bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecularly Imprinted Polymer-Quantum Dot Materials in Optical Sensors: An Overview of Their Synthesis and Applications
Authors: Díaz-Álvarez Myriam , Martín-Esteban Antonio
Published: March 2021

In the last decades analytical methods have focused on the determination of target analytes at very low concentration levels. This has been accomplished through the use of traditional analytical methods that usually require high reagent consumption, expensive equipment and long pretreatment steps. Thus, there is a demand for simple, rapid, highly selective and user-friendly detection procedures. Quantum dots (QDs) are semiconductor fluorescent nanomaterials with unique optoelectronic properties that have shown great potential for the development of fluorescence probes. Besides, the combination of QDs with molecularly imprinted polymer (MIPs), synthetic materials with selective recognition, have been proposed as useful materials in the development of optical sensors. The resulting MIP-QDs optical sensors integrate the advantages of both techniques: the high sensitivity of QDs-based fluorescence sensors and the high selectivity of MIPs. This review gives a brief overview of the strategies for the synthesis of MIPs-QDs based optical sensors, highlighting the modifications in the synthesis procedure that improve the sensor performance. Finally, a revision of recent applications in sensing and bioimaging is presented.
Microfluidic Impedance Biosensor Chips Using Sensing Layers Based on DNA-Based Self-Assembled Monolayers for Label-Free Detection of Proteins
Authors: Alsabbagh Khaled , Hornung Tim , Voigt Achim , Sadir Sahba , Rajabi Taleieh , Länge Kerstin
Published: March 2021

A microfluidic chip for electrochemical impedance spectroscopy (EIS) is presented as bio-sensor for label-free detection of proteins by using the example of cardiac troponin I. Troponin I is one of the most specific diagnostic serum biomarkers for myocardial infarction. The microfluidic impedance biosensor chip presented here consists of a microscope glass slide serving as base plate, sputtered electrodes, and a polydimethylsiloxane (PDMS) microchannel. Electrode functionalization protocols were developed considering a possible charge transfer through the sensing layer, in addition to analyte-specific binding by corresponding antibodies and reduction of nonspecific protein adsorption to prevent false-positive signals. Reagents tested for self-assembled monolayers (SAMs) on gold electrodes included thiolated hydrocarbons and thiolated oligonucleotides, where SAMs based on the latter showed a better performance. The corresponding antibody was covalently coupled on the SAM using carbodiimide chemistry. Sampling and measurement took only a few minutes. Application of a human serum albumin (HSA) sample, 1000 ng/mL, led to negligible impedance changes, while application of a troponin I sample, 1 ng/mL, led to a significant shift in the Nyquist plot. The results are promising regarding specific detection of clinically relevant concentrations of biomarkers, such as cardiac markers, with the newly developed microfluidic impedance biosensor chip.
The Andalusian Registry of Donors for Biomedical Research: Five Years of History
Authors: Aguilar-Quesada Rocío , Aroca-Siendones Inés , de la Torre Leticia , Panadero-Fajardo Sonia , Rejón Juan David , Sánchez-López Ana María , Miranda Blanca
Published: March 2021

The mission of the Andalusian Public Health System Biobank is to offer the best options for biological samples of human origin and associated clinical information, protecting the rights of citizens who donate their samples for research. Since the Andalusian Biobank provides high-quality biological samples of all types in a specified format, adapting the preanalytical phase according to the requirements of the research, prospective collection and distribution of samples are being prioritized in order to contribute to the sustainability of the Biobank. The Andalusian Registry of Donors for Biomedical Research is a tool for the recruitment of donors and the prospective collection of samples. Its operation is based on the informed consent of donors for their incorporation into the Registry and contact with possible donors under request from specific projects. An additional advantage of this unique initiative is to ensure that societal actors work together throughout the entire research process, establishing alliances with patient associations and groups to develop joint actions and promote biomedical research. Here, we describe the creation, ethical–legal aspects, management and results of the Andalusian Registry of Donors for Biomedical Research after five years of operation.
Slow Walking in Individuals with Chronic Post-Stroke Hemiparesis: Speed Mediated Effects of Gait Kinetics and Ankle Kinematics
Authors: Liang Jing Nong , Ho Kai-Yu , Lee Yun-Ju , Ackley Corey , Aki Kiley , Arias Joshua , Trinh Jassie
Published: March 2021

Post-stroke rehabilitation often aims to increase walking speeds, as faster walking is associated with improved functional status and quality of life. However, for successful community ambulation, ability to modulate (increase and decrease) walking speeds is more important than walking continuously at constant speeds. Increasing paretic propulsive forces to increase walking speed has been extensively examined; however, little is known about the mechanics of slow walking post-stroke. The primary purpose of this study was to identify the effects of increased and decreased walking speeds on post-stroke kinetics and ankle kinematics. Fifteen individuals with chronic post-stroke hemiparesis and 15 non-neurologically impaired controls walked over an instrumented treadmill under: slow, self-selected, and fast walking speeds. We examined the peak propulsive forces, propulsive impulse, peak braking forces, braking impulse, and ankle kinematics under each condition. When walking at slow walking speeds, paretic limbs were unable to reduce braking impulse and peak propulsive force or modulate ankle kinematics. Impaired modulation of paretic gait kinetics during slow walking places people post-stroke at high risks for slip-related falls. These findings suggest the need for developing gait retraining paradigms for slow walking in individuals chronically post-stroke that target the ability of the paretic limb to modulate braking forces.
Nusinersen Wearing-Off in Adult 5q-Spinal Muscular Atrophy Patients
Authors: Osmanovic Alma , Schreiber-Katz Olivia , Petri Susanne
Published: March 2021

