bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic and Transcriptional Adaptations Improve Physical Performance of Zebrafish
Authors: Heinkele Franziska J. , Lou Bowen , Erben Vanessa , Bennewitz Katrin , Poschet Gernot , Sticht Carsten , Kroll Jens
Published: October 2021

Obesity is a worldwide public health problem with increasing prevalence and affects 80% of diabetes mellitus type 2 cases. Zebrafish (Danio rerio) is an established model organism for studying obesity and diabetes including diabetic microvascular complications. We aimed to determine whether physical activity is an appropriate tool to examine training effects in zebrafish and to analyse metabolic and transcriptional processes in trained zebrafish. A 2- and 8-week experimental training phase protocol with adult zebrafish in a swim tunnel system was established. We examined zebrafish basic characteristics before and after training such as body weight, body length and maximum speed and considered overfeeding as an additional parameter in the 8-weeks training protocol. Ultimately, the effects of training and overfeeding on blood glucose, muscle core metabolism and liver gene expression using RNA-Seq were investigated. Zebrafish maximum speed was correlated with body length and was significantly increased after 2 weeks of training. Maximum swim speed further increased after 8 weeks of training in both the normal-fed and the overfed groups, but training was found not to be sufficient in preventing weight gain in overfed fish. Metabolome and transcriptome profiling in trained fish exhibited increased blood glucose levels in the short-term and upregulated energy supply pathways as well as response to oxidative stress in the long-term. In conclusion, swim training is a valuable tool to study the effects of physical activity in zebrafish, which is accompanied by metabolic and transcriptional adaptations.
Filter Feeding and Carbon and Nitrogen Assimilation of a Freshwater Bivalve (Unio douglasiae) on a Toxic Cyanobacterium (Microcystis aeruginosa)
Authors: Hwang Soon-Jin , Lee Yun-Ju , Kim Min-Seob , Kim Baik-Ho
Published: October 2021

We investigated the possible intake of toxic cyanobacteria (Microcystis aeruginosa) as a nutrient resource for a filter-feeder bivalve (Unio douglasiae) based on the measurement of feeding and assimilation rates of carbon and nitrogen in a limited space with no current for 72 h using 13C and 15N dual isotope tracers. With high clearance rates, the unionid rapidly removed Microcystis cells within 24 h, but only a small amount of carbon and nitrogen were incorporated into the tissues. Even with the low assimilation rates, the mussels showed more favorable uptake of carbon than of nitrogen from toxic Microcystis water, and of tissues, the gills and gut accumulated more carbon and nitrogen than the muscle and mantle. Collectively, our findings indicate that although Unio douglasiae effectively uptake toxic Microcystis cells, they can assimilate only low amounts of nutrients into tissues within three days, despite a non-flowing system.
A Novel Method for Performance Measurement of Public Educational Institutions Using Machine Learning Models
Authors: Alam Talha Mahboob , Mushtaq Mubbashar , Shaukat Kamran , Hameed Ibrahim A. , Umer Sarwar Muhammad , Luo Suhuai
Published: October 2021

Lack of education is a major concern in underdeveloped countries because it leads to poor human and economic development. The level of education in public institutions varies across all regions around the globe. Current disparities in access to education worldwide are mostly due to systemic regional differences and the distribution of resources. Previous research focused on evaluating students’ academic performance, but less has been done to measure the performance of educational institutions. Key performance indicators for the evaluation of institutional performance differ from student performance indicators. There is a dire need to evaluate educational institutions’ performance based on their disparities and academic results on a large scale. This study proposes a model to measure institutional performance based on key performance indicators through data mining techniques. Various feature selection methods were used to extract the key performance indicators. Several machine learning models, namely, J48 decision tree, support vector machines, random forest, rotation forest, and artificial neural networks were employed to build an efficient model. The results of the study were based on different factors, i.e., the number of schools in a specific region, teachers, school locations, enrolment, and availability of necessary facilities that contribute to school performance. It was also observed that urban regions performed well compared to rural regions due to the improved availability of educational facilities and resources. The results showed that artificial neural networks outperformed other models and achieved an accuracy of 82.9% when the relief-F based feature selection method was used. This study will help support efforts in governance for performance monitoring, policy formulation, target-setting, evaluation, and reform to address the issues and challenges in education worldwide.
SCAMPER Monitoring Platform to Measure PM10 Emission Rates from Unpaved Roads in Real-Time
Authors: Fitz Dennis R. , Bumiller Kurt
Published: October 2021

The SCAMPER method for measuring PM10 emission rates from roadways was used to evaluate mitigation methods for public unpaved roads and a treated mine haul road. The SCAMPER method uses a small trailer to measure PM10 concentrations behind a vehicle at a point that is representative of the mean PM10 concentration in the vehicle’s wake. This concentration multiplied by the frontal area has been shown to be a reasonable estimate of the emission rate in units of grams per meter traveled. On public roads it was towed by a 2006 Ford Expedition and on a mine haul road it was towed behind both the Expedition and an earth mover weighing over 150 tons fully loaded. Since the SCAMPER is capable of measuring emission rates on both paved and unpaved roadways, a direct comparison of the effectiveness of mitigation methods with respect to a similar paved road was possible.
Air Pollution and Outdoor Recreation on Urban Trails: A Case Study of the Elizabeth River Trail, Norfolk
Authors: McCann James E. , Zajchowski Chris A. B. , Hill Eddie L. , Zhu Xihe
Published: October 2021

