bluuebunny/crossref_metadata_2025 huggingface dataset:
The Cx43 Carboxyl-Terminal Mimetic Peptide αCT1 Protects Endothelial Barrier Function in a ZO1 Binding-Competent Manner
Authors: Strauss Randy E. , Mezache Louisa , Veeraraghavan Rengasayee , Gourdie Robert G.
Published: August 2021

The Cx43 carboxyl-terminus (CT) mimetic peptide, αCT1, originally designed to bind to Zonula Occludens 1 (ZO1) and thereby inhibit Cx43/ZO1 interaction, was used as a tool to probe the role of Cx43/ZO1 association in regulation of epithelial/endothelial barrier function. Using both in vitro and ex vivo methods of barrier function measurement, including Electric Cell-Substrate Impedance Sensing (ECIS), a TRITC-dextran Transwell permeability assay, and a FITC-dextran cardiovascular leakage protocol involving Langendorff-perfused mouse hearts, αCT1 was found to protect the endothelium from thrombin-induced breakdown in cell–cell contacts. Barrier protection was accompanied by significant remodeling of the F-actin cytoskeleton, characterized by a redistribution of F-actin away from the cytoplasmic and nuclear regions of the cell, towards the endothelial cell periphery, in association with alterations in cellular chiral orientation distribution. In line with observations of increased cortical F-actin, αCT1 upregulated cell–cell border localization of endothelial VE-cadherin, the tight junction protein Zonula Occludens 1 (ZO1), and the Gap Junction Protein (GJ) Connexin43 (Cx43). A ZO1 binding-incompetent variant of αCT1, αCT1-I, indicated that these effects on barrier function and barrier-associated proteins, were likely associated with Cx43 CT sequences retaining ability to interact with ZO1. These results implicate the Cx43 CT and its interaction with ZO1, in the regulation of endothelial barrier function, while revealing the therapeutic potential of αCT1 in the treatment of vascular edema.
C-Reactive Protein Is an Independent Predictor of 30-Day Bacterial Infection Post-Liver Transplantation
Authors: Yu Jiong , Shi Xiaowei , Ma Jing , Chen Ronggao , Dong Siyi , Lu Sen , Wu Jian , Yan Cuilin , Wu Jian , Zheng Shusen , Li Lanjuan , Xu Xiao , Cao Hongcui
Published: August 2021

The relationship between aseptic systemic inflammation and postoperative bacterial infection is unclear. We investigated the correlation of systemic inflammation biomarkers with 30-day clinically significant bacterial infections (CSI) after liver transplantation (LT). This retrospective study enrolled 940 patients who received LT and were followed for 30 days. The primary end point was 30-day CSI events. The cohort was divided into exploratory (n = 508) and validation (n = 432) sets according to different centers. Area under the receiver operated characteristic (AUROC) and Cox regression models were fitted to study the association between baseline systemic inflammation levels and CSI after LT. A total of 255 bacterial infectious events in 209 recipients occurred. Among systemic inflammation parameters, baseline C-reactive protein (CRP) was independently associated with 30-day CSI in the exploratory group. The combination of CRP and organ failure number showed a good discrimination for 30-day CSI (AUROC = 0.80, 95% CI, 0.76–0.84) and the results were confirmed in an external verification group. Additionally, CRP levels were correlated with bacterial product lipopolysaccharide. In conclusion, our study suggests that pre-transplantation CRP is independent of other prognostic factors for 30-day CSI post-LT, and can be integrated into tools for assessing the risk of bacterial infection post-LT or as a component of prognostic models.
Structural and Functional Insights into the Biofilm-Associated BceF Tyrosine Kinase Domain from Burkholderia cepacia
Authors: Mayer Michal , Matiuhin Yulia , Nawatha Mickal , Tabachnikov Orly , Fish Inbar , Schutz Nili , Dvir Hay , Landau Meytal
Published: August 2021

BceF is a bacterial tyrosine kinase (BY-kinase) from Burkholderia cepacia, a Gram-negative bacterium accountable for respiratory infections in immunocompromised and cystic fibrosis patients. BceF is involved in the production of exopolysaccharides secreted to the biofilm matrix and promotes resistant and aggressive infections. BY-kinases share no homology with mammalian kinases, and thereby offer a means to develop novel and specific antivirulence drugs. Here, we report the crystal structure of the BceF kinase domain at 1.85 Å resolution. The isolated BceF kinase domain is assembled as a dimer in solution and crystallized as a dimer in the asymmetric unit with endogenous adenosine-diphosphate bound at the active sites. The low enzymatic efficiency measured in solution may be explained by the partial obstruction of the active sites at the crystallographic dimer interface. This study provides insights into self-assembly and the specific activity of isolated catalytic domains. Several unique variations around the active site compared to other BY-kinases may allow for structure-based design of specific inhibitors to target Burkholderia cepacia virulence.
Integrin β4 as a Potential Diagnostic and Therapeutic Tumor Marker
Authors: Yang Haoyu , Xu Zixuan , Peng Yuqian , Wang Jiali , Xiang Yang
Published: August 2021

