Conclusions from a UK Scoping Review
Authors: McDermott Elizabeth , Nelson Rosie , Weeks Harri
Published: January 2021

This scoping review of UK evidence aimed to describe what is known about Lesbian, Gay, Bisexual, and Trans (LGBT+) health inequalities in relation to cancer, mental health, and palliative care to inform research, policy and public health interventions. Using a scoping review methodology, we identified studies from database searches, citation tracking, and expert consultation. The in/exclusion criteria was based on the PICOS framework. The data were charted and then summarised to map the theoretical approaches and the main types of evidence and identify knowledge gaps. In total, 279 articles were screened and 83 were included in the final review. We found that there is limited UK research examining LGBT+ health inequality in cancer, mental health and palliative care. We would argue that this thin evidence base is partly due to national policy discussions of LGBT+ health inequality that are framed within a depoliticised ‘it’s getting better’ narrative, and an unwillingness to adequately acknowledge the unjust social and economic relations that produce LGBT+ health inequality. In addition, LGBT+ health inequality is depoliticised by existing public health explanatory theories, models and frameworks that exclude sexual orientation and gender diversity as dimensions of power that interlock with those of socio-economic, race and ethnicity. This is a barrier to developing public health interventions that can successfully tackle LGBT+ health inequality
The Role of Research in Guiding Treatment for Women’s Health: A Qualitative Study of Traditional Chinese Medicine Acupuncturists
Authors: Armour Mike , Betts Debra , Roberts Kate , Armour Susanne , Smith Caroline A.
Published: January 2021

Background: Surveys of acupuncture practitioners worldwide have shown an increase in the use of acupuncture to treat women’s health conditions over the last ten years. Published studies have explored the effectiveness of acupuncture for various conditions such as period pain, fertility, and labor induction. However, it is unclear what role, if any, peer-reviewed research plays in guiding practice. Methods: Acupuncturists with a significant women’s health caseload were interviewed online in three small groups to explore factors that contribute to acupuncturists’ clinical decision made around treatment approaches and research. Results: Eleven practitioners participated in the focus groups. The overarching theme that emerged was one of ‘Not mainstream but a stream.’ This captured two themes relating to acupuncture as a distinct practice: ‘working with what you’ve got’ as well as ‘finding the right lens’, illustrating practitioners’ perception of research needing to be more relevant to clinical practice. Conclusions: Acupuncture practitioners treating women’s health conditions reported a disconnect between their clinical practice and the design of clinical trials, predominantly due to what they perceived as a lack of individualization of treatment. Case histories were popular as a learning tool and could be used to support increasing research literacy.
A Commentary on Blue Zones®: A Critical Review of Age-Friendly Environments in the 21st Century and Beyond
Authors: Marston Hannah R. , Niles-Yokum Kelly , Silva Paula Alexandra
Published: January 2021

This paper explores the intersection of the World Health Organization’s (WHO) concepts of age-friendly communities and The Blue Zones® checklists and how the potential of integrating the two frameworks for the development of a contemporary framework can address the current gaps in the literature as well as consider the inclusion of technology and environmental press. The commentary presented here sets out initial thoughts and explorations that have the potential to impact societies on a global scale and provides recommendations for a roadmap to consider new ways to think about the impact of health and wellbeing of older adults and their families. Additionally, this paper highlights both the strengths and the weaknesses of the aforementioned checklists and frameworks by examining the literature including the WHO age-friendly framework, the smart age-friendly ecosystem (SAfE) framework and the Blue Zones® checklists. We argue that gaps exist in the current literature and take a critical approach as a way to be inclusive of technology and the environments in which older adults live. This commentary contributes to the fields of gerontology, gerontechnology, anthropology, and geography, because we are proposing a roadmap which sets out the need for future work which requires multi- and interdisciplinary research to be conducted for the respective checklists to evolve.
FuNet: A Novel Road Extraction Network with Fusion of Location Data and Remote Sensing Imagery
Authors: Zhou Kai , Xie Yan , Gao Zhan , Miao Fang , Zhang Lei
Published: January 2021