The antisense oligonucleotide nusinersen was the first drug treatment available for all types of 5q-spinal muscular atrophy (SMA). The dosing regime has been derived from pivotal clinical trials in infants and children. The efficacy of nusinersen in severely affected adult SMA patients is still questionable, as no placebo-controlled trials have been conducted. In the present study, we systematically examined wearing-off phenomena during nusinersen maintenance dosing using a patient-centered approach. We found that adult SMA patients perceived wearing-off after nearly half of 51 investigated nusinersen administrations, primarily within the last month prior to the next administration. Symptoms and functions affected were mainly general strength and arm and leg muscle function next to endurance and independence in daily routine. Lack of walking ability and higher body mass index were characteristic phenotypic features in patients with consistent wearing-off effects. We assume that specific SMA phenotypes might benefit from higher dosing, shorter treatment intervals, change of treatment administration or a combination of all. Efforts towards treatment optimization may result in higher efficacy in distinct phenotypes.
Gray-Matter Expansion of Social Brain Networks in Individuals High in Public Self-Consciousness
Authors: Morita Tomoyo , Asada Minoru , Naito Eiichi
Published: March 2021

Self-consciousness is a personality trait associated with an individual’s concern regarding observable (public) and unobservable (private) aspects of self. Prompted by previous functional magnetic resonance imaging (MRI) studies, we examined possible gray-matter expansions in emotion-related and default mode networks in individuals with higher public or private self-consciousness. One hundred healthy young adults answered the Japanese version of the Self-Consciousness Scale (SCS) questionnaire and underwent structural MRI. A voxel-based morphometry analysis revealed that individuals scoring higher on the public SCS showed expansions of gray matter in the emotion-related regions of the cingulate and insular cortices and in the default mode network of the precuneus and medial prefrontal cortex. In addition, these gray-matter expansions were particularly related to the trait of “concern about being evaluated by others”, which was one of the subfactors constituting public self-consciousness. Conversely, no relationship was observed between gray-matter volume in any brain regions and the private SCS scores. This is the first study showing that the personal trait of concern regarding public aspects of the self may cause long-term substantial structural changes in social brain networks.
Factors Affecting Voluntary Self-Isolation Behavior to Cope with a Pandemic: Empirical Evidence from Colombia vs. Spain in Times of COVID-19
Authors: Escandon-Barbosa Diana , Hurtado Andrea , Gomez Alina
Published: March 2021

Global pandemics are not a new phenomenon. They have occurred at different points in time and can be of different scales. COVID-19 appeared in 2020 and its spread has reached more than 60 countries worldwide. This research aims to analyze voluntary self-isolation behavior used to cope with the COVID-19 pandemic. As part of this study, we carried out sampling in Colombia and Spain, which share similar cultural characteristics but which have substantial social and economic differences. A multi-group model was used to test the application of the theory of planned behavior and the theory of reasoned action in order to analyze self-isolation behavior. The results show that there are differences in self-isolation behavior between both countries, especially with regard to attitudes towards self-isolation and volitional behavior.
Perceptions of Hospitality and Safety Are Two Sides of the Same Coin
Authors: Groen Brenda , van Sprang Hester
Published: March 2021

Entering a building is a ‘moment of truth’ and may invoke feelings of hospitableness. Physical environments and staff behaviour deliver ‘clues’ that may result in the experience of hospitality. The focus in a reception area may be on mitigation of risks, or on a hospitable atmosphere, with either a host or a security officer at the entrance. However, the division of tasks to either the pleasing host or the controlling security officer to a certain extent disavows the overlap between perceptions of hospitality and safety. This exploratory qualitative study combines a group interview with three managers responsible for hospitality and security in reception areas and Critical Incidents by staff and visitors (N = 51). Thematic coding was based on The Egg Aggregated Model and the Experience of Hospitality Scale. Results show that hospitality and safety are indeed two sides of the same coin. Usually people do accept security measures, provided that staff act in a hospitable way. A lack of security measures may seem ‘inviting’, but also decreases the perception of care for your visitor, and may cause uncertainty and therefore decrease comfort. A correct risk perception, flexible appliance of security measures, and a friendly approach connect aspects of ‘safe’ and ‘hospitable’ sentiments.
Elevated Expression of Glycerol-3-Phosphate Phosphatase as a Biomarker of Poor Prognosis and Aggressive Prostate Cancer
Authors: Lounis Mohamed Amine , Ouellet Veronique , Péant Benjamin , Caron Christine , Li Zhenhong , Al-Mass Anfal , Madiraju S. R. Murthy , Mes-Masson Anne-Marie , Prentki Marc , Saad Fred
Published: March 2021

