bluuebunny/crossref_metadata_2025 huggingface dataset:
A Configurable Architecture for Two Degree-of-Freedom Variable Stiffness Actuators to Match the Compliant Behavior of Human Joints
Authors: Lemerle Simon , Catalano Manuel G. , Bicchi Antonio , Grioli Giorgio
Published: March 2021

Living beings modulate the impedance of their joints to interact proficiently, robustly, and safely with the environment. These observations inspired the design of soft articulated robots with the development of Variable Impedance and Variable Stiffness Actuators. However, designing them remains a challenging task due to their mechanical complexity, encumbrance, and weight, but also due to the different specifications that the wide range of applications requires. For instance, as prostheses or parts of humanoid systems, there is currently a need for multi-degree-of-freedom joints that have abilities similar to those of human articulations. Toward this goal, we propose a new compact and configurable design for a two-degree-of-freedom variable stiffness joint that can match the passive behavior of a human wrist and ankle. Using only three motors, this joint can control its equilibrium orientation around two perpendicular axes and its overall stiffness as a one-dimensional parameter, like the co-contraction of human muscles. The kinematic architecture builds upon a state-of-the-art rigid parallel mechanism with the addition of nonlinear elastic elements to allow the control of the stiffness. The mechanical parameters of the proposed system can be optimized to match desired passive compliant behaviors and to fit various applications (e.g., prosthetic wrists or ankles, artificial wrists, etc.). After describing the joint structure, we detail the kinetostatic analysis to derive the compliant behavior as a function of the design parameters and to prove the variable stiffness ability of the system. Besides, we provide sets of design parameters to match the passive compliance of either a human wrist or ankle. Moreover, to show the versatility of the proposed joint architecture and as guidelines for the future designer, we describe the influence of the main design parameters on the system stiffness characteristic and show the potential of the design for more complex applications.
Born in Captivity: The Experiences of Puerto Rican Birth Workers and Their Clients in Quarantine
Authors: Reyes Emaline
Published: March 2021

In this article, I seek to understand how the COVID-19 pandemic has impacted childbirth in Puerto Rico, an island that was already in recovery following the occurrence of two devastating hurricanes in the fall of 2017 and a major earthquake in the winter of 2020. Thus, I argue that it is important to discuss not only how individual disasters impact birth, but also how their compounding effects do so. In order to address these research questions, I conducted remote interviews with Puerto Rican birth workers and researchers. During times of crisis, this pandemic included, home and midwife-attended births have become increasingly more popular. However, Puerto Rican midwives and doulas currently have less institutional support than ever. In a time of quarantine when home births are rising, we need to consider whether society is designed to facilitate these models of care. In Puerto Rico, pre-pandemic, there was a less than 1% home birth rate and there still is a lack of legal recognition and protections for homebirth midwives. As this article demonstrates, an acknowledgment of the near-invisible labors of these birth workers is needed, in addition to supplies, support, and protections for them—and not just in times of “crisis.”
Effect of Dietary Vegetable Sources Rich in Unsaturated Fatty Acids on Milk Production, Composition, and Cheese Fatty Acid Profile in Sheep: A Meta-Analysis
Authors: Vargas-Bello-Pérez Einar , Darabighane Babak , Miccoli Florencia E. , Gómez-Cortés Pilar , Gonzalez-Ronquillo Manuel , Mele Marcello
Published: March 2021

A meta-analysis was conducted to analyze the effects of different dietary vegetable sources rich in unsaturated FA (UFA) on sheep cheese FA profile. This study also quantified the overall effect of feeding sheep with vegetable sources rich in UFA (linseed, flaxseed, sunflower seed, canola, olive oil, bran oil, and olive cake), on milk yield (MY) and milk composition. A literature search was conducted to identify papers published from 2000 to 2019. Effect size for all parameters was calculated as standardized mean difference. Heterogeneity was determined using I2 statistic, while meta-regression was used to examine factors influencing heterogeneity. Effect size was not significant for MY, milk fat percentage (MFP), and milk protein percentage (MPP). Dietary inclusion of vegetable sources rich in UFA decreased the effect size for C12:0, C14:0, and C16:0 and increased the effect size for C18:0, C18:1 t-11, C18:1 c-9, C18:2 c-9, t-11, C18:2 n-6, and C18:3 n-3. Heterogeneity was significant for MY, MFP, MPP, and overall cheese FA profile. Meta-regression revealed days in milk as a contributing factor to the heterogeneity observed in MFP and MPP. Meta-regression showed that ripening time is one of the factors affecting cheese FA profile heterogeneity while the type of feeding system(preserved roughages vs. pasture) had no effect on heterogeneity. Overall, inclusion of dietary vegetable sources rich in UFA in sheep diets would be an effective nutritional strategy to decrease saturated FA and increase polyunsaturated FA contents in cheeses without detrimental effects on MY, MFF, and MPP.
Task Planning for Multiple-Satellite Space-Situational-Awareness Systems
Authors: Chen Yutao , Tian Guoqing , Guo Junyou , Huang Jie
Published: March 2021