Road semantic segmentation is unique and difficult. Road extraction from remote sensing imagery often produce fragmented road segments leading to road network disconnection due to the occlusion of trees, buildings, shadows, cloud, etc. In this paper, we propose a novel fusion network (FuNet) with fusion of remote sensing imagery and location data, which plays an important role of location data in road connectivity reasoning. A universal iteration reinforcement (IteR) module is embedded into FuNet to enhance the ability of network learning. We designed the IteR formula to repeatedly integrate original information and prediction information and designed the reinforcement loss function to control the accuracy of road prediction output. Another contribution of this paper is the use of histogram equalization data pre-processing to enhance image contrast and improve the accuracy by nearly 1%. We take the excellent D-LinkNet as the backbone network, designing experiments based on the open dataset. The experiment result shows that our method improves over the compared advanced road extraction methods, which not only increases the accuracy of road extraction, but also improves the road topological connectivity.
Traffic Inequality and Relations in Maritime Silk Road: A Network Flow Analysis
Authors: Mou Naixia , Ren Haonan , Zheng Yunhao , Chen Jinhai , Niu Jiqiang , Yang Tengfei , Zhang Lingxian , Liu Feng
Published: January 2021

Maritime traffic can reflect the diverse and complex relations between countries and regions, such as economic trade and geopolitics. Based on the AIS (Automatic Identification System) trajectory data of ships, this study constructs the Maritime Silk Road traffic network. In this study, we used a complex network theory along with social network analysis and network flow analysis to analyze the spatial distribution characteristics of maritime traffic flow of the Maritime Silk Road; further, we empirically demonstrate the traffic inequality in the route. On this basis, we explore the role of the country in the maritime traffic system and the resulting traffic relations. There are three main results of this study. (1) The inequality in the maritime traffic of the Maritime Silk Road has led to obvious regional differences. Europe, west Asia, northeast Asia, and southeast Asia are the dominant regions of the Maritime Silk Road. (2) Different countries play different maritime traffic roles. Italy, Singapore, and China are the core countries in the maritime traffic network of the Maritime Silk Road; Greece, Turkey, Cyprus, Lebanon, and Israel have built a structure of maritime traffic flow in the eastern Mediterranean Sea, and Saudi Arabia serves as a bridge for maritime trade between Asia and Europe. (3) The maritime traffic relations show the characteristics of regionalization; countries in west Asia and the European Mediterranean region are clearly polarized, and competition–synergy relations have become the main form of maritime traffic relations among the countries in the dominant regions. Our results can provide a scientific reference for the coordinated development of regional shipping, improvement of maritime competition, cooperation strategies for countries, and adjustments in the organizational structure of ports along the Maritime Silk Road.
Factors Affecting the Progression of Infection-Related Glomerulonephritis to Chronic Kidney Disease
Authors: Oda Takashi , Yoshizawa Nobuyuki
Published: January 2021

Acute glomerulonephritis (AGN) triggered by infection is still one of the major causes of acute kidney injury. During the previous two decades, there has been a major paradigm shift in the epidemiology of AGN. The incidence of poststreptococcal acute glomerulonephritis (PSAGN), which develops after the cure of group A Streptococcus infection in children has decreased, whereas adult AGN cases have been increasing, and those associated with nonstreptococcal infections, particularly infections by Staphylococcus, are now as common as PSAGN. In adult AGN patients, particularly older patients with comorbidities, infections are usually ongoing at the time when glomerulonephritis is diagnosed; thus, the term “infection-related glomerulonephritis (IRGN)” has recently been popularly used instead of “post-infectious AGN”. The prognosis of children with PSAGN is generally considered excellent compared with that of adult IRGN cases. However, long-term epidemiological analysis demonstrated that an episode of PSAGN in childhood is a strong risk factor for chronic kidney disease (CKD), even after the complete remission of PSAGN. Although the precise mechanism of the transition from IRGN to CKD remains unknown, its clarification is important as it will lead to the prevention of CKD. In this review, we therefore focus on the possible factors that may contribute to the progression of IRGN into CKD. Four factors, namely, persistent infection, genetic background of the host’s complement system, tubulointerstitial changes, and pre-existing histological damage, are discussed.
Repetitive Traumatic Brain Injury Causes Neuroinflammation before Tau Pathology in Adolescent P301S Mice
Authors: Izzy Saef , Brown-Whalen Alexander , Yahya Taha , Sarro-Schwartz Aliyah , Jin Gina , Chung Joon Yong , Lule Sevda , Morsett Liza M. , Alquraini Ali , Wu Limin , Hickman Suzanne E. , Whalen Michael J. , El Khoury Joseph
Published: January 2021

