bluuebunny/crossref_metadata_2025 huggingface dataset:
Acoustilytix™: A Web-Based Automated Ultrasonic Vocalization Scoring Platform
Authors: Ashley Catherine B. , Snyder Ryan D. , Shepherd James E. , Cervantes Catalina , Mittal Nitish , Fleming Sheila , Bailey Jaxon , Nievera Maisie D. , Souleimanova Sharmin Islam , Nyaoga Bill , Lichtenfeld Lauren , Chen Alicia R. , Maddox W. Todd , Duvauchelle Christine L.
Published: June 2021

Ultrasonic vocalizations (USVs) are known to reflect emotional processing, brain neurochemistry, and brain function. Collecting and processing USV data is manual, time-intensive, and costly, creating a significant bottleneck by limiting researchers’ ability to employ fully effective and nuanced experimental designs and serving as a barrier to entry for other researchers. In this report, we provide a snapshot of the current development and testing of Acoustilytix™, a web-based automated USV scoring tool. Acoustilytix implements machine learning methodology in the USV detection and classification process and is recording-environment-agnostic. We summarize the user features identified as desirable by USV researchers and how these were implemented. These include the ability to easily upload USV files, output a list of detected USVs with associated parameters in csv format, and the ability to manually verify or modify an automatically detected call. With no user intervention or tuning, Acoustilytix achieves 93% sensitivity (a measure of how accurately Acoustilytix detects true calls) and 73% precision (a measure of how accurately Acoustilytix avoids false positives) in call detection across four unique recording environments and was superior to the popular DeepSqueak algorithm (sensitivity = 88%; precision = 41%). Future work will include integration and implementation of machine-learning-based call type classification prediction that will recommend a call type to the user for each detected call. Call classification accuracy is currently in the 71–79% accuracy range, which will continue to improve as more USV files are scored by expert scorers, providing more training data for the classification model. We also describe a recently developed feature of Acoustilytix that offers a fast and effective way to train hand-scorers using automated learning principles without the need for an expert hand-scorer to be present and is built upon a foundation of learning science. The key is that trainees are given practice classifying hundreds of calls with immediate corrective feedback based on an expert’s USV classification. We showed that this approach is highly effective with inter-rater reliability (i.e., kappa statistics) between trainees and the expert ranging from 0.30–0.75 (average = 0.55) after only 1000–2000 calls of training. We conclude with a brief discussion of future improvements to the Acoustilytix platform.
To Name or Not to Name: Eye Movements and Semantic Processing in RAN and Reading
Authors: Chau Luan Tuyen , Dimitrova Vulchanova Mila , Talcott Joel B.
Published: June 2021

This study examined the well-established relationship between rapid naming and reading. Rapid automatized naming (RAN) has long been demonstrated as a strong predictor of reading abilities. Despite extensive research spanning over 4 decades, the underlying mechanisms of these causes remain a subject of inquiry. The current study investigated the role of eye movements and semantic processing in defining the RAN-reading relationship. The participants in this study were 42 English-speaking undergraduate students at a British university. The materials included a word reading task, two conventional RAN tasks (object and digit), and two RAN-like categorization tasks (object and digit). The results obtained suggested the interdependence between rapid naming and semantic processing. Hierarchical multiple regression analyses revealed that oculomotor control remains an integral part of variability in RAN and reading performance. Taken together, our results suggest that RAN and reading measures are correlated because both require rapid and accurate retrieval of phonological representations, semantic properties of visual stimuli, and stable co-ordination of eye movements.
Probable Pain on the Pain Assessment in Impaired Cognition (PAIC15) Instrument: Assessing Sensitivity and Specificity of Cut-Offs against Three Standards
Authors: van der Steen Jenny T. , Westzaan Andrew , Hanemaayer Kimberley , Muhamad Muhamad , de Waal Margot W. M. , Achterberg Wilco P.
Published: June 2021

Observational pain scales can help to identify pain in persons with dementia who may have difficulty expressing pain verbally. The Pain Assessment in Impaired Cognition-15 (PAIC15) covers 15 items that indicate pain, but it is unclear how probable pain is, for each summed score (range 0–45). We aimed to determine sensitivity and specificity of cut-offs for probable pain on the PAIC15 against three standards: (1) self-report when able, (2) the established Pain Assessment in Advanced Dementia (PAINAD) cut-off of 2, and (3) observer’s overall estimate based on a series of systematic observations. We used data of 238 nursing home residents with dementia who were observed by their physician in training or nursing staff in the context of an evidence-based medicine (EBM) training study, with re-assessment after 2 months in 137 residents. The area under the ROC curve was excellent against the PAINAD cut-off (≥0.8) but acceptable or less than acceptable for the other two standards. Across standards and criteria for optimal sensitivity and specificity, PAIC15 scores of 3 and higher represent possible pain for screening in practice, with sensitivity and specificity against self-report in the 0.5 to 0.7 range. While sensitivity for screening in practice may be too low, a cut-off of 4 is reasonable to indicate probable pain in research.
Brain Connectivity Affecting Gait Function after Unilateral Supratentorial Stroke
Authors: Lee Hyun-Ah , Kim Dae-Hyun
Published: June 2021

