bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Incorporating AR into a Board Game on Learning Outcomes and Emotions in Health Education
Authors: Lin Hao-Chiang Koong , Lin Yu-Hsuan , Wang Tao-Hua , Su Lun-Ke , Huang Yueh-Min
Published: October 2020

In traditional school education, the content of health education courses cannot be easily linked to daily life experiences. This results in the low application of acquired knowledge and hinders students from gaining hands-on experience and a sense of accomplishment through courses, thereby lowering the learners’ engagement and willingness to learn. This study designed a board game integrated with augmented reality (AR) for health education; incorporated the card-game, slides, and learning-sheets (CSLS) gamification teaching model into the learning process; and discussed the effectiveness of board games with augmented reality in improving learning outcomes and emotions. The research participants were 52 senior high school students, who were assigned to the experimental (AR health education board game) or control (health education board game) group in the teaching experiment. The research findings reveal the following. The two groups were significantly different in terms of (1) learning outcomes, (2) negative emotions, (3) flow state in the game.
The Structure and Composition of Puerto Rico’s Urban Mangroves
Authors: Branoff Benjamin L. , Martinuzzi Sebastián
Published: October 2020

This study characterizes the structure and composition of mangrove forests across urban gradients in Puerto Rico. It then uses a suite of hydrologic, water chemistry, and land cover variables to test for the relative importance of urban intensity alongside flooding and water chemistry in explaining observed variability in forest structure and composition. Three separate statistical tests suggest a significant but limited influence of urbanness on forest composition and structure. In the most urban sites, the diameters of the largest trees were 27% larger, but all structural measurements were best explained by surface water chemistry, primarily nitrogen concentrations. Concentrations of ammonium and total Kjeldahl nitrogen best explained stem density, tree girth and canopy height. The most urban forests also contained 5.0 more species per hectare, on average, than the least urban forests, and simple regression suggests that urban metrics were the most powerful predictors of forest composition. The most urban forests were more dominated by Laguncularia racemosa, while both Avicennia germinans and Rhizophora mangle were found to be less abundant in the most urban sites, a trend that may be linked to the influence of precipitation and tidal connectivity on porewater salinity across the urban gradient. In multiple regression, no statistical difference was detected in the importance of surrounding land cover, flooding, or water quality in explaining the variance in either composition or structural metrics. This suggests that while a given forest metric may be strongly linked to either land cover, water quality, or flooding, all three are likely important and should be considered when characterizing these forests. With more human dependents in urban areas, the provisioning of important ecosystem services may be influenced by land use variables in addition to the more commonly measured metrics of water chemistry and flooding.
Collembolan Assemblages Response to Wild Boars (Sus scrofa L.) Rooting in Pine Forest Soil
Authors: Sławski Marek , Sławska Małgorzata
Published: October 2020

Collembola are an important component of soil communities in all terrestrial ecosystems. In temperate coniferous forests, they are one of the most numerous invertebrate groups, and disturbances that change their density and structure may have negative effects on soil fertility and productivity. Our goal was to determine whether intensive rooting in the forest floor by wild boars affects edaphic Collembola. Soil samples from three paired rooted and non-rooted plots in Scots pine stands were taken twice a year to study the impact of such bioturbation on forest collembolan assemblages. Substantial changes in the taxonomic and functional structure of the collembolan assemblages were identified in all disturbed plots. The abundance and number of species significantly decreased in the bioturbated forest floor. The shares of atmobiotic and hemiedaphic springtails increased at the expense of epedaphic forms. Most of the differences were evident shortly after grubbing but were not significant a few months later. The decline in moisture in disturbed soil could be an explanatory factor causing the differences in the structure and abundance of collembolan assemblages between the bioturbated and intact plots. Our study revealed that large mammals ubiquitous in forest ecosystems can be an important disturbing factor for soil microarthropods. Intensive wild boar rooting in the forest floor had a strong negative effect on the occurrence and abundance of Collembola. This kind of bioturbation also modified the functional structure of assemblages, which in turn may have important consequences for the soil food web and above- and belowground interactions.
Hydrodynamic Responses of a 6 MW Spar-Type Floating Offshore Wind Turbine in Regular Waves and Uniform Current
Authors: Zheng Zhiping , Chen Jikang , Liang Hui , Zhao Yongsheng , Shao Yanlin
Published: October 2020

In order to improve the understanding of hydrodynamic performances of spar-type Floating Offshore Wind Turbines (FOWTs), in particular the effect of wave-current-structure interaction, a moored 6MW spar-type FOWT in regular waves and uniform current is considered. The wind loads are not considered at this stage. We apply the potential-flow theory and perturbation method to solve the weakly-nonlinear problem up to the second order. Unlike the conventional formulations in the inertial frame of reference, which involve higher derivatives on the body surface, the present method based on the perturbation method in the non-inertial body-fixed coordinate system can potentially avoid theoretical inconsistency at sharp edges and associated numerical difficulties. A cubic Boundary Element Method (BEM) is employed to solve the resulting boundary-value problems (BVPs) in the time domain. The convective terms in the free-surface conditions are dealt with using a newly developed conditionally stable explicit scheme, which is an approximation of the implicit Crank–Nicolson scheme. The numerical model is firstly verified against three reference cases, where benchmark results are available, showing excellent agreement. Numerical results are also compared with a recent model test, with a fairly good agreement though differences are witnessed. Drag loads based on Morison’s equation and relative velocities are also applied to quantify the influence of the viscous loads. To account for nonlinear restoring forces from the mooring system, a catenary line model is implemented and coupled with the time-domain hydrodynamic solver. For the considered spar-type FOWT in regular-wave and current conditions, the current has non-negligible effects on the motions at low frequencies, and a strong influence on the mean wave-drift forces. The second-order sum-frequency responses are found to be negligibly small compared with their corresponding linear components. The viscous drag loads do not show a strong influence on the motions responses, while their contribution to the wave-drift forces being notable, which increases with increasing wave steepness.
Sankofa Time
Authors: Jackson Antoinette T.
Published: October 2020