The limitations of the biomarker prostate-specific antigen (PSA) necessitate the pursuit of biomarkers capable of better identifying high-risk prostate cancer (PC) patients in order to improve their therapeutic management and outcomes. Aggressive prostate tumors characteristically exhibit high rates of glycolysis and lipogenesis. Glycerol 3-phosphate phosphatase (G3PP), also known as phosphoglycolate phosphatase (PGP), is a recently identified mammalian enzyme, shown to play a role in the regulation of glucose metabolism, lipogenesis, lipolysis, and cellular nutrient-excess detoxification. We hypothesized that G3PP may relieve metabolic stress in cancer cells and assessed the association of its expression with PC patient prognosis. Using immunohistochemical staining, we assessed the epithelial expression of G3PP in two different radical prostatectomy (RP) cohorts with a total of 1797 patients, for whom information on biochemical recurrence (BCR), metastasis, and mortality was available. The association between biomarker expression, biochemical recurrence (BCR), bone metastasis, and prostate cancer-specific survival was established using log-rank and multivariable Cox regression analyses. High expression of G3PP in PC epithelial cells is associated with an increased risk of BCR, bone metastasis, and PC-specific mortality. Multivariate analysis revealed high G3PP expression in tumors as an independent predictor of BCR and bone metastasis development. High G3PP expression in tumors from patients eligible for prostatectomies is a new and independent prognostic biomarker of poor prognosis and aggressive PC for recurrence, bone metastasis, and mortality.
Establishing the Clinical Utility of ctDNA Analysis for Diagnosis, Prognosis, and Treatment Monitoring of Retinoblastoma: The Aqueous Humor Liquid Biopsy
Authors: Xu Liya , Kim Mary E. , Polski Ashley , Prabakar Rishvanth K. , Shen Lishuang , Peng Chen-Ching , Reid Mark W. , Chévez-Barrios Patricia , Kim Jonathan W. , Shah Rachana , Jubran Rima , Kuhn Peter , Cobrinik David , Biegel Jaclyn A. , Gai Xiaowu , Hicks James , Berry Jesse L.
Published: March 2021

Because direct tumor biopsy is prohibited for retinoblastoma (RB), eye-specific molecular biomarkers are not used in clinical practice for RB. Recently, we demonstrated that the aqueous humor (AH) is a rich liquid biopsy source of cell-free tumor DNA. Herein, we detail clinically-relevant molecular biomarkers from the first year of prospective validation data. Seven eyes from 6 RB patients who had AH sampled at diagnosis and throughout therapy with ≥12 months of follow-up were included. Cell-free DNA (cfDNA) from each sample was isolated and sequenced to assess genome-wide somatic copy number alterations (SCNAs), followed by targeted resequencing for pathogenic variants using a RB1 and MYCN custom hybridization panel. Tumoral genomic information was detected in 100% of diagnostic AH samples. Of the seven diagnostic AH samples, 5/7 were positive for RB SCNAs. Mutational analysis identified RB1 variants in 5/7 AH samples, including the 2 samples in which no SCNAs were detected. Two eyes failed therapy and required enucleation; both had poor prognostic biomarkers (chromosome 6p gain or MYCN amplification) present in the AH at the time of diagnosis. In the context of previously established pre-analytical, analytical, and clinical validity, this provides evidence for larger, prospective studies to further establish the clinical utility of the AH liquid biopsy and its applications to precision oncology for RB.
Combined Systemic and Hepatic Artery Infusion Pump Chemo-Therapy as a Liver-Directed Therapy for Colorectal Liver Metastasis-Review of Literature and Case Discussion
Authors: Chaudhry Salman , Fields Ryan C. , Grierson Patrick M. , Lim Kian-Huat
Published: March 2021

Colorectal cancer (CRC) is the third most prevalent malignancy and the second most common cause of death in the US. Liver is the most common site of colorectal metastases. About 13% of patients with colorectal cancer have liver metastasis on initial presentation and 50% develop them during the disease course. Although systemic chemotherapy and immunotherapy are the mainstay treatment for patients with metastatic disease, for selected patients with predominant liver metastasis, liver-directed approaches may provide prolonged disease control when combined with systemic treatments. Hepatic artery infusion pump (HAIP) chemotherapy is an approach which allows direct infusion of chemotherapeutic into the liver and is especially useful in the setting of multifocal liver metastases. When combined with systemic chemotherapy, HAIP improves the response rate, provides more durable disease control, and in some patients leads to successful resection. To ensure safety, use of HAIP requires multidisciplinary collaboration between interventional radiologists, medical oncologists, hepatobiliary surgeons and treatment nurses. Here, we review the benefits and potential risks with this approach and provide our single institution experience on two CRC patients successfully treated with HAIP in combination with systemic chemotherapy. We provide our recommendations in adopting this technique in the current era for patient with colorectal liver metastases.
Pain Progression at Initiation of Cabazitaxel in Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Post Hoc Analysis of the PROSELICA Study
Authors: Delanoy Nicolas , Robbrecht Debbie , Eisenberger Mario , Sartor Oliver , de Wit Ronald , Mercier Florence , Geffriaud-Ricouard Christine , de Bono Johann , Oudard Stéphane
Published: March 2021