Gait dysfunction is a leading cause of long-term disability after stroke. The mechanisms underlying recovery of gait function are unknown. We retrospectively evaluated the association between structural connectivity and gait function in 127 patients with unilateral supratentorial stroke (>1 month after stroke). All patients underwent T1-weighted, diffusion tensor imaging and functional ambulation categorization. Voxel-wise linear regression analyses of the images were conducted using fractional anisotropy, mean diffusivity, and mode of anisotropy mapping as dependent variables, while the functional ambulation category was used as an independent variable with age and days after stroke as covariates. The functional ambulation category was positively associated with increased fractional anisotropy in the lesioned cortico-ponto-cerebellar system, corona radiata of the non-lesioned corticospinal tract pathway, bilateral medial lemniscus in the brainstem, and the corpus callosum. The functional ambulation category was also positively associated with increased mode of anisotropy in the lesioned posterior corpus callosum. In conclusion, structural connectivity associated with motor coordination and feedback affects gait function after stroke. Diffusion tensor imaging for evaluating structural connectivity can help to predict gait recovery and target rehabilitation goals after stroke.
Effects of Infills in the Seismic Performance of an RC Factory Building in Pakistan
Authors: Khan Nisar , Monti Giorgio , Nuti Camillo , Vailati Marco
Published: June 2021

Infilled reinforced concrete (IRC) frames are a very common construction typology, not only in developing countries such as Pakistan but also in southern Europe and Western countries, due to their ease of construction and less technical skills required for the construction. Their performance during past earthquakes has been in some cases satisfactory and in other cases inadequate. Significant effort has been made among researchers to improve such performance, but few have highlighted the influence of construction materials used in the infill walls. In some building codes, infills are still considered as non-structural elements, both in the design of new buildings and, sometimes, in the assessment of existing buildings. This is mainly due to some difficulties in modeling their mechanical behavior and also the large variety of typologies, which are difficult to categorize. Some building codes, for example, Eurocode, already address the influence of infill walls in design, but there is still a lack of homogeneity among different codes. For example, the Pakistan building code (PBC) does not address infills, despite being a common construction technique in the country. Past earthquake survey records show that construction materials and infill types significantly affect the seismic response of buildings, thus highlighting the importance of investigating such parameters. This is the object of this work, where a numerical model for infill walls is introduced, which aims at predicting their failure mode, as a function of some essential parameters, such as the friction coefficient between mortar and brick surface and mortar strength, usually disregarded in previous models. A comprehensive case study is presented of a three-story IRC frame located in the city of Mirpur, Pakistan, hit by an earthquake of magnitude 5.9 on 24 September 2019. The results obtained from the numerical model show good agreement with the damage patterns observed in situ, thus highlighting the importance of correctly modeling the infill walls when seismically designing or assessing Pakistani buildings that make use of this technology.
Targeted Cancer Therapy Using Compounds Activated by Light
Authors: Dunkel Petra , Ilaš Janez
Published: June 2021

Cancer chemotherapy is affected by a modest selectivity and toxic side effects of pharmacological interventions. Among novel approaches to overcome this limitation and to bring to therapy more potent and selective agents is the use of light for selective activation of anticancer compounds. In this review, we focus on the anticancer applications of two light-activated approaches still in the experimental phase: photoremovable protecting groups (“photocages”) and photoswitches. We describe the structural considerations behind the development of novel compounds and the plethora of assays used to confirm whether the photochemical and pharmacological properties are meeting the stringent criteria for an efficient in vivo light-dependent activation. Despite its immense potential, light activation brings many challenges, and the complexity of the task is very demanding. Currently, we are still deeply in the phase of pharmacological tools, but the vivid research and rapid development bring the light of hope for potential clinical use.
Quantification of Differential Response of Tumour and Normal Cells to Microbeam Radiation in the Absence of FLASH Effects
Authors: Steel Harriet , Brüningk Sarah C. , Box Carol , Oelfke Uwe , Bartzsch Stefan H.
Published: June 2021

Microbeam radiotherapy (MRT) is a preclinical method of delivering spatially-fractionated radiotherapy aiming to improve the therapeutic window between normal tissue complication and tumour control. Previously, MRT was limited to ultra-high dose rate synchrotron facilities. The aim of this study was to investigate in vitro effects of MRT on tumour and normal cells at conventional dose rates produced by a bench-top X-ray source. Two normal and two tumour cell lines were exposed to homogeneous broad beam (BB) radiation, MRT, or were separately irradiated with peak or valley doses before being mixed. Clonogenic survival was assessed and compared to BB-estimated surviving fractions calculated by the linear-quadratic (LQ)-model. All cell lines showed similar BB sensitivity. BB LQ-model predictions exceeded the survival of cell lines following MRT or mixed beam irradiation. This effect was stronger in tumour compared to normal cell lines. Dose mixing experiments could reproduce MRT survival. We observed a differential response of tumour and normal cells to spatially fractionated irradiations in vitro, indicating increased tumour cell sensitivity. Importantly, this was observed at dose rates precluding the presence of FLASH effects. The LQ-model did not predict cell survival when the cell population received split irradiation doses, indicating that factors other than local dose influenced survival after irradiation.
Prognostic Impact and Risk Factors of Infections in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib
Authors: Mauro Francesca Romana , Giannarelli Diana , Visentin Andrea , Reda Gianluigi , Sportoletti Paolo , Frustaci Anna Maria , Chiarenza Annalisa , Ciolli Stefania , Vitale Candida , Laurenti Luca , De Paoli Lorenzo , Murru Roberta , Gentile Massimo , Rigolin Gian Matteo , Levato Luciano , Giordano Annamaria , Del Poeta Giovanni , Stelitano Caterina , Ielo Claudia , Noto Alessandro , Guarente Valerio , Molica Stefano , Coscia Marta , Tedeschi Alessandra , Gaidano Gianluca , Cuneo Antonio , Foà Robin , Martelli Maurizio , Girmenia Corrado , Gentile Giuseppe , Trentin Livio
Published: June 2021