Repetitive closed head injury (rCHI) is commonly encountered in young athletes engaged in contact and collision sports. Traumatic brain injury (TBI) including rCHI has been reported to be an important risk factor for several tauopathies in studies of adult humans and animals. However, the link between rCHI and the progression of tau pathology in adolescents remains to be elucidated. We evaluated whether rCHI can trigger the initial acceleration of pathological tau in adolescent mice and impact the long-term outcomes post-injury. To this end, we subjected adolescent transgenic mice expressing the P301S tau mutation to mild rCHI and assessed tau hyperphosphorylation, tangle formation, markers of neuroinflammation, and behavioral deficits at 40 days post rCHI. We report that rCHI did not accelerate tau pathology and did not worsen behavioral outcomes compared to control mice. However, rCHI induced cortical and hippocampal microgliosis and corpus callosum astrocytosis in P301S mice by 40 days post-injury. In contrast, we did not find significant microgliosis or astrocytosis after rCHI in age-matched WT mice or sham-injured P301S mice. Our data suggest that neuroinflammation precedes the development of Tau pathology in this rCHI model of adolescent repetitive mild TBI.
CD73+ CD127high Long-Term Memory CD4 T Cells Are Highly Proliferative in Response to Recall Antigens and Are Early Targets in HIV-1 Infection
Authors: Seddiki Nabila , Zaunders John , Phetsouphanh Chan , Brezar Vedran , Xu Yin , McGuire Helen M. , Bailey Michelle , McBride Kristin , Hey-Cunningham Will , Munier Cynthia Mee Ling , Cook Laura , Kent Stephen , Lloyd Andrew , Cameron Barbara , Fazekas de St Groth Barbara , Koelsch Kersten , Danta Mark , Hocini Hakim , Levy Yves , Kelleher Anthony D.
Published: January 2021

HIV-1 infection rapidly leads to a loss of the proliferative response of memory CD4+ T lymphocytes, when cultured with recall antigens. We report here that CD73 expression defines a subset of resting memory CD4+ T cells in peripheral blood, which highly express the α-chain of the IL-7 receptor (CD127), but not CD38 or Ki-67, yet are highly proliferative in response to mitogen and recall antigens, and to IL-7, in vitro. These cells also preferentially express CCR5 and produce IL-2. We reasoned that CD73+ memory CD4+ T cells decrease very early in HIV-1 infection. Indeed, CD73+ memory CD4+ T cells comprised a median of 7.5% (interquartile range: 4.5–10.4%) of CD4+ T cells in peripheral blood from healthy adults, but were decreased in primary HIV-1 infection to a median of 3.7% (IQR: 2.6–6.4%; p = 0.002); and in chronic HIV-1 infection to 1.9% (IQR: 1.1–3%; p < 0.0001), and were not restored by antiretroviral therapy. Moreover, we found that a significant proportion of CD73+ memory CD4+ T cells were skewed to a gut-homing phenotype, expressing integrins α4 and β7, CXCR3, CCR6, CD161 and CD26. Accordingly, 20% of CD4+ T cells present in gut biopsies were CD73+. In HIV+ subjects, purified CD73+ resting memory CD4+ T cells in PBMC were infected with HIV-1 DNA, determined by real-time PCR, to the same level as for purified CD73-negative CD4+ T cells, both in untreated and treated subjects. Therefore, the proliferative CD73+ subset of memory CD4+ T cells is disproportionately reduced in HIV-1 infection, but, unexpectedly, their IL-7 dependent long-term resting phenotype suggests that residual infected cells in this subset may contribute significantly to the very long-lived HIV proviral DNA reservoir in treated subjects.
Extracellular Matrix in Calcific Aortic Valve Disease: Architecture, Dynamic and Perspectives
Authors: Di Vito Anna , Donato Annalidia , Presta Ivan , Mancuso Teresa , Brunetti Francesco Saverio , Mastroroberto Pasquale , Amorosi Andrea , Malara Natalia , Donato Giuseppe
Published: January 2021