Poor air quality represents a significant health risk for individuals engaging in recreation activities outdoors in urban parks and trails. This study investigated temporal variability in particulate matter (PM) exposure along an urban waterfront trail. We also used recreation choice frameworks to examine the effects of visitors’ perceptions of air quality (AQ) and health benefits on trail use. Average air quality during the collection period was “good” (PM10) to “moderate” (PM2.5). We found that PM density was significantly higher (p < 0.001), though still in the “moderate” range, at 7–9 a.m., 11 a.m.–1 p.m., and 3–5 p.m., and on weekends. Visitors’ self-reported perceptions of health outcomes, but not air quality, significantly predicted trail use. Results suggest that these experiential factors may affect recreational choices depending on other factors, such as salience. Further research is merited to determine how experiential factors can be integrated with other theories of motivation to understand recreational decision-making.
The Impact on Urban Air Quality of the COVID-19 Lockdown Periods in 2020: The Case of Nicosia, Cyprus
Authors: Alexandrou Giorgos , Mouzourides Petros , Eleftheriou Andreas , Neophytou Marina K.-A.
Published: October 2021

The purpose of this study is to assess the impact of the lockdown measures in 2020 on the urban air quality in Nicosia capital city, in Cyprus—an island-country in the East Mediterranean—which is often affected by transboundary dust pollution. The study focuses on three criteria pollutants, nitrogen dioxide (NO2), carbon monoxide (CO) and Particulate Matter (PM10), taken from three Air Quality Monitoring Stations; two urban stations and one reference-background. The results of this study show that the decrease in traffic, which is the main source of high concentrations of pollutants in the urban area, reached up to 66.5% during the lockdown. At the beginning of the lockdown period, it exhibited a downward trend of 29% for CO concentration, and downward trend 43% for NO2 and PM10 concentrations. The NO2 concentration exhibited an upward trend towards the end of the lockdown; with the indication that this was due to meteorological conditions relevant to the monitoring stations and the transport of NO2 concentrations from sources that cannot be tracked. PM10 concentrations exhibited a varying behaviour as observed in the trends, where the decreasing trend was followed by an increasing trend due to transboundary air pollution episodes occurring in the same period.
Novel Xanthone Derivatives Impair Growth and Invasiveness of Colon Cancer Cells In Vitro
Authors: Rech Jakub , Sypniewski Daniel , Żelaszczyk Dorota , Szkaradek Natalia , Rogóż Wojciech , Waszkielewicz Anna , Marona Henryk , Bednarek Ilona
Published: October 2021

Natural xanthones are a large group of compounds from which promising anticancer properties could be further developed by chemical modifications. This study aimed to investigate the influence of four novel xanthone derivatives based on a naturally occurring xanthone skeleton on the invasiveness of colon cancer cells in vitro. First, the concentrations required to inhibit growth of three colorectal cancer cell lines to 50% (GI50) of all the studied compounds, as well as the natural xanthones used as a reference (gambogic acid and α-mangostin), have been established (MTS reduction test). Next, the assays determining several aspects of the GI25 xanthones influence on colorectal cancer cells, including cytotoxicity, migration and invasion potential, interaction with extracellular matrix and endothelial cells, as well as expression of selected invasiveness related genes have been performed. Our results demonstrate that these novel xanthone derivatives impair colorectal cancer proliferation, motility, adhesion to extracellular matrix and to endothelial cells, and also induce apoptosis and cell death. Moreover, their activity is comparable to cisplatin and 5-fluorouracil, used as reference compounds. Conducted research indicates our compounds for further research and development as novel drugs in colorectal cancer treatment.
Antibacterial and Antifungal Properties of Silver Nanoparticles—Effect of a Surface-Stabilizing Agent
Authors: Gibała Agnieszka , Żeliszewska Paulina , Gosiewski Tomasz , Krawczyk Agnieszka , Duraczyńska Dorota , Szaleniec Joanna , Szaleniec Maciej , Oćwieja Magdalena
Published: October 2021

The biocidal properties of silver nanoparticles (AgNPs) prepared with the use of biologically active compounds seem to be especially significant for biological and medical application. Therefore, the aim of this research was to determine and compare the antibacterial and fungicidal properties of fifteen types of AgNPs. The main hypothesis was that the biological activity of AgNPs characterized by comparable size distributions, shapes, and ion release profiles is dependent on the properties of stabilizing agent molecules adsorbed on their surfaces. Escherichia coli and Staphylococcus aureus were selected as models of two types of bacterial cells. Candida albicans was selected for the research as a representative type of eukaryotic microorganism. The conducted studies reveal that larger AgNPs can be more biocidal than smaller ones. It was found that positively charged arginine-stabilized AgNPs (ARGSBAgNPs) were the most biocidal among all studied nanoparticles. The strongest fungicidal properties were detected for negatively charged EGCGAgNPs obtained using (−)-epigallocatechin gallate (EGCG). It was concluded that, by applying a specific stabilizing agent, one can tune the selectivity of AgNP toxicity towards desired pathogens. It was established that E. coli was more sensitive to AgNP exposure than S. aureus regardless of AgNP size and surface properties.
Biomolecules Orchestrating Cardiovascular Calcification
Authors: Tintut Yin , Honda Henry M. , Demer Linda L.
Published: October 2021