Space situational awareness (SSA) plays an important role in maintaining space advantages. Task planning is one of the key technologies in SSA to allocate multiple tasks to multiple satellites, so that a satellite may be allocated to supervise multiple space objects, and a space object may be supervised by multiple satellites. This paper proposes a hierarchical and distributed task-planning framework for SSA systems with focus on fast and effective task planning customized for SSA. In the framework, a global task-planner layer performs satellite and object clustering, so that satellites are clustered into multiple unique clusters on the basis of their positions, while objects are clustered into multiple possibly intersecting clusters, hence allowing for a single object to be supervised by multiple satellites. In each satellite cluster, a local task planner performs distributed task planning using the contract-net protocol (CNP) on the basis of the position and velocity of satellites and objects. In addition, a customized discrete particle swarm optimization (DPSO) algorithm was developed to search for the optimal task-planning result in the CNP. Simulation results showed that the proposed framework can effectively achieve task planning among multiple satellites and space objects. The efficiency and scalability of the proposed framework are demonstrated through static and dynamic orbital simulations.
Effects of the Inclusion of Different Levels of Dietary Sunflower Hulls on the Colostrum Compositions of Ewes
Authors: Alobre Mohsen M. , Abdelrahman Mutassim M. , Alhidary Ibrahim A. , Alharthi Abdulrahman S. , Aljumaah Riyadh S.
Published: March 2021

This study investigated the effects of supplementing different levels of sunflower hulls (SFH) to the complete feed of late-gestation pregnant ewes on the nutritive and fatty acids profile of colostrum at three and 48 h postpartum. In this study, 24 primiparous lactating Naemi ewes were randomly selected at parturition from four dietary groups as follows: (1) C (control), total mixed ration (TMR; 0% SFH), (2) S12, TMR1 with 12% SFH (level 1), (3) S20, TMR2 with 20% SFH (level 2), and (4) S28, TMR3 with 28% SFH (level 3). The body condition scores were estimated 30 days prepartum. Colostrum samples were collected at three and 48 h postpartum to measure the nutritive values and fatty acids profiles. Data were analyzed as a complete randomized design with repeated measures and via Pearson’s correlation and regression analyses. The results indicated a numerical correlation (R2 = 0.42; p < 0.09) between the body condition score and both colostrum fat and total solids. SFH increased the colostrum fat % (p < 0.05), especially for S12 and S20, following a cubic trend. Additionally, the colostrum from S12 and S20 ewes had a higher proportion of unsaturated fatty acids (USFAs), omega3 and lower levels of saturated fatty acids (SFAs), other than margaric acid (C17) and stearic acid (C18), SFA/USFA, and omega 6/omega 3. Furthermore, the regression analysis of the fatty acid classes and indices indicated a quadratic relationship between the parameters and SFH levels. The results confirm that the inclusion of SFH at levels greater than 20% may have a negative effect on some fatty acid parameters as a result of the high lignin intake. In conclusion, up to 20% SFH can be used in a complete feed for pregnant ewes without negative effects on the colostrum fat content and fatty acids profiles.
Evaluation of the FitBark Activity Monitor for Measuring Physical Activity in Dogs
Authors: Colpoys Jessica , DeCock Dean
Published: March 2021

Accelerometers track changes in physical activity which can indicate health and welfare concerns in dogs. The FitBark 2 (FitBark) is an accelerometer for use with dogs; however, no studies have externally validated this tool. The objective of this study was to evaluate FitBark criterion validity by correlating FitBark activity data to dog step count. Dogs (n = 26) were fitted with a collar-mounted FitBark and individually recorded for 30 min using a three-phase approach: (1) off-leash room explore; (2) human–dog interaction; and (3) on-leash walk. Video analysis was used to count the number of times the front right paw touched the ground (step count). Dog step count and FitBark activity were moderately correlated across all phases (r = 0.65, p < 0.001). High correlations between step count and FitBark activity were observed during phases 1 (r = 0.795, p < 0.001) and 2 (r = 0.758, p < 0.001), and a low correlation was observed during phase 3 (r = 0.498, p < 0.001). In conclusion, the FitBark is a valid tool for tracking physical activity in off-leash dogs; however, more work should be done to identify the best method of tracking on-leash activity.
Worldwide Prevalence of Small Ruminant Lentiviruses in Sheep: A Systematic Review and Meta-Analysis
Authors: de Miguel Ricardo , Arrieta Marta , Rodríguez-Largo Ana , Echeverría Irache , Resendiz Raúl , Pérez Estela , Ruiz Héctor , Pérez Marta , de Andrés Damián , Reina Ramsés , de Blas Ignacio , Luján Lluís
Published: March 2021

Small Ruminant Lentiviruses (SRLV) are highly prevalent retroviruses with significant genetic diversity and antigenic heterogeneity that cause a progressive wasting disease of sheep called Maedi-visna. This work provides a systematic review and meta-analysis of the last 40 years (1981–2020) of scientific publications on SRLV individual and flock prevalence. Fifty-eight publications and 314 studies were included. Most articles used a single diagnostic test to estimate prevalence (77.6%), whereas articles using three or more tests were scarce (6.9%). Serological tests are more frequently used than direct methods and ELISA has progressively replaced AGID over the last decades. SRLV infection in sheep is widespread across the world, with Europe showing the highest individual prevalence (40.9%) and being the geographical area in which most studies have been performed. Africa, Asia, and North America show values between 16.7% to 21.8% at the individual level. South and Central America show the lowest individual SRLV prevalence (1.7%). There was a strong positive correlation between individual and flock prevalence (ρ = 0.728; p ≤ 0.001). Despite the global importance of small ruminants, the coverage of knowledge on SRLV prevalence is patchy and inconsistent. There is a lack of a gold standard method and a defined sampling strategy among countries and continents.
Impact of Censored or Penalized Data in the Genetic Evaluation of Two Longevity Indicator Traits Using Random Regression Models in North American Angus Cattle
Authors: Oliveira Hinayah R. , Miller Stephen P. , Brito Luiz F. , Schenkel Flavio S.
Published: March 2021