Ibrutinib represents extraordinary progress in the treatment of chronic lymphocytic leukemia (CLL). However, treatment-related adverse events limit the benefit of this agent. This observational, multicenter study focused on the incidence, risk factors, and prognostic impact of infections in 494 patients with CLL treated with an ibrutinib-based treatment. Ibrutinib was given to 89 (18%) previously untreated patients (combined with rituximab, 24) and 405 (82%) relapsed/refractory patients. Pneumonia (PN), grade ≥3 non-opportunistic infections (NOI), and opportunistic infections (OI) were recorded in 32% of patients with an overall incidence rate per 100 person-year of 15.3% (PN, 10%; NOI, 3.3%; OI, 2%). Infections were the reason for the permanent discontinuation of ibrutinib in 9% of patients. Patients who experienced pneumonia or a severe infection showed a significantly inferior survival than those who were infection-free (p < 0.0001). A scoring system based on the three factors associated with a significant and independent impact on infections—PN or severe infection in the year before starting ibrutinib, chronic obstructive pulmonary disease, ≥2 prior treatments—identified patients with a two- to threefold increase in the rate of infections. In conclusion, the results of this study highlight the adverse impact of infectious events on the outcomes of CLL patients treated with ibrutinib.
Proteomic Profiling of Tissue Exosomes Indicates Continuous Release of Malignant Exosomes in Urinary Bladder Cancer Patients, Even with Pathologically Undetectable Tumour
Authors: Eldh Maria , Mints Michael , Hiltbrunner Stefanie , Ladjevardi Sam , Alamdari Farhood , Johansson Markus , Jakubczyk Tomasz , Veerman Rosanne E. , Winqvist Ola , Sherif Amir , Gabrielsson Susanne
Published: June 2021

Invasive urothelial bladder cancer (UBC) has high recurrence rates even after radical cystectomy (RC). Exosomes are membrane-bound nanovesicles, which have been shown to contribute to carcinogenesis and metastasis. We previously showed that urinary exosomes display a malignant profile in UBC patients despite the absence of detectable tumour. Here, we investigated exosomes from sampling sites close to or distant from the former tumour, aiming to understand the effect of the tumour on the local milieu. Ten patients scheduled for cystectomy after transurethral bladder resection (TUR-B), without remaining detectable tumour, were included. Exosomes were isolated from tissue explants of both the previous tumour site and distant bladder tissue. Proteins were quantified by mass spectrometry in seven patients. Exosomes from the previous tumour site were enriched in inflammatory but not cancer-related pathways compared to distant tissue. However, the 69 most abundant proteins in tissue-derived exosomes regardless of site, 20 of which were also found in urinary exosomes from our previous study, were enriched for cancer-related metabolic pathways and associated with poor prognosis in an external mRNA dataset. The enrichment of cancer-related pathways in the most abundant proteins, regardless of sampling site, confirms our hypothesis that despite the absence of detectable tumour, the entire bladder releases exosomes that contribute to metastasis and highlights the need for early RC.
The Relationship between Body Mass Index and Mammographic Density during a Premenopausal Weight Loss Intervention Study
Authors: Atakpa Emma C. , Brentnall Adam R. , Astley Susan , Cuzick Jack , Evans D. Gareth , Warren Ruth M. L. , Howell Anthony , Harvie Michelle
Published: June 2021

We evaluated the association between short-term change in body mass index (BMI) and breast density during a 1 year weight-loss intervention (Manchester, UK). We included 65 premenopausal women (35–45 years, ≥7 kg adult weight gain, family history of breast cancer). BMI and breast density (semi-automated area-based, automated volume-based) were measured at baseline, 1 year, and 2 years after study entry (1 year post intervention). Cross-sectional (between-women) and short-term change (within-women) associations between BMI and breast density were measured using repeated-measures correlation coefficients and multivariable linear mixed models. BMI was positively correlated with dense volume between-women (r = 0.41, 95%CI: 0.17, 0.61), but less so within-women (r = 0.08, 95%CI: −0.16, 0.28). There was little association with dense area (between-women r = −0.12, 95%CI: −0.38, 0.16; within-women r = 0.01, 95%CI: −0.24, 0.25). BMI and breast fat were positively correlated (volume: between r = 0.77, 95%CI: 0.69, 0.84, within r = 0.58, 95%CI: 0.36, 0.75; area: between r = 0.74, 95%CI: 0.63, 0.82, within r = 0.45, 95%CI: 0.23, 0.63). Multivariable models reported similar associations. Exploratory analysis suggested associations between BMI gain from 20 years and density measures (standard deviation change per +5 kg/m2 BMI: dense area: +0.61 (95%CI: 0.12, 1.09); fat volume: −0.31 (95%CI: −0.62, 0.00)). Short-term BMI change is likely to be positively associated with breast fat, but we found little association with dense tissue, although power was limited by small sample size.
Regulation of mRNA Translation by Hormone Receptors in Breast and Prostate Cancer
Authors: Xie Jianling , Kusnadi Eric P. , Furic Luc , Selth Luke A.
Published: June 2021