Background: In the PROSELICA phase III trial (NCT01308580), cabazitaxel 20 mg/m2 (CABA20) was non-inferior to cabazitaxel 25 mg/m2 (CABA25) in mCRPC patients previously treated with docetaxel (DOC). The present post hoc analysis evaluates how the type of progression at randomization affected outcomes. Methods: Progression type at randomization was defined as follows: PSA progression only (PSA-p; no radiological progression (RADIO-p), no pain), RADIO-p (±PSA-p, no pain), or pain progression (PAIN-p, ±PSA-p, ±RADIO-p). Relationships between progression type and overall survival (OS), radiological progression-free survival (rPFS), and PSA response (confirmed PSA decrease ≥ 50%) were analyzed. Results: All randomized patients (n = 1200) had received prior DOC, and 25.7% had received prior abiraterone or enzalutamide. Progression type at randomization was evaluable in 1075 patients (PSA-p = 24.4%, RADIO-p = 20.8%, PAIN-p = 54.8%). Pain progression was associated with clinical and biological features of aggressive disease. Median OS from CABA initiation or date of mCRPC diagnosis, all arms combined, was shorter in the PAIN-p group than in the RADIO-p or the PSA-p groups (12.0 versus 16.8 and 18.4 months, respectively, p < 0.001). In multivariate analysis, all arms combined, PAIN-p was an independent predictor of poor OS (HR = 1.44, p < 0.001). PSA response, rPFS, and OS were numerically higher with CABA25 versus CABA20 in patients with PAIN-p. Conclusions: This post hoc analysis of the PROSELICA phase III study shows that pain progression at initiation of CABA in mCRPC patients previously treated with DOC is associated with a poor prognosis. Disease progression should be carefully monitored, even in the absence of PSA rise.
An AI-Powered Blood Test to Detect Cancer Using NanoDSF
Authors: Tsvetkov Philipp O. , Eyraud Rémi , Ayache Stéphane , Bougaev Anton A. , Malesinski Soazig , Benazha Hamed , Gorokhova Svetlana , Buffat Christophe , Dehais Caroline , Sanson Marc , Bielle Franck , Figarella Branger Dominique , Chinot Olivier , Tabouret Emeline , Devred François
Published: March 2021

Glioblastoma is the most frequent and aggressive primary brain tumor. Its diagnosis is based on resection or biopsy that could be especially difficult and dangerous in the case of deep location or patient comorbidities. Monitoring disease evolution and progression also requires repeated biopsies that are often not feasible. Therefore, there is an urgent need to develop biomarkers to diagnose and follow glioblastoma evolution in a minimally invasive way. In the present study, we described a novel cancer detection method based on plasma denaturation profiles obtained by a non-conventional use of differential scanning fluorimetry. Using blood samples from 84 glioma patients and 63 healthy controls, we showed that their denaturation profiles can be automatically distinguished with the help of machine learning algorithms with 92% accuracy. Proposed high throughput workflow can be applied to any type of cancer and could become a powerful pan-cancer diagnostic and monitoring tool requiring only a simple blood test.
Comment on Roelofs, K.A.; et al. Detecting Progression of Melanocytic Choroidal Tumors by Sequential Imaging: Is Ultrasonography Necessary? Cancers 2020, 12, 1856
Authors: Capasso Luigi , Gioia Marco , De Bernardo Maddalena , Rosa Nicola
Published: March 2021

We read with great interest the paper by Roelofs et al [...]
Neutrophil-to-Lymphocyte Ratio Predicts Development of Immune-Related Adverse Events and Outcomes from Immune Checkpoint Blockade: A Case-Control Study
Authors: Lee Pei Yi , Oen Kellynn Qi Xuan , Lim Grace Rui Si , Hartono Juanda Leo , Muthiah Mark , Huang Daniel Q. , Teo Felicia Su Wei , Li Andrew Yunkai , Mak Anselm , Chandran Nisha Suyien , Tan Chris Lixian , Yang Peiling , Tai E Shyong , Ng Kay Wei Ping , Vijayan Joy , Chan Yee Cheun , Tan Li Ling , Lee Martin Beng-Huat , Chua Horng Ruey , Hong Wei Zhen , Yap Eng Soo , Lim Dawn K. , Yuen Yew Sen , Chan Yiong Huak , Aminkeng Folefac , Wong Alvin Seng Cheong , Huang Yiqing , Tay Sen Hee
Published: March 2021

The utility of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) utility in predicting immune-related adverse events (irAEs) and survival have not been well studied in the context of treatment with immune checkpoint inhibitors (ICIs). We performed a case-control study of cancer patients who received at least one dose of ICI in a tertiary hospital. We examined NLR and PLR in irAE cases and controls. Logistic and Cox regression models were used to identify independent risk factors for irAEs, progression-free survival (PFS), and overall survival (OS). The study included 91 patients with irAEs and 56 controls. Multiple logistic regression showed that NLR < 3 at baseline was associated with higher occurrence of irAEs. Multivariate Cox regression showed that development of irAEs and reduction in NLR from baseline to week 6 were associated with longer PFS. Higher NLR values at baseline and/or week 6 were independently associated with shorter OS. A reduction in NLR from baseline to week 6 was associated with longer OS. In this study of cancer patients treated with ICIs, NLR has a bidirectional relationship with adverse outcomes. Lower NLR was associated with increased occurrence of irAEs while higher NLR values were associated with worse clinical outcomes.
HERC1 Regulates Breast Cancer Cells Migration and Invasion
Authors: Rossi Fabiana Alejandra , Calvo Roitberg Ezequiel Hernán , Enriqué Steinberg Juliana Haydeé , Joshi Molishree Umesh , Espinosa Joaquín Maximiliano , Rossi Mario
Published: March 2021

Tumor cell migration and invasion into adjacent tissues is one of the hallmarks of cancer and the first step towards secondary tumors formation, which represents the leading cause of cancer-related deaths. This process is considered an unmet clinical need in the treatment of this disease, particularly in breast cancers characterized by high aggressiveness and metastatic potential. To identify and characterize genes with novel functions as regulators of tumor cell migration and invasion, we performed a genetic loss-of-function screen using a shRNA library directed against the Ubiquitin Proteasome System (UPS) in a highly invasive breast cancer derived cell line. Among the candidates, we validated HERC1 as a gene regulating cell migration and invasion. Furthermore, using animal models, our results indicate that HERC1 silencing affects primary tumor growth and lung colonization. Finally, we conducted an in silico analysis using publicly available protein expression data and observed an inverse correlation between HERC1 expression levels and breast cancer patients’ overall survival. Altogether, our findings demonstrate that HERC1 might represent a novel therapeutic target for the development or improvement of breast cancer treatment.
Promotional Effect of Pd Addition on the Catalytic Activity of Composite Pt-Pd/AlSBA-15–β Catalyst for Enhanced n-Heptane Hydroisomerization
Authors: Jaroszewska Karolina , Fedyna Monika , Masalska Aleksandra , Łużny Rafał , Trawczyński Janusz
Published: March 2021