Calcific Aortic Valve Disease (CAVD) is the most common valvular heart disease in developed countries and in the ageing population. It is strongly correlated to median age, affecting up to 13% of the population over the age of 65. Pathophysiological analysis indicates CAVD as a result of an active and degenerative disease, starting with sclerosis and chronic inflammation and then leaflet calcification, which ultimately can account for aortic stenosis. Although CAVD has been firstly recognized as a passive event mostly resulting from a degenerative aging process, much evidences suggests that calcification arises from different active processes, involving both aortic valve-resident cells (valve endothelial cells, valve interstitial cells, mesenchymal stem cells, innate immunity cells) and circulating cells (circulating mesenchymal cells, immunity cells). Moreover, a role for the cell-derived “matrix vesicles” and extracellular matrix (ECM) components has also been recognized. The aim of this work is to review the cellular and molecular alterations occurring in aortic valve during CAVD pathogenesis, focusing on the role of ECM in the natural course of the disease.
TNAP as a New Player in Chronic Inflammatory Conditions and Metabolism
Authors: Graser Stephanie , Liedtke Daniel , Jakob Franz
Published: January 2021

This review summarizes important information on the ectoenzyme tissue-nonspecific alkaline phosphatase (TNAP) and gives a brief insight into the symptoms, diagnostics, and treatment of the rare disease Hypophosphatasia (HPP), which is resulting from mutations in the TNAP encoding ALPL gene. We emphasize the role of TNAP beyond its well-known contribution to mineralization processes. Therefore, above all, the impact of the enzyme on central molecular processes in the nervous system and on inflammation is presented here.
Functions of Muscarinic Receptor Subtypes in Gastrointestinal Smooth Muscle: A Review of Studies with Receptor-Knockout Mice
Authors: Tanahashi Yasuyuki , Komori Seiichi , Matsuyama Hayato , Kitazawa Takio , Unno Toshihiro
Published: January 2021

Parasympathetic signalling via muscarinic acetylcholine receptors (mAChRs) regulates gastrointestinal smooth muscle function. In most instances, the mAChR population in smooth muscle consists mainly of M2 and M3 subtypes in a roughly 80% to 20% mixture. Stimulation of these mAChRs triggers a complex array of biochemical and electrical events in the cell via associated G proteins, leading to smooth muscle contraction and facilitating gastrointestinal motility. Major signalling events induced by mAChRs include adenylyl cyclase inhibition, phosphoinositide hydrolysis, intracellular Ca2+ mobilisation, myofilament Ca2+ sensitisation, generation of non-selective cationic and chloride currents, K+ current modulation, inhibition or potentiation of voltage-dependent Ca2+ currents and membrane depolarisation. A lack of ligands with a high degree of receptor subtype selectivity and the frequent contribution of multiple receptor subtypes to responses in the same cell type have hampered studies on the signal transduction mechanisms and functions of individual mAChR subtypes. Therefore, novel strategies such as genetic manipulation are required to elucidate both the contributions of specific AChR subtypes to smooth muscle function and the underlying molecular mechanisms. In this article, we review recent studies on muscarinic function in gastrointestinal smooth muscle using mAChR subtype-knockout mice.
Effects of Alzheimer-Like Pathology on Homocysteine and Homocysteic Acid Levels—An Exploratory In Vivo Kinetic Study
Authors: Nieraad Hendrik , de Bruin Natasja , Arne Olga , Hofmann Martine C. J. , Gurke Robert , Schmidt Dominik , Ritter Marcel , Parnham Michael J. , Geisslinger Gerd
Published: January 2021