This study aimed to evaluate the impact of different proportions (i.e., 20%, 40%, 60% and 80%) of censored (CEN) or penalized (PEN) data in the prediction of breeding values (EBVs), genetic parameters, and computational efficiency for two longevity indicators (i.e., traditional and functional longevity; TL and FL, respectively). In addition, three different criteria were proposed for PEN: (1) assuming that all cows with censored records were culled one year after their last reported calving; (2) assuming that cows with censored records older than nine years were culled one year after their last reported calving, while censored (missing) records were kept for cows younger than nine years; and (3) assuming that cows with censored records older than nine years were culled one year after their last reported calving, while cows younger than nine years were culled two years after their last reported calving. All analyses were performed using random regression models based on fourth order Legendre orthogonal polynomials. The proportion of commonly selected animals and EBV correlations were calculated between the complete dataset (i.e., without censored or penalized data; COM) and all simulated proportions of CEN or PEN. The computational efficiency was evaluated based on the total computing time taken by each scenario to complete 150,000 Bayesian iterations. In summary, increasing the CEN proportion significantly (p-value < 0.05 by paired t-tests) decreased the heritability estimates for both TL and FL. When compared to CEN, PEN tended to yield heritabilities closer to COM, especially for FL. Moreover, similar heritability patterns were observed for all three penalization criteria. High proportions of commonly selected animals and EBV correlations were found between COM and CEN with 20% censored data (for both TL and FL), and COM and all levels of PEN (for FL). The proportions of commonly selected animals and EBV correlations were lower for PEN than CEN for TL, which suggests that the criteria used for PEN are not adequate for TL. Analyses using COM and CEN took longer to finish than PEN analyses. In addition, increasing the amount of censored records also tended to increase the computational time. A high proportion (>20%) of censored data has a negative impact in the genetic evaluation of longevity. The penalization criteria proposed in this study are useful for genetic evaluations of FL, but they are not recommended when analyzing TL.
Experiments with Neural Networks in the Identification and Control of a Magnetic Levitation System Using a Low-Cost Platform
Authors: Silva Bruno E. , Barbosa Ramiro S.
Published: March 2021

In this article, we designed and implemented neural controllers to control a nonlinear and unstable magnetic levitation system composed of an electromagnet and a magnetic disk. The objective was to evaluate the implementation and performance of neural control algorithms in a low-cost hardware. In a first phase, we designed two classical controllers with the objective to provide the training data for the neural controllers. After, we identified several neural models of the levitation system using Nonlinear AutoRegressive eXogenous (NARX)-type neural networks that were used to emulate the forward dynamics of the system. Finally, we designed and implemented three neural control structures: the inverse controller, the internal model controller, and the model reference controller for the control of the levitation system. The neural controllers were tested on a low-cost Arduino control platform through MATLAB/Simulink. The experimental results proved the good performance of the neural controllers.
Drought in South Asia: A Review of Drought Assessment and Prediction in South Asian Countries
Authors: Chandrasekara Sewwandhi S.K. , Kwon Hyun-Han , Vithanage Meththika , Obeysekera Jayantha , Kim Tae-Woong
Published: March 2021

South Asian countries have been experiencing frequent drought incidents recently, and due to this reason, many scientific studies have been carried out to explore drought in South Asia. In this context, we review scientific studies related to drought in South Asia. The study initially identifies the importance of drought-related studies and discusses drought types for South Asian regions. The representative examples of drought events, severity, frequency, and duration in South Asian countries are identified. The Standardized Precipitation Index (SPI) was mostly adopted in South Asian countries to quantify and monitor droughts. Nevertheless, the absence of drought quantification studies in Bhutan and the Maldives is of great concern. Future studies to generate a combined drought severity map for the South Asian region are required. Moreover, the drought prediction and projection in the regions is rarely studied. Furthermore, the teleconnection between drought and large-scale atmospheric circulations in the South Asia has not been discussed in detail in most of the scientific literature. Therefore, as a take-home message, there is an urgent need for scientific studies related to drought quantification for some regions in South Asia, prediction and projection of drought for an individual country (or as a region), and drought teleconnection to atmospheric circulation.
The Association between HDL-C and Subclinical Atherosclerosis Depends on CETP Plasma Concentration: Insights from the IMPROVE Study
Authors: Colombo Gualtiero , Bianconi Vanessa , Bonomi Alice , Simonelli Sara , Amato Mauro , Frigerio Beatrice , Ravani Alessio , Vitali Cecilia , Sansaro Daniela , Coggi Daniela , Mannarino Massimo , Savonen Kai , Kurl Sudhir , Gigante Bruna , Smit Andries , Giral Philippe , Tremoli Elena , Calabresi Laura , Veglia Fabrizio , Pirro Matteo , Baldassarre Damiano , on behalf of the IMPROVE Study Group
Published: March 2021