Breast and prostate cancer are the second and third leading causes of death amongst all cancer types, respectively. Pathogenesis of these malignancies is characterised by dysregulation of sex hormone signalling pathways, mediated by the estrogen receptor-α (ER) in breast cancer and androgen receptor (AR) in prostate cancer. ER and AR are transcription factors whose aberrant function drives oncogenic transcriptional programs to promote cancer growth and progression. While ER/AR are known to stimulate cell growth and survival by modulating gene transcription, emerging findings indicate that their effects in neoplasia are also mediated by dysregulation of protein synthesis (i.e., mRNA translation). This suggests that ER/AR can coordinately perturb both transcriptional and translational programs, resulting in the establishment of proteomes that promote malignancy. In this review, we will discuss relatively understudied aspects of ER and AR activity in regulating protein synthesis as well as the potential of targeting mRNA translation in breast and prostate cancer.
Prognostic Factors Affecting Survival after Pulmonary Resection of Metastatic Renal Cell Carcinoma: A Multicenter Experience
Authors: Meacci Elisa , Nachira Dania , Zanfrini Edoardo , Evangelista Jessica , Triumbari Elizabeth Katherine Anna , Congedo Maria Teresa , Petracca Ciavarella Leonardo , Chiappetta Marco , Vita Maria Letizia , Schinzari Giovanni , Rossi Ernesto , Tortora Giampaolo , Lucchi Marco , Ambrogi Marcello , Calabrò Fabrizia , Petrella Francesco , Spaggiari Lorenzo , Mammana Marco , Lloret Madrid Andrea , Rea Federico , Tabacco Diomira , Margaritora Stefano
Published: June 2021

In this paper we aimed to address the role of pulmonary metastasectomy (PM) in patients affected by Lung Metastases (LM) from Renal Cell Carcinoma (RCC) and to analyse prognostic factors affecting overall survival (OS), disease-free interval (DFI) between primary RCC and first LM, and disease-free survival (DFS) after PM and before lung recurrence. Medical records of 210 patients who underwent PM from RCC in 4 Italian Thoracic Centres, from January 2000 to September 2019, were collected and analysed. All patients underwent RCC resection before lung surgery. The main RCC histology was clear cells (188, 89.5%). The 5- and 10-year OS from the first lung operation were 60% and 34%, respectively. LM synchronous with RCC (p = 0.01) and (Karnofsky Performance Status Scale) KPSS < 80% (p < 0.001) negatively influenced OS. Five- and 10-year DFI were 54% and 28%, respectively. The main factors negatively influencing DFI were: male gender (p = 0.039), KPSS < 80% (p = 0.009) and lactate dehydrogenase > 1.5 times 140 U/L (p = 0.001). Five- and 10-year disease-free survival were 54% and 28%, respectively; multiple LM (p = 0.036), KPSS < 80% (p = 0.001) and histology of RCC other than clear cells negatively influenced disease-free survival. Conclusions: patients with KPSS > 80%, single metachronous LM with a long DFI from RCC diagnosis, and clear cell histology, benefit from pulmonary metastasectomy.
HPV Genotyping by Molecular Mapping of Tissue Samples in Vaginal Intraepithelial Neoplasia (VaIN) and Vaginal Squamous Cell Carcinoma (VaSCC)
Authors: Zhang Shitai , Saito Mayumi , Okayama Kaori , Okodo Mitsuaki , Kurose Nozomu , Sakamoto Jinichi , Sasagawa Toshiyuki
Published: June 2021

HPV genotypes were determined in 63 vaginal intraepithelial neoplasia (VaIN) and 7 vaginal squamous cell carcinomas (VaSCC). Of these, 37 cases had VaIN alone, and 26 cases had both VaIN and cervical intraepithelial neoplasia (CIN) or condyloma. HPV typing was performed in scraped cells by Genosearch-31 (GS-31) and in the archived tissues by uniplex E6/E7 PCR. In a total of 49 VaIN1, 17 VaIN2/3, and 7 VaSCC tissues, the prevalence of HPV was 91.2% in VaIN (VaIN1: 87.8%, VaIN2/3: 100%) and 85.7% in VaSCC. Comparing HPV results in scraped cell and tissue, 46.2% of high-risk (HR) types and 68.1% of any HPV types that had been identified in cell samples were not present in corresponding tissues. HPV types in VaIN and CIN lesions differed in 92.3% (24/26) of cases with multiple lesions. These results suggest that there are many preclinical HPV infections in the vagina or the cervix, and VaIN and CIN are independently developed. The manual microdissection procedure of tissue revealed one HPV type in one lesion. Seventeen HPV types, including high-risk (HR), possible high-risk (pHR), and low-risk (LR), were identified in 43 VaIN1 lesions. In higher grade lesions, six HR (HPV16, 18, 51, 52, 56, 58), one pHR (HPV66), and one LR (HPV42) HPV types were identified in 17 VaIN2/3, and six HPV types, including HPV16, 45, 58, and 68 (HR), and HPV53 and 67 (pHR), were detected in each case of VaSCC. The vagina appears to be the reservoir for any mucosal HPV type, and HR- or pHR-HPV types are causative agents for vaginal malignancies.
Glycyrrhizin Derivatives Suppress Cancer Chemoresistance by Inhibiting Progesterone Receptor Membrane Component 1
Authors: Kabe Yasuaki , Koike Ikko , Yamamoto Tatsuya , Hirai Miwa , Kanai Ayaka , Furuhata Ryogo , Tsugawa Hitoshi , Harada Erisa , Sugase Kenji , Hanadate Kazue , Yoshikawa Nobuji , Hayashi Hiroaki , Noda Masanori , Uchiyama Susumu , Yamazaki Hiroki , Tanaka Hirotoshi , Kobayashi Takuya , Handa Hiroshi , Suematsu Makoto
Published: June 2021