Amongst the Akan people of Ghana, the word “Sankofa” can be broken down into three syllables— “san” (return), “ko” (go), and “fa” (take)—that can be translated into “go back and take it,” or more philosophically, go back to learn. It is often represented by the Andinkra symbol of a bird with its feet facing forward and its head tucked behind; an apt metaphor for the practice of genealogical research. In Black communities in the United States, it is often evoked in attempts to reflect upon and engage with an African past.
Lower Limb Strength Profile in Elderly with Different Pathologies: Comparisons with Healthy Subjects
Authors: Bullo Valentina , Roma Enrico , Gobbo Stefano , Duregon Federica , Bergamo Manuele , Bianchini Gioia , Doria Eleonora , Cugusi Lucia , di Blasio Andrea , Bocalini Danilo Sales , Ermolao Andrea , Bergamin Marco
Published: October 2020

Sarcopenia and muscle strength reduction are a frequent disorder in non-communicable chronic diseases. The aims of this study are: (a) to verify if the absolute and relative to body weight muscle strength of lower limb is affected by the presence of pathology; (b) to verify if the trends are different among knee and ankles joints. One-hundred and forty-five elderly were recruited (16 liver transplant recipients, 48 kidney transplant recipients, 52 elderly with obesity, 30 healthy elderly). Muscular strength of lower limb was evaluated. Evaluation protocol included maximal isometric knee extension, maximal isokinetic knee extension and flexion, maximal isokinetic ankle (both right and left) extension and flexion. A statistically significant interaction between measurement and group membership was found for absolute strength measure (F (4.23, 170.56) = 3.316, p = 0.011, partial η2 (η2p) = 0.076), and relative strength measure(F (4.44, 174.72) = 16.407, p < 0.01, partial η2 (η2p) = 0.294). Elderly patients living with kidney transplants showed the lower level of absolute muscular strength, while relative muscular strength is mainly lacking in the elderly with obesity. The strength profile of elderly subjects is affected by obesity, liver transplantation, and kidney transplantation.
The Impact of COVID-19 on Physician Burnout Globally: A Review
Authors: Amanullah Shabbir , Ramesh Shankar Rashmi
Published: October 2020

Background: The current pandemic, COVID-19, has added to the already high levels of stress that medical professionals face globally. While most health professionals have had to shoulder the burden, physicians are not often recognized as being vulnerable and hence little attention is paid to morbidity and mortality within this group. Objective: To analyse and summarise the current knowledge on factors/potential factors contributing to burnout amongst healthcare professionals amidst the pandemic. This review also makes a few recommendations on how best to prepare intervention programmes for physicians. Methods: In August 2020, a systematic review was performed using the database Medline and Embase (OVID) to search for relevant papers on the impact of COVID-19 on physician burnout–the database was searched for terms such as “COVID-19 OR pandemic” AND “burnout” AND “healthcare professional OR physician”. A manual search was done for other relevant studies included in this review. Results: Five primary studies met the inclusion criteria. A further nine studies were included which evaluated the impact of occupational factors (n = 2), gender differences (n = 4) and increased workload/sleep deprivation (n = 3) on burnout prior to the pandemic. Additionally, five reviews were analysed to support our recommendations. Results from the studies generally showed that the introduction of COVID-19 has heightened existing challenges that physicians face such as increasing workload, which is directly correlated with increased burnout. However, exposure to COVID-19 does not necessarily correlate with increased burnout and is an area for more research. Conclusions: There is some evidence showing that techniques such as mindfulness may help relieve burnout. However, given the small number of studies focusing on physician burnout amidst a pandemic, conclusions should be taken with caution. More studies are needed to support these findings.
Examining Facilitators of HPV Vaccination Uptake in Men Who Have Sex with Men: A Cross-Sectional Survey Design
Authors: Stearns Selma , Quaife Samantha L. , Forster Alice
Published: October 2020

Men who have sex with men (MSM) in England are eligible for vaccination against human papillomavirus (HPV) via specialist sexual health services and HIV clinics. Uptake among clinic attendees is incomplete, but the reason for this is unclear. We do not know who is accessing and being offered the vaccine. This cross-sectional study conducted in England examined socio-demographic correlates of vaccine uptake for MSM and how frequently the vaccine is being offered in clinics. MSM completed an online questionnaire asking about socio-demographic characteristics, whether they had recently attended a sexual health or HIV clinic, and if so, whether they had been offered the vaccine, and vaccination status. Around 52% of MSM (N = 115; mean age = 30.2) had received at least one dose of the vaccine, and 70% of clinic attendees had been offered the vaccine. MSM were more likely to have initiated the vaccine series if they were homosexual (versus bisexual; OR: 5.22; 95% CI: 1.55–17.51) or had heard about the vaccine from one or two types of sources (versus no sources: OR: 14.70; 95% CI: 4.00–54.00 and OR: 26.00; 5.74–117.77 respectively). Initiation was not associated with age, ethnicity, education level, or number of sexual partners. Hepatitis B vaccination status was associated with vaccination initiation only in unadjusted models. The majority of eligible MSM are being offered the vaccine in clinics. Socio-demographic differences in uptake of the HPV vaccine among MSM may lead to inequalities in HPV-related disease.
Recent Advances in Health Impact Assessment and Health in All Policies Implementation: Lessons from an International Convening in Barcelona
Authors: Rogerson Bethany , Lindberg Ruth , Baum Fran , Dora Carlos , Haigh Fiona , Simoncelli Arielle McInnis , Parry Williams Lee , Peralta Genandrialine , Pollack Porter Keshia M. , Solar Orielle
Published: October 2020