The impact of cholesteryl ester transfer protein (CETP) on atherosclerosis is highly debated. This study aimed to investigate the associations between plasma CETP or CETP genotypes and carotid intima-media thickness (cIMT) and the influence of high-density lipoprotein cholesterol (HDL-C) on these associations. Plasma CETP and HDL-C concentrations were measured in 552 subjects free of any pharmacological treatment from the IMPROVE cohort, which includes 3711 European subjects at high cardiovascular risk. CETP single-nucleotide polymorphisms (SNPs) and cIMT measures (cIMTmax; cIMTmean–max of bifurcations, common and internal carotids; plaque-free common carotid [PF CC]-IMTmean) were available for the full cohort. In drug-free subjects, plasma CETP correlated with HDL-C levels (r = 0.19, p < 0.0001), but not with cIMT variables. When stratified according to HDL-C quartiles, CETP positively correlated with cIMTmax and cIMTmean–max, but not with PF CC-IMTmean, in the top HDL-C quartile only. Positive associations between the CETP concentration and cIMTmax or cIMTmean–max were found in the top HDL-C quartile, whereas HDL-C levels were negatively correlated with cIMTmax and cIMTmean–max when the CETP concentration was below the median (HDL-C × CETP interaction, p = 0.001 and p = 0.003 for cIMTmax and cIMTmean–max, respectively). In the full cohort, three CETP SNPs (rs34760410, rs12920974, rs12708968) were positively associated with cIMTmax. rs12444708 exhibited a significant interaction with HDL-C levels in the prediction of cIMTmax. In conclusion, a significant interplay was found between plasma CETP and/or CETP genotype and HDL-C in the prediction of carotid plaque thickness, as indexed by cIMTmax. This suggests that the association of HDL-C with carotid atherosclerosis is CETP-dependent.
Iron Oxide-Based Magneto-Optical Nanocomposites for In Vivo Biomedical Applications
Authors: Lamichhane Nisha , Sharma Shalini , Parul  , Verma Anita , Roy Indrajit , Sen Tapas
Published: March 2021

Iron oxide nanoparticles (IONPs) have played a pivotal role in the development of nanomedicine owing to their versatile functions at the nanoscale, which facilitates targeted delivery, high contrast imaging, and on-demand therapy. Some biomedical inadequacies of IONPs on their own, such as the poor resolution of IONP-based Magnetic Resonance Imaging (MRI), can be overcome by co-incorporating optical probes onto them, which can be either molecule- or nanoparticulate-based. Optical probe incorporated IONPs, together with two prominent non-ionizing radiation sources (i.e., magnetic field and light), enable a myriad of biomedical applications from early detection to targeted treatment of various diseases. In this context, many research articles are in the public domain on magneto-optical nanoparticles; discussed in detail are fabrication strategies for their application in the biomedical field; however, lacking is a comprehensive review on real-life applications in vivo, their toxicity, and the prospect of bench-to-bedside clinical studies. Therefore, in this review, we focused on selecting such important nanocomposites where IONPs become the magnetic component, conjugated with various types of optical probes; we clearly classified them into class 1 to class 6 categories and present only in vivo studies. In addition, we briefly discuss the potential toxicity of such nanocomposites and their respective challenges for clinical translations.
Intratumoural Cytochrome P450 Expression in Breast Cancer: Impact on Standard of Care Treatment and New Efforts to Develop Tumour-Selective Therapies
Authors: Sneha Smarakan , Baker Simon C. , Green Andrew , Storr Sarah , Aiyappa Radhika , Martin Stewart , Pors Klaus
Published: March 2021

Despite significant advances in treatment strategies over the past decade, selective treatment of breast cancer with limited side-effects still remains a great challenge. The cytochrome P450 (CYP) family of enzymes contribute to cancer cell proliferation, cell signaling and drug metabolism with implications for treatment outcomes. A clearer understanding of CYP expression is important in the pathogenesis of breast cancer as several isoforms play critical roles in metabolising steroid hormones and xenobiotics that contribute to the genesis of breast cancer. The purpose of this review is to provide an update on how the presence of CYPs impacts on standard of care (SoC) drugs used to treat breast cancer as well as discuss opportunities to exploit CYP expression for therapeutic intervention. Finally, we provide our thoughts on future work in CYP research with the aim of supporting ongoing efforts to develop drugs with improved therapeutic index for patient benefit.
Tactile Processing and Quality of Sleep in Autism Spectrum Disorders
Authors: Jamioł-Milc Dominika , Bloch Mirosława , Liput Magdalena , Stachowska Laura , Skonieczna-Żydecka Karolina
Published: March 2021

Individuals with autism spectrum disorders (ASDs) commonly experience problems with the processing of tactile stimuli and poor quality of sleep. The aim of the present study was to analyze whether tactile stimuli modulation (TSM) disorders might be linked to insomnia prevalence in ASD individuals. We hypothesized that sleep disorders in children with ASD may result from improper tactile under/over responsivity. The study included 27 children diagnosed with ASD, aged 6.8 (±2.9 years) with male dominance (n = 22, 81.5%). To evaluate the pattern of TSM we used a clinical interview with a parent, and guided and spontaneous observation of the patients. Sleep disorders were diagnosed using the Athens Insomnia Scale. Of all the children diagnosed with TSM, 20 patients (74.1%) had an over-responsivity pattern and 7 children (25.9%) had an under-responsivity pattern. Of the patients, 11 children (40.7%) met the diagnostic criteria for insomnia. The data indicated a statistical tendency for higher prevalence of insomnia in individuals diagnosed with tactile under-responsivity (p = 0.051). We concluded that under-responsivity toward tactile stimuli may be partly responsible for poor sleep quality in ASD. There is an urgent need to treat sleep and sensory disruptions which may intensify behavioral difficulties in ASD.
Multitarget Stool mRNA Test for Detecting Colorectal Cancer Lesions Including Advanced Adenomas
Authors: Herring Elizabeth , Tremblay Éric , McFadden Nathalie , Kanaoka Shigeru , Beaulieu Jean-François
Published: March 2021