Vascular calcification, once considered a degenerative, end-stage, and inevitable condition, is now recognized as a complex process regulated in a manner similar to skeletal bone at the molecular and cellular levels. Since the initial discovery of bone morphogenetic protein in calcified human atherosclerotic lesions, decades of research have now led to the recognition that the regulatory mechanisms and the biomolecules that control cardiovascular calcification overlap with those controlling skeletal mineralization. In this review, we focus on key biomolecules driving the ectopic calcification in the circulation and their regulation by metabolic, hormonal, and inflammatory stimuli. Although calcium deposits in the vessel wall introduce rupture stress at their edges facing applied tensile stress, they simultaneously reduce rupture stress at the orthogonal edges, leaving the net risk of plaque rupture and consequent cardiac events depending on local material strength. A clinically important consequence of the shared mechanisms between the vascular and bone tissues is that therapeutic agents designed to inhibit vascular calcification may adversely affect skeletal mineralization and vice versa. Thus, it is essential to consider both systems when developing therapeutic strategies.
Paper-Based Airborne Bacteria Collection and DNA Extraction Kit
Authors: Seok Youngung , Lee Joonseok , Kim Min-Gon
Published: October 2021

The critical risk from airborne infectious diseases, bio-weapons, and harmful bacteria is currently the highest it has ever been in human history. The requirement for monitoring airborne pathogens has gradually increased to defend against bioterrorism or prevent pandemics, especially via simple and low-cost platforms which can be applied in resource-limited settings. Here, we developed a paper-based airborne bacteria collection and DNA extraction kit suitable for simple application with minimal instruments. Airborne sample collection and DNA extraction for PCR analysis were integrated in the paper kit. We created an easy-to-use paper-based air monitoring system using 3D printing technology combined with an air pump. The operation time of the entire process, comprising air sampling, bacterial cell lysis, purification and concentration of DNA, and elution of the DNA analyte, was within 20 min. All the investigations and optimum settings were tested in a custom-designed closed cabinet system. In the fabricated cabinet system, the paper kit operated effectively at a temperature of 25–35 °C and 30–70% relative humidity for air containing 10–106 CFU Staphylococcus aureus. This paper kit could be applied for simple, rapid, and cost-effective airborne pathogen monitoring.
Sleep-Related Rhythmic Movement Disorder in Young Children with Down Syndrome: Prevalence and Clinical Features
Authors: Kose Ceren , Wood Izabelle , Gwyther Amy , Basnet Susiksha , Gaskell Chloe , Gringras Paul , Elphick Heather , Evans Hazel , Hill Catherine M.
Published: October 2021

Sleep-related Rhythmic Movement Disorder (RMD) affects around 1% of UK pre-school children. Little is known about RMD in Down syndrome (DS). We aimed to determine: (a) the prevalence of RMD in children with DS aged 1.5–8 years; (b) phenotypic and sleep quality differences between children with DS and RMD and sex- and age-matched DS controls; and (c) night-to-night variability in rhythmic movements (RMs). Parents who previously reported RMs from a DS research registry of 202 children were contacted. If clinical history suggested RMD, home videosomnography (3 nights) was used to confirm RMs and actigraphy (5 nights) was used to assess sleep quality. Phenotype was explored by demographic, strengths and difficulties, Q-CHAT-10/social communication and life events questionnaires. Eight children had confirmed RMD. Minimal and estimated maximal prevalence were 4.10% and 15.38%, respectively. Sleep efficiency was significantly lower in RMD-cases (69.1%) versus controls (85.2%), but there were no other phenotypic differences. There was considerable intra-individual night-to-night variability in RMs. In conclusion, RMD has a high prevalence in children with DS, varies from night to night and is associated with poor sleep quality but, in this small sample, no daytime phenotypic differences were found compared to controls. Children with DS should be screened for RMD, which is amenable to treatment.
Mir-21 Suppression Promotes Mouse Hepatocarcinogenesis
Authors: Correia de Sousa Marta , Calo Nicolas , Sobolewski Cyril , Gjorgjieva Monika , Clément Sophie , Maeder Christine , Dolicka Dobrochna , Fournier Margot , Vinet Laurent , Montet Xavier , Dufour Jean-François , Humar Bostjan , Negro Francesco , Sempoux Christine , Foti Michelangelo
Published: October 2021

The microRNA 21 (miR-21) is upregulated in almost all known human cancers and is considered a highly potent oncogene and potential therapeutic target for cancer treatment. In the liver, miR-21 was reported to promote hepatic steatosis and inflammation, but whether miR-21 also drives hepatocarcinogenesis remains poorly investigated in vivo. Here we show using both carcinogen (Diethylnitrosamine, DEN) or genetically (PTEN deficiency)-induced mouse models of hepatocellular carcinoma (HCC), total or hepatocyte-specific genetic deletion of this microRNA fosters HCC development—contrasting the expected oncogenic role of miR-21. Gene and protein expression analyses of mouse liver tissues further indicate that total or hepatocyte-specific miR-21 deficiency is associated with an increased expression of oncogenes such as Cdc25a, subtle deregulations of the MAPK, HiPPO, and STAT3 signaling pathways, as well as alterations of the inflammatory/immune anti-tumoral responses in the liver. Together, our data show that miR-21 deficiency promotes a pro-tumoral microenvironment, which over time fosters HCC development via pleiotropic and complex mechanisms. These results question the current dogma of miR-21 being a potent oncomiR in the liver and call for cautiousness when considering miR-21 inhibition for therapeutic purposes in HCC.
Endometrial PTEN Deficiency Leads to SMAD2/3 Nuclear Translocation
Authors: Eritja Núria , Navaridas Raúl , Ruiz-Mitjana Anna , Vidal-Sabanés Maria , Egea Joaquim , Encinas Mario , Matias-Guiu Xavier , Dolcet Xavier
Published: October 2021