Health Impact Assessment (HIA) and Health in All Policies (HiAP) are policy tools used to include health considerations in decision-making processes across sectors such as transportation, education, and criminal justice that can play a role in improving health and equity. This article summarizes proceedings from an international convening of HIA and HiAP experts held in July 2019 in Barcelona, Spain. The presentations and panel discussions included different models, best practices, and lessons learned, including from government, international banks, think tanks, and academia. Participants discussed ideas from around the world for cross-sector collaboration to advance health. The convening covered the following topics: community engagement, building greater understanding of and support for HiAP, and exploring how mandates for HIA and HiAP approaches may advance health and equity.
Visual Status in a Portuguese Population with Intellectual Disability
Authors: Serra Pedro , Costa Regina , Almeida Nuno , Baptista António
Published: October 2020

Background: Neurosensory deprivation associated with vision is a well-known fact in people with intellectual disability (ID). This work aims to report the visual status of a population with ID in Portugal. Methods: A vision screening protocol was conducted during two Special Olympics events. The vision protocol included personal medical history, ocular health evaluation, and clinical measures, such as visual acuity (VA), binocular vision, colour vision, refractive error, and intraocular pressure. This protocol was administered to 134 subjects. Results: Half of the subjects reported that they had never attended or they did not remember having attended a previous eye exam. Additionally, 10% of them had not attended an eye exam in the immediate past three years. Half the subjects failed the VA test and 13% presented moderate Visual Impairment (VI) (VA worse than 0.5 logMAR in the best eye). Manifest ocular deviation was found in 25% of the subjects and the most common ocular health dysfunction conditions were conjunctiva hyperaemia, meibomian gland dysfunction, and lens anomalies. Refractive error correction allowed a reduction in the level of moderate VI to 3.7%. Conclusions: The population analysed showed a poor eye care attendance rate and vision-related conditions are in agreement with previous reports. The development of national strategies to promote the awareness for routine eye care in people with ID and improving accessibility to eye care services may mitigate many of the most prevalent conditions encountered.
Their Economy and Our Health: Communicating Climate Change to the Divided American Public
Authors: Chu Haoran , Yang Janet
Published: October 2020

Climate change poses severe economic and public health threats to societies around the world. However, little is known about how selectively emphasizing its impacts on different issues and in different locations influence public engagement in climate change mitigation. Utilizing an experimental survey with adult participants, this study investigates the effect of issue framing and distance framing on risk perception and policy support related to climate change. The impacts of political ideology, environmental value, and belief in climate science on message effect are also examined. Based on the results of ANOVA (Analysis of Variance) and OLS (Ordinary Least Squares) regression, we found that compared with the economy frame, the public health frame led to greater polarization in risk perception and policy support between liberals and conservatives, and these relationships were mediated by environmental value and belief in climate science. Similarly, distance framing also increased ideological polarization in risk perception and policy support.
First Identification of RNA-Binding Proteins That Regulate Alternative Exons in the Dystrophin Gene
Authors: Miro Julie , Bougé Anne-Laure , Murauer Eva , Beyne Emmanuelle , Da Cunha Dylan , Claustres Mireille , Koenig Michel , Tuffery-Giraud Sylvie
Published: October 2020

The Duchenne muscular dystrophy (DMD) gene has a complex expression pattern regulated by multiple tissue-specific promoters and by alternative splicing (AS) of the resulting transcripts. Here, we used an RNAi-based approach coupled with DMD-targeted RNA-seq to identify RNA-binding proteins (RBPs) that regulate splicing of its skeletal muscle isoform (Dp427m) in a human muscular cell line. A total of 16 RBPs comprising the major regulators of muscle-specific splicing events were tested. We show that distinct combinations of RBPs maintain the correct inclusion in the Dp427m of exons that undergo spatio-temporal AS in other dystrophin isoforms. In particular, our findings revealed the complex networks of RBPs contributing to the splicing of the two short DMD exons 71 and 78, the inclusion of exon 78 in the adult Dp427m isoform being crucial for muscle function. Among the RBPs tested, QKI and DDX5/DDX17 proteins are important determinants of DMD exon inclusion. This is the first large-scale study to determine which RBP proteins act on the physiological splicing of the DMD gene. Our data shed light on molecular mechanisms contributing to the expression of the different dystrophin isoforms, which could be influenced by a change in the function or expression level of the identified RBPs.
Safety and Molecular-Toxicological Implications of Cannabidiol-Rich Cannabis Extract and Methylsulfonylmethane Co-Administration
Authors: Kutanzi Kristy R. , Ewing Laura E. , Skinner Charles M. , Quick Charles M. , Kennon-McGill Stefanie , McGill Mitchell R. , Walker Larry A. , ElSohly Mahmoud A. , Gurley Bill J. , Koturbash Igor
Published: October 2020