Integrin β4 (ITGβ4) is a class of transmembrane adhesion molecules composed of hemidesmosomes (HDs). Its unique long intracellular domain provides intricate signal transduction functions. These signal transduction effects are especially prominent in tumors. Many recent studies have shown that integrin β4 is differentially expressed in various tumors, and it plays a vital role in tumor invasion, proliferation, epithelial–mesenchymal transition, and angiogenesis. Therefore, we categorize the research related to integrin β4, starting from its structure and function in tumor tissues, and provide a basic description. Based on its structure and function, we believe that integrin β4 can be used as a tumor marker. In clinical practice, it is described as a diagnostic marker for the targeted treatment of cancer and will be helpful in the clinical diagnosis and treatment of tumors.
C-KIT Expression in Orbital Cavernous Venous Hemangiomas
Authors: Atallah Mizhir , Edison Natalia , Levi Esther , Elmalah Irit , Briscoe Daniel
Published: August 2021

Orbital (slow flow) cavernous venous hemangiomas (OCVH) are the most common benign orbital tumors in adults. The c-KIT is a tyrosine kinase receptor, which is expressed on several types of cells, is thought to play a key role in tumor pathogenesis. The purpose of this study was to evaluate the presence of the receptor c-KIT in OCVH. Our retrospective study examined 16 orbital cavernous venous hemangiomas from 16 cases operated on between 2006–2016 at Emek Medical Center. The mean tumor size was 18.4 mm. Symptoms appeared between 6 months and 22 years before operation. All specimens were analyzed for the c-KIT receptor through immunohistochemistry. The c-KIT was expressed by the endothelium in all 16 preparates. Staining was strong in two cases, moderate in six, and weak in eight cases, with no statistically significant correlation between staining and tumor size (p = 0.69) or the symptom duration (p = 0.15). We conclude that c-KIT may play an important role in the pathogenesis of OCVH. This pilot study is significant in that tumor-targeted therapy such as Imatinib Mesylate and Sunitinib may have a role in treating surgically complicated cases located in the orbital apex. A large multicenter collaborative study is necessary to examine the role of c-KIT in OCVH.
Label-Free Detection and Spectrometrically Quantitative Analysis of the Cancer Biomarker CA125 Based on Lyotropic Chromonic Liquid Crystal
Authors: Shaban Hassanein , Lee Mon-Juan , Lee Wei
Published: August 2021

Compared with thermotropic liquid crystals (LCs), the biosensing potential of lyotropic chromonic liquid crystals (LCLCs), which are more biocompatible because of their hydrophilic nature, has scarcely been investigated. In this study, the nematic phase, a mesophase shared by both thermotropic LCs and LCLCs, of disodium cromoglycate (DSCG) was employed as the sensing mesogen in the LCLC-based biosensor. The biosensing platform was constructed so that the LCLC was homogeneously aligned by the planar anchoring strength of polyimide, but was disrupted in the presence of proteins such as bovine serum albumin (BSA) or the cancer biomarker CA125 captured by the anti-CA125 antibody, with the level of disturbance (and the optical signal thus produced) predominated by the amount of the analyte. The concentration- and wavelength-dependent optical response was analyzed by transmission spectrometry in the visible light spectrum with parallel or crossed polarizers. The concentration of CA125 can be quantified with spectrometrically derived parameters in a linear calibration curve. The limit of detection for both BSA and CA125 of the LCLC-based biosensor was superior or comparable to that of thermotropic LC-based biosensing techniques. Our results provide, to the best of our knowledge, the first evidence that LCLCs can be applied in spectrometrically quantitative biosensing.
Application of Micropore Device for Accurate, Easy, and Rapid Discrimination of Saccharomyces pastorianus from Dekkera spp.
Authors: Yokota Kazumichi , Takeo Asae , Abe Hiroko , Kurokawa Yuji , Hashimoto Muneaki , Kajimoto Kazuaki , Tanaka Masato , Murayama Sanae , Nakajima Yoshihiro , Taniguchi Masateru , Kataoka Masatoshi
Published: August 2021