Current approved non-invasive screening methods for colorectal cancer (CRC) include FIT and DNA-FIT testing, but their efficacy for detecting precancerous lesions that are susceptible to progressing to CRC such as advanced adenomas (AA) remains limited, thus requiring further options to improve the detection of CRC lesions at earlier stages. One of these is host mRNA stool testing. The aims of the present study were to identify specific stool mRNA targets that can predict AA and to investigate their stability under a clinical-like setting. A panel of mRNA targets was tested on stool samples obtained from 102 patients including 78 CRC stage I-III and 24 AA as well as 32 healthy controls. Area under the receiver operating characteristic (ROC) curves were calculated to establish sensitivities and specificities for individual and combined targets. Stability experiments were performed on freshly obtained specimens. Six of the tested targets were found to be specifically increased in the stools of patients with CRC and three in the stools of both AA and CRC patients. After optimization for the choice of the 5 best markers for AA and CRC, ROC curve analysis revealed overall sensitivities of 75% and 89% for AA and CRC, respectively, for a ≥95% specificity, and up to 75% and 95% for AA and CRC, respectively, when combined with the FIT score. Targets were found to be stable in the stools up to 3 days at room temperature. In conclusion, these studies show that the detection of host mRNA in the stools is a valid approach for the screening of colorectal cancerous lesions at all stages and is applicable to a clinical-like setup.
Single-Cell Deconvolution of Head and Neck Squamous Cell Carcinoma
Authors: Qi Zongtai , Liu Yating , Mints Michael , Mullins Riley , Sample Reilly , Law Travis , Barrett Thomas , Mazul Angela L. , Jackson Ryan S. , Kang Stephen Y. , Pipkorn Patrik , Parikh Anuraag S. , Tirosh Itay , Dougherty Joseph , Puram Sidharth V.
Published: March 2021

Complexities in cell-type composition have rightfully led to skepticism and caution in the interpretation of bulk transcriptomic analyses. Recent studies have shown that deconvolution algorithms can be utilized to computationally estimate cell-type proportions from the gene expression data of bulk blood samples, but their performance when applied to tumor tissues, including those from head and neck, remains poorly characterized. Here, we use single-cell data (~6000 single cells) collected from 21 head and neck squamous cell carcinoma (HNSCC) samples to generate cell-type-specific gene expression signatures. We leverage bulk RNA-seq data from >500 HNSCC samples profiled by The Cancer Genome Atlas (TCGA), and using single-cell data as a reference, apply two newly developed deconvolution algorithms (CIBERSORTx and MuSiC) to the bulk transcriptome data to quantitatively estimate cell-type proportions for each tumor in TCGA. We show that these two algorithms produce similar estimates of constituent/major cell-type proportions and that a high T-cell fraction correlates with improved survival. By further characterizing T-cell subpopulations, we identify that regulatory T-cells (Tregs) were the major contributor to this improved survival. Lastly, we assessed gene expression, specifically in the Treg population, and found that TNFRSF4 (Tumor Necrosis Factor Receptor Superfamily Member 4) was differentially expressed in the core Treg subpopulation. Moreover, higher TNFRSF4 expression was associated with greater survival, suggesting that TNFRSF4 could play a key role in mechanisms underlying the contribution of Treg in HNSCC outcomes.
The Role of Autophagy and lncRNAs in the Maintenance of Cancer Stem Cells
Authors: Jahangiri Leila , Ishola Tala , Pucci Perla , Trigg Ricky M. , Pereira Joao , Williams John A. , Cavanagh Megan L. , Gkoutos Georgios V. , Tsaprouni Loukia , Turner Suzanne D.
Published: March 2021

Cancer stem cells (CSCs) possess properties such as self-renewal, resistance to apoptotic cues, quiescence, and DNA-damage repair capacity. Moreover, CSCs strongly influence the tumour microenvironment (TME) and may account for cancer progression, recurrence, and relapse. CSCs represent a distinct subpopulation in tumours and the detection, characterisation, and understanding of the regulatory landscape and cellular processes that govern their maintenance may pave the way to improving prognosis, selective targeted therapy, and therapy outcomes. In this review, we have discussed the characteristics of CSCs identified in various cancer types and the role of autophagy and long noncoding RNAs (lncRNAs) in maintaining the homeostasis of CSCs. Further, we have discussed methods to detect CSCs and strategies for treatment and relapse, taking into account the requirement to inhibit CSC growth and survival within the complex backdrop of cellular processes, microenvironmental interactions, and regulatory networks associated with cancer. Finally, we critique the computationally reinforced triangle of factors inclusive of CSC properties, the process of autophagy, and lncRNA and their associated networks with respect to hypoxia, epithelial-to-mesenchymal transition (EMT), and signalling pathways.
Single-Cell Expression Landscape of SARS-CoV-2 Receptor ACE2 and Host Proteases in Normal and Malignant Lung Tissues from Pulmonary Adenocarcinoma Patients
Authors: Han Guangchun , Sinjab Ansam , Hara Kieko , Treekitkarnmongkol Warapen , Brennan Patrick , Chang Kyle , Bogatenkova Elena , Sanchez-Espiridion Beatriz , Behrens Carmen , Solis Luisa M. , Gao Boning , Girard Luc , Zhang Jianjun , Sepesi Boris , Cascone Tina , Byers Lauren A. , Gibbons Don L. , Chen Jichao , Moghaddam Seyed Javad , Ostrin Edwin J. , Scheet Paul , Fujimoto Junya , Shay Jerry , Heymach John V. , Minna John D. , Dubinett Steven , Wistuba Ignacio I. , Stevenson Christopher S. , Spira Avrum E. , Wang Linghua , Kadara Humam
Published: March 2021