Progesterone receptor membrane component 1 (PGRMC1) is highly expressed in various cancer cells and contributes to tumor progression. We have previously shown that PGRMC1 forms a unique heme-stacking functional dimer to enhance EGF receptor (EGFR) activity required for cancer proliferation and chemoresistance, and the dimer dissociates by carbon monoxide to attenuate its biological actions. Here, we determined that glycyrrhizin (GL), which is conventionally used to ameliorate inflammation, specifically binds to heme-dimerized PGRMC1. Binding analyses using isothermal titration calorimetry revealed that some GL derivatives, including its glucoside-derivative (GlucoGL), bind to PGRMC1 potently, whereas its aglycone, glycyrrhetinic acid (GA), does not bind. GL and GlucoGL inhibit the interaction between PGRMC1 and EGFR, thereby suppressing EGFR-mediated signaling required for cancer progression. GL and GlucoGL significantly enhanced EGFR inhibitor erlotinib- or cisplatin (CDDP)-induced cell death in human colon cancer HCT116 cells. In addition, GL derivatives suppressed the intracellular uptake of low-density lipoprotein (LDL) by inhibiting the interaction between PGRMC1 and the LDL receptor (LDLR). Effects on other pathways cannot be excluded. Treatment with GlucoGL and CDDP significantly suppressed tumor growth following xenograft transplantation in mice. Collectively, this study indicates that GL derivatives are novel inhibitors of PGRMC1 that suppress cancer progression, and our findings provide new insights for cancer treatment.
Investigation of the Effect of KIR–HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients
Authors: Umemura Takeji , Joshita Satoru , Saito Hiromi , Wakabayashi Shun-ichi , Kobayashi Hiroyuki , Yamashita Yuki , Sugiura Ayumi , Yamazaki Tomoo , Ota Masao
Published: June 2021

Natural killer cells are partially mediated through the binding of killer cell immunoglobulin-like receptors (KIR) with human leukocyte antigen (HLA) class I ligands. This investigation examined the risk of hepatocellular carcinoma (HCC) in relation to KIR–HLA pairs in patients with compensated hepatitis C virus (HCV)-associated cirrhosis. A total of 211 Japanese compensated HCV cirrhotic cases were retrospectively enrolled. After KIR, HLA-A, HLA-Bw, and HLA-C typing, associations between HLA, KIR, and KIR–HLA combinations and HCC development were evaluated using the Cox proportional hazards model with the stepwise method. During a median follow-up period of 6.6 years, 69.7% of patients exhibited HCC. The proportions of HLA-Bw4 and the KIR3DL1 + HLA-Bw4 pair were significantly higher in patients with HCC than in those without (78.9% vs. 64.1%; odds ratio (OR)—2.10, 95% confidence interval (CI)—1.10–4.01; p = 0.023 and 76.2% vs. 60.9%, odds ratio—2.05, p = 0.024, respectively). Multivariate analysis revealed the factors of male gender (hazard ratio (HR)—1.56, 95% CI—1.12–2.17; p = 0.009), α-fetoprotein > 5.6 ng/mL (HR—1.56, 95% CI—1.10–2.10; p = 0.011), and KIR3DL1 + HLA-Bw4 (HR—1.69, 95% CI—1.15–2.48; p = 0.007) as independent risk factors for developing HCC. Furthermore, the cumulative incidence of HCC was significantly higher in patients with KIR3DL1 + HLA-Bw4 than in those without (log-rank test; p = 0.013). The above findings suggest KIR3DL1 + HLA-Bw4, in addition to HLA-Bw4, as a novel KIR–HLA pair possibly associated with HCC development in HCV cirrhosis. HCV-associated cirrhotic patients with the risk factors of male gender, α-fetoprotein > 5.6 ng/mL, and KIR3DL1 + HLA-Bw4 may require careful surveillance for HCC onset.
Modifications in the Composition of CuO/ZnO/Al2O3 Catalyst for the Synthesis of Methanol by CO2 Hydrogenation
Authors: Trifan Bianca , Lasobras Javier , Soler Jaime , Herguido Javier , Menéndez Miguel
Published: June 2021

Renewable methanol, obtained from CO2 and hydrogen provided from renewable energy, was proposed to close the CO2 loop. In industry, methanol synthesis using the catalyst CuO/ZnO/Al2O3 occurs at a high pressure. We intend to make certain modification on the traditional catalyst to work at lower pressure, maintaining high selectivity. Therefore, three heterogeneous catalysts were synthesized by coprecipitation to improve the activity and the selectivity to methanol under mild conditions of temperature and pressure. Certain modifications on the traditional catalyst Cu/Zn/Al2O3 were employed such as the modification of the synthesis time and the addition of Pd as a dopant agent. The most efficient catalyst among those tested was a palladium-doped catalyst, 5% Pd/Cu/Zn/Al2O3. This had a selectivity of 64% at 210 °C and 5 bar.
Non-Porous Sulfonic Acid Catalysts Derived from Vacuum Residue Asphaltenes for Glycerol Valorization via Ketalization with Acetone
Authors: Samoilov Vadim , Kniazeva Mariia , Kuchinskaya Tatyana , Foss Lev , Borisov Dmitry , Yakubov Makhmut , Maximov Anton
Published: June 2021

In this study, an approach for the preparation of heterogeneous acid catalysts based on asphaltenes isolated from vacuum residue is proposed. Varying the conditions for the sulfonation of asphaltenes made it possible to obtain materials with an acid value of 1.16 to 2.76 meq g−1 and a total sulfur content of 6.4 to 12.3 wt%. The samples obtained were characterized by acid-base titration, nitrogen adsorption, sulfur elemental analysis and transmission electron microscopy techniques, and were studied as potential acid catalysts in the ketalization reaction between glycerol and acetone. Sulfonated asphaltenes (SA) were characterized by a homogeneous distribution of sulfonic groups over the granule surface and an almost complete absence of a porous structure. The ketalization reaction in the presence of SA proceeded without intradiffusion restrictions; as a result of which, their activity was higher than for known heterogeneous catalysts. The most active SA sample (total acid value, 1.16 meq g−1) had an apparent activation energy of 18.0 kJ mol−1, which was lower than the value obtained for the zeolite BEA-40 (29–53 kJ mol−1) and the Amberlyst 36 resin (27 kJ mol−1), and was close to the value for the homogeneous p-TSA catalyst (14.5 kJ mol−1). The SA heterogeneous catalysts did not show any acid leaching and had no loss of activity after five catalytic cycles, with the total turnover number TON = 7247.
The PKD-Dependent Biogenesis of TGN-to-Plasma Membrane Transport Carriers
Authors: Wakana Yuichi , Campelo Felix
Published: June 2021