TGF-β has a dichotomous function, acting as tumor suppressor in premalignant cells but as a tumor promoter for cancerous cells. These contradictory functions of TGF-β are caused by different cellular contexts, including both intracellular and environmental determinants. The TGF-β/SMAD and the PI3K/PTEN/AKT signal transduction pathways have an important role in the regulation of epithelial cell homeostasis and perturbations in either of these two pathways’ contributions to endometrial carcinogenesis. We have previously demonstrated that both PTEN and SMAD2/3 display tumor-suppressive functions in the endometrium, and genetic ablation of either gene results in sustained activation of PI3K/AKT signaling that suppresses TGF-β-induced apoptosis and enhances cell proliferation of mouse endometrial cells. However, the molecular and cellular effects of PTEN deficiency on TGF-β/SMAD2/3 signaling remain controversial. Here, using an in vitro and in vivo model of endometrial carcinogenesis, we have demonstrated that loss of PTEN leads to a constitutive SMAD2/3 nuclear translocation. To ascertain the function of nuclear SMAD2/3 downstream of PTEN deficiency, we analyzed the effects of double deletion PTEN and SMAD2/3 in mouse endometrial organoids. Double PTEN/SMAD2/3 ablation results in a further increase of cell proliferation and enlarged endometrial organoids compared to those harboring single PTEN, suggesting that nuclear translocation of SMAD2/3 constrains tumorigenesis induced by PTEN deficiency.
Delineating the Switch between Senescence and Apoptosis in Cervical Cancer Cells under Ciclopirox Treatment
Authors: Herrmann Anja L. , Kuhn Bianca J. , Holzer Angela , Krijgsveld Jeroen , Hoppe-Seyler Karin , Hoppe-Seyler Felix
Published: October 2021

The iron-chelating drug ciclopirox (CPX) may possess therapeutic potential for cancer treatment, including cervical cancer. As is observed for other chemotherapeutic drugs, CPX can induce senescence or apoptosis in cervical cancer cells which could differently affect their therapy response. The present study aims to gain insights into the determinants which govern the switch between senescence and apoptosis in cervical cancer cells. We performed proteome analyses, proliferation studies by live-cell imaging and colony formation assays, senescence and apoptosis assays, and combination treatments of CPX with inhibitors of oxidative phosphorylation (OXPHOS) or glycolysis. We found that CPX downregulates OXPHOS factors and facilitates the induction of apoptosis under limited glucose availability, an effect which is shared by classical OXPHOS inhibitors. Under increased glucose availability, however, CPX-induced apoptosis is prevented and senescence is induced, an activity which is not exerted by classical OXPHOS inhibitors, but by other iron chelators. Moreover, we show that the combination of CPX with glycolysis inhibitors blocks cervical cancer proliferation in a synergistic manner. Collectively, our results reveal that the phenotypic response of cervical cancer cells towards CPX is strongly dependent on glucose availability, link the pro-apoptotic and pro-senescent activities of CPX to its bifunctionality as an OXPHOS inhibitor and iron chelator, respectively, and provide a rationale for combining CPX with glycolysis inhibitors.
Validation of microRNA-199b as A Promising Predictor of Outcome and Response to Neoadjuvant Treatment in Locally Advanced Rectal Cancer Patients
Authors: Cristóbal Ion , Santos Andrea , Rubio Jaime , Caramés Cristina , Zazo Sandra , Sanz-Álvarez Marta , Luque Melani , Madoz-Gúrpide Juan , Rojo Federico , García-Foncillas Jesús
Published: October 2021

The absence of established predictive markers with value to anticipate response to neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) represents a current major challenge in locally advanced rectal cancer (LARC). The tumor suppressor microRNA (miR)-199b has been reported to play a key role determining 5-FU sensitivity of colorectal cancer cells through the regulation of several signaling pathways, and has emerged as a novel molecular target to overcome the 5-FU resistant phenotype. Moreover, miR-199b downregulation was described as a common alteration that predicts lack of response to preoperative CRT in LARC but this issue needs to be confirmed in independent larger cohorts. Here, we evaluate the clinical impact of miR-199b in LARC and perform additional analyses to further clarify its potential relevance as novel marker in this disease. Thus, miR-199b expression was quantified by real-time-PCR in a cohort of 185 LARC patients, observing this miR downregulated in 22.2% of cases and significantly associated with higher tumor size (p = 0.026) and positive lymph node after CRT (p = 0.005), and higher pathological stage (p = 0.004). Notably, this alteration showed a strong independent predictive value of poor pathological response to neoadjuvant CRT (p = 0.004). Moreover, the subgroup of cases with low miR-199b levels had a markedly shorter overall (p < 001) and event-free survival (p < 0.001), and multivariate analyses showed that miR-199b deregulation represents an independent prognosticator for patient outcome in LARC. Interestingly, the prognostic impact of this miR was strongly significant in both younger and elderly patients, and was very effective determining patient recurrence (p = 0.004). Finally, we compared miR-199b expression profiles in a set of cases with pre and post-treatment samples available, observing that only a minimal response leads to miR-199b increase levels, further suggesting its potential clinical and therapeutic relevance as a promising marker and novel molecular target for the management of LARC.
The RXR Agonist MSU42011 Is Effective for the Treatment of Preclinical HER2+ Breast Cancer and Kras-Driven Lung Cancer
Authors: Leal Ana S. , Moerland Jessica A. , Zhang Di , Carapellucci Sarah , Lockwood Beth , Krieger-Burke Teresa , Aleiwi Bilal , Ellsworth Edmund , Liby Karen T.
Published: October 2021