Cannabidiol (CBD) is a biologically active, non-psychotropic component of Cannabis sativa whose popularity has grown exponentially in recent years. Besides a wealth of potential health benefits, ingestion of CBD poses risks for a number of side effects, of which hepatotoxicity and CBD/herb-drug interactions are of particular concern. Here, we investigated the interaction potential between the cannabidiol-rich cannabis extract (CRCE) and methylsulfonylmethane (MSM), a popular dietary supplement, in the mouse model. For this purpose, 8-week-old male C57BL6/J mice received MSM-containing water (80 mg/100 mL) ad libitum for 17 days. During the last three days of treatment, mice received three doses of CRCE administered in sesame oil via oral gavage (123 mg/kg/day). Administration of MSM alone did not result in any evidence of liver toxicity and did not induce expression of mouse cytochrome P450 (CYP) enzymes. Administration of CRCE did produce significant (p < 0.05) increases in Cyp1a2, Cyp2b10, Cyp2c29, Cyp3a4, Cyp3a11, Cyp2c65, and Cyp2c66 messenger RNA, however, this effect was not amplified by MSM/CRCE co-treatment. Similarly, no evidence of liver toxicity was observed in MSM/CRCE dosed mice. In conclusion, short-term MSM/CRCE co-administration did not demonstrate any evidence of hepatotoxicity in the mouse model.
High-Resolution Respirometry Reveals MPP+ Mitochondrial Toxicity Mechanism in a Cellular Model of Parkinson’s Disease
Authors: Risiglione Pierpaolo , Leggio Loredana , Cubisino Salvatore A. M. , Reina Simona , Paternò Greta , Marchetti Bianca , Magrì Andrea , Iraci Nunzio , Messina Angela
Published: October 2020

MPP+ is the active metabolite of MPTP, a molecule structurally similar to the herbicide Paraquat, known to injure the dopaminergic neurons of the nigrostriatal system in Parkinson’s disease models. Within the cells, MPP+ accumulates in mitochondria where it inhibits complex I of the electron transport chain, resulting in ATP depletion and neuronal impairment/death. So far, MPP+ is recognized as a valuable tool to mimic dopaminergic degeneration in various cell lines. However, despite a large number of studies, a detailed characterization of mitochondrial respiration in neuronal cells upon MPP+ treatment is still missing. By using high-resolution respirometry, we deeply investigated oxygen consumption related to each respiratory state in differentiated neuroblastoma cells exposed to the neurotoxin. Our results indicated the presence of extended mitochondrial damage at the inner membrane level, supported by increased LEAK respiration, and a drastic drop in oxygen flow devoted to ADP phosphorylation in respirometry measurements. Furthermore, prior to complex I inhibition, an enhancement of complex II activity was observed, suggesting the occurrence of some compensatory effect. Overall our findings provide a mechanistic insight on the mitochondrial toxicity mediated by MPP+, relevant for the standardization of studies that employ this neurotoxin as a disease model.
Investigation of the Impact from IL-2, IL-7, and IL-15 on the Growth and Signaling of Activated CD4+ T Cells
Authors: Coppola Canaan , Hopkins Brooks , Huhn Steven , Du Zhimei , Huang Zuyi , Kelly William J.
Published: October 2020

While CAR-T therapy is a growing and promising area of cancer research, it is limited by high cost and the difficulty of consistently culturing T-cells to therapeutically relevant concentrations ex-vivo. Cytokines IL-2, IL-7 and IL-15 have been found to stimulate the growth of T cells, however, the optimized combination of these three cytokines for T cell proliferation is unknown. In this study, we designed an integrated experimental and modeling approach to optimize cytokine supplementation for rapid expansion in clinical applications. We assessed the growth data for statistical improvements over no cytokine supplementation and used a systems biology approach to identify genes with the highest magnitude of expression change from control at several time points. Further, we developed a predictive mathematical model to project the growth rate for various cytokine combinations, and investigate genes and reactions regulated by cytokines in activated CD4+ T cells. The most favorable conditions from the T cell growth study and from the predictive model align to include the full range of IL-2 and IL-7 studied, and at lower levels of IL-15 (6 ng/mL or 36 ng/mL). The highest growth rates were observed where either IL-2 or IL-7 was at the highest concentration tested (15 ng/mL for IL-2 and 80 ng/mL for IL-7) while the other was at the lowest (1 ng/mL for IL-2 and 6 ng/mL for IL-7), or where both IL-2 and IL-7 concentrations are moderate-corresponding to condition keys 200, 020, and 110 respectively. This suggests a synergistic interaction of IL-2 and IL-7 with regards to promoting optimal proliferation and survival of the activated CD4+ T cells. Transcriptomic data analysis identified the genes and transcriptional regulators up/down-regulated by each of the cytokines IL-2, IL-7, and IL-15. It was found that the genes with persistent expressing changes were associated with major pathways involved in cell growth and proliferation. In addition to influencing T cell metabolism, the three cytokines were found to regulate specific genes involved in TCR, JAK/STAT, MAPK, AKT and PI3K-AKT signaling. The developed Fuzzy model that can predict the growth rate of activated CD4+ T cells for various combinations of cytokines, along with identified optimal cytokine cocktails and important genes found in transcriptomic data, can pave the way for optimizing activated CD4 T cells by regulating cytokines in the clinical setting.
Linagliptin Ameliorates Hepatic Steatosis via Non-Canonical Mechanisms in Mice Treated with a Dual Inhibitor of Insulin Receptor and IGF-1 Receptor
Authors: Okuyama Tomoko , Shirakawa Jun , Tajima Kazuki , Ino Yoko , Vethe Heidrun , Togashi Yu , Kyohara Mayu , Inoue Ryota , Miyashita Daisuke , Li Jinghe , Goto Nozomi , Ichikawa Taiga , Yamasaki Shingo , Ohnuma Haruka , Takayanagi Rie , Kimura Yayoi , Hirano Hisashi , Terauchi Yasuo
Published: October 2020