Hyperhomocysteinemia has been suggested potentially to contribute to a variety of pathologies, such as Alzheimer’s disease (AD). While the impact of hyperhomocysteinemia on AD has been investigated extensively, there are scarce data on the effect of AD on hyperhomocysteinemia. The aim of this in vivo study was to investigate the kinetics of homocysteine (HCys) and homocysteic acid (HCA) and effects of AD-like pathology on the endogenous levels. The mice received a B-vitamin deficient diet for eight weeks, followed by the return to a balanced control diet for another eight weeks. Serum, urine, and brain tissues of AppNL-G-F knock-in and C57BL/6J wild type mice were analyzed for HCys and HCA using LC-MS/MS methods. Hyperhomocysteinemic levels were found in wild type and knock-in mice due to the consumption of the deficient diet for eight weeks, followed by a rapid normalization of the levels after the return to control chow. Hyperhomocysteinemic AppNL-G-F mice had significantly higher HCys in all matrices, but not HCA, compared to wild type control. Higher serum concentrations were associated with elevated levels in both the brain and in urine. Our findings confirm a significant impact of AD-like pathology on hyperhomocysteinemia in the AppNL-G-F mouse model. The immediate normalization of HCys and HCA after the supply of B-vitamins strengthens the idea of a B-vitamin intervention as a potentially preventive treatment option for HCys-related disorders such as AD.
Enhancing the Physiochemical Properties of Puerarin via L-Proline Co-Crystallization: Synthesis, Characterization, and Dissolution Studies of Two Phases of Pharmaceutical Co-Crystals
Authors: Inam Muhammad , Liu Lu , Wang Jian-Wei , Yu Ka-Xi , Phan Chi-Uyen , Shen Jie , Zhang Wen-Hua , Tang Guping , Hu Xiurong
Published: January 2021

Puerarin (PUE) is a Chinese traditional medicine known to enhance glucose uptake into the insulin cells to downregulate the blood glucose levels in the treatment of type II diabetes. Nevertheless, the bioavailability of pristine PUE is limited due to its poor solubility and low intestinal permeability. In this work, we demonstrate that the solubility of PUE can be significantly enhanced via its co-crystallization with L-Proline (PRO). Two crystalline phases, namely, the solvate-free form [PUE][PRO] (I) and the solvated form [PUE]2[PRO]∙EtOH∙(H2O)2 (II) are isolated. These two phases are characterized by single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), Fourier-transformed infrared (FT-IR) spectra, nuclear magnetic resonance (NMR), and thermogravimetric analysis in association with differential scanning calorimetry (TGA-DSC). The solubility and dissolution rate of both I and II in water, gastrointestinal tract at pH 1.2, and phosphate buffer at pH 6.8 indicates a nearly doubled increase as compared to the pristine PUE. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of pristine PUE, I and II against murine colon cancer cell lines CT-26 and human kidney cell lines HEK-293 indicated that neither compound exhibits obvious cytotoxicity after 24 h. This work showcases that the readily available and biocompatible PRO can be a promising adjuvant to enhance the physicochemical properties of PUE toward orally administered drug formulation with improved pharmacokinetics.
Analyzing Low-Level mtDNA Heteroplasmy—Pitfalls and Challenges from Bench to Benchmarking
Authors: Fazzini Federica , Fendt Liane , Schönherr Sebastian , Forer Lukas , Schöpf Bernd , Streiter Gertraud , Losso Jamie Lee , Kloss-Brandstätter Anita , Kronenberg Florian , Weissensteiner Hansi
Published: January 2021

Massive parallel sequencing technologies are promising a highly sensitive detection of low-level mutations, especially in mitochondrial DNA (mtDNA) studies. However, processes from DNA extraction and library construction to bioinformatic analysis include several varying tasks. Further, there is no validated recommendation for the comprehensive procedure. In this study, we examined potential pitfalls on the sequencing results based on two-person mtDNA mixtures. Therefore, we compared three DNA polymerases, six different variant callers in five mixtures between 50% and 0.5% variant allele frequencies generated with two different amplification protocols. In total, 48 samples were sequenced on Illumina MiSeq. Low-level variant calling at the 1% variant level and below was performed by comparing trimming and PCR duplicate removal as well as six different variant callers. The results indicate that sensitivity, specificity, and precision highly depend on the investigated polymerase but also vary based on the analysis tools. Our data highlight the advantage of prior standardization and validation of the individual laboratory setup with a DNA mixture model. Finally, we provide an artificial heteroplasmy benchmark dataset that can help improve somatic variant callers or pipelines, which may be of great interest for research related to cancer and aging.
MicroRNA-Mediated Gene Regulatory Mechanisms in Mammalian Female Reproductive Health
Authors: Gebremedhn Samuel , Ali Asghar , Hossain Munir , Hoelker Michael , Salilew-Wondim Dessie , Anthony Russell V. , Tesfaye Dawit
Published: January 2021

Mammalian reproductive health affects the entire reproductive cycle starting with the ovarian function through implantation and fetal growth. Various environmental and physiological factors contribute to disturbed reproductive health status leading to infertility problems in mammalian species. In the last couple of decades a significant number of studies have been conducted to investigate the transcriptome of reproductive tissues and organs in relation to the various reproductive health issues including endometritis, polycystic ovarian syndrome (PCOS), intrauterine growth restriction (IUGR), preeclampsia, and various age-associated reproductive disorders. Among others, the post-transcriptional regulation of genes by small noncoding miRNAs contributes to the observed transcriptome dysregulation associated with reproductive pathophysiological conditions. MicroRNAs as a class of non-coding RNAs are also known to be involved in various pathophysiological conditions either in cellular cytoplasm or they can be released to the extracellular fluid via membrane-bounded extracellular vesicles and proteins. The present review summarizes the cellular and extracellular miRNAs and their association with the etiology of major reproductive pathologies including PCOS, endometritis, IUGR and age-associated disorders in various mammalian species.
The Grapevine E3 Ubiquitin Ligase VriATL156 Confers Resistance against the Downy Mildew Pathogen Plasmopara viticola
Authors: Vandelle Elodie , Ariani Pietro , Regaiolo Alice , Danzi Davide , Lovato Arianna , Zadra Claudia , Vitulo Nicola , Gambino Giorgio , Polverari Annalisa
Published: January 2021

Downy mildew, caused by Plasmopara viticola, is one of the most severe diseases of grapevine (Vitis vinifera L.). Genetic resistance is an effective and sustainable control strategy, but major resistance genes (encoding receptors for specific pathogen effectors) introgressed from wild Vitis species, although effective, may be non-durable because the pathogen can evolve to avoid specific recognition. Previous transcriptomic studies in the resistant species Vitis riparia highlighted the activation of signal transduction components during infection. The transfer of such components to V. vinifera might confer less specific and therefore more durable resistance. Here, we describe the generation of transgenic V. vinifera lines constitutively expressing the V. riparia E3 ubiquitin ligase gene VriATL156. Phenotypic and molecular analysis revealed that the transgenic plants were less susceptible to P. viticola than vector-only controls, confirming the role of this E3 ubiquitin ligase in the innate immune response. Two independent transgenic lines were selected for detailed analysis of the resistance phenotype by RNA-Seq and microscopy, revealing the profound reprogramming of transcription to achieve resistance that operates from the earliest stages of pathogen infection. The introduction of VriATL156 into elite grapevine cultivars could therefore provide an effective and sustainable control measure against downy mildew.
De Novo Profiling of Long Non-Coding RNAs Involved in MC-LR-Induced Liver Injury in Whitefish: Discovery and Perspectives
Authors: Florczyk Maciej , Brzuzan Paweł , Woźny Maciej
Published: January 2021

Microcystin-LR (MC-LR) is a potent hepatotoxin for which a substantial gap in knowledge persists regarding the underlying molecular mechanisms of liver toxicity and injury. Although long non-coding RNAs (lncRNAs) have been extensively studied in model organisms, our knowledge concerning the role of lncRNAs in liver injury is limited. Given that lncRNAs show low levels of sequence conservation, their role becomes even more unclear in non-model organisms without an annotated genome, like whitefish (Coregonus lavaretus). The objective of this study was to discover and profile aberrantly expressed polyadenylated lncRNAs that are involved in MC-LR-induced liver injury in whitefish. Using RNA sequencing (RNA-Seq) data, we de novo assembled a high-quality whitefish liver transcriptome. This enabled us to find 94 differentially expressed (DE) putative evolutionary conserved lncRNAs, such as MALAT1, HOTTIP, HOTAIR or HULC, and 4429 DE putative novel whitefish lncRNAs, which differed from annotated protein-coding transcripts (PCTs) in terms of minimum free energy, guanine-cytosine (GC) base-pair content and length. Additionally, we identified DE non-coding transcripts that might be 3′ autonomous untranslated regions (3′UTRs) of mRNAs. We found both evolutionary conserved lncRNAs as well as novel whitefish lncRNAs that could serve as biomarkers of liver injury.
Biomineralization of Collagen-Based Materials for Hard Tissue Repair
Authors: Yu Le , Wei Mei
Published: January 2021

Hydroxyapatite (HA) reinforced collagen fibrils serve as the basic building blocks of natural bone and dentin. Mineralization of collagen fibrils play an essential role in ensuring the structural and mechanical functionalities of hard tissues such as bone and dentin. Biomineralization of collagen can be divided into intrafibrillar and extrafibrillar mineralization in terms of HA distribution relative to collagen fibrils. Intrafibrillar mineralization is termed when HA minerals are incorporated within the gap zone of collagen fibrils, while extrafibrillar mineralization refers to the minerals that are formed on the surface of collagen fibrils. However, the mechanisms resulting in these two types of mineralization still remain debatable. In this review, the evolution of both classical and non-classical biomineralization theories is summarized. Different intrafibrillar mineralization mechanisms, including polymer induced liquid precursor (PILP), capillary action, electrostatic attraction, size exclusion, Gibbs-Donnan equilibrium, and interfacial energy guided theories, are discussed. Exemplary strategies to induce biomimetic intrafibrillar mineralization using non-collagenous proteins (NCPs), polymer analogs, small molecules, and fluidic shear stress are discussed, and recent applications of mineralized collagen fibers for bone regeneration and dentin repair are included. Finally, conclusions are drawn on these proposed mechanisms, and the future trend of collagen-based materials for bone regeneration and tooth repair is speculated.
ABT-751 Induces Multiple Anticancer Effects in Urinary Bladder Urothelial Carcinoma-Derived Cells: Highlighting the Induction of Cytostasis through the Inhibition of SKP2 at Both Transcriptional and Post-Translational Levels
Authors: Dehghanian Seyedeh Zahra , Pan Cheng-Tang , Lee Jasmine Marianne , Shiue Yow-Ling
Published: January 2021

The objective was to investigate the anti-cancer effects and underlying molecular mechanisms of cytostasis which were activated by an anti-microtubule drug, ABT-751, in two urinary bladder urothelial carcinoma (UBUC)-derived cell lines, BFTC905 and J82, with distinct genetic backgrounds. A series of in vitro assays demonstrated that ABT-751 induced G2/M cell cycle arrest, decreased cell number in the S phase of the cell cycle and suppressed colony formation/independent cell growth, accompanied with alterations of the protein levels of several cell cycle regulators. In addition, ABT-751 treatment significantly hurdled cell migration and invasion along with the regulation of epithelial–mesenchymal transition-related proteins. ABT-751 triggered autophagy and apoptosis, downregulated the mechanistic target of rapamycin kinase (MTOR) and upregulated several pro-apoptotic proteins that are involved in extrinsic and intrinsic apoptotic pathways. Inhibition of autophagosome and autolysosome enhanced apoptosis was also observed. Through the inhibition of the NFκB signaling pathway, ABT-751 suppressed S-phase kinase associated protein 2 (SKP2) transcription and subsequent translation by downregulation of active/phospho-AKT serine/threonine kinase 1 (AKT1), component of inhibitor of nuclear factor kappa B kinase complex (CHUK), NFKB inhibitor alpha (NFKBIA), nuclear RELA proto-oncogene, NFκB subunit (RELA) and maintained a strong interaction between NFKBIA and RELA to prevent RELA nuclear translocation for SKP2 transcription. ABT-751 downregulated stable/phospho-SKP2 including pSKP2(S64) and pSKP2(S72), which targeted cyclin-dependent kinase inhibitors for degradation through the inactivation of AKT. Our results suggested that ABT-751 may act as an anti-cancer drug by inhibiting cell migration, invasion yet inducing cell cycle arrest, autophagy and apoptosis in distinct UBUC-derived cells. Particularly, the upstream molecular mechanism of its anticancer effects was identified as ABT-751-induced cytostasis through the inhibition of SKP2 at both transcriptional and post-translational levels to stabilize cyclin dependent kinase inhibitor 1A (CDKN1A) and CDKN1B proteins.