Membrane trafficking is essential for processing and transport of proteins and lipids and to establish cell compartmentation and tissue organization. Cells respond to their needs and control the quantity and quality of protein secretion accordingly. In this review, we focus on a particular membrane trafficking route from the trans-Golgi network (TGN) to the cell surface: protein kinase D (PKD)-dependent pathway for constitutive secretion mediated by carriers of the TGN to the cell surface (CARTS). Recent findings highlight the importance of lipid signaling by organelle membrane contact sites (MCSs) in this pathway. Finally, we discuss our current understanding of multiple signaling pathways for membrane trafficking regulation mediated by PKD, G protein-coupled receptors (GPCRs), growth factors, metabolites, and mechanosensors.
MicroRNAs in Prion Diseases—From Molecular Mechanisms to Insights in Translational Medicine
Authors: Contiliani Danyel Fernandes , Ribeiro Yasmin de Araújo , de Moraes Vitor Nolasco , Pereira Tiago Campos
Published: June 2021

MicroRNAs (miRNAs) are small non-coding RNA molecules able to post-transcriptionally regulate gene expression via base-pairing with partially complementary sequences of target transcripts. Prion diseases comprise a singular group of neurodegenerative conditions caused by endogenous, misfolded pathogenic (prion) proteins, associated with molecular aggregates. In humans, classical prion diseases include Creutzfeldt–Jakob disease, fatal familial insomnia, Gerstmann–Sträussler–Scheinker syndrome, and kuru. The aim of this review is to present the connections between miRNAs and prions, exploring how the interaction of both molecular actors may help understand the susceptibility, onset, progression, and pathological findings typical of such disorders, as well as the interface with some prion-like disorders, such as Alzheimer’s. Additionally, due to the inter-regulation of prions and miRNAs in health and disease, potential biomarkers for non-invasive miRNA-based diagnostics, as well as possible miRNA-based therapies to restore the levels of deregulated miRNAs on prion diseases, are also discussed. Since a cure or effective treatment for prion disorders still pose challenges, miRNA-based therapies emerge as an interesting alternative strategy to tackle such defying medical conditions.
The Voltage-Gated Sodium Channel Beta4 Subunit Maintains Epithelial Phenotype in Mammary Cells
Authors: Doray Adélaïde , Lemoine Roxane , Severin Marc , Chadet Stéphanie , Lopez-Charcas Osbaldo , Héraud Audrey , Baron Christophe , Besson Pierre , Monteil Arnaud , Pedersen Stine Falsig , Roger Sébastien
Published: June 2021

The SCN4B gene, coding for the NaVβ4 subunit of voltage-gated sodium channels, was recently found to be expressed in normal epithelial cells and down-regulated in several cancers. However, its function in normal epithelial cells has not been characterized. In this study, we demonstrated that reducing NaVβ4 expression in MCF10A non-cancer mammary epithelial cells generated important morphological changes observed both in two-dimensional cultures and in three-dimensional cysts. Most notably, the loss of NaVβ4 induced a complete loss of epithelial organisation in cysts and increased proteolytic activity towards the extracellular matrix. Loss of epithelial morphology was associated with an increased degradation of β-catenin, reduced E-cadherin expression and induction of mesenchymal markers N-cadherin, vimentin, and α-SMA expression. Overall, our results suggest that Navβ4 may participate in the maintenance of the epithelial phenotype in mammary cells and that its downregulation might be a determining step in early carcinogenesis.
Silibinin Regulates Tumor Progression and Tumorsphere Formation by Suppressing PD-L1 Expression in Non-Small Cell Lung Cancer (NSCLC) Cells
Authors: Rugamba Alexis , Kang Dong Young , Sp Nipin , Jo Eun Seong , Lee Jin-Moo , Bae Se Won , Jang Kyoung-Jin
Published: June 2021

Recently, natural compounds have been used globally for cancer treatment studies. Silibinin is a natural compound extracted from Silybum marianum (milk thistle), which has been suggested as an anticancer drug through various studies. Studies on its activity in various cancers are undergoing. This study demonstrated the molecular signaling behind the anticancer activity of silibinin in non-small cell lung cancer (NSCLC). Quantitative real-time polymerase chain reaction and Western blotting analysis were performed for molecular signaling analysis. Wound healing assay, invasion assay, and in vitro angiogenesis were performed for the anticancer activity of silibinin. The results indicated that silibinin inhibited A549, H292, and H460 cell proliferation in a concentration-dependent manner, as confirmed by the induction of G0/G1 cell cycle arrest and apoptosis and the inhibition of tumor angiogenesis, migration, and invasion. This study also assessed the role of silibinin in suppressing tumorsphere formation using the tumorsphere formation assay. By binding to the epidermal growth factor receptor (EGFR), silibinin downregulated phosphorylated EGFR expression, which then inhibited its downstream targets, the JAK2/STAT5 and PI3K/AKT pathways, and thereby reduced matrix metalloproteinase, PD-L1, and vascular endothelial growth factor expression. Binding analysis demonstrated that STAT5 binds to the PD-L1 promoter region in the nucleus and silibinin inhibited the STAT5/PD-L1 complex. Altogether, silibinin could be considered as a candidate for tumor immunotherapy and cancer stem cell-targeted therapy.
Cytokinin Modulates Cellular Trafficking and the Cytoskeleton, Enhancing Defense Responses
Authors: Pizarro Lorena , Munoz Daniela , Marash Iftah , Gupta Rupali , Anand Gautam , Leibman-Markus Meirav , Bar Maya
Published: June 2021