Hierarchical AlSBA-15–zeolite materials were utilized as a supports for preparing hydroisomerization catalysts. Detailed consideration was given to: (i) the effect of the zeolite type introduced into AlSBA-15–zeolite composites (where zeolite is β, mordenite or ZSM-5) as well as (ii) the promotion effect of Pd addition. The composites showed higher activity in isomerization as compared to Pt/AlSBA-15. The enhanced isomerization efficiency were explained by the appropriate metallic and acidic function as well as suitable transport properties. The modification of the hydrogenating function by Pd incorporation increases the hydroisomerization efficiency of Pt-Pd/AlSBA-15–β catalyst. Over bimetallic Pt-Pd/AlSBA-15–β, the high yields of isomers (68 wt%) with respect to 50 wt% for a control catalyst. The most promising Pt-Pd/AlSBA-15–β catalyst allows to improve research octane number from 0 to the 74 value.
Selective and Efficient Olefin Epoxidation by Robust Magnetic Mo Nanocatalysts
Authors: Fernandes Cristina I. , Vaz Pedro D. , Nunes Carla D.
Published: March 2021

Iron oxide magnetic nanoparticles were synthesized with different sizes (11 and 30 nm). Subsequently they were shelled with a silica layer allowing grafting of an organic phosphine ligand that coordinated to the [MoI2(CO)3] organometallic core. The silica layer was prepared by the Stöber method using either mechanical (both 11 and 30 nm nanoparticles) or ultrasound (30 nm only) stirring. The latter nanoparticles once coated with silica were obtained with less aggregation, which was beneficial for the final material holding the organometallic moiety. The Mo loadings were found to be 0.20, 0.18, and 0.34 mmolMo·g−1 for MNP30-Si-phos-Mo,MNP11-Si-phos-Mo, and MNP30-Sius-phos-Mo, respectively, with the ligand-to-metal ratio reaching 4.6, 4.8, and 3.2, by the same order, confirming coordination of the Mo moieties to two phos ligands. Structural characterization obtained from powder X-ray diffraction (XRD), scanning electron microscopy (SEM)/ transmission electron microscopy (TEM) analysis, and Fourier-transform infrared (FTIR) spectroscopy data confirmed the successful synthesis of all nanomaterials. Olefin epoxidation of several substrates catalyzed by these organometallic nano-hybrid materials using tert-butyl hydroperoxide (tbhp) as oxidant, achieved very good results. Extensive testing of the catalysts showed that they are highly active, selective, recyclable, and efficient concerning oxidant consumption.
Molecular and Genetic Profiling for Precision Medicines in Pulmonary Arterial Hypertension
Authors: Fazal Shahood , Bisserier Malik , Hadri Lahouaria
Published: March 2021

Pulmonary arterial hypertension (PAH) is a rare and chronic lung disease characterized by progressive occlusion of the small pulmonary arteries, which is associated with structural and functional alteration of the smooth muscle cells and endothelial cells within the pulmonary vasculature. Excessive vascular remodeling is, in part, responsible for high pulmonary vascular resistance and the mean pulmonary arterial pressure, increasing the transpulmonary gradient and the right ventricular “pressure overload”, which may result in right ventricular (RV) dysfunction and failure. Current technological advances in multi-omics approaches, high-throughput sequencing, and computational methods have provided valuable tools in molecular profiling and led to the identification of numerous genetic variants in PAH patients. In this review, we summarized the pathogenesis, classification, and current treatments of the PAH disease. Additionally, we outlined the latest next-generation sequencing technologies and the consequences of common genetic variants underlying PAH susceptibility and disease progression. Finally, we discuss the importance of molecular genetic testing for precision medicine in PAH and the future of genomic medicines, including gene-editing technologies and gene therapies, as emerging alternative approaches to overcome genetic disorders in PAH.
Trends in Articular Cartilage Tissue Engineering: 3D Mesenchymal Stem Cell Sheets as Candidates for Engineered Hyaline-Like Cartilage
Authors: Thorp Hallie , Kim Kyungsook , Kondo Makoto , Maak Travis , Grainger David W. , Okano Teruo
Published: March 2021