Traceability analysis, such as identification and discrimination of yeasts used for fermentation, is important for ensuring manufacturing efficiency and product safety during brewing. However, conventional methods based on morphological and physiological properties have disadvantages such as time consumption and low sensitivity. In this study, the resistive pulse method (RPM) was employed to discriminate between Saccharomyces pastorianus and Dekkera anomala and S. pastorianus and D. bruxellensis by measuring the ionic current response of cells flowing through a microsized pore. The height and shape of the pulse signal were used for the simultaneous measurement of the size, shape, and surface charge of individual cells. Accurate discrimination of S. pastorianus from Dekkera spp. was observed with a recall rate of 96.3 ± 0.8%. Furthermore, budding S. pastorianus was quantitatively detected by evaluating the shape of the waveform of the current ionic blockade. We showed a proof-of-concept demonstration of RPM for the detection of contamination of Dekkera spp. in S. pastorianus and for monitoring the fermentation of S. pastorianus through the quantitative detection of budding cells.
The Relation of Callous–Unemotional Traits and Bullying in Early Adolescence Is Independent from Sex and Age and Moderated by Conduct Problems
Authors: Catone Gennaro , Almerico Luisa , Pezzella Anna , Riccio Maria Pia , Bravaccio Carmela , Bernardo Pia , Muratori Pietro , Pascotto Antonio , Pisano Simone , Senese Vincenzo Paolo
Published: August 2021

In youths, callous–unemotional (CU) traits and conduct problems (CP) are independently associated with bullying perpetration and these effects are also observed when controlling for sex. Moreover, research indicates that the co-existence of high levels of both CU and CP further increase the risk. Although several studies have examined the relationship between CU traits and traditional bullying, few have also included a measure of cyberbullying and very few of them have focused the early adolescence. The aim of this study was to replicate and extend these findings in a large sample of Italian early adolescents considering both traditional and cyberbullying behaviors. Data were extracted from the Bullying and Youth Mental Health Naples study (BYMHNS) which included 2959 students of 10–15 years of age. CP, CU traits, traditional bullying behaviors, and cyberbullying behaviors were assessed by multi-item self-report scales. As expected, we replicated the significant and specific association between CU traits and traditional bullying, extending the findings to cyberbullying. In addition, in the latter case the effect was moderated by CP. The theoretical and clinical implications of these results were discussed.
Verbal Short-Term Memory Disturbance in the Primary Progressive Aphasias: Challenges and Distinctions in a Clinical Setting
Authors: Foxe David , Cheung Sau Chi , Cordato Nicholas J. , Burrell James R. , Ahmed Rebekah M. , Taylor-Rubin Cathleen , Irish Muireann , Piguet Olivier
Published: August 2021

Impaired verbal ‘phonological’ short-term memory is considered a cardinal feature of the logopenic variant of primary progressive aphasia (lv-PPA) and is assumed to underpin most of the language deficits in this syndrome. Clinically, examination of verbal short-term memory in individuals presenting with PPA is common practice and serves two objectives: (i) to help understand the possible mechanisms underlying the patient’s language profile and (ii) to help differentiate lv-PPA from other PPA variants or from other dementia syndromes. Distinction between lv-PPA and the non-fluent variant of PPA (nfv-PPA), however, can be especially challenging due to overlapping language profiles and comparable psychometric performances on verbal short-term memory tests. Here, we present case vignettes of the three PPA variants (lv-PPA, nfv-PPA, and the semantic variant (sv-PPA)) and typical Alzheimer’s disease (AD). These vignettes provide a detailed description of the short-term and working memory profiles typically found in these patients and highlight how speech output and language comprehension deficits across the PPA variants differentially interfere with verbal memory performance. We demonstrate that a combination of verbal short-term and working memory measures provides crucial information regarding the cognitive mechanisms underlying language disturbances in PPA. In addition, we propose that analogous visuospatial span tasks are essential for the assessment of PPA as they measure memory capacity without language contamination.
Body Image Quality of Life Related to Light Physical Activity and Sedentary Behavior among Young Adults with Overweight/Obesity
Authors: Faro Jamie M. , Whiteley Jessica A. , Hayman Laura L. , Napolitano Melissa A.
Published: August 2021