Abnormal hepatic insulin signaling is a cause or consequence of hepatic steatosis. DPP-4 inhibitors might be protective against fatty liver. We previously reported that the systemic inhibition of insulin receptor (IR) and IGF-1 receptor (IGF1R) by the administration of OSI-906 (linsitinib), a dual IR/IGF1R inhibitor, induced glucose intolerance, hepatic steatosis, and lipoatrophy in mice. In the present study, we investigated the effects of a DPP-4 inhibitor, linagliptin, on hepatic steatosis in OSI-906-treated mice. Unlike high-fat diet-induced hepatic steatosis, OSI-906-induced hepatic steatosis is not characterized by elevations in inflammatory responses or oxidative stress levels. Linagliptin improved OSI-906-induced hepatic steatosis via an insulin-signaling-independent pathway, without altering glucose levels, free fatty acid levels, gluconeogenic gene expressions in the liver, or visceral fat atrophy. Hepatic quantitative proteomic and phosphoproteomic analyses revealed that perilipin-2 (PLIN2), major urinary protein 20 (MUP20), cytochrome P450 2b10 (CYP2B10), and nicotinamide N-methyltransferase (NNMT) are possibly involved in the process of the amelioration of hepatic steatosis by linagliptin. Thus, linagliptin improved hepatic steatosis induced by IR and IGF1R inhibition via a previously unknown mechanism that did not involve gluconeogenesis, lipogenesis, or inflammation, suggesting the non-canonical actions of DPP-4 inhibitors in the treatment of hepatic steatosis under insulin-resistant conditions.
Correction: Haddad, J.G., et al. Doratoxylon apetalum, an Indigenous Medicinal Plant from Mascarene Islands, Is a Potent Inhibitor of Zika and Dengue Virus Infection in Human Cells Int. J. Mol. Sci. 2019, 20, 2382
Authors: Haddad Juliano G. , Koishi Andrea Cristine , Gaudry Arnaud , Nunes Duarte dos Santos Claudia , Viranaicken Wildriss , Desprès Philippe , Kalamouni Chaker El
Published: October 2020

The author wishes to make the following correction to this paper [...]
Sanfilippo Syndrome: Molecular Basis, Disease Models and Therapeutic Approaches
Authors: Benetó Noelia , Vilageliu Lluïsa , Grinberg Daniel , Canals Isaac
Published: October 2020

Sanfilippo syndrome or mucopolysaccharidosis III is a lysosomal storage disorder caused by mutations in genes responsible for the degradation of heparan sulfate, a glycosaminoglycan located in the extracellular membrane. Undegraded heparan sulfate molecules accumulate within lysosomes leading to cellular dysfunction and pathology in several organs, with severe central nervous system degeneration as the main phenotypical feature. The exact molecular and cellular mechanisms by which impaired degradation and storage lead to cellular dysfunction and neuronal degeneration are still not fully understood. Here, we compile the knowledge on this issue and review all available animal and cellular models that can be used to contribute to increase our understanding of Sanfilippo syndrome disease mechanisms. Moreover, we provide an update in advances regarding the different and most successful therapeutic approaches that are currently under study to treat Sanfilippo syndrome patients and discuss the potential of new tools such as induced pluripotent stem cells to be used for disease modeling and therapy development.
The Neutrophil: The Underdog That Packs a Punch in the Fight against Cancer
Authors: Ustyanovska Avtenyuk Natasha , Visser Nienke , Bremer Edwin , Wiersma Valerie R.
Published: October 2020

The advent of immunotherapy has had a major impact on the outcome and overall survival in many types of cancer. Current immunotherapeutic strategies typically aim to (re)activate anticancer T cell immunity, although the targeting of macrophage-mediated anticancer innate immunity has also emerged in recent years. Neutrophils, although comprising ≈ 60% of all white blood cells in the circulation, are still largely overlooked in this respect. Nevertheless, neutrophils have evident anticancer activity and can induce phagocytosis, trogocytosis, as well as the direct cytotoxic elimination of cancer cells. Furthermore, therapeutic tumor-targeting monoclonal antibodies trigger anticancer immune responses through all innate Fc-receptor expressing cells, including neutrophils. Indeed, the depletion of neutrophils strongly reduced the efficacy of monoclonal antibody treatment and increased tumor progression in various preclinical studies. In addition, the infusion of neutrophils in murine cancer models reduced tumor progression. However, evidence on the anticancer effects of neutrophils is fragmentary and mostly obtained in in vitro assays or murine models with reports on anticancer neutrophil activity in humans lagging behind. In this review, we aim to give an overview of the available knowledge of anticancer activity by neutrophils. Furthermore, we will describe strategies being explored for the therapeutic activation of anticancer neutrophil activity.
Discovery and Evaluation of Enantiopure 9H-pyrimido[4,5-b]indoles as Nanomolar GSK-3β Inhibitors with Improved Metabolic Stability
Authors: Andreev Stanislav , Pantsar Tatu , El-Gokha Ahmed , Ansideri Francesco , Kudolo Mark , Anton Débora Bublitz , Sita Giulia , Romasco Jenny , Geibel Christian , Lämmerhofer Michael , Goettert Márcia Ines , Tarozzi Andrea , Laufer Stefan A. , Koch Pierre
Published: October 2020