The plant hormone cytokinin (CK) plays central roles in plant development and throughout plant life. The perception of CKs initiating their signaling cascade is mediated by histidine kinase receptors (AHKs). Traditionally thought to be perceived mostly at the endoplasmic reticulum (ER) due to receptor localization, CK was recently reported to be perceived at the plasma membrane (PM), with CK and its AHK receptors being trafficked between the PM and the ER. Some of the downstream mechanisms CK employs to regulate developmental processes are unknown. A seminal report in this field demonstrated that CK regulates auxin-mediated lateral root organogenesis by regulating the endocytic recycling of the auxin carrier PIN1, but since then, few works have addressed this issue. Modulation of the cellular cytoskeleton and trafficking could potentially be a mechanism executing responses downstream of CK signaling. We recently reported that CK affects the trafficking of the pattern recognition receptor LeEIX2, influencing the resultant defense output. We have also recently found that CK affects cellular trafficking and the actin cytoskeleton in fungi. In this work, we take an in-depth look at the effects of CK on cellular trafficking and on the actin cytoskeleton in plant cells. We find that CK influences the actin cytoskeleton and endomembrane compartments, both in the context of defense signaling—where CK acts to amplify the signal—as well as in steady state. We show that CK affects the distribution of FLS2, increasing its presence in the plasma membrane. Furthermore, CK enhances the cellular response to flg22, and flg22 sensing activates the CK response. Our results are in agreement with what we previously reported for fungi, suggesting a fundamental role for CK in regulating cellular integrity and trafficking as a mechanism for controlling and executing CK-mediated processes.
Investigation into the Re-Arrangement of Copper Foams Pre- and Post-CO2 Electrocatalysis
Authors: Rudd Jennifer A. , Hernandez-Aldave Sandra , Kazimierska Ewa , Hamdy Louise B. , Bain Odin J. E. , Barron Andrew R. , Andreoli Enrico
Published: June 2021

The utilization of carbon dioxide is a major incentive for the growing field of carbon capture. Carbon dioxide could be an abundant building block to generate higher-value chemical products. Herein, we fabricated a porous copper electrode capable of catalyzing the reduction of carbon dioxide into higher-value products, such as ethylene, ethanol and propanol. We investigated the formation of the foams under different conditions, not only analyzing their morphological and crystal structure, but also documenting their performance as a catalyst. In particular, we studied the response of the foams to CO2 electrolysis, including the effect of urea as a potential additive to enhance CO2 catalysis. Before electrolysis, the pristine and urea-modified foam copper electrodes consisted of a mixture of cuboctahedra and dendrites. After 35 min of electrolysis, the cuboctahedra and dendrites underwent structural rearrangement affecting catalysis performance. We found that alterations in the morphology, crystallinity and surface composition of the catalyst were conducive to the deactivation of the copper foams.
Children of Smoking and Non-Smoking Households’ Perceptions of Physical Activity, Cardiorespiratory Fitness, and Exercise
Authors: Parnell Melissa , Gee Ivan , Foweather Lawrence , Whyte Greg , Knowles Zoe
Published: June 2021

Previous research has shown secondhand tobacco smoke to be detrimental to children’s health. This qualitative study aimed to explore children from low socioeconomic status (SES) families and their reasons for being physically active, attitudes towards physical activity (PA), fitness and exercise, perceived barriers and facilitators to PA, self-perceptions of fitness and physical ability, and how these differ for children from smoking and non-smoking households. A total of 38 children (9–11 years; 50% female; 42% smoking households) from the deprived areas of North West England participated in focus groups (n = 8), which were analysed by utilizing thematic analysis. The findings support hypothesised mediators of PA in children including self-efficacy, enjoyment, perceived benefit, and social support. Fewer than a quarter of all children were aware of the PA guidelines with varying explanations, while the majority of children perceived their own fitness to be high. Variances also emerged between important barriers (e.g., sedentary behaviour and environmental factors) and facilitators (e.g., psychological factors and PA opportunity) for children from smoking and non-smoking households. This unique study provided a voice to children from low SES and smoking households and these child perspectives could be used to create relevant and effective strategies for interventions to improve PA, fitness, and health.
Adipose Tissue Immunomodulation and Treg/Th17 Imbalance in the Impaired Glucose Metabolism of Children with Obesity
Authors: Croce Stefania , Avanzini Maria Antonietta , Regalbuto Corrado , Cordaro Erika , Vinci Federica , Zuccotti Gianvincenzo , Calcaterra Valeria
Published: June 2021

In the last few decades, obesity has increased dramatically in pediatric patients. Obesity is a chronic disease correlated with systemic inflammation, characterized by the presence of CD4 and CD8 T cell infiltration and modified immune response, which contributes to the development of obesity related diseases and metabolic disorders, including impaired glucose metabolism. In particular, Treg and Th17 cells are dynamically balanced under healthy conditions, but imbalance occurs in inflammatory and pathological states, such as obesity. Some studies demonstrated that peripheral Treg and Th17 cells exhibit increased imbalance with worsening of glucose metabolic dysfunction, already in children with obesity. In this review, we considered the role of adipose tissue immunomodulation and the potential role played by Treg/T17 imbalance on the impaired glucose metabolism in pediatric obesity. In the patient care, immune monitoring could play an important role to define preventive strategies of pediatric metabolic disease treatments.
Identifying Circulating MicroRNA in Kawasaki Disease by Next-Generation Sequencing Approach
Authors: Weng Ken-Pen , Cheng Ching-Feng , Chien Kuang-Jen , Ger Luo-Ping , Huang Shih-Hui , Tsai Kuo-Wang
Published: June 2021