The novel coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic. Severely symptomatic COVID-19 is associated with lung inflammation, pneumonia, and respiratory failure, thereby raising concerns of elevated risk of COVID-19-associated mortality among lung cancer patients. Angiotensin-converting enzyme 2 (ACE2) is the major receptor for SARS-CoV-2 entry into lung cells. The single-cell expression landscape of ACE2 and other SARS-CoV-2-related genes in pulmonary tissues of lung cancer patients remains unknown. We sought to delineate single-cell expression profiles of ACE2 and other SARS-CoV-2-related genes in pulmonary tissues of lung adenocarcinoma (LUAD) patients. We examined the expression levels and cellular distribution of ACE2 and SARS-CoV-2-priming proteases TMPRSS2 and TMPRSS4 in 5 LUADs and 14 matched normal tissues by single-cell RNA-sequencing (scRNA-seq) analysis. scRNA-seq of 186,916 cells revealed epithelial-specific expression of ACE2, TMPRSS2, and TMPRSS4. Analysis of 70,030 LUAD- and normal-derived epithelial cells showed that ACE2 levels were highest in normal alveolar type 2 (AT2) cells and that TMPRSS2 was expressed in 65% of normal AT2 cells. Conversely, the expression of TMPRSS4 was highest and most frequently detected (75%) in lung cells with malignant features. ACE2-positive cells co-expressed genes implicated in lung pathobiology, including COPD-associated HHIP, and the scavengers CD36 and DMBT1. Notably, the viral scavenger DMBT1 was significantly positively correlated with ACE2 expression in AT2 cells. We describe normal and tumor lung epithelial populations that express SARS-CoV-2 receptor and proteases, as well as major host defense genes, thus comprising potential treatment targets for COVID-19 particularly among lung cancer patients.
CHPF Regulates the Aggressive Phenotypes of Hepatocellular Carcinoma Cells via the Modulation of the Decorin and TGF-β Pathways
Authors: Liu Chiung-Hui , Wu Bo-Rui , Ho Ying-Jui , Chu Yin-Hung , Hsu Wei-Cheng , Tseng To-Jung , Li Ju-Pi , Liao Wen-Chieh
Published: March 2021

Aberrant composition of glycans in the tumor microenvironment (TME) and abnormal expression of extracellular matrix proteins are hallmarks of hepatocellular carcinoma (HCC); however, the mechanisms responsible for establishing the TME remain unclear. We demonstrate that the chondroitin polymerizing factor (CHPF), an enzyme that mediates the elongation of chondroitin sulfate (CS), is a critical elicitor of the malignant characteristics of HCC as it modifies the potent tumor suppressor, decorin (DCN). CHPF expression is frequently downregulated in HCC tumors, which is associated with the poor overall survival of HCC patients. We observed that restoring CHPF expression suppressed HCC cell growth, migration, and invasion in vitro and in vivo. Mechanistic investigations revealed that TGF-β signaling is associated with CHPF-induced phenotype changes. We found that DCN, as a TGF-β regulator, is modified by CHPF, and that it affects the distribution of DCN on the surface of HCC cells. Importantly, our results confirm that CHPF and DCN expression levels are positively correlated in primary HCC tissues. Taken together, our results suggest that CHPF dysregulation contributes to the malignancy of HCC cells, and our study provides novel insights into the significance of CS, which affects DCN expression in the TME.
Efficacy of Multimodal Analgesia for Postoperative Pain Management in Head and Neck Cancer Patients
Authors: Hinther Ashley , Nakoneshny Steven C. , Chandarana Shamir P. , Matthews T. Wayne , Hart Robert , Schrag Christiaan , Matthews Jennifer , McKenzie C. David , Fick Gordon H. , Dort Joseph C.
Published: March 2021

Postoperative opioid use has been linked to the subsequent development of opioid dependency. Multimodal analgesia (MMA) can reduce the use of opioids in the postoperative period, but MMA has not been well-studied after major head and neck surgery. Our goal is to explore the association between MMA and postoperative opioid use and pain control in patients undergoing major head and neck surgery. We performed a retrospective study in adult (age ≥ 18 years) patients undergoing primary head and neck cancer resection with free-flap reconstruction. All patients were treated using an established care pathway. The baseline group was treated between January 2015–December 2015 (n = 41), prior to the implementation of MMA, and were compared to an MMA-treated cohort treated between December 2017–June 2019 (n = 97). The primary outcome was the proportion of opioids prescribed and oral morphine equivalents (OMEs) consumed during the hospitalization. The secondary outcome was pain control. We found that the post-MMA group consumed fewer opioids in the postoperative period compared to the pre-MMA group. Prior to post-operative day (POD) 6, pain control was better in the post-MMA group; however, the pain control lines intersect on POD 6 and the pre-MMA group appeared to have better pain control from PODs 7–10. In conclusion, our data suggest MMA is an effective method of pain control and opioid reduction in patients undergoing surgery for head and neck cancer with free flap reconstruction. MMA use was associated with a significant decrease in the quantity of opioids consumed postoperatively. The MMA protocol was associated with improved pain management early in the postoperative course. Finally, the MMA protocol is a feasible method of pain control and may reduce the adverse side effects associated with opioid use.
Cancer Stem Cells: Significance in Origin, Pathogenesis and Treatment of Glioblastoma
Authors: Biserova Karina , Jakovlevs Arvids , Uljanovs Romans , Strumfa Ilze
Published: March 2021