Glycogen synthase kinase-3β (GSK-3β) is a potential target in the field of Alzheimer’s disease drug discovery. We recently reported a new class of 9H-pyrimido[4,5-b]indole-based GSK-3β inhibitors, of which 3-(3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)propanenitrile (1) demonstrated promising inhibitory potency. However, this compound underwent rapid degradation by human liver microsomes. Starting from 1, we prepared a series of amide-based derivatives and studied their structure–activity relationships against GSK-3β supported by 1 µs molecular dynamics simulations. The biological potency of this series was substantially enhanced by identifying the eutomer configuration at the stereocenter. Moreover, the introduction of an amide bond proved to be an effective strategy to eliminate the metabolic hotspot. The most potent compounds, (R)-3-(3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)-3-oxopropanenitrile ((R)-2) and (R)-1-(3-((7-bromo-9Hpyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)propan-1-one ((R)-28), exhibited IC50 values of 480 nM and 360 nM, respectively, and displayed improved metabolic stability. Their favorable biological profile is complemented by minimal cytotoxicity and neuroprotective properties.
Leptin Downregulates Angulin-1 in Active Crohn’s Disease via STAT3
Authors: Hu Jia-Chen , Bojarski Christian , Branchi Federica , Fromm Michael , Krug Susanne
Published: October 2020

Crohn’s disease (CD) has an altered intestinal barrier function, yet the underlying mechanisms remain to be disclosed. The tricellular tight junction protein tricellulin is involved in the maintenance of the paracellular macromolecule barrier and features an unchanged expression level in CD but a shifted localization. As angulins are known to regulate the localization of tricellulin, we hypothesized the involvement of angulins in CD. Using human biopsies, we found angulin-1 was downregulated in active CD compared with both controls and CD in remission. In T84 and Caco-2 monolayers, leptin, a cytokine secreted by fat tissue and affected in CD, decreased angulin-1 expression. This effect was completely blocked by STAT3 inhibitors, Stattic and WP1066, but only partially by JAK2 inhibitor AG490. The effect of leptin was also seen at a functional level as we observed in Caco-2 cells an increased permeability for FITC-dextran 4 kDa indicating an impaired barrier against macromolecule uptake. In conclusion, we were able to show that in active CD angulin-1 expression is downregulated, which leads to increased macromolecule permeability and is inducible by leptin via STAT3. This suggests that angulin-1 and leptin secretion are potential targets for intervention in CD to restore the impaired intestinal barrier.
In Cellulo Evaluation of the Therapeutic Potential of NHC Platinum Compounds in Metastatic Cutaneous Melanoma
Authors: Charignon Elsa , Bouché Mathilde , Clave-Darcissac Caroline , Dahm Georges , Ichim Gabriel , Clotagatide Anthony , Mertani Hichem C. , Telouk Philippe , Caramel Julie , Diaz Jean-Jacques , Bellemin-Laponnaz Stéphane , Bouvet Philippe , Billotey Claire
Published: October 2020

We describe here the evaluation of the cytotoxic efficacy of two platinum (II) complexes bearing an N-heterocyclic carbene (NHC) ligand, a pyridine ligand and bromide or iodide ligands on a panel of human metastatic cutaneous melanoma cell lines representing different genetic subsets including BRAF-inhibitor-resistant cell lines, namely A375, SK-MEL-28, MeWo, HMCB, A375-R, SK-MEL-5-R and 501MEL-R. Cisplatin and dacarbazine were also studied for comparison purposes. Remarkably, the iodine-labelled Pt-NHC complex strongly inhibited proliferation of all tested melanoma cells after 1-h exposure, likely due to its rapid uptake by melanoma cells. The mechanism of this inhibitory activity involves the formation of DNA double-strand breaks and apoptosis. Considering the intrinsic chemoresistance of metastatic melanoma cells of current systemic treatments, these findings are promising and could give research opportunities in the future to improve the prognosis of patients suffering from unresectable metastatic melanoma that are not eligible or that do not respond to the most effective drugs available to date, namely BRAF inhibitors and the anti-PD-1 monoclonal antibody (mAb).
Hereditary Hypofibrinogenemia with Hepatic Storage
Authors: Asselta Rosanna , Paraboschi Elvezia Maria , Duga Stefano
Published: October 2020

Fibrinogen is a 340-kDa plasma glycoprotein constituted by two sets of symmetrical trimers, each formed by the Aα, Bβ, and γ chains (respectively coded by the FGA, FGB, and FGG genes). Quantitative fibrinogen deficiencies (hypofibrinogenemia, afibrinogenemia) are rare congenital disorders characterized by low or unmeasurable plasma fibrinogen antigen levels. Their genetic basis is represented by mutations within the fibrinogen genes. To date, only eight mutations, all affecting a small region of the fibrinogen γ chain, have been reported to cause hereditary hypofibrinogenemia with hepatic storage (HHHS), a disorder characterized by protein aggregation in the endoplasmic reticulum, hypofibrinogenemia, and liver disease of variable severity. Here, we will briefly review the clinic characteristics of HHHS patients and the histological feature of their hepatic inclusions, and we will focus on the molecular genetic basis of this peculiar type of coagulopathy.
Molecular Mechanisms of SGLT2 Inhibitor on Cardiorenal Protection
Authors: Hou Yi-Chou , Zheng Cai-Mei , Yen Tzung-Hai , Lu Kuo-Cheng
Published: October 2020