Sedentary behaviors, low levels of physical activity (PA), and low body image quality of life have been identified during college years and associated with poor health outcomes. Public health efforts have recently focused on decreasing sedentary time by increasing light physical activity, both of which have been associated with body image quality of life, though mainly through self-report. In this cross-sectional study, we examined objective actigraphy and survey data from 404 of 459 young adults with overweight and obesity (mean age 23.3 ± 4.4 years, 78.4% female, 55.4% white). PA was measured using an accelerometer worn during waking hours for >10 h/day for four days. Body image quality of life was assessed using the Body Image Quality of Life Inventory Scale. Body image was positively correlated with light PA (r = 0.15) and inversely correlated with BMI (Pearson’s r = −0.20) and sedentary time (r = −0.10), but not moderate PA, vigorous PA, or MVPA. Light PA and sedentary time were significantly inversely correlated (r = −0.38). When controlling for covariates, higher body image quality of life was significantly associated with higher levels of light PA (β = 0.39; p < 0.01) and lower sedentary time (β = −0.39; p = 0.02). Participants with lower body image quality of life enrolled in weight loss interventions may benefit from prescriptions of light PA in conjunction with decreasing sedentary behaviors.
Seismic Hazard Assessment of Shigo Kas Hydro-Power Project (Khyber Pakhtunkhwa, Pakistan)
Authors: Abid Muhammad , Isleem Haytham F. , Shahzada Khan , Khan Afed Ullah , Kamal Shah Muhammad , Saeed Salman , Aslam Fahid
Published: August 2021

In this paper, a seismic hazard assessment (SHA) of the Shigo Kas hydropower project has been performed by deterministic and probabilistic approaches. The previously developed MATLAB-based code has been used for deterministic SHA, incorporating local site effects through deep soil analysis. On the other hand, for probabilistic SHA, CRISIS 2007 has been used through diffuse areal source zones. The latest updated earthquake instrumental and historical catalogs have been developed. Based on the recommendations of the International Commission on Large Dams, peak ground acceleration (PGA) values for the maximum credible earthquake (MCE), safety evaluation earthquake (SEE), design basis earthquake (DBE) and operating basis earthquake (OBE) have been assessed, which are 0.50 g, 0.68 g, 0.35 g and 0.24 g, respectively, at the intake location, and 0.50 g, 0.61 g, 0.30 g and 0.22 g, respectively, at the powerhouse location. Hazard maps have been developed for scenario-based earthquakes (MCE) and for the peak ground acceleration of 145-, 475- and 2500-year return periods. The de-aggregation process has evaluated the combined effects of magnitude and distance. At a distance of 30 to 70 km from the earthquake source, earthquakes of magnitude 5 Mw to 5.6 Mw and 5.9 Mw to 6.5 Mw are more hazardous for the current project.
Aberrant Plasma Cell Contamination of Peripheral Blood Stem Cell Autografts, Assessed by Next-Generation Flow Cytometry, Is a Negative Predictor for Deep Response Post Autologous Transplantation in Multiple Myeloma; A Prospective Study in 199 Patients
Authors: Kostopoulos Ioannis V. , Eleutherakis-Papaiakovou Evangelos , Rousakis Pantelis , Ntanasis-Stathopoulos Ioannis , Panteli Chrysanthi , Orologas-Stavrou Nikolaos , Kanellias Nikolaos , Malandrakis Panagiotis , Liacos Christine-Ivy , Papaioannou Nikos E. , Papanota Aristea-Maria , Migkou Magdalini , Fotiou Despina , Gavriatopoulou Maria , Angelis Nikolaos V. , Kastritis Efstathios , Dimopoulos Meletios-Athanasios , Tsitsilonis Ourania E. , Terpos Evangelos
Published: August 2021

High-dose chemotherapy with autologous stem cell support (ASCT) is the standard of care for eligible newly diagnosed Multiple Myeloma (MM) patients. Stem cell graft contamination by aberrant plasma cells (APCs) has been considered a possible predictive marker of subsequent clinical outcome, but the limited reports to date present unclear conclusions. We prospectively estimated the frequency of graft contamination using highly sensitive next-generation flow cytometry and evaluated its clinical impact in 199 myeloma patients who underwent an ASCT. Contamination (con+) was detected in 79/199 patients at a median level 2 × 10−5. Its presence and levels were correlated with response to induction treatment, with 94%, 71% and 43% achieving CR, VGPR and PR, respectively. Importantly, con+ grafts conferred 2-fold and 2.8-fold higher patient-risk of not achieving or delaying reaching CR (4 vs. 11 months) and MRD negativity (5 vs. 18 months) post ASCT, respectively. Our data also provide evidence of a potentially skewed bone marrow (BM) reconstitution due to unpurged grafts, since con+ derived BM had significantly higher prevalence of memory B cells. These data, together with the absence of significant associations with baseline clinical features, highlight graft contamination as a potential biomarker with independent prognostic value for deeper responses, including MRD negativity. Longer follow-up will reveal if this corresponds to PFS or OS advantage.
Heavy Metals in the Environment and Thyroid Cancer
Authors: Gianì Fiorenza , Masto Roberta , Trovato Maria Antonietta , Malandrino Pasqualino , Russo Marco , Pellegriti Gabriella , Vigneri Paolo , Vigneri Riccardo
Published: August 2021