Cancer stem cells (CSCs), known also as tumor-initiating cells, are quiescent, pluripotent, self-renewing neoplastic cells that were first identified in hematologic tumors and soon after in solid malignancies. CSCs have attracted remarkable research interest due to their role in tumor resistance to chemotherapy and radiation treatment as well as recurrence. Extensive research has been devoted to the role of CSCs in glioblastoma multiforme (GBM), the most common primary brain tumor in adults, which is characterized by a dismal prognosis because of its aggressive course and poor response to treatment. The aim of the current paper is to provide an overview of current knowledge on the role of cancer stem cells in the pathogenesis and treatment resistance of glioblastoma. The six regulatory mechanisms of glioma stem cells (GSCs)—tumor microenvironment, niche concept, metabolism, immunity, genetics, and epigenetics—are reviewed. The molecular markers used to identify GSCs are described. The role of GSCs in the treatment resistance of glioblastoma is reviewed, along with future treatment options targeting GSCs. Stem cells of glioblastoma thus represent both a driving mechanism of major treatment difficulties and a possible target for more effective future approaches.
RNA Localization and Local Translation in Glia in Neurological and Neurodegenerative Diseases: Lessons from Neurons
Authors: Blanco-Urrejola Maite , Gaminde-Blasco Adhara , Gamarra María , de la Cruz Aida , Vecino Elena , Alberdi Elena , Baleriola Jimena
Published: March 2021

Cell polarity is crucial for almost every cell in our body to establish distinct structural and functional domains. Polarized cells have an asymmetrical morphology and therefore their proteins need to be asymmetrically distributed to support their function. Subcellular protein distribution is typically achieved by localization peptides within the protein sequence. However, protein delivery to distinct cellular compartments can rely, not only on the transport of the protein itself but also on the transport of the mRNA that is then translated at target sites. This phenomenon is known as local protein synthesis. Local protein synthesis relies on the transport of mRNAs to subcellular domains and their translation to proteins at target sites by the also localized translation machinery. Neurons and glia specially depend upon the accurate subcellular distribution of their proteome to fulfil their polarized functions. In this sense, local protein synthesis has revealed itself as a crucial mechanism that regulates proper protein homeostasis in subcellular compartments. Thus, deregulation of mRNA transport and/or of localized translation can lead to neurological and neurodegenerative diseases. Local translation has been more extensively studied in neurons than in glia. In this review article, we will summarize the state-of-the art research on local protein synthesis in neuronal function and dysfunction, and we will discuss the possibility that local translation in glia and deregulation thereof contributes to neurological and neurodegenerative diseases.
Using Stakeholder Involvement, Expert Knowledge and Naturalistic Implementation to Co-Design a Complex Intervention to Support Children’s Inclusion and Participation in Schools: The CIRCLE Framework
Authors: Maciver Donald , Hunter Cathleen , Johnston Lorna , Forsyth Kirsty
Published: March 2021

Whist inclusion is recommended for most children most of the time it remains difficult to implement. In this paper, we present the process undertaken to review and redesign a pre-existing complex intervention (The CIRCLE Framework) which was designed to enhance teachers confidence and competence in provision of universal first level supports for 5–12 year old children with additional support needs. The approach presented draws on the Medical Research Council guidance for the development of complex interventions. A series of ten co-design workshops with 70 stakeholders was completed, applying interactive and participatory methods. Analysing outputs of each workshop revealed recurring design ideas that became the main aspects of the new framework and associated manuals. Intervention content, theoretical frameworks, manuals to support use in practice and implementation strategies were developed. On completion, the updated intervention was extended up to 18 years of age and redistributed to all teachers in the participating local authority. We present the main conclusions and interpretations around the design and naturalistic implementation of the framework, and reflections on use in practice, including a detailed list of recommendations for implementation across schools and staff.
Keeping Hope Possible Toolkit: The Development and Evaluation of a Psychosocial Intervention for Parents of Infants, Children and Adolescents with Life Limiting and Life Threatening Illnesses
Authors: Bally Jill M. G. , Burles Meridith , Spurr Shelley , Holtslander Lorraine , Hodgson-Viden Heather , Sinha Roona , Zimmer Marcelline
Published: March 2021

Background: Globally, many infants and children are diagnosed with illnesses that impose limitations on their well-being and life course trajectory. Children’s care becomes the central focus of family life. Inadequate support for parents is detrimental to their well-being and management of their child’s care and support needs. Methods: The second phase of this evaluation study followed a quasi-experimental crossover design to test a theory-based psychosocial intervention, the Keeping Hope Possible Toolkit. Fifty-nine participants were randomly assigned to one of two sequence groups, with measures of hope, feelings of control, distress, and uncertainty completed pre- and post-intervention, and at a three-month follow-up. Qualitative interviews sought to assess participant experiences with the intervention, along with acceptability and feasibility. Results: Significant influence on parental distress was found, and the qualitative findings reveal benefits of the intervention for parental wellbeing. The intervention effectively offered practical and emotional support to diverse family caregivers. Conclusions: The evidence-informed KHP intervention can be used by healthcare providers to intervene with family caregivers to support their dynamic emotions including hope, need to live in the moment and remember self, and social preferences. In doing so, parents’ critical caregiving activities can be sustained and their child’s health and wellbeing optimized.
“You Can’t Go to the Park, You Can’t Go Here, You Can’t Go There”: Exploring Parental Experiences of COVID-19 and Its Impact on Their Children’s Movement Behaviours
Authors: Riazi Negin , Wunderlich Kelly , Gierc Madelaine , Brussoni Mariana , Moore Sarah , Tremblay Mark , Faulkner Guy
Published: March 2021