The development of sodium-glucose transporter 2 inhibitor (SGLT2i) broadens the therapeutic strategies in treating diabetes mellitus. By inhibiting sodium and glucose reabsorption from the proximal tubules, the improvement in insulin resistance and natriuresis improved the cardiovascular mortality in diabetes mellitus (DM) patients. It has been known that SGLT2i also provided renoprotection by lowering the intraglomerular hypertension by modulating the pre- and post- glomerular vascular tone. The application of SGLT2i also provided metabolic and hemodynamic benefits in molecular aspects. The recent DAPA-CKD trial and EMPEROR-Reduced trial provided clinical evidence of renal and cardiac protection, even in non-DM patients. Therefore, the aim of the review is to clarify the hemodynamic and metabolic modulation of SGLT2i from the molecular mechanism.
Differentiation Induction of Human Stem Cells for Corneal Epithelial Regeneration
Authors: Theerakittayakorn Kasem , Thi Nguyen Hong , Musika Jidapa , Kunkanjanawan Hataiwan , Imsoonthornruksa Sumeth , Somredngan Sirilak , Ketudat-Cairns Mariena , Parnpai Rangsun
Published: October 2020

Deficiency of corneal epithelium causes vision impairment or blindness in severe cases. Transplantation of corneal epithelial cells is an effective treatment but the availability of the tissue source for those cells is inadequate. Stem cells can be induced to differentiate to corneal epithelial cells and used in the treatment. Multipotent stem cells (mesenchymal stem cells) and pluripotent stem cells (embryonic stem cells and induced pluripotent stem cells) are promising cells to address the problem. Various protocols have been developed to induce differentiation of the stem cells into corneal epithelial cells. The feasibility and efficacy of both human stem cells and animal stem cells have been investigated for corneal epithelium regeneration. However, some physiological aspects of animal stem cells are different from those of human stem cells, the protocols suited for animal stem cells might not be suitable for human stem cells. Therefore, in this review, only the investigations of corneal epithelial differentiation of human stem cells are taken into account. The available protocols for inducing the differentiation of human stem cells into corneal epithelial cells are gathered and compared. Also, the pathways involving in the differentiation are provided to elucidate the relevant mechanisms.
Preparation of Defined Chitosan Oligosaccharides Using Chitin Deacetylases
Authors: Bonin Martin , Sreekumar Sruthi , Cord-Landwehr Stefan , Moerschbacher Bruno M.
Published: October 2020

During the past decade, detailed studies using well-defined ‘second generation’ chitosans have amply proved that both their material properties and their biological activities are dependent on their molecular structure, in particular on their degree of polymerisation (DP) and their fraction of acetylation (FA). Recent evidence suggests that the pattern of acetylation (PA), i.e., the sequence of acetylated and non-acetylated residues along the linear polymer, is equally important, but chitosan polymers with defined, non-random PA are not yet available. One way in which the PA will influence the bioactivities of chitosan polymers is their enzymatic degradation by sequence-dependent chitosan hydrolases present in the target tissues. The PA of the polymer substrates in conjunction with the subsite preferences of the hydrolases determine the type of oligomeric products and the kinetics of their production and further degradation. Thus, the bioactivities of chitosan polymers will at least in part be carried by the chitosan oligomers produced from them, possibly through their interaction with pattern recognition receptors in target cells. In contrast to polymers, partially acetylated chitosan oligosaccharides (paCOS) can be fully characterised concerning their DP, FA, and PA, and chitin deacetylases (CDAs) with different and known regio-selectivities are currently emerging as efficient tools to produce fully defined paCOS in quantities sufficient to probe their bioactivities. In this review, we describe the current state of the art on how CDAs can be used in forward and reverse mode to produce all of the possible paCOS dimers, trimers, and tetramers, most of the pentamers and many of the hexamers. In addition, we describe the biotechnological production of the required fully acetylated and fully deacetylated oligomer substrates, as well as the purification and characterisation of the paCOS products.
Targeting Autophagy in Breast Cancer
Authors: Cocco Stefania , Leone Alessandra , Piezzo Michela , Caputo Roberta , Di Lauro Vincenzo , Di Rella Francesca , Fusco Giuseppina , Capozzi Monica , Gioia Germira di , Budillon Alfredo , De Laurentiis Michelino
Published: October 2020

Breast cancer is a heterogeneous disease consisting of different biological subtypes, with differences in terms of incidence, response to diverse treatments, risk of disease progression, and sites of metastases. In the last years, several molecular targets have emerged and new drugs, targeting PI3K/Akt/mTOR and cyclinD/CDK/pRb pathways and tumor microenvironment have been integrated into clinical practice. However, it is clear now that breast cancer is able to develop resistance to these drugs and the identification of the underlying molecular mechanisms is paramount to drive further drug development. Autophagy is a highly conserved homeostatic process that can be activated in response to antineoplastic agents as a cytoprotective mechanism. Inhibition of autophagy could enhance tumor cell death by diverse anti-cancer therapies, representing an attractive approach to control mechanisms of drug resistance. In this manuscript, we present a review of autophagy focusing on its interplay with targeted drugs used for breast cancer treatment.
Molecular Regulation of the Polycomb Repressive-Deubiquitinase
Authors: Reddington Cameron J. , Fellner Matthias , Burgess Abigail E. , Mace Peter D.
Published: October 2020