In recent decades, the incidence of thyroid cancer has increased more than most other cancers, paralleling the generalized worldwide increase in metal pollution. This review provides an overview of the evidence supporting a possible causative link between the increase in heavy metals in the environment and thyroid cancer. The major novelty is that human thyroid stem/progenitor cells (thyrospheres) chronically exposed to different metals at slightly increased environmentally relevant concentrations show a biphasic increase in proliferation typical of hormesis. The molecular mechanisms include, for all metals investigated, the activation of the extracellular signal-regulated kinase (ERK1/2) pathway. A metal mixture, at the same concentration of individual metals, was more effective. Under the same conditions, mature thyrocytes were unaffected. Preliminary data with tungsten indicate that, after chronic exposure, additional abnormalities may occur and persist in thyrocytes derived from exposed thyrospheres, leading to a progeny population of transformation-prone thyroid cells. In a rat model predisposed to develop thyroid cancer, long-term exposure to low levels of metals accelerated and worsened histological signs of malignancy in the thyroid. These studies provide new insight on metal toxicity and carcinogenicity occurring in thyroid cells at a low stage of differentiation when chronically exposed to metal concentrations that are slightly increased, albeit still in the “normal” range.
Microbiota-Associated Metabolites and Related Immunoregulation in Colorectal Cancer
Authors: Chen Yan , Chen Ying-Xuan
Published: August 2021

A growing body of research has found close links between the human gut microbiota and colorectal cancer (CRC), associated with the direct actions of specific bacteria and the activities of microbiota-derived metabolites, which are implicated in complex immune responses, thus influencing carcinogenesis. Diet has a significant impact on the structure of the microbiota and also undergoes microbial metabolism. Some metabolites, such as short-chain fatty acids (SCFAs) and indole derivatives, act as protectors against cancer by regulating immune responses, while others may promote cancer. However, the specific influence of these metabolites on the host is conditional. We reviewed the recent insights on the relationships among diet, microbiota-derived metabolites, and CRC, focusing on their intricate immunomodulatory responses, which might influence the progression of colorectal cancer.
Circulating Cell-Free DNA as Biomarker of Taxane Resistance in Metastatic Castration-Resistant Prostate Cancer
Authors: Francini Edoardo , Ou Fang-Shu , Rhoades Justin , Wolfe Eric G. , O’Connor Edward P. , Ha Gavin , Gydush Gregory , Kelleher Kaitlin M. , Bhatt Rupal S. , Balk Steven P. , Sweeney Christopher J. , Adalsteinsson Viktor A. , Taplin Mary-Ellen , Choudhury Atish D.
Published: August 2021

There are no biomarkers predictive of resistance to docetaxel or cabazitaxel validated for patients with metastatic castration-resistant prostate cancer (mCRPC). We assessed the association between ABCB1 amplification and primary resistance to docetaxel or cabazitaxel for patients with mCRPC, using circulating cell-free DNA (cfDNA). Patients with ≥1 plasma sample drawn within 12 months before starting docetaxel (cohort A) or cabazitaxel (cohort B) for mCRPC were identified from the Dana–Farber Cancer Institute IRB approved database. Sparse whole genome sequencing was performed on the selected cfDNA samples and tumor fractions were estimated using the computational tool ichorCNA. We evaluated the association between ABCB1 amplification or other copy number alterations and primary resistance to docetaxel or cabazitaxel. Of the selected 176 patients, 45 samples in cohort A and 21 samples in cohort B had sufficient tumor content. No significant association was found between ABCB1 amplification and primary resistance to docetaxel (p = 0.58; odds ratio (OR) = 1.49) or cabazitaxel (p = 0.97; OR = 1.06). No significant association was found between exploratory biomarkers and primary resistance to docetaxel or cabazitaxel. In this study, ABCB1 amplification did not predict primary resistance to docetaxel or cabazitaxel for mCRPC. Future studies including ABCB1 amplification in a suite of putative biomarkers and a larger cohort may aid in drawing definitive conclusions.
RARβ Expression in Keratinocytes from Potentially Malignant Oral Lesions: The Functional Consequences of Re-Expression by De-Methylating Agents
Authors: Radhakrishnan Raghu , Crane Hannah L. , Daigneault Marc , Padam Kanaka Sai Ram , Hunter Keith D.
Published: August 2021