(1) Background: Notwithstanding numerous therapeutic advances, 176,000 deaths from breast and lung cancers will occur in the United States in 2021 alone. The tumor microenvironment and its modulation by drugs have gained increasing attention and relevance, especially with the introduction of immunotherapy as a standard of care in clinical practice. Retinoid X receptors (RXRs) are members of the nuclear receptor superfamily and upon ligand binding, function as transcription factors to modulate multiple cell functions. Bexarotene, the only FDA-approved RXR agonist, is still used to treat cutaneous T-cell lymphoma. (2) Methods: To test the immunomodulatory and anti-tumor effects of MSU42011, a new RXR agonist, we used two different immunocompetent murine models (MMTV-Neu mice, a HER2 positive model of breast cancer and the A/J mouse model, in which vinyl carbamate is used to initiate lung tumorigenesis) and an immunodeficient xenograft lung cancer model. (3) Results: Treatment of established tumors in immunocompetent models of HER2-positive breast cancer and Kras-driven lung cancer with MSU42011 significantly decreased the tumor burden and increased the ratio of CD8/CD4, CD25 T cells, which correlates with enhanced anti-tumor efficacy. Moreover, the combination of MSU42011 and immunotherapy (anti-PDL1 and anti-PD1 antibodies) significantly (p < 0.05) reduced tumor size vs. individual treatments. However, MSU42011 was ineffective in an athymic human A549 lung cancer xenograft model, supporting an immunomodulatory mechanism of action. (4) Conclusions: Collectively, these data suggest that the RXR agonist MSU42011 can be used to modulate the tumor microenvironment in breast and lung cancer.
Level of Combined Estrogen and Progesterone Receptor Expression Determines the Eligibility for Adjuvant Endocrine Therapy in Breast Cancer Patients
Authors: Ahn Jee Hyun , Choi Soon Bo , Park Jung Min , Kim Jee Ye , Park Hyung Seok , Kim Seung Il , Park Byeong-Woo , Park Seho
Published: October 2021

Hormone receptor (HR)-positive breast cancer has a heterogeneous pattern according to the level of receptor expression. Patients whose breast cancers express low levels of estrogen receptor (ER) or progesterone receptor (PgR) may be eligible for adjuvant endocrine therapy, but limited data are available to support this notion. We aimed to determine whether HR expression level is related to prognosis. Tumors from 6042 patients with breast cancer were retrospectively analyzed for combined HR levels of ER and PgR. Low expression was defined as ER 1–10% and PgR 1–20%. Four HR groups were identified by combining ER and PgR expression levels. Patients whose tumors expressed high levels of a single receptor showed the worst survival outcomes, and their risk continuously increased even after the 10-year follow-up. Endocrine therapy had a significant benefit for patients whose tumors expressed high HR levels and a favorable tendency for patients with tumors expressing low HR levels. We established the possible benefit of endocrine therapy for patients whose breast tumors expressed low HR levels. Thus, HR level was a prognostic factor and might be a determinant of extended therapy, especially for patients with high expression of a single receptor.
Targeting Ovarian Carcinoma with TSP-1:CD47 Antagonist TAX2 Activates Anti-Tumor Immunity
Authors: Jeanne Albin , Sarazin Thomas , Charlé Magalie , Moali Catherine , Fichel Caroline , Boulagnon-Rombi Camille , Callewaert Maïté , Andry Marie-Christine , Diesis Eric , Delolme Frédéric , Rioult Damien , Dedieu Stéphane
Published: October 2021

TAX2 peptide is a cyclic peptide that acts as an orthosteric antagonist for thrombospondin-1 (TSP-1) interaction with CD47. TAX2 was first described for its anti-angiogenic activities and showed anti-cancer efficacy in numerous preclinical models. Here, we aimed at providing an extensive molecular characterization of TAX2 mode of action, while evaluating its potential in ovarian cancer therapy. Multidisciplinary approaches were used to qualify a TAX2 drug candidate in terms of stability, solubility and potency. Then, efficacy studies, together with benchmark experiments, were performed in relevant mouse models of ovarian carcinoma. TAX2 peptide appears to be stable and soluble in clinically relevant solvents, while displaying a favorable safety profile. Moreover, clinical data mining allowed for the identification of TSP-1 as a relevant pharmacological target in ovarian cancer. In mice, TAX2 therapy inhibits ovarian tumor growth and metastatic dissemination, while activating anti-cancer adaptive immunity. Interestingly, TAX2 also synergizes when administered in combination with anti-PD-1 immune checkpoint inhibitiors. Altogether, our data expose TAX2 as an optimized candidate with advanced preclinical characterization. Using relevant syngeneic ovarian carcinoma models, we highlighted TAX2’s ability to convert poorly immunogenic tumors into ones displaying effective anti-tumor T-cell immunity.
Ferulic Acid in Animal Models of Alzheimer’s Disease: A Systematic Review of Preclinical Studies
Authors: Wang Er-Jin , Wu Ming-Yue , Lu Jia-Hong
Published: October 2021