Post-translational modification of histone proteins plays a major role in histone–DNA packaging and ultimately gene expression. Attachment of ubiquitin to the C-terminal tail of histone H2A (H2AK119Ub in mammals) is particularly relevant to the repression of gene transcription, and is removed by the Polycomb Repressive-Deubiquitinase (PR-DUB) complex. Here, we outline recent advances in the understanding of PR-DUB regulation, which have come through structural studies of the Drosophila melanogaster PR-DUB, biochemical investigation of the human PR-DUB, and functional studies of proteins that associate with the PR-DUB. In humans, mutations in components of the PR-DUB frequently give rise to malignant mesothelioma, melanomas, and renal cell carcinoma, and increase disease risk from carcinogens. Diverse mechanisms may underlie disruption of the PR-DUB across this spectrum of disease. Comparing and contrasting the PR-DUB in mammals and Drosophila reiterates the importance of H2AK119Ub through evolution, provides clues as to how the PR-DUB is dysregulated in disease, and may enable new treatment approaches in cancers where the PR-DUB is disrupted.
Intensive Care Unit-Acquired Weakness: Not Just Another Muscle Atrophying Condition
Authors: Lad Heta , Saumur Tyler M. , Herridge Margaret S. , dos Santos Claudia C. , Mathur Sunita , Batt Jane , Gilbert Penney M.
Published: October 2020

Intensive care unit-acquired weakness (ICUAW) occurs in critically ill patients stemming from the critical illness itself, and results in sustained disability long after the ICU stay. Weakness can be attributed to muscle wasting, impaired contractility, neuropathy, and major pathways associated with muscle protein degradation such as the ubiquitin proteasome system and dysregulated autophagy. Furthermore, it is characterized by the preferential loss of myosin, a distinct feature of the condition. While many risk factors for ICUAW have been identified, effective interventions to offset these changes remain elusive. In addition, our understanding of the mechanisms underlying the long-term, sustained weakness observed in a subset of patients after discharge is minimal. Herein, we discuss the various proposed pathways involved in the pathophysiology of ICUAW, with a focus on the mechanisms underpinning skeletal muscle wasting and impaired contractility, and the animal models used to study them. Furthermore, we will explore the contributions of inflammation, steroid use, and paralysis to the development of ICUAW and how it pertains to those with the corona virus disease of 2019 (COVID-19). We then elaborate on interventions tested as a means to offset these decrements in muscle function that occur as a result of critical illness, and we propose new strategies to explore the molecular mechanisms of ICUAW, including serum-related biomarkers and 3D human skeletal muscle culture models.
Role of Post-Translational Modifications of cGAS in Innate Immunity
Authors: Wu Yakun , Li Shitao
Published: October 2020

Cyclic GMP–AMP synthase (cGAS) is the synthase that generates the second messenger cyclic GMP–AMP (cGAMP) upon DNA binding. cGAS was first discovered as the cytosolic DNA sensor that detects DNA exposed in the cytoplasm either from pathogens or cellular damage. Activated cGAS instigates the signaling cascades to activate type I interferon (IFN) expression, critical for host defense and autoimmune diseases. In addition, cGAS plays a role in senescence, DNA repair, apoptosis, and tumorigenesis. Recently, various post-translational modifications (PTMs) of cGAS have been reported, such as phosphorylation, ubiquitination, acetylation, glutamylation, and sumoylation. These PTMs profoundly affect cGAS functions. Thus, here we review the recent reported PTMs of cGAS and how these PTMs regulate cGAS enzymatic activity, DNA binding, and protein stability, and discuss the potential future directions.
Assessment of the Biological Control Potential of Common Carabid Beetle Species for Autumn- and Winter-Active Pests (Gastropoda, Lepidoptera, Diptera: Tipulidae) in Annual Ryegrass in Western Oregon
Authors: Reich Inga , Jessie Casi , Ahn Seung-Joon , Choi Man-Yeon , Williams Christopher , Gormally Mike , Mc Donnell Rory
Published: October 2020

While carabid beetles have been shown to feed on a variety of crop pests, little is known about their species assemblages in US annual ryegrass crops, where invertebrate pests, particularly slugs, lepidopteran larvae and craneflies, incur major financial costs. This study assesses the biological control potential of carabid beetles for autumn- and winter-active pests in annual ryegrass grown for seed by: (a) investigating the spatial and temporal overlap of carabids with key pests; and (b) molecular gut content analysis using qPCR. Introduced Nebria brevicollis was the only common carabid that was active during pest emergence in autumn, with 18.6% and 8.3% of N. brevicollis collected between September and October testing positive for lepidopteran and cranefly DNA, respectively, but only 1.7% testing positive for slug DNA. While pest DNA was also detected in the guts of the other common carabid species—Agonum muelleri, Calosoma cancellatum and Poecilus laetulus—these were active only during spring and summer, when crop damage by pests is less critical. None of the four carabid species was affected by disk tilling and only N. brevicollis was significantly associated with a vegetated field margin. However, as its impact on native ecosystems is unknown, we do not recommend managing for this species.