Loss of RARβ2 expression by promoter methylation is an early event in oral carcinogenesis. Understanding the mechanisms and consequences of RARβ loss may aid in understanding the disappointing results of retinoid chemoprevention trials. This study aimed to describe the effects of all-trans retinoic acid (ATRA) and the de-methylating agent 5-Aza-2′ deoxycytidine (5-AZA-CdR) on a panel of immortal potentially malignant oral lesion (PMOL) cell cultures. RARβ expression was assessed in PMOL tissues by immunohistochemistry. Cells were treated with ATRA ± 5-AZA-CdR, and the effects on the cell cycle and senescence were assessed. In PMOL tissues, RARβ expression was variable, but lower in biopsies which gave rise to immortal cell cultures. Treatment of iPMOL cells with ATRA resulted in little change in RARβ expression, but the addition of 5-AZA-CdR resulted in significant increases. The effects on the cell cycle and senescence were variable and may be related to 5-AZA-CdR, as this has wider effects on the cell cycle. Overall, the response of iPMOL cells to ATRA and 5-AZA-CdR treatment was variable and is dependent on several factors, including RARβ-promoter methylation. These findings may help to explain the lack of consistent effect of retinoids in PMOLs seen in chemoprevention trials.
Magnetic Resonance Relaxometry for Tumor Cell Density Imaging for Glioma: An Exploratory Study via 11C-Methionine PET and Its Validation via Stereotactic Tissue Sampling
Authors: Kinoshita Manabu , Uchikoshi Masato , Tateishi Souichiro , Miyazaki Shohei , Sakai Mio , Ozaki Tomohiko , Asai Katsunori , Fujita Yuya , Matsuhashi Takahiro , Kanemura Yonehiro , Shimosegawa Eku , Hatazawa Jun , Nakatsuka Shin-ichi , Kishima Haruhiko , Nakanishi Katsuyuki
Published: August 2021

One of the most crucial yet challenging issues for glioma patient care is visualizing non-contrast-enhancing tumor regions. In this study, to test the hypothesis that quantitative magnetic resonance relaxometry reflects glioma tumor load within tissue and that it can be an imaging surrogate for visualizing non-contrast-enhancing tumors, we investigated the correlation between T1- and T2-weighted relaxation times, apparent diffusion coefficient (ADC) on magnetic resonance imaging, and 11C-methionine (MET) on positron emission tomography (PET). Moreover, we compared the T1- and T2-relaxation times and ADC with tumor cell density (TCD) findings obtained via stereotactic image-guided tissue sampling. Regions that presented a T1-relaxation time of >1850 ms but <3200 ms or a T2-relaxation time of >115 ms but <225 ms under 3 T indicated a high MET uptake. In addition, the stereotactic tissue sampling findings confirmed that the T1-relaxation time of 1850–3200 ms significantly indicated a higher TCD (p = 0.04). However, ADC was unable to show a significant correlation with MET uptake or with TCD. Finally, synthetically synthesized tumor load images from the T1- and T2-relaxation maps were able to visualize MET uptake presented on PET.
Potential Valorization of Organic Waste Streams to Valuable Organic Acids through Microbial Conversion: A South African Case Study
Authors: Njokweni Sesethu Gift , Steyn Annica , Botes Marelize , Viljoen-Bloom Marinda , van Zyl Willem Heber
Published: August 2021

The notion of a “biobased economy” in the context of a developing country such as South Africa (SA) necessitates the development of technologies that utilize sustainable feedstocks, have simple and robust operations, are feasible at small scale and produce a variety of valuable bioproducts, thus fitting the biorefinery concept. This case study focuses on the microbial production of higher-value products from selected organic waste streams abundant in the South African agricultural sector using microbes adapted to utilize different parts of biomass waste streams. A ruminant-based carboxylate platform based on mixed or undefined anaerobic co-cultures of rumen microorganisms can convert the carbohydrate polymers in the lignocellulosic part of organic waste streams to carboxylic acids that can be upgraded to biofuels or green chemicals. Furthermore, yeast and fungi can convert the simpler carbohydrates (such as the sugars and malic acid in grape and apple pomace) to ethanol and high-value carboxylic acids, such as lactic, fumaric, succinic and citric acid. This review will discuss the combinational use of the ruminal carboxylate platform and native or recombinant yeasts to valorize biomass waste streams through the production of higher-value organic acids with various applications.
Hyaluronan and Its Receptors: Key Mediators of Immune Cell Entry and Trafficking in the Lymphatic System
Authors: Johnson Louise A. , Jackson David G.
Published: August 2021