Articular cartilage defects represent an inciting factor for future osteoarthritis (OA) and degenerative joint disease progression. Despite multiple clinically available therapies that succeed in providing short term pain reduction and restoration of limited mobility, current treatments do not reliably regenerate native hyaline cartilage or halt cartilage degeneration at these defect sites. Novel therapeutics aimed at addressing limitations of current clinical cartilage regeneration therapies increasingly focus on allogeneic cells, specifically mesenchymal stem cells (MSCs), as potent, banked, and available cell sources that express chondrogenic lineage commitment capabilities. Innovative tissue engineering approaches employing allogeneic MSCs aim to develop three-dimensional (3D), chondrogenically differentiated constructs for direct and immediate replacement of hyaline cartilage, improve local site tissue integration, and optimize treatment outcomes. Among emerging tissue engineering technologies, advancements in cell sheet tissue engineering offer promising capabilities for achieving both in vitro hyaline-like differentiation and effective transplantation, based on controlled 3D cellular interactions and retained cellular adhesion molecules. This review focuses on 3D MSC-based tissue engineering approaches for fabricating “ready-to-use” hyaline-like cartilage constructs for future rapid in vivo regenerative cartilage therapies. We highlight current approaches and future directions regarding development of MSC-derived cartilage therapies, emphasizing cell sheet tissue engineering, with specific focus on regulating 3D cellular interactions for controlled chondrogenic differentiation and post-differentiation transplantation capabilities.
The Phosphoarginine Phosphatase PtpB from Staphylococcus aureus Is Involved in Bacterial Stress Adaptation during Infection
Authors: Elhawy Mohamed Ibrahem , Huc-Brandt Sylvaine , Pätzold Linda , Gannoun-Zaki Laila , Abdrabou Ahmed Mohamed Mostafa , Bischoff Markus , Molle Virginie
Published: March 2021

Staphylococcus aureus continues to be a public health threat, especially in hospital settings. Studies aimed at deciphering the molecular and cellular mechanisms that underlie pathogenesis, host adaptation, and virulence are required to develop effective treatment strategies. Numerous host-pathogen interactions were found to be dependent on phosphatases-mediated regulation. This study focused on the analysis of the role of the low-molecular weight phosphatase PtpB, in particular, during infection. Deletion of ptpB in S. aureus strain SA564 significantly reduced the capacity of the mutant to withstand intracellular killing by THP-1 macrophages. When injected into normoglycemic C57BL/6 mice, the SA564 ΔptpB mutant displayed markedly reduced bacterial loads in liver and kidney tissues in a murine S. aureus abscess model when compared to the wild type. We also observed that PtpB phosphatase-activity was sensitive to oxidative stress. Our quantitative transcript analyses revealed that PtpB affects the transcription of various genes involved in oxidative stress adaptation and infectivity. Thus, this study disclosed first insights into the physiological role of PtpB during host interaction allowing us to link phosphatase-dependent regulation to oxidative bacterial stress adaptation during infection.
Identification of Ku70 Domain-Specific Interactors Using BioID2
Authors: Abbasi Sanna , Schild-Poulter Caroline
Published: March 2021

Since its inception, proximity-dependent biotin identification (BioID), an in vivo biochemical screening method to identify proximal protein interactors, has seen extensive developments. Improvements and variants of the original BioID technique are being reported regularly, each expanding upon the existing potential of the original technique. While this is advancing our capabilities to study protein interactions under different contexts, we have yet to explore the full potential of the existing BioID variants already at our disposal. Here, we used BioID2 in an innovative manner to identify and map domain-specific protein interactions for the human Ku70 protein. Four HEK293 cell lines were created, each stably expressing various BioID2-tagged Ku70 segments designed to collectively identify factors that interact with different regions of Ku70. Historically, although many interactions have been mapped to the C-terminus of the Ku70 protein, few have been mapped to the N-terminal von Willebrand A-like domain, a canonical protein-binding domain ideally situated as a site for protein interaction. Using this segmented approach, we were able to identify domain-specific interactors as well as evaluate advantages and drawbacks of the BioID2 technique. Our study identifies several potential new Ku70 interactors and validates RNF113A and Spindly as proteins that contact or co-localize with Ku in a Ku70 vWA domain-specific manner.
Prognostic Cancer Gene Expression Signatures: Current Status and Challenges
Authors: Qian Yuquan , Daza Jimmy , Itzel Timo , Betge Johannes , Zhan Tianzuo , Marmé Frederik , Teufel Andreas
Published: March 2021

Current staging systems of cancer are mainly based on the anatomical extent of disease. They need refinement by biological parameters to improve stratification of patients for tumor therapy or surveillance strategies. Thanks to developments in genomic, transcriptomic, and big-data technologies, we are now able to explore molecular characteristics of tumors in detail and determine their clinical relevance. This has led to numerous prognostic and predictive gene expression signatures that have the potential to establish a classification of tumor subgroups by biological determinants. However, only a few gene signatures have reached the stage of clinical implementation so far. In this review article, we summarize the current status, and present and future challenges of prognostic gene signatures in three relevant cancer entities: breast cancer, colorectal cancer, and hepatocellular carcinoma.
One Brain—All Cells: A Comprehensive Protocol to Isolate All Principal CNS-Resident Cell Types from Brain and Spinal Cord of Adult Healthy and EAE Mice
Authors: Schroeter Christina B. , Herrmann Alexander M. , Bock Stefanie , Vogelsang Anna , Eichler Susann , Albrecht Philipp , Meuth Sven G. , Ruck Tobias
Published: March 2021

In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, the role of each central nervous system (CNS)-resident cell type during inflammation, neurodegeneration, and remission has been frequently addressed. Although protocols for the isolation of different individual CNS-resident cell types exist, none can harvest all of them within a single experiment. In addition, isolation of individual cells is more demanding in adult mice and even more so from the inflamed CNS. Here, we present a protocol for the simultaneous purification of viable single-cell suspensions of all principal CNS-resident cell types (microglia, oligodendrocytes, astrocytes, and neurons) from adult mice—applicable in healthy mice as well as in EAE. After dissociation of the brain and spinal cord from adult mice, microglia, oligodendrocytes, astrocytes and, neurons were isolated via magnetic-activated cell sorting (MACS). Validations comprised flow cytometry, immunocytochemistry, as well as functional analyses (immunoassay and Sholl analysis). The purity of each cell isolation averaged 90%. All cells displayed cell-type-specific morphologies and expressed specific surface markers. In conclusion, this new protocol for the simultaneous isolation of all major CNS-resident cell types from one CNS offers a sophisticated and comprehensive way to investigate complex cellular networks ex vivo and simultaneously reduce mice numbers to be sacrificed.
Heme Oxygenase-1 Contributes to Both the Engulfment and the Anti-Inflammatory Program of Macrophages during Efferocytosis
Authors: Fige Éva , Szendrei Judit , Sós László , Kraszewska Izabela , Potor László , Balla József , Szondy Zsuzsa
Published: March 2021