Alzheimer’s disease (AD) is a neurodegenerative disease with a high incidence in the elderly. Many preclinical studies show that a natural product, ferulic acid (FA), displays neuroprotective effects in AD models. This review aims to systematically review and meta-analyze published pre-clinical researches about the effects, mechanism, and clinical prospects of FA in the treatment of AD. According to the pre-determined search strategy and inclusion criteria, a total of 344 animals in 12 papers were included in the meta-analysis. We used the fixed effects model to analyze data and I2 and p values to indicate heterogeneity. Results show that FA treatment can effectively improve rodents’ spatial memory ability in MWM and Y maze experiments (I2 ≥ 70, p < 0.005), and reduce the deposition of Aβ in the brains of various model animals (I2 ≥ 50, p < 0.005). The potential mechanisms include anti-amyloidogenesis, anti-inflammation, anti-oxidation, mitochondrial protection, and inhibition of apoptosis. In conclusion, we systematically review and meta-analyze the literature reporting the effects of FA treatment on AD rodent models and solidify the benefits of FA in reducing Aβ deposition and improving memory in preclinical experiments. We also point out the limitations in the current research design and provide a strategy for the production research of FA in the future.
Regulation of T Cells in Cancer by Nitric Oxide
Authors: Navasardyan Inesa , Bonavida Benjamin
Published: October 2021

The T cell-mediated immune response is primarily involved in the fight against infectious diseases and cancer and its underlying mechanisms are complex. The anti-tumor T cell response is regulated by various T cell subsets and other cells and tissues in the tumor microenvironment (TME). Various mechanisms are involved in the regulation of these various effector cells. One mechanism is the iNOS/.NO that has been reported to be intimately involved in the regulation and differentiation of the various cells that regulate the anti-tumor CD8 T cells. Both endogenous and exogenous .NO are implicated in this regulation. Importantly, the exposure of T cells to .NO had different effects on the immune response, depending on the .NO concentration and time of exposure. For instance, iNOS in T cells regulates activation-induced cell death and inhibits Treg induction. Effector CD8 T cells exposed to .NO result in the upregulation of death receptors and enhance their anti-tumor cytotoxic activity. .NO-Tregs suppress CD4 Th17 cells and their differentiation. Myeloid-derived suppressor cells (MDSCs) expressing iNOS inhibit T cell functions via .NO and inhibit anti-tumor CD8 T cells. Therefore, both .NO donors and .NO inhibitors are potential therapeutics tailored to specific target cells that regulate the T cell effector anti-tumor response.
Integrated Proteomic and Transcriptomic Analysis of Gonads Reveal Disruption of Germ Cell Proliferation and Division, and Energy Storage in Glycogen in Sterile Triploid Pacific Oysters (Crassostrea gigas)
Authors: Chen Chen , Yu Hong , Li Qi
Published: October 2021

Triploid oysters have poor gonadal development, which can not only bring higher economic benefits but also have a potential application in the genetic containment of aquaculture. However, the key factors that influence germ cell development in triploid oysters remain unclear. In this study, data-independent acquisition coupled to transcriptomics was applied to identify genes/proteins related to sterility in triploid Crassostrea gigas. Eighty-four genes were differentially expressed at both the protein and mRNA levels between fertile and sterile females. For male oysters, 207 genes were differentially expressed in the transcriptomic and proteomic analysis. A large proportion of downregulated genes were related to cell division, which may hinder germ cell proliferation and cause apoptosis. In sterile triploid females, a primary cause of sterility may be downregulation in the expression levels of certain mitotic cell cycle-related genes. In sterile triploid males, downregulation of genes related to cell cycle and sperm motility indicated that the disruption of mitosis or meiosis and flagella defects may be linked with the blocking of spermatogenesis. Additionally, the genes upregulated in sterile oysters were mainly associated with the biosynthesis of glycogen and fat, suggesting that sterility in triploids stimulates the synthesis of glycogen and energy conservation in gonad tissue.
The Use of Human Serum Samples to Study Malignant Transformation: A Pilot Study
Authors: Holowatyj Andreana N. , Gigic Biljana , Warby Christy A. , Ose Jennifer , Lin Tengda , Schrotz-King Petra , Ulrich Cornelia M. , Bernard Jamie J.
Published: October 2021