Entry to the afferent lymphatics marks the first committed step for immune cell migration from tissues to draining lymph nodes both for the generation of immune responses and for timely resolution of tissue inflammation. This critical process occurs primarily at specialised discontinuous junctions in initial lymphatic capillaries, directed by chemokines released from lymphatic endothelium and orchestrated by adhesion between lymphatic receptors and their immune cell ligands. Prominent amongst the latter is the large glycosaminoglycan hyaluronan (HA) that can form a bulky glycocalyx on the surface of certain tissue-migrating leucocytes and whose engagement with its key lymphatic receptor LYVE-1 mediates docking and entry of dendritic cells to afferent lymphatics. Here we outline the latest insights into the molecular mechanisms by which the HA glycocalyx together with LYVE-1 and the related leucocyte receptor CD44 co-operate in immune cell entry, and how the process is facilitated by the unusual character of LYVE-1 • HA-binding interactions. In addition, we describe how pro-inflammatory breakdown products of HA may also contribute to lymphatic entry by transducing signals through LYVE-1 for lymphangiogenesis and increased junctional permeability. Lastly, we outline some future perspectives and highlight the LYVE-1 • HA axis as a potential target for immunotherapy.
Physiological Shear Stress Enhances Differentiation, Mucus-Formation and Structural 3D Organization of Intestinal Epithelial Cells In Vitro
Authors: Lindner Marcus , Laporte Anna , Block Stephan , Elomaa Laura , Weinhart Marie
Published: August 2021

Gastrointestinal (GI) mucus plays a pivotal role in the tissue homoeostasis and functionality of the gut. However, due to the shortage of affordable, realistic in vitro GI models with a physiologically relevant mucus layer, studies with deeper insights into structural and compositional changes upon chemical or physical manipulation of the system are rare. To obtain an improved mucus-containing cell model, we developed easy-to-use, reusable culture chambers that facilitated the application of GI shear stresses (0.002–0.08 dyn∙cm−2) to cells on solid surfaces or membranes of cell culture inserts in bioreactor systems, thus making them readily accessible for subsequent analyses, e.g., by confocal microscopy or transepithelial electrical resistance (TEER) measurement. The human mucus-producing epithelial HT29-MTX cell-line exhibited superior reorganization into 3-dimensional villi-like structures with highly proliferative tips under dynamic culture conditions when compared to static culture (up to 180 vs. 80 µm in height). Additionally, the median mucus layer thickness was significantly increased under flow (50 ± 24 vs. 29 ± 14 µm (static)), with a simultaneous accelerated maturation of the cells into a goblet-like phenotype. We demonstrated the strong impact of culture conditions on the differentiation and reorganization of HT29-MTX cells. The results comprise valuable advances towards the improvement of existing GI and mucus models or the development of novel systems using our newly designed culture chambers.
Applying Bioinformatic Platforms, In Vitro, and In Vivo Functional Assays in the Characterization of Genetic Variants in the GH/IGF Pathway Affecting Growth and Development
Authors: Domené Sabina , Scaglia Paula A. , Gutiérrez Mariana L. , Domené Horacio M.
Published: August 2021

Heritability accounts for over 80% of adult human height, indicating that genetic variability is the main determinant of stature. The rapid technological development of Next-Generation Sequencing (NGS), particularly Whole Exome Sequencing (WES), has resulted in the characterization of several genetic conditions affecting growth and development. The greatest challenge of NGS remains the high number of candidate variants identified. In silico bioinformatic tools represent the first approach for classifying these variants. However, solving the complicated problem of variant interpretation requires the use of experimental approaches such as in vitro and, when needed, in vivo functional assays. In this review, we will discuss a rational approach to apply to the gene variants identified in children with growth and developmental defects including: (i) bioinformatic tools; (ii) in silico modeling tools; (iii) in vitro functional assays; and (iv) the development of in vivo models. While bioinformatic tools are useful for a preliminary selection of potentially pathogenic variants, in vitro—and sometimes also in vivo—functional assays are further required to unequivocally determine the pathogenicity of a novel genetic variant. This long, time-consuming, and expensive process is the only scientifically proven method to determine causality between a genetic variant and a human genetic disease.
Generation, Characterization, and Application of Inducible Proliferative Adult Human Epicardium-Derived Cells
Authors: Ge Yang , Smits Anke M. , Liu Jia , Zhang Juan , van Brakel Thomas J. , Goumans Marie José T. H. , Jongbloed Monique R. M. , de Vries Antoine A. F.
Published: August 2021