Heme oxygenase-1 (HO-1) plays a vital role in the catabolism of heme and yields equimolar amounts of biliverdin, carbon monoxide, and free iron. We report that macrophages engulfing either the low amount of heme-containing apoptotic thymocytes or the high amount of heme-containing eryptotic red blood cells (eRBCs) strongly upregulate HO-1. The induction by apoptotic thymocytes is dependent on soluble signals, which do not include adenylate cyclase activators but induce the p38 mitogen-activated protein (MAP) kinase pathway, while in the case of eRBCs, it is cell uptake-dependent. Both pathways might involve the regulation of BTB and CNC homology 1 (BACH1), which is the repressor transcription regulator factor of the HO-1 gene. Long-term continuous efferocytosis of apoptotic thymocytes is not affected by the loss of HO-1, but that of eRBCs is inhibited. This latter is related to an internal signaling pathway that prevents the efferocytosis-induced increase in Rac1 activity. While the uptake of apoptotic cells suppressed the basal pro-inflammatory cytokine production in wild-type macrophages, in the absence of HO-1, engulfing macrophages produced enhanced amounts of pro-inflammatory cytokines. Our data demonstrate that HO-1 is required for both the engulfment and the anti-inflammatory response parts of the efferocytosis program.
PARP10 Multi-Site Auto- and Histone MARylation Visualized by Acid-Urea Gel Electrophoresis
Authors: García-Saura Antonio Ginés , Schüler Herwig
Published: March 2021

Poly-ADP-ribose polymerase (PARP)-family ADP-ribosyltransferases function in various signaling pathways, predominantly in the nucleus and cytosol. Although PARP inhibitors are in clinical practice for cancer therapy, the enzymatic activities of individual PARP family members are yet insufficiently understood. We studied PARP10, a mono-ADP-ribosyltransferase and potential drug target. Using acid-urea gel electrophoresis, we found that the isolated catalytic domain of PARP10 auto-ADP-ribosylates (MARylates) at eight or more acceptor residues. We isolated individual species with either singular or several modifications and then analyzed them by mass spectrometry. The results confirmed multi-site MARylation in a random order and identified four acceptor residues. The mutagenesis of singular acceptor residues had a minor impact on the overall auto-MARylation level and no effect on the MARylation of histone H3.1. Together, our results suggest that PARP10 automodification may have functions in the regulation of intramolecular or partner binding events, rather than of its enzymatic catalysis. This contributes to a better understanding of PARP10 functions, and, in the long run, to gauging the consequences of PARP inhibitor actions.
New Interpretation of X-ray Diffraction Pattern of Vitreous Silica
Authors: Cheng Shangcong
Published: March 2021

The striking feature of X-ray diffraction pattern of vitreous silica is that the center of its intense but broad ring is located at nearly the same position as the strongest diffraction ring of β-cristobalite. Two fundamentally different explanations to the diffraction patterns were appeared about 90 years ago, one based on the smallest crystals of β-cristobalite and the other based on the non-crystalline continuous random network. This work briefly outlines the facts supporting and objecting these two hypotheses, and aims to present a new interpretation based on a medium-range ordering structure on the facets of clusters formed in the glass transition process. It will be shown that the new interpretation provides a more satisfactory explanation of the diffraction pattern and physical properties of silica glass, and offers considerable valuable information regarding the nature of glass and glass transition.
Family Functioning in Families of Adolescents with Mental Health Disorders: The Role of Parenting Alliance
Authors: Baena Sofía , Jiménez Lucía , Lorence Bárbara , Hidalgo Mᵃ Victoria
Published: March 2021

This study primarily examined the predictive role of emotional and behavioral disorders in family cohesion and the moderating role of parenting alliance. Adolescents’ mental health issues are a major concern, with important implications for individuals and their families. However, the impact of mental disorders on family processes has been less widely studied. Participants in this study were 72 parents of adolescent beneficiaries of mental health services. Questionnaires assessed family cohesion, parenting alliance, and sociodemographic factors. Results indicated that emotional and behavioral disorders did not have an influence on family cohesion. They also suggested that parenting alliance may be a protective factor for family cohesion. This paper highlights the role of parenting alliance as a potential protective factor in positive family processes. These findings support the importance of focusing on the parental subsystem in therapy, and the need to incorporate a positive parenting perspective when working with these families.
The Effect of NUDT15, TPMT, APEX1, and ITPA Genetic Variations on Mercaptopurine Treatment of Pediatric Acute Lymphoblastic Leukemia
Authors: Lee Jae Min , Shim Ye Jee , Kim Do-Hoon , Jung Nani , Ha Jung-Sook
Published: March 2021