Obesity and excess adiposity account for approximately 20% of all cancer cases; however, biomarkers of risk remain to be elucidated. While fibroblast growth factor-2 (FGF2) is emerging as an attractive candidate biomarker for visceral adipose tissue mass, the role of circulating FGF2 in malignant transformation remains unknown. Moreover, functional assays for biomarker discovery are limited. We sought to determine if human serum could stimulate the 3D growth of a non-tumorigenic cell line. This type of anchorage-independent 3D growth in soft agar is a surrogate marker for acquired tumorigenicity of cell lines. We found that human serum from cancer-free men and women has the potential to stimulate growth in soft agar of non-tumorigenic epithelial JB6 P+ cells. We examined circulating levels of FGF2 in humans in malignant transformation in vitro in a pilot study of n = 33 men and women. Serum FGF2 levels were not associated with colony formation in epithelial cells (r = 0.05, p = 0.80); however, a fibroblast growth factor receptor-1 (FGFR1) selective inhibitor significantly blocked serum-stimulated transformation, suggesting that FGF2 activation of FGFR1 may be necessary, but not sufficient for the transforming effects of human serum. This pilot study indicates that the FGF2/FGFR1 axis plays a role in JB6 P+ malignant transformation and describes an assay to determine critical serum factors that have the potential to promote tumorigenesis.
The Inhibitory Receptor GPR56 (Adgrg1) Is Specifically Expressed by Tissue-Resident Memory T Cells in Mice But Dispensable for Their Differentiation and Function In Vivo
Authors: Hsiao Cheng-Chih , Kragten Natasja A. M. , Piao Xianhua , Hamann Jörg , van Gisbergen Klaas P. J. M.
Published: October 2021

Tissue-resident memory T (TRM) cells with potent antiviral and antibacterial functions protect the epithelial and mucosal surfaces of our bodies against infection with pathogens. The strong proinflammatory activities of TRM cells suggest requirement for expression of inhibitory molecules to restrain these memory T cells under steady state conditions. We previously identified the adhesion G protein-coupled receptor GPR56 as an inhibitory receptor of human cytotoxic lymphocytes that regulates their cytotoxic effector functions. Here, we explored the expression pattern, expression regulation, and function of GPR56 on pathogen-specific CD8+ T cells using two infection models. We observed that GPR56 is expressed on TRM cells during acute infection and is upregulated by the TRM cell-inducing cytokine TGF-β and the TRM cell-associated transcription factor Hobit. However, GPR56 appeared dispensable for CD8+ T-cell differentiation and function upon acute infection with LCMV as well as Listeria monocytogenes. Thus, TRM cells specifically acquire the inhibitory receptor GPR56, but the impact of this receptor on TRM cells after acute infection does not appear essential to regulate effector functions of TRM cells.
Modeling Traumatic Brain Injury in Human Cerebral Organoids
Authors: Ramirez Santiago , Mukherjee Abhisek , Sepulveda Sofia , Becerra-Calixto Andrea , Bravo-Vasquez Nicolas , Gherardelli Camila , Chavez Melissa , Soto Claudio
Published: October 2021

Traumatic brain injury (TBI) is a head injury that disrupts the normal brain structure and function. TBI has been extensively studied using various in vitro and in vivo models. Most of the studies have been done with rodent models, which may respond differently to TBI than human nerve cells. Taking advantage of the recent development of cerebral organoids (COs) derived from human induced pluripotent stem cells (iPSCs), which resemble the architecture of specific human brain regions, here, we adapted the controlled cortical impact (CCI) model to induce TBI in human COs as a novel in vitro platform. To adapt the CCI procedure into COs, we have developed a phantom brain matrix, matching the mechanical characteristics of the brain, altogether with an empty mouse skull as a platform to allow the use of the stereotactic CCI equipment on COs. After the CCI procedure, COs were histologically prepared to evaluate neurons and astrocyte populations using the microtubule-associated protein 2 (MAP2) and the glial fibrillary acidic protein (GFAP). Moreover, a marker of metabolic response, the neuron-specific enolase (NSE), and cellular death using cleaved caspase 3 were also analyzed. Our results show that human COs recapitulate the primary pathological changes of TBI, including metabolic alterations related to neuronal damage, neuronal loss, and astrogliosis. This novel approach using human COs to model TBI in vitro holds great potential and opens new alternatives for understanding brain abnormalities produced by TBI, and for the development and testing of new therapeutic approaches.
Impact of the Coronavirus Pandemic on High-Risk Infant Follow-Up (HRIF) Programs: A Survey of Academic Programs
Authors: Panda Sanjeet , Somu Rashmi , Maitre Nathalie , Levin Garrett , Singh Ajay Pratap
Published: October 2021

Objective: The impact of the COVID-19 pandemic on the functioning and services of academic high-risk infant follow-up (HRIF) clinics throughout North America. Study Design: Prospective 25-question questionnaire survey through REDCAP links that was sent over 10 weeks, to 105 US and 10 Canadian programs. Finally, 59 of 105 US programs and 5 of 10 Canadian responses were analyzed using SAS version 9.4. Results: In the US, 67% of programs reported closures between 1–5 months, whereas in Canada 80% of programs closed for 1–3 months. In the US 86% of programs provided telemedicine visits and only 42.5% provided multidisciplinary HRIF telemedicine visits. We enumerated innovative approaches specifically for the conduct of Telemedicine visits, the need for the standardization of various tests and services in a telemedicine setting, and to emphasize the urgent need for more government funding to improve follow-up and developmental services to this fragile group of newborns.
The Impact of Formal School Entry on Children’s Social Relationships with Parents, Siblings, and Friends
Authors: Heuser-Spura Katharina M. , Jaekel Julia , Wolke Dieter
Published: October 2021