Rationale: In recent decades, the great potential of human epicardium-derived cells (EPDCs) as an endogenous cell source for cardiac regeneration has been recognized. The limited availability and low proliferation capacity of primary human EPDCs and phenotypic differences between EPDCs obtained from different individuals hampers their reproducible use for experimental studies. Aim: To generate and characterize inducible proliferative adult human EPDCs for use in fundamental and applied research. Methods and results: Inducible proliferation of human EPDCs was achieved by doxycycline-controlled expression of simian virus 40 large T antigen (LT) with a repressor-based lentiviral Tet-On system. In the presence of doxycycline, these inducible EPDCs (iEPDCs) displayed high and long-term proliferation capacity. After doxycycline removal, LT expression ceased and the iEPDCs regained their cuboidal epithelial morphology. Similar to primary EPDCs, iEPDCs underwent an epithelial-to-mesenchymal transition (EMT) after stimulation with transforming growth factor β3. This was confirmed by reverse transcription-quantitative polymerase chain reaction analysis of epithelial and mesenchymal marker gene expression and (immuno) cytochemical staining. Collagen gel-based cell invasion assays demonstrated that mesenchymal iEPDCs, like primary EPDCs, possess increased invasion and migration capacities as compared to their epithelial counterparts. Mesenchymal iEPDCs co-cultured with sympathetic ganglia stimulated neurite outgrowth similarly to primary EPDCs. Conclusion: Using an inducible LT expression system, inducible proliferative adult human EPDCs were generated displaying high proliferative capacity in the presence of doxycycline. These iEPDCs maintain essential epicardial characteristics with respect to morphology, EMT ability, and paracrine signaling following doxycycline removal. This renders iEPDCs a highly useful new in vitro model for studying human epicardial properties.
miR193a-5p Mediated ZNF746 and c-Myc Signaling Axis Is Critically Involved in Morusin Induced Apoptosis in Colorectal Cancer Cells
Authors: Park Woon-Yi , Lee Hyo-Jung , Sim Deok-Yong , Im Eunji , Park Ji-Eon , Ahn Chi-Hoon , Shim Bum-Sang , Kim Sung-Hoon
Published: August 2021

Novel target therapy is on the spotlight for effective cancer therapy. Hence, in the present study, the underlying apoptotic mechanism of Morusin was explored in association with miR193a-5p mediated ZNF746/c-Myc signaling axis in colorectal cancer cells (CRCs). Herein, Morusin reduced the viability and the number of colonies in HCT116 and SW480 CRCs. Additionally, Morusin increased sub-G1 population, cleavages of poly (ADP-ribose) polymerase (PARP) and caspase-3 and inhibited the expression of zinc finger protein 746 (ZNF746) and c-Myc in HCT116 and SW480 cells. Conversely, overexpression of ZNF746 suppressed the ability of Morusin to abrogate the expression of c-Myc in HCT116 cells, as ZNF746 enhanced the stability of c-Myc via their direct binding through nuclear colocalization in HCT116 cells by immunofluorescence and immunoprecipitation. Notably, Morusin upregulated miR193a-5p as a tumor suppressor, while miR193a-5p inhibitor masked the ability of Morusin to reduce the expression of ZNF746, c-Myc, and pro-PARP in HCT116 cells. To our knowledge, these findings provide the novel insight on miR193a-5p mediated inhibition of ZNF746/c-Myc signaling in Morusin induced apoptosis in CRCs.
Microglia-Derived Small Extracellular Vesicles Reduce Glioma Growth by Modifying Tumor Cell Metabolism and Enhancing Glutamate Clearance through miR-124
Authors: Serpe Carmela , Monaco Lucia , Relucenti Michela , Iovino Ludovica , Familiari Pietro , Scavizzi Ferdinando , Raspa Marcello , Familiari Giuseppe , Civiero Laura , D’Agnano Igea , Limatola Cristina , Catalano Myriam
Published: August 2021

Brain homeostasis needs continuous exchange of intercellular information among neurons, glial cells, and immune cells, namely microglial cells. Extracellular vesicles (EVs) are active players of this process. All the cells of the body, including the brain, release at least two subtypes of EVs, the medium/large EVs (m/lEVs) and small EVs (sEVs). sEVs released by microglia play an important role in brain patrolling in physio-pathological processes. One of the most common and malignant forms of brain cancer is glioblastoma. Altered intercellular communications constitute a base for the onset and the development of the disease. In this work, we used microglia-derived sEVs to assay their effects in vitro on murine glioma cells and in vivo in a glioma model on C57BL6/N mice. Our findings indicated that sEVs carry messages to cancer cells that modify glioma cell metabolism, reducing lactate, nitric oxide (NO), and glutamate (Glu) release. sEVs affect Glu homeostasis, increasing the expression of Glu transporter Glt-1 on astrocytes. We demonstrated that these effects are mediated by miR-124 contained in microglia-released sEVs. The in vivo benefit of microglia-derived sEVs results in a significantly reduced tumor mass and an increased survival of glioma-bearing mice, depending on miR-124.
Silicon Carbide Wafer Machining by Using a Single Filament Plasma at Atmospheric Pressure
Authors: Yoo Seungryul , Seok Dong Chan , Lee Kang Il , Jung Yong Ho , Choi Yong Sup
Published: August 2021

SiC wafers were etched using a filament plasma of He:NF3:O2 (helium:nitrogen trifluoride:oxygen) mixed gas at atmospheric pressure. When 0.5–2 sccm of NF3 was mixed