Mercaptopurine (MP) is a commonly used maintenance regimen for childhood acute lymphoblastic leukemia (ALL). However, 6-MP has a narrow therapeutic index, which causes dose-limiting toxicities in hematopoietic tissues. Recent studies reported several candidate pharmacogenetic markers such as TPMT, NUDT15, ITPA, and APEX1, which predict the possibility of 6-MP related toxicities. The aim of this study is to evaluate the effect of major variants of these genes on 6-MP intolerances and toxicities in pediatric acute lymphoblastic leukemia (ALL) patients. A total of 83 pediatric ALL patients were included (56 males and 27 females). The NUDT15 c.415C>T (rs116855232), NUDT15 c.55_56insGAGTCG (rs746071566), ITPA c.94C>A (rs1127354), ITPA c.IVS2+21A>C (rs7270101), APEX c.190A>G (rs2307486), and TPMT variants were analyzed by sanger sequencing. Correlations between indexes of 6-MP-related toxicities or 6-MP intolerance (absolute neutrophil count [ANC] at several time point, days of ANC < 1 × 103/mm3, days of ANC < 0.5 × 103/mm3, frequency of febrile neutropenia, maximum AST and ALT, 6-MP dose and 6-MP dose intensity during maintenance therapy) and genetic variations were analyzed. The NUDT15 c.415C>T allele carrier showed significantly low 6-MP doses at the final maintenance therapy period than the wild type carrier (p = 0.007). The 6-MP dose intensities at the sixth and final maintenance period were also significantly low in NUDT15 c.415C>T carriers (p = 0.003 and 0.008, respectively). However, indexes for neutropenia, days of febrile neutropenia, maximum AST, and ALT levels were not associated with the presence of c.415C>T as well as other analyzed variants. When analyzing the effect of the coexistence of NUDT15 c.415C>T and ITPA c.94C>A, no significant differences were found between the NUDT15 c.415C>T carrier and carrier with both variations. The NUDT15 c.415C>T was the most useful marker to predict 6-MP intolerance among analyzed variants in our study population. Although we could not find association of those variants with 6-MP induced toxicities and the synergistic effects of those variants, a well-planed larger scale study would be helpful in clarifying new candidates and their clinical effects.
Exploring Short-Term Climate Change Effects on Rangelands and Broad-Leaved Forests by Free Satellite Data in Aosta Valley (Northwest Italy)
Authors: Orusa Tommaso , Borgogno Mondino Enrico
Published: March 2021

Satellite remote sensing is a power tool for the long-term monitoring of vegetation. This work, with reference to a regional case study, investigates remote sensing potentialities for describing the annual phenology of rangelands and broad-leaved forests at the landscape level with the aim of detecting eventual effects of climate change in the Alpine region of the Aosta Valley (Northwest (NW) Italy). A first analysis was aimed at estimating phenological metrics (PMs) from satellite images time series and testing the presence of trends along time. A further investigation concerned evapotranspiration from vegetation (ET) and its variation along the years. Additionally, in both the cases the following meteorological patterns were considered: air temperature anomalies, precipitation trends and the timing of yearly seasonal snow melt. The analysis was based on the time series (TS) of different MODIS collections datasets together with Climate Hazards Group InfraRed Precipitation with Station data (CHIRPS) collection obtained through Google Earth Engine. Ground weather stations data from the Centro Funzionale VdA ranging from 2000 to 2019 were used. In particular, the MOD13Q1 v.6, MOD16A2 and MOD10A1 v.6 collections were used to derive PMs, ET and snow cover maps. The SRTM (shuttle radar topography mission) DTM (digital terrain model) was also used to describe local topography while the Coordination of Information on the Environment (CORINE) land cover map was adopted to investigate land use classes. Averagely in the area, rangelands and broad-leaved forests showed that the length of season is getting longer, with a general advance of the SOS (start of the season) and a delay in the EOS (end of the season). With reference to ET, significant increasing trends were generally observed. The water requirement from vegetation appeared to have averagely risen about 0.05 Kg·m−2 (about 0.5%) per year in the period 2000–2019, for a total increase of about 1 Kg·m−2 in 20 years (corresponding to a percentage difference in water requirement from vegetation of about 8%). This aspect can be particularly relevant in the bottom of the central valley, where the precipitations have shown a statistically significant decreasing trend in the period 2000–2019 (conversely, no significant variation was found in the whole territory). Additionally, the snowpack timing persistence showed a general reduction trend. PMs and ET and air temperature anomalies, as well as snow cover melting, proved to have significantly changed their values in the last 20 years, with a continuous progressive trend. The results encourage the adoption of remote sensing to monitor climate change effects on alpine vegetation, with particular focus on the relationship between phenology and other abiotic factors permitting an effective technological transfer.
Edible Coating from Enzymatically Reticulated Whey Protein-Pectin to Improve Shelf Life of Roasted Peanuts
Authors: Rossi-Márquez Giovanna , Helguera María , Briones Manuel , Dávalos-Saucedo Cristian Aarón , Di Pierro Prospero
Published: March 2021

Edible coatings are a viable alternative method to enhance food shelf life that can be designed using different biopolymers. This study evaluated the effect of a whey protein–pectin coating reticulated by microbial transglutaminase (mTG) on improving roasted peanuts’ shelf life. Peroxide value, water content, peanut color, and the solution’s contact angle were studied. The latter was improved by the presence of the enzyme. The results showed that the presence of the coating on the peanut surface reduces the peroxide value and water content, probably as a consequence of an improved barrier effect due to the presence of mTG, which protects the kernel. Enzymatically reticulated whey protein–pectin coatings are a promising alternative to enhance the shelf life of roasted peanut kernels using natural ingredients.