The COVID-19 outbreak and related public health guidelines have changed the daily lives of Canadians and restricted opportunities for healthy movement behaviours for children. The purpose of this study was to explore how parents experienced the pandemic-related restrictions and how they impacted their children’s movement behaviours. Methods: Twenty-nine semi-structured one-on-one interviews were conducted (June–July 2020) with parents of children (5–11 years old) in Ontario and British Columbia. Interviews lasted between 24–104 min, were audio-recorded, transcribed verbatim, and thematically analyzed. Results: Findings emphasized various individual (e.g., motivation), interpersonal (e.g., parent work schedule), built (e.g., closure of parks) and natural environment (e.g., weather) factors related to children’s movement behaviours. The findings highlighted the loss of structured activities and destinations for children’s physical activity, and restricted opportunities for outdoor play exacerbated by shrinking childhood independent mobility. Conclusion: Families are adapting to many pandemic-related challenges including adhering to public health restrictions, parents juggling multiple roles, conducting work and school from home, as well as exacerbating factors like weather. It will be important to continue to encourage outdoor time, support policies and practice that facilitate independent mobility, and develop centralized resources that help families in the maintenance of healthy movement behaviours.
Review of Functional Treatments for Modified Wood
Authors: Spear Morwenna J. , Curling Simon F. , Dimitriou Athanasios , Ormondroyd Graham A.
Published: March 2021

Wood modification is now widely recognized as offering enhanced properties of wood and overcoming issues such as dimensional instability and biodegradability which affect natural wood. Typical wood modification systems use chemical modification, impregnation modification or thermal modification, and these vary in the properties achieved. As control and understanding of the wood modification systems has progressed, further opportunities have arisen to add extra functionalities to the modified wood. These include UV stabilisation, fire retardancy, or enhanced suitability for paints and coatings. Thus, wood may become a multi-functional material through a series of modifications, treatments or reactions, to create a high-performance material with previously impossible properties. In this paper we review systems that combine the well-established wood modification procedures with secondary techniques or modifications to deliver emerging technologies with multi-functionality. The new applications targeted using this additional functionality are diverse and range from increased electrical conductivity, creation of sensors or responsive materials, improvement of wellbeing in the built environment, and enhanced fire and flame protection. We identified two parallel and connected themes: (1) the functionalisation of modified timber and (2) the modification of timber to provide (multi)-functionality. A wide range of nanotechnology concepts have been harnessed by this new generation of wood modifications and wood treatments. As this field is rapidly expanding, we also include within the review trends from current research in order to gauge the state of the art, and likely direction of travel of the industry.
Pharmacophore-Guided Identification of Natural Products as Potential Inhibitors of Mycobacterium ulcerans Cystathionine γ-Synthase MetB
Authors: Kwofie Samuel K. , Dolling Nigel N. O. , Donkoh Emmanuel , Laryea Godwin M. , Mosi Lydia , Miller Whelton A. , Adinortey Michael B. , Wilson Michael D.
Published: March 2021

Buruli ulcer caused by Mycobacterium ulcerans (M. ulcerans) is identified by a pain-free cyst or edema which develops into a massive skin ulcer if left untreated. There are reports of chemoresistance, toxicity, noncompliance, and poor efficacy of current therapeutic options. Previously, we used cheminformatics approaches to identify potential antimycobacterial compounds targeting major receptors in M. ulcerans. In this paper, we sought to identify potential bioactive compounds by targeting Cystathionine gamma-synthase (CGS) MetB, a key receptor involved in methionine synthesis. Inhibition of methionine synthesis restricts the growth of M. ulcerans. Two potent inhibitors Juglone (IC50 0.7 +/− 0.7 µmol/L) and 9-hydroxy-alpha-lapachone (IC50 0.9 +/− 0.1 µmol/L) were used to generate 3D chemical feature pharmacophore model via LigandScout with a score of 0.9719. The validated model was screened against a pre-filtered library of 2530 African natural products. Compounds with fit scores above 66.40 were docked against the structure of CGS to generate hits. Three compounds, namely Gentisic 5-O glucoside (an isolate of African tree Alchornea cordifolia), Isoscutellarein (an isolate of Theobroma plant) and ZINC05854400, were identified as potential bioactive molecules with high binding affinities of −7.1, −8.4 and −8.4 kcal/mol against CGS, respectively. Novel structural insight into the binding mechanisms was elucidated using LigPlot+ and molecular dynamics simulations. All three molecules were predicted to possess antibacterial, anti-ulcerative, and dermatological properties. These compounds have the propensity to disrupt the methionine synthesis mechanisms with the potential of stagnating the growth of M. ulcerans. As a result of reasonably good pharmacological profiling, the three drug-like compounds are potential novel scaffolds that can be optimized into antimycobacterial molecules.