Kawasaki disease (KD) typically occurs in children aged under 5 years and can cause coronary artery lesions (CALs). Early diagnosis and treatment with intravenous immunoglobulin can reduce the occurrence of CALs; therefore, identifying a good biomarker for diagnosing KD is essential. Here, using next-generation sequencing in patients with recurrent KD, those with viral infection, and healthy controls, we identified dysregulated circulating microRNAs as diagnostic biomarkers for KD. Pathway enrichment analysis illustrated the putative role of these miRNAs in KD progression. Their expression levels were validated using real-time polymerase chain reaction (qPCR). Fifteen dysregulated circulating miRNAs (fold changes >2 and <0.5) were differentially expressed in the recurrent KD group compared with the viral infection and control groups. These miRNAs were significantly involved in the transforming growth factor-β, epithelial–mesenchymal transition, and cell apoptosis signaling pathways. Notably, their expression levels were frequently restored after intravenous immunoglobulin treatment. Among the candidates, miR-24-3p expression level was significantly higher in patients with recurrent KD compared with healthy controls or viral infection controls (p < 0.001). Receiver operating characteristic analysis revealed that high miR-24-3p expression levels may be a potential biomarker for KD diagnosis. In conclusion, we identified miR-24-3p significantly higher in KD patients, which may be a potential diagnostic biomarker for KD.
DNA Methylation Profiling for the Diagnosis and Prognosis of Patients with Nontuberculous Mycobacterium Lung Disease
Authors: Oh Jee Youn , Ko Young Kyung , Gim Jeong-An
Published: June 2021

The incidence of nontuberculous Mycobacterium (NTM) lung disease is rapidly increasing; however, its diagnosis and prognosis remain unclear while selecting patients who will respond to appropriate treatment. Differences in DNA methylation patterns between NTM patients with good or poor prognosis could provide important therapeutic targets. We used the Illumina MethylationEPIC (850k) DNA methylation microarray to determine the pattern between differentially methylated regions (DMRs) in NTM patients with good or poor prognosis (n = 4/group). Moreover, we merged and compared 20 healthy controls from previous Illumina Methylation450k DNA methylation microarray data. We selected and visualized the DMRs in the form of heatmaps, and enriched terms associated with these DMRs were identified by functional annotation with the “pathfinder” package. In total, 461 and 293 DMRs (|Log2 fold change| > 0.1 and P < 0.03) were more methylated in patients with four poor and four good prognoses, respectively. Furthermore, 337 and 771 DMRs (|Log2 fold change| > 0.08 and P < 0.001) were more methylated in eight NTM patients and 20 healthy controls, respectively. TGFBr1 was significantly less methylated, whereas HLA-DR1 and HLA-DR5 were more methylated in patients with poor prognosis (compared to those with good prognosis). LRP5, E2F1, and ADCY3 were the top three less-methylated genes in NTM patients (compared with the controls). The mTOR and Wnt signaling pathway-related genes were less methylated in patients with NTM. Collectively, genes related to Th1- cell differentiation, such as TGFBr1 and HLA-DR, may be used as biomarkers for predicting the treatment response in patients with NTM lung disease.
A Pilot Study of 24-h Motor Activity Patterns in Multiple Sclerosis: Pre-Planned Follow-Up at 2 Years
Authors: Tonetti Lorenzo , Camilli Federico , Giovagnoli Sara , Natale Vincenzo , Lugaresi Alessandra
Published: June 2021

Early multiple sclerosis (MS) predictive markers of disease activity/prognosis have been proposed but are not universally accepted. Aim of this pilot prospective study is to verify whether a peculiar hyperactivity, observed at baseline (T0) in early relapsing-remitting (RR) MS patients, could represent a further prognostic marker. Here we report results collected at T0 and at a 24-month follow-up (T1). Eighteen RRMS patients (11 females, median Expanded Disability Status Scale-EDSS score 1.25, range EDSS score 0–2) were monitored at T0 (mean age 32.33 ± 7.51) and T1 (median EDSS score 1.5, range EDSS score 0–2.5). Patients were grouped into two groups: responders (R, 14 patients) and non-responders (NR, 4 patients) to treatment at T1. Each patient wore an actigraph for one week to record the 24-h motor activity pattern. At T0, NR presented significantly lower motor activity than R between around 9:00 and 13:00. At T1, NR were characterized by significantly lower motor activity than R between around 12:00 and 17:00. Overall, these data suggest that through the 24-h motor activity pattern, we can fairly segregate at T0 patients who will show a therapeutic failure, possibly related to a more active disease, at T1. These patients are characterized by a reduced morning level of motor activation. Further studies on larger populations are needed to confirm these preliminary findings.
Selected Aspects of Pavement Texture Influence on Tire Rolling Resistance
Authors: Ejsmont Jerzy , Sommer Slawomir
Published: June 2021

Tire rolling resistance has a significant influence on fuel consumption in cars and trucks and on CO2 emissions. Rolling resistance depends on the tire construction, pavement texture and stiffness, as well as environmental and traffic conditions. This article presents a pilot study on the impact of pavement texture on the rolling resistance of passenger car tires. Reasons why Mean Profile Depth is not a good descriptor of pavement characteristics from the point of view of rolling resistance are presented, and an experimental method which takes into account tire deformation on texture and partial enveloping is described. A method based on testing the volume and depth of tire tread deformation is also proposed.