The normative transition to formal schooling confronts children with social challenges but also opportunities. Longitudinal research on how school entry impacts children’s family and friend-ship relationships is scarce. This study investigated social relationship qualities with parents, siblings, and friends among 1110 children (49.9% female) from the prospective, population-based Bavarian Longitudinal Study at 6 years (before school entry) and 8 years using a forced-choice card-sorting task. Multivariate analyses of variance revealed significant effects of age (i.e., school entry) on social relationship qualities with mothers (Pillai’s Trace (PT) = 0.28, F(9, 1101) = 47.73, p < 0.001), fathers (PT = 0.14, F(9, 1101) = 19.47, p < 0.001), siblings (PT = 0.27, F(9, 1101) = 46.14, p < 0.001), and friends (PT = 0.21, F(9, 1101) = 32.57, p < 0.001). On average, children reported higher levels of parental comfort after school entry. Companionable qualities increased in relationships with friends, whereas sibling relationships became more conflictual from preschool to early school age. Findings provide unique insights into how social relationships develop from preschool to early school age, supporting evidence of the growing importance of friends. Conflict was predominant and increasing in sibling relationships and should be considered more in future research.
Recommendation Algorithm Using Clustering-Based UPCSim (CB-UPCSim)
Authors: Widiyaningtyas Triyanna , Hidayah Indriana , Adji Teguh Bharata
Published: October 2021

One of the well-known recommendation systems is memory-based collaborative filtering that utilizes similarity metrics. Recently, the similarity metrics have taken into account the user rating and user behavior scores. The user behavior score indicates the user preference in each product type (genre). The added user behavior score to the similarity metric results in more complex computation. To reduce the complex computation, we combined the clustering method and user behavior score-based similarity. The clustering method applies k-means clustering by determination of the number of clusters using the Silhouette Coefficient. Whereas the user behavior score-based similarity utilizes User Profile Correlation-based Similarity (UPCSim). The experimental results with the MovieLens 100k dataset showed a faster computation time of 4.16 s. In addition, the Mean Absolute Error (MAE) and Root Mean Square Error (RMSE) values decreased by 1.88% and 1.46% compared to the baseline algorithm.
Atomic Insights into Fracture Characteristics of Twisted Tri-Layer Graphene
Authors: Shoaib Hassan , Peng Qing , Alsayoud Abduljabar Q.
Published: October 2021

Graphene twistronics have recently gained significant attention due their superconductive behavior as a consequence of their tunable electronic properties. Although the electronic properties of twisted graphene have been extensively studied, the mechanical properties and integrity of twisted trilayer graphene (tTLG) under loading is still elusive. We investigated the fracture mechanics of tTLG with a twist angle of ±1.53° utilizing molecular dynamics simulation. This twist angle was chosen because it is known to exhibit highly superconductive behavior. The results indicate that tTLG does not preserve the excellent mechanical properties typically associated with graphene, with toughness and fracture strain values much lower in comparison. The Young’s modulus was an exception with values relatively close to pristine graphene, whereas the tensile strength was found to be roughly half of the intrinsic strength of graphene. The fracture toughness, fracture strain and strength converge as the crack length increases, reaching 0.26 J/m3, 0.0217 and 39.9 GPa at a crack length of 8 nm, respectively. The Griffth critical strain energy is 19.98 J/m2 and the critical stress intensity factor Kc is 4.47 MPa M1/2, in good agreement with that of monolayer graphene in the experiment. Our atomic insights might be helpful in the material design of twisted trilayer graphene-based electronics.
Improved Performance of GaN-Based Ultraviolet LEDs with the Stair-like Si-Doping n-GaN Structure
Authors: Fan Xiaomeng , Xu Shengrui , Tao Hongchang , Peng Ruoshi , Du Jinjuan , Zhao Ying , Zhang Jinfeng , Zhang Jincheng , Hao Yue
Published: October 2021

A method to improve the performance of ultraviolet light-emitting diodes (UV-LEDs) with stair-like Si-doping GaN layer is investigated. The high-resolution X-ray diffraction shows that the UV-LED with stair-like Si-doping GaN layer possesses better quality and a lower dislocation density. In addition, the experimental results demonstrate that light output power and wall plug efficiency of UV-LED with stair-like Si-doping GaN are significantly improved. Through the analysis of the experimental and simulation results, we can infer that there are two reasons for the improvement of photoelectric characteristics: reduction of dislocation density and alleviating of current crowding of UV-LEDs by introduced stair-like Si-doping GaN.
On the Bending and Vibration Analysis of Functionally Graded Magneto-Electro-Elastic Timoshenko Microbeams
Authors: Hong Jun , Wang Shaopeng , Zhang Gongye , Mi Changwen
Published: October 2021

In this paper, a new magneto-electro-elastic functionally graded Timoshenko microbeam model is developed by using the variational formulation. The new model incorporates the extended modified couple stress theory in order to describe the microstructure effect. The power-law variation through the thickness direction of the two-phase microbeams is considered. By the direct application of the derived general formulation, the static bending and free vibration behavior of the newly developed functionally graded material microbeams are analytically determined. Parametric studies qualitatively demonstrate the microstructural effect as well as the magneto-electro-elastic multi-field coupling effect. The proposed model and its classic counterpart produce significant differences for thin graded magneto-electro-elastic Timoshenko microbeams. The thinner the microbeam is, the larger the difference becomes.