bluuebunny/crossref_metadata_2025 huggingface dataset:
The Homeless People in China During the COVID-19 Pandemic: Victims of the Strict Pandemic Control Measures of the Government
Authors: Wang Ying , Hua Lei , Zou Shuyun , Deng Taofeng , Chen Yongqi , Cao Wanying , Wu Chuhan , Zhou Yujie , Zou Hua
Published: August 2021

Background: By implementing aggressive control measures, China has rapidly and effectively controlled the Coronavirus disease 2019 (COVID-19) pandemic. However, the neglected homeless population may become victims of that perceived success. Due to political sensitivity, we know little about them.

Aims: This study aimed to investigate how the pandemic and the pandemic control strategies of the government affected the lives of the homeless people in mainland China.

Methods: A total of 103 eligible participants experiencing absolute homelessness were recruited from Guangzhou City during July and August 2020. Surveys measured demographic characteristics including health status, changes in daily living, and actions of the government toward the homeless during the pandemic. Sankey diagrams and ordered logit regression models were used to examine the impact on the homeless of inhumane government efforts to drive the homeless away. Qualitative materials were analyzed by using an inductive approach to provide more details.

Results: First, the homeless people in Guangzhou tended to be male, aged 40 to 64 years, less well-educated, and they originated from outside Guangdong although they were living in the city center. Most had little connection with their families. After a long period of homelessness, almost half of the participants were in poor health with various conditions, which made them extremely vulnerable to COVID-19. Second, the pandemic caused a substantial decline in incomes of homeless people, had less of a negative impact on their food intake, and affected sleep time in different ways. Third, during the COVID-19 pandemic, humanitarian aid from local governments of China decreased, whereas inhumane efforts to drive the homeless away intensified. Fourth, quantitative models and qualitative materials demonstrate the devastating effect of the strict pandemic control strategy of the government on the lives of homeless people, which may further cause their health problems.

Conclusion: This study for the first time illustrated the characteristic features of the street homeless population in mainland China and their living situation during the COVID-19 pandemic, and most importantly demonstrated the devastating effect of the strict pandemic control of the government, which has been considered a great success in previous studies, on lives of homeless people. Urgent measures should be taken to ensure the protection of the homeless population and prevent an impending humanitarian crisis.
Learning From Older Adults to Promote Independent Physical Activity Using Mobile Health (mHealth)
Authors: Nebeker Camille , Zlatar Zvinka Z.
Published: August 2021

Background: Healthy aging is critically important for several reasons, including economic impact and quality of life. As the population of older adults rapidly increases, identifying acceptable ways to promote healthy aging is a priority. Technologies that can facilitate health promotion and risk reduction behaviors may be a solution, but only if these mobile health (mHealth) tools can be used by the older adult population. Within the context of a physical activity intervention, this study gathered participant's opinions about the use of an mHealth device to learn about acceptance and to identify areas for improvement.

Methods: The Independent Walking for Brain Health study (NCT03058146) was designed to evaluate the effectiveness of a wearable mHealth technology in facilitating adherence to a physical activity prescription among participants in free-living environments. An Exit Survey was conducted following intervention completion to gauge participant's perceptions and solicit feedback regarding the overall study design, including exercise promotion strategies and concerns specific to the technology (e.g., privacy), that could inform more acceptable mHealth interventions in the future. The Digital Health Checklist and Framework was used to guide the analysis focusing on the domains of Privacy, Access and Usability, and Data Management.

Results: Participants (n = 41) were in their early 70's (mean = 71.6) and were predominantly female (75.6%) and White (92.7%). Most were college educated (16.9 years) and enjoyed using technology in their everyday life (85.4%). Key challenges included privacy concerns, device accuracy, usability, and data access. Specifically, participants want to know what is being learned about them and want control over how their identifiable data may be used. Overall, participants were able to use the device despite the design challenges.

Conclusions: Understanding participant's perceptions of the challenges and concerns introduced by mHealth is important, as acceptance will influence adoption and adherence to the study protocol. While this study learned from participants at studycompletion, we recommend that researchers consider what might influence participant acceptance of the technology (access, data management, privacy, risks) and build these into the mHealth study design process. We provide recommendations for future mHealth studies with older adults.
An Empirical Study on the Influence of the Basic Medical Insurance for Urban and Rural Residents on Family Financial Asset Allocation
Authors: Li Shenglin , Yang Yifei
Published: August 2021

This paper empirically examined whether participation in the Basic Medical Insurance for Urban and Rural Residents impacted families' allocation to risk assets and risk-free assets using the Heckman two-step method, which is based on the China Household Finance Survey micro data of 2013, 2015, and 2017. The results showed that participation in the Basic Medical Insurance for Urban and Rural Residents can promote families' reasonable choice between risk assets and risk-free assets to a certain extent. To be specific, the risk asset investments are squeezed out for the originally risk-seeking families, while the risk-free asset investments are squeezed out for the originally risk-adverse families. We tested the robustness of the benchmark model and the mediating effect model with different definitions of risk assets and risk-free assets. Also, the analysis of the mechanism showed that this increases families' risk perception—turning their risk attitude more cautious and their investment attitude more rational. To further consolidate the social security attributes of the Basic Medical Insurance for Urban and Rural Residents, behind its high coverage, we should also pay attention to its influence on the investment preferences of families with different social and economic statuses, thereby giving full play to its role in promoting the development of China's financial market. In future research, we can also try to use measurement models such as PSM-DID models, and find the connections and progressive relations between different models, in order to obtain the inquiry results of different dimensions. For the direction of further research in the future, we believe that can be used to test whether the conclusion whose data configuration of the basic medical insurance for family financial assets choice influence is a universal in developing countries, to explore the developing countries to promote the health security system for the influence of its national household financial asset allocation and the corresponding policy recommendations.

JEL Classification: D14, G11, H55, I18.
Ordinal SuStaIn: Subtype and Stage Inference for Clinical Scores, Visual Ratings, and Other Ordinal Data
Authors: Young Alexandra L. , Vogel Jacob W. , Aksman Leon M. , Wijeratne Peter A. , Eshaghi Arman , Oxtoby Neil P. , Williams Steven C. R. , Alexander Daniel C. ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: August 2021

Subtype and Stage Inference (SuStaIn) is an unsupervised learning algorithm that uniquely enables the identification of subgroups of individuals with distinct pseudo-temporal disease progression patterns from cross-sectional datasets. SuStaIn has been used to identify data-driven subgroups and perform patient stratification in neurodegenerative diseases and in lung diseases from continuous biomarker measurements predominantly obtained from imaging. However, the SuStaIn algorithm is not currently applicable to discrete ordinal data, such as visual ratings of images, neuropathological ratings, and clinical and neuropsychological test scores, restricting the applicability of SuStaIn to a narrower range of settings. Here we propose ‘Ordinal SuStaIn’, an ordinal version of the SuStaIn algorithm that uses a scored events model of disease progression to enable the application of SuStaIn to ordinal data. We demonstrate the validity of Ordinal SuStaIn by benchmarking the performance of the algorithm on simulated data. We further demonstrate that Ordinal SuStaIn out-performs the existing continuous version of SuStaIn (Z-score SuStaIn) on discrete scored data, providing much more accurate subtype progression patterns, better subtyping and staging of individuals, and accurate uncertainty estimates. We then apply Ordinal SuStaIn to six different sub-scales of the Clinical Dementia Rating scale (CDR) using data from the Alzheimer’s disease Neuroimaging Initiative (ADNI) study to identify individuals with distinct patterns of functional decline. Using data from 819 ADNI1 participants we identified three distinct CDR subtype progression patterns, which were independently verified using data from 790 ADNI2 participants. Our results provide insight into patterns of decline in daily activities in Alzheimer’s disease and a mechanism for stratifying individuals into groups with difficulties in different domains. Ordinal SuStaIn is broadly applicable across different types of ratings data, including visual ratings from imaging, neuropathological ratings and clinical or behavioural ratings data.
Grasp Stability Prediction for a Dexterous Robotic Hand Combining Depth Vision and Haptic Bayesian Exploration
Authors: Siddiqui Muhammad Sami , Coppola Claudio , Solak Gokhan , Jamone Lorenzo
Published: August 2021

Grasp stability prediction of unknown objects is crucial to enable autonomous robotic manipulation in an unstructured environment. Even if prior information about the object is available, real-time local exploration might be necessary to mitigate object modelling inaccuracies. This paper presents an approach to predict safe grasps of unknown objects using depth vision and a dexterous robot hand equipped with tactile feedback. Our approach does not assume any prior knowledge about the objects. First, an object pose estimation is obtained from RGB-D sensing; then, the object is explored haptically to maximise a given grasp metric. We compare two probabilistic methods (i.e. standard and unscented Bayesian Optimisation) against random exploration (i.e. uniform grid search). Our experimental results demonstrate that these probabilistic methods can provide confident predictions after a limited number of exploratory observations, and that unscented Bayesian Optimisation can find safer grasps, taking into account the uncertainty in robot sensing and grasp execution.
Maternal and Fetal Outcomes After Interferon Exposure During Pregnancy: A Systematic Review With Meta-Analysis
Authors: Zhang Mengmeng , Fu Shan , Ren Danfeng , Wu Yuchao , Yao Naijuan , Ni Tianzhi , Feng YaLi , Chen Yaolong , Chen Tianyan , Zhao Yingren , Liu Jinfeng
Published: August 2021

Interferon (IFN) treatment is widely applied in viral hepatitis and multiple myeloproliferative diseases. However, there is considerable controversy on how to deal with unintended pregnancy during IFN treatment, even selective termination is suggested by hepatologists. To settle this clinical dilemma, we conducted a systematic review to retrieve all published articles involving IFN exposure during pregnancy up until March 31, 2021. Only 8 case reports that were relevant with outcomes of pregnant women with viral hepatitis exposed to IFN-α were retrieved, and 17 studies reporting pregnancy outcomes after exposure to type I IFNs involving 3,543 pregnancies were eligible for meta-analysis. No birth defect was reported in the case reports of pregnant women with viral hepatitis. The meta-analysis showed that risks of pregnancy outcomes and birth defects were not increased after exposure to IFN-α. Further comprehensive meta-analysis concerning the IFN-α and IFN-β exposure demonstrated that the risks of live birth (OR 0.89, 95% CI: 0.62–1.27), spontaneous abortion (OR 1.09, 95% CI: 0.73–1.63), stillbirth (OR 1.38, 95% CI: 0.51–3.72), preterm delivery (OR 1.24, 95% CI: 0.85–1.81), and maternal complications (OR 0.72, 95% CI: 0.38–1.38) were not increased in patients exposed to IFNs. The pooled estimates of live birth, spontaneous abortion, stillbirth, preterm delivery, and maternal complications were 85.2, 9.4, 0, 7.5, and 6.5%, respectively. Importantly, the risk of birth defects was not increased (OR 0.68, 95% CI: 0.39–1.20) after IFN exposure, with a pooled rate of 0.51%. Therefore, IFN exposure does not increase the prevalence of spontaneous abortion, stillbirth, preterm delivery, and birth defects. Clinical decision should be made after weighing up all the evidence.
Linking Zoonosis Emergence to Farmland Invasion by Fluctuating Herbivores: Common Vole Populations and Tularemia Outbreaks in NW Spain
Authors: Herrero-Cófreces Silvia , Mougeot François , Lambin Xavier , Luque-Larena Juan José
Published: August 2021

The expansion and intensification of agriculture are driving profound changes in ecosystems worldwide, favoring the (re)emergence of many human infectious diseases. Muroid rodents are a key host group for zoonotic infectious pathogens and frequently invade farming environments, promoting disease transmission and spillover. Understanding the role that fluctuating populations of farm dwelling rodents play in the epidemiology of zoonotic diseases is paramount to improve prevention schemes. Here, we review a decade of research on the colonization of farming environments in NW Spain by common voles (Microtus arvalis) and its public health impacts, specifically periodic tularemia outbreaks in humans. The spread of this colonizing rodent was analogous to an invasion process and was putatively triggered by the transformation and irrigation of agricultural habitats that created a novel terrestrial-aquatic interface. This irruptive rodent host is an effective amplifier for the Francisella tularensis bacterium during population outbreaks, and human tularemia episodes are tightly linked in time and space to periodic (cyclic) variations in vole abundance. Beyond the information accumulated to date, several key knowledge gaps about this pathogen-rodent epidemiological link remain unaddressed, namely (i) did colonizing vole introduce or amplified pre-existing F. tularensis? (ii) which features of the “Francisella—Microtus” relationship are crucial for the epidemiology of tularemia? (iii) how virulent and persistent F. tularensis infection is for voles under natural conditions? and (iv) where does the bacterium persist during inter-epizootics? Future research should focus on more integrated, community-based approaches in order to understand the details and dynamics of disease circulation in ecosystems colonized by highly fluctuating hosts.
Unraveling the Genetic Diversity and Population Structure of Bangladeshi Indigenous Cattle Populations Using 50K SNP Markers
Authors: Bhuiyan Mohammad Shamsul Alam , Lee Soo-Hyun , Hossain Sheikh Mohammad Jahangir , Deb Gautam Kumar , Afroz Most Farhana , Lee Seung-Hwan , Bhuiyan Abul Kashem Fazlul Haque
Published: August 2021

Understanding the genetic basis of locally adapted indigenous cattle populations is essential to design appropriate strategies and programs for their genetic improvement and conservation. Here, we report genetic diversity measures, population differentiation, and structure of 218 animals sampled from six indicine cattle populations of Bangladesh. Animals were genotyped with Illumina Bovine SNP50K BeadChip along with genotyped data of 505 individuals included from 19 zebu and taurine breeds worldwide. The principal component analysis (PCA) showed clear geographic separation between taurine and indicine lineages where Bangladeshi indigenous cattle clustered with South Asian zebu populations. However, overlapped clusters in PCA, heterozygosity estimates, and Neighbor-Joining phylogenetic tree analysis revealed weak genetic differentiation among the indigenous cattle populations of Bangladesh. The admixture analysis at K = 5 and 9 suggests distinct genetic structure of the studied populations along with 1 to 4% of taurine ancestry. The effective population size suggested a limited pool of ancestors particularly for Sahiwal and North Bengal Grey cattle. In conclusion, these findings shed insights into the genetic architecture of six indigenous cattle populations of Bangladesh for the first time and suggested as distinct gene pools without potential admixture with zebu or taurine populations.
Antimicrobial Synergy Testing: Comparing the Tobramycin and Ceftazidime Gradient Diffusion Methodology Used in Assessing Synergy in Cystic Fibrosis-Derived Multidrug-Resistant Pseudomonas aeruginosa
Authors: Okoliegbe Ijeoma N. , Hijazi Karolin , Cooper Kim , Ironside Corinne , Gould Ian M.
Published: August 2021

The need for synergy testing is driven by the necessity to extend the antimicrobial spectrum, reducing drug dosage/toxicity and the development of resistance. Despite the abundance of synergy testing methods, there is the absence of a gold standard and a lack of synergy correlation among methods. The most popular method (checkerboard) is labor-intensive and is not practical for clinical use. Most clinical laboratories use several gradient synergy methods which are quicker/easier to use. This study sought to evaluate three gradient synergy methods (direct overlay, cross, MIC:MIC ratio) with the checkerboard, and compare two interpretative criteria (the fractional inhibitory concentration index (FICI) and susceptibility breakpoint index (SBPI)) regarding these methods. We tested 70 multidrug-resistant Pseudomonas aeruginosa, using a tobramycin and ceftazidime combination. The agreement between the checkerboard and gradient methods was 60 to 77% for FICI, while agreements for SBPI that ranged between 67 and 82.86% were statistically significant (p ≤ 0.001). High kappa agreements were observed using SBPI (Ƙ > 0.356) compared to FICI (Ƙ < 0.291) criteria, and the MIC:MIC method demonstrated the highest, albeit moderate, intraclass correlation coefficient (ICC = 0.542) estimate. Isolate resistance profiles suggest method-dependent synergism for isolates, with ceftazidime susceptibility after increased exposure. The results show that when interpretative criteria are considered, gradient diffusion (especially MIC:MIC) is a valuable and practical method that can inform the treatment of cystic fibrosis patients who are chronically infected with P. aeruginosa.
Assigning Defined Daily/Course Doses for Antimicrobials in Turkeys to Enable a Cross-Country Quantification and Comparison of Antimicrobial Use
Authors: Joosten Philip , Sarrazin Steven , Chauvin Claire , Moyano Gabriel , Wadepohl Katharina , Van Gompel Liese , Wagenaar Jaap A. , Dewulf Jeroen ,   on behalf of the [EFFORT group]
Published: August 2021

Antimicrobial resistance (AMR) threatens our public health and is mainly driven by antimicrobial usage (AMU). For this reason the World Health Organization calls for detailed monitoring of AMU over all animal sectors involved. Therefore, we aimed to quantify AMU on turkey farms. First, turkey-specific Defined Daily Dose (DDDturkey) was determined. These were compared to the broiler alternative from the European Surveillance of Veterinary Antimicrobial Consumption (DDDvet), that mention DDDvet as a proxy for other poultry species. DDDturkey ranged from being 81.5% smaller to 48.5% larger compared to its DDDvet alternative for broilers. Second, antimicrobial treatments were registered on 60 turkey farms divided over France, Germany and Spain between 2014 and 2016 (20 flocks per country). Afterwards, AMU was quantified using treatment incidence (TI) per 100 days. TI expresses the percentage of the rearing period that the turkeys were treated with a standard dose of antimicrobials. Minimum, median and maximum TI at flock level and based on DDDturkey = 0.0, 10.0 and 65.7, respectively. Yet, a huge variation in amounts of antimicrobials used at flock level was observed, both within and between countries. Seven farms (12%) did not use any antimicrobials. Aminopenicillins, polymyxins, and fluoroquinolones were responsible for 72.2% of total AMU. The proportion of treating farms peaked on week five of the production cycle (41.7%), and 79.4% of the total AMU was administered in the first half of production. To conclude, not all DDDvet values for broilers can be applied to turkeys. Additionally, the results of AMU show potential for reducing and improving AMU on turkey farms, especially concerning the usage of critically important antimicrobials.
Wide Spectrum of Active Compounds in Sea Buckthorn (Hippophae rhamnoides) for Disease Prevention and Food Production
Authors: Jaśniewska Agnieszka , Diowksz Anna
Published: August 2021

Growing demand for value-added products and functional foods is encouraging manufacturers to consider new additives that can enrich their products and help combat lifestyle diseases. The healthy properties of sea buckthorn have been recognized for centuries. This plant has a high content of bioactive compounds, including antioxidants, phytosterols, essential fatty acids, and amino acids, as well as vitamins C, K, and E. It also has a low content of sugar and a wide spectrum of volatiles, which contribute to its unique aroma. Sea buckthorn shows antimicrobial and antiviral properties, and is a potential nutraceutical or cosmeceutical. It was proven to help treat cardiovascular disease, tumors, and diabetes, as well as gastrointestinal and skin problems. The numerous health benefits of sea buckthorn make it a good candidate for incorporation into novel food products.
1,3-Dicaffeoylquinic Acid as an Active Compound of Arctium lappa Root Extract Ameliorates Depressive-Like Behavior by Regulating Hippocampal Nitric Oxide Synthesis in Ovariectomized Mice
Authors: Lim Dong Wook , Kim Minji , Yoon Minseok , Lee Jaekwang , Lee Changho , Um Min Young
Published: August 2021

Menopause is a risk factor for depression. Although 1,3-dicaffeoylquinic acid (1,3-diCQA), a phenolic compound in Arctium lappa (A. lappa) root, has various health benefits, its effects on menopausal depression remain to be determined. Therefore, this study investigates the antidepressant-like effects of 1,3-diCQA from an A. lappa root extract (AE) and the associated molecular mechanisms. Ovariectomized (OVX) mice were orally administered AE for 20 weeks, following which depression-like behaviors were assessed. Although the mice exhibited depression-like behaviors, AE administration mitigated these symptoms by activating the ERK–CREB–BDNF pathway and increasing nNOS levels in the hippocampus. Similarly, a significant increase in nNOS-derived NO production and activation of the ERK–CREB–BDNF pathway was observed in the primary hippocampal neurons. Although this stimulatory effect of 1,3-diCQA was not significantly affected by treatment with estrogen receptor agonist or antagonist, it was inhibited by 7-NI, an nNOS inhibitor. Moreover, mice treated with 1,3-diCQA exhibited a marked improvement in their forced swimming test and tail suspension test immobility, while pretreatment with 7-NI reversed the antidepressant-like effects of 1,3-diCQA. Our results suggest that 1,3-diCQA regulates nNOS in an estrogen recepters-independent manner to increase NO production in OVX mice.
Polycyclic Aromatic Hydrocarbons in Malt
Authors: Mastanjević Krešimir , Krstanović Vinko , Kovačević Dragan , Kartalović Brankica , Habschied Kristina
Published: August 2021

The kilning of malt occurs at different temperatures, depending on the desired color and aromas. Higher temperatures applied during kilning can be involved in polycyclic aromatic hydrocarbons (PAHs) formation in malt. PAHs are undesirable and designated as health hazards, it is important to quantify and qualify them in different malts. Since the European Food Safety Authority (EFSA) gave strict recommendations about PAHs in different foods, but omitted malt as a potential hazardous raw material that can cause health damage to beer consumers, the aim of this investigation was to assess the presence of 16 PAHs (naphthalene (Nap), acenaphthylene (Anl), acenaphthene (Ane), fluorene (Flu), anthracene (Ant), phenanthrene (Phen), fluoranthene (Flt), benz[a]anthracene (BaA), pyrene (Pyr), chrysene (Chry), benzo[b]fluoranthene (BbF), benzo[k]fluoranthene (BkF), benzo[a]pyrene (BaP), dibenz[a,h]anthracene (DahA), benzo[ghi]perylene (BghiP), and indeno[1,2,3-cd]pyrene (InP)) in different, commercially available malts (amber, black, pilsner, and cara-120). The results showed that PAHs are present in different malts, with some in high amounts (BaA in black malt was 737 µg/kg). Minimal levels of BaA were detected in the amber malt, 60.53 µg/kg. The PAH4 (BaP, BaA, BbF, and Chry) sums are identical to the BaA concentrations in all malts and greatly exceed the EFSA prescribed levels for PAH4 in processed cereal-based foods (1 µg/kg).
Young and Undamaged rMSA Improves the Healthspan and Lifespan of Mice
Authors: Tang Jiaze , Ju Anji , Li Boya , Zhang Shaosen , Gong Yuanchao , Ma Boyuan , Jiang Yi , Liu Hongyi , Fu Yan , Luo Yongzhang
Published: August 2021

Improvement of longevity is an eternal dream of human beings. The accumulation of protein damages is considered as a major cause of aging. Here, we report that the injection of exogenous recombinant mouse serum albumin (rMSA) reduced the total damages of serum albumin in C57BL/6N mice, with higher level of free-thiols, lower levels of carbonyls and advanced glycation end-products as well as homocysteines in rMSA-treated mice. The healthspan and lifespan of C57BL/6N mice were significantly improved by rMSA. The grip strength of rMSA-treated female and male mice increased by 29.6% and 17.4%, respectively. Meanwhile, the percentage of successful escape increased 23.0% in rMSA-treated male mice using the Barnes Maze test. Moreover, the median lifespan extensions were 17.6% for female and 20.3% for male, respectively. The rMSA used in this study is young and almost undamaged. We define the concept “young and undamaged” to any protein without any unnecessary modifications by four parameters: intact free thiol (if any), no carbonylation, no advanced glycation end-product, and no homocysteinylation. Here, “young and undamaged” exogenous rMSA used in the present study is much younger and less damaged than the endogenous serum albumin purified from young mice at 1.5 months of age. We predict that undamaged proteins altogether can further improve the healthspan and lifespan of mice.
Well-Known and Novel Players in Endothelial Dysfunction: Updates on a Notch(ed) Landscape
Authors: Fortini Francesca , Vieceli Dalla Sega Francesco , Marracino Luisa , Severi Paolo , Rapezzi Claudio , Rizzo Paola , Ferrari Roberto
Published: August 2021

Endothelial dysfunction characterizes every aspect of the so-called cardiovascular continuum, a series of events ranging from hypertension to the development of atherosclerosis and, finally, to coronary heart disease, thrombus formation, myocardial infarction, and heart failure. Endothelial dysfunction is the main prognostic factor for the progression of vascular disorders, which responds to drug intervention and lifestyle changes. Virtually all of the drugs used to prevent cardiovascular disorders, such as long-used and new antilipidemic agents and inhibitors of angiotensin enzyme (ACEi), exert an important effect on the endothelium. Endothelial dysfunction is a central feature of coronavirus disease -19 (COVID-19), and it is now clear that life-risk complications of the disease are prompted by alterations of the endothelium induced by viral infection. As a consequence, the progression of COVID-19 is worse in the subjects in whom endothelial dysfunction is already present, such as elderly, diabetic, obese, and hypertensive patients. Importantly, circulating biomarkers of endothelial activation and injury predict the severity and mortality of the disease and can be used to evaluate the efficacy of treatments. The purpose of this review is to provide updates on endothelial function by discussing its clinical relevance in the cardiovascular continuum, the latest insights from molecular and cellular biology, and their implications for clinical practice, with a focus on new actors, such as the Notch signaling and emerging therapies for cardiovascular disease.
Follistatin-Like Proteins: Structure, Functions and Biomedical Importance
Authors: Parfenova Olga K. , Kukes Vladimir G. , Grishin Dmitry V.
Published: August 2021

Main forms of cellular signal transmission are known to be autocrine and paracrine signaling. Several cells secrete messengers called autocrine or paracrine agents that can bind the corresponding receptors on the surface of the cells themselves or their microenvironment. Follistatin and follistatin-like proteins can be called one of the most important bifunctional messengers capable of displaying both autocrine and paracrine activity. Whilst they are not as diverse as protein hormones or protein kinases, there are only five types of proteins. However, unlike protein kinases, there are no minor proteins among them; each follistatin-like protein performs an important physiological function. These proteins are involved in a variety of signaling pathways and biological processes, having the ability to bind to receptors such as DIP2A, TLR4, BMP and some others. The activation or experimentally induced knockout of the protein-coding genes often leads to fatal consequences for individual cells and the whole body as follistatin-like proteins indirectly regulate the cell cycle, tissue differentiation, metabolic pathways, and participate in the transmission chains of the pro-inflammatory intracellular signal. Abnormal course of these processes can cause the development of oncology or apoptosis, programmed cell death. There is still no comprehensive understanding of the spectrum of mechanisms of action of follistatin-like proteins, so the systematization and study of their cellular functions and regulation is an important direction of modern molecular and cell biology. Therefore, this review focuses on follistatin-related proteins that affect multiple targets and have direct or indirect effects on cellular signaling pathways, as well as to characterize the directions of their practical application in the field of biomedicine.
Rifaximin Prevents T-Lymphocytes and Macrophages Infiltration in Cerebellum and Restores Motor Incoordination in Rats with Mild Liver Damage
Authors: Balzano Tiziano , Leone Paola , Ivaylova Gergana , Castro M. Carmen , Reyes Lestteriel , Ramón Chusé , Malaguarnera Michele , Llansola Marta , Felipo Vicente
Published: August 2021

In patients with liver cirrhosis, minimal hepatic encephalopathy (MHE) is triggered by a shift in peripheral inflammation, promoting lymphocyte infiltration into the brain. Rifaximin improves neurological function in MHE by normalizing peripheral inflammation. Patients who died with steatohepatitis showed T-lymphocyte infiltration and neuroinflammation in the cerebellum, suggesting that MHE may already occur in these patients. The aims of this work were to assess, in a rat model of mild liver damage similar to steatohepatitis, whether: (1) the rats show impaired motor coordination in the early phases of liver damage; (2) this is associated with changes in the immune system and infiltration of immune cells into the brain; and (3) rifaximin improves motor incoordination, associated with improved peripheral inflammation, reduced infiltration of immune cells and neuroinflammation in the cerebellum, and restoration of the alterations in neurotransmission. Liver damage was induced by carbon tetrachloride (CCl4) injection over four weeks. Peripheral inflammation, immune cell infiltration, neuroinflammation, and neurotransmission in the cerebellum and motor coordination were assessed. Mild liver damage induces neuroinflammation and altered neurotransmission in the cerebellum and motor incoordination. These alterations are associated with increased TNFa, CCL20, and CX3CL1 in plasma and cerebellum, IL-17 and IL-15 in plasma, and CCL2 in cerebellum. This promotes T-lymphocyte and macrophage infiltration in the cerebellum. Early treatment with rifaximin prevents the shift in peripheral inflammation, immune cell infiltration, neuroinflammation, and motor incoordination. This report provides new clues regarding the mechanisms of the beneficial effects of rifaximin, suggesting that early rifaximin treatment could prevent neurological impairment in patients with steatohepatitis.
An ID-Associated Application to Facilitate Patient-Tailored Management of Multiple Sclerosis
Authors: Lang Michael , Rau Daniela , Cepek Lukas , Cürten Fia , Ringbauer Stefan , Mayr Martin
Published: August 2021

Despite improvements in diagnosis and treatment, multiple sclerosis (MS) is the leading neurological cause of disability in young adults. As a chronic disease, MS requires complex and challenging management. In this context, eHealth has gained an increasing relevance. Here, we aim to summarize beneficial features of a mobile app recently implemented in clinical MS routine as well as beyond MS. PatientConcept is a CE-certified, ID-associated multilingual software application allowing patients to record relevant health data without disclosing any identifying data. Patients can voluntarily share their health data with selected physicians. Since its implementation in 2018, about 3000 MS patients have used PatientConcept. Initially developed as a physician–patient communication platform, the app maps risk management plans of all current disease modifying therapies and thereby facilitates adherence to specified monitoring appointments. It also allows continuous monitoring of various PROs (Patient Reported Outcomes), enabling a broad overview of the disease course. In addition, various studies/projects currently assess monitoring, follow-up, diagnostics and telemetric evaluations of patients with other diseases beyond MS. Altogether, PatientConcept offers a broad range of possibilities to support physician–patient communication, implementation of risk management plans and assessment of PROs. It is a promising tool to facilitate patient-tailored management of MS and other chronic diseases.
CD44 Promotes Lung Cancer Cell Metastasis through ERK–ZEB1 Signaling
Authors: Wang Yen-Yun , Vadhan Anupama , Chen Ping-Ho , Lee Yen-Lung , Chao Chih-Yeh , Cheng Kuang-Hung , Chang Yu-Chiuan , Hu Stephen Chu-Sung , Yuan Shyng-Shiou F.
Published: August 2021

Lung cancer is a malignancy with high mortality worldwide, and metastasis occurs at a high frequency even when cancer spread is not detectable at primary operation. Cancer stemness plays an important role in malignant cancer behavior, treatment resistance, and cancer metastasis. Therefore, understanding the molecular pathogenesis behind cancer-stemness-mediated metastasis and developing effective approaches to prevent metastasis are key issues for improving cancer treatment. In this study, we investigated the role of CD44 stemness marker in lung cancer using in vitro and clinical studies. Immunohistochemical staining of lung cancer tissue specimens revealed that primary tumors with higher CD44 expression showed increased metastasis to regional lymph nodes. Flow cytometry analysis suggested that CD44 positive cells were enriched in the metastatic lymph nodes compared to the primary tumors. CD44 overexpression significantly increased migration and invasion abilities of lung cancer cells through CD44-induced ERK phosphorylation, ZEB1 upregulation, and Claudin-1 downregulation. Furthermore, ERK inhibition suppressed the migration and invasion abilities of CD44-overexpressing lung cancer cells. In summary, our in vitro and clinical results indicate that CD44 may be a potential prognostic and therapeutic marker for lung cancer patients.
Tissue Architecture Influences the Biological Effectiveness of Boron Neutron Capture Therapy in In Vitro/In Silico Three-Dimensional Self-Assembly Cell Models of Pancreatic Cancers
Authors: Yu Lin-Sheng , Jhunjhunwala Megha , Hong Shiao-Ya , Yu Lin-Yen , Lin Wey-Ran , Chen Chi-Shuo
Published: August 2021

Pancreatic cancer is a leading cause of cancer death, and boron neutron capture therapy (BNCT) is one of the promising radiotherapy techniques for patients with pancreatic cancer. In this study, we evaluated the biological effectiveness of BNCT at multicellular levels using in vitro and in silico models. To recapture the phenotypic characteristic of pancreatic tumors, we developed a cell self-assembly approach with human pancreatic cancer cells Panc-1 and BxPC-3 cocultured with MRC-5 fibroblasts. On substrate with physiological stiffness, tumor cells self-assembled into 3D spheroids, and the cocultured fibroblasts further facilitated the assembly process, which recapture the influence of tumor stroma. Interestingly, after 1.2 MW neutron irradiation, lower survival rates and higher apoptosis (increasing by 4-fold for Panc-1 and 1.5-fold for BxPC-3) were observed in 3D spheroids, instead of in 2D monolayers. The unexpected low tolerance of 3D spheroids to BNCT highlights the unique characteristics of BNCT over conventional radiotherapy. The uptake of boron-containing compound boronophenylalanine (BPA) and the alteration of E-cadherin can partially contribute to the observed susceptibility. In addition to biological effects, the probability of induced α-particle exposure correlated to the multicellular organization was speculated to affect the cellular responses to BNCT. A Monte Carlo (MC) simulation was also established to further interpret the observed survival. Intracellular boron distribution in the multicellular structure and related treatment resistance were reconstructed in silico. Simulation results demonstrated that the physical architecture is one of the essential factors for biological effectiveness in BNCT, which supports our in vitro findings. In summary, we developed in vitro and in silico self-assembly 3D models to evaluate the effectiveness of BNCT on pancreatic tumors. Considering the easy-access of this 3D cell-assembly platform, this study may not only contribute to the current understanding of BNCT but is also expected to be applied to evaluate the BNCT efficacy for individualized treatment plans in the future.
Matching Quantitative MRI Parameters with Histological Features of Treatment-Naïve IDH Wild-Type Glioma
Authors: Maurer Gabriele D. , Tichy Julia , Harter Patrick N. , Nöth Ulrike , Weise Lutz , Quick-Weller Johanna , Deichmann Ralf , Steinbach Joachim P. , Bähr Oliver , Hattingen Elke
Published: August 2021

Quantitative MRI allows to probe tissue properties by measuring relaxation times and may thus detect subtle changes in tissue composition. In this work we analyzed different relaxation times (T1, T2, T2* and T2′) and histological features in 321 samples that were acquired from 25 patients with newly diagnosed IDH wild-type glioma. Quantitative relaxation times before intravenous application of gadolinium-based contrast agent (GBCA), T1 relaxation time after GBCA as well as the relative difference between T1 relaxation times pre-to-post GBCA (T1rel) were compared with histopathologic features such as the presence of tumor cells, cell and vessel density, endogenous markers for hypoxia and cell proliferation. Image-guided stereotactic biopsy allowed for the attribution of each tissue specimen to its corresponding position in the respective relaxation time map. Compared to normal tissue, T1 and T2 relaxation times and T1rel were prolonged in samples containing tumor cells. The presence of vascular proliferates was associated with higher T1rel values. Immunopositivity for lactate dehydrogenase A (LDHA) involved slightly longer T1 relaxation times. However, low T2′ values, suggesting high amounts of deoxyhemoglobin, were found in samples with elevated vessel densities, but not in samples with increased immunopositivity for LDHA. Taken together, some of our observations were consistent with previous findings but the correlation of quantitative MRI and histologic parameters did not confirm all our pathophysiology-based assumptions.
Patterns of Whole Exome Sequencing in Resected Cholangiocarcinoma
Authors: Thornblade Lucas W. , Wong Paul , Li Daneng , Warner Susanne G. , Chang Sue , Raoof Mustafa , Kessler Jonathan , Amini Arya , Lin James , Chung Vincent , Singh Gagandeep , Fong Yuman , Melstrom Laleh G.
Published: August 2021

Background: With minimally effective chemotherapy options, cholangiocarcinoma patients have 5 year survival rate of 10%. Tumor genetic profiling (TGP) can identify mutations susceptible to targeted therapies. We sought to describe the use of TGP and frequency of actionable results in resected cholangiocarcinoma. Methods: A retrospective review of patients undergoing curative intent resection at a comprehensive cancer center (2010–2020). Clinicopathologic and partial or whole exome sequencing data were reviewed. Results: 114 patients (mean age 65 ± 11 years, 45% female) underwent resection of cholangiocarcinoma (46% poorly differentiated, 54% intrahepatic, 36% node positive, 75% margin negative). Additionally, 32% of patients underwent TGP, yielding a mean of 3.1 actionable mutations per patient (range 0–14). Mutations aligned with a median of one drug per patient (range 0–11). Common mutations included TP53 (33%), KRAS (31%), IDH1/2 (14%), FGFR (14%), and BRAF (8%). Targeted therapies were administered in only 4% of patients (23% of eligible sequenced patients). After a median 22 months, 23% had recurrence and 29% were deceased. Discussion: TGP for cholangiocarcinoma has increased over the last decade with targeted therapies identified in most sequenced tumors, impacting treatment in a quarter of eligible patients. Precision medicine will play a central role in the future care of cholangiocarcinoma.
LNX1 Contributes to Cell Cycle Progression and Cisplatin Resistance
Authors: Jang Minsu , Park Rackhyun , Park Yea-In , Park Yeonjeong , Lee Jin I. , Namkoong Sim , Lee Eun-Ju , Park Junsoo
Published: August 2021

The ligand of numb-protein X1 (LNX1) acts as a proto-oncogene by inhibiting p53 stability; however, the regulation of LNX1 expression has not been investigated. In this study, we screened chemicals to identify factors that potentially regulate LNX1 expression. We found that LNX1 expression levels were decreased by DNA damage, including that by cisplatin. Upon treatment with lipopolysaccharide (LPS) and phorbol 12-myristate 13-acetate (PMA), LNX1 expression levels increased. In addition, cell-cycle progression increased upon LNX1 expression; the levels of S and G2/M populations were correlated with LNX1 expression. Moreover, in CRISPR-Cas9-mediated LNX1 knockout cells, we observed a delay in cell-cycle progression and a downregulation of genes encoding the cell-cycle markers cyclin D1 and cyclin E1. Finally, the upregulation of LNX1-activated cell-cycle progression and increased resistance to cisplatin-mediated cell death. Taken together, these results suggest that LNX1 contributes to cell-cycle progression and cisplatin resistance.
Genetic Alterations in Childhood Acute Lymphoblastic Leukemia: Interactions with Clinical Features and Treatment Response
Authors: Lee Shawn H. R. , Li Zhenhua , Tai Si Ting , Oh Bernice L. Z. , Yeoh Allen E. J.
Published: August 2021

Acute lymphoblastic leukemia (ALL) is the most common cancer among children. This aggressive cancer comprises multiple molecular subtypes, each harboring a distinct constellation of somatic, and to a lesser extent, inherited genetic alterations. With recent advances in genomic analyses such as next-generation sequencing techniques, we can now clearly identify >20 different genetic subtypes in ALL. Clinically, identifying these genetic subtypes will better refine risk stratification and determine the optimal intensity of therapy for each patient. Underpinning each genetic subtype are unique clinical and therapeutic characteristics, such as age and presenting white blood cell (WBC) count. More importantly, within each genetic subtype, there is much less variability in treatment response and survival outcomes compared with current risk factors such as National Cancer Institute (NCI) criteria. We review how this new taxonomy of genetic subtypes in childhood ALL interacts with clinical risk factors used widely, i.e., age, presenting WBC, IKZF1del, treatment response, and outcomes.
MicroRNAs Patterns as Potential Tools for Diagnostic and Prognostic Follow-Up in Cancer Survivorship
Authors: Conti Ilaria , Simioni Carolina , Varano Gabriele , Brenna Cinzia , Costanzi Eva , Neri Luca Maria
Published: August 2021

Advances in screening methods and pharmacological treatments are increasing the life expectancy of cancer patients. During recent decades, the community of long-term disease-free cancer survivors (LCS) has grown exponentially, raising the issues related to cancer follow-up. Cancer relapse and other cancer-related diseases, as well as lifestyle, influence cancer survival. Recently, the regulatory role of microRNAs (miRNAs) in gene expression and their involvement in human diseases, including cancer, has been identified. Extracellular circulating miRNAs (ECmiRNAs) have been found in biological fluids and specific ECmiRNAs have been associated with cancer development and progression or with a therapy response. Here, we focus on the pivotal role of ECmiRNAs as biomarkers in cancer diagnosis and prognosis. Then, we discuss the relevance of ECmiRNAs expression in cancer survivors for the identification of specific ECmiRNAs profiles as potential tools to assess cancer outcome and to control LCS follow-up.
Theoretical and Experimental Research on Ammonia Sensing Properties of Sulfur-Doped Graphene Oxide
Authors: Yu Yao , Liao Zhijia , Meng Fanli , Yuan Zhenyu
Published: August 2021

In this paper, gas sensing characteristics of sulfur-doped graphene oxide (S-GO) are firstly presented. The results of the sensing test revealed that, at room temperature (20 °C), S-GO has the optimal sensitivity to NH3. The S-GO gas sensor has a relatively short response and recovery time for the NH3 detection. Further, the sensing limit of ammonia at room temperature is 0.5 ppm. Theoretical models of graphene and S-doped graphene are established, and electrical properties of the graphene and S-doped graphene are calculated. The enhanced sensing performance was ascribed to the electrical properties’ improvement after the graphene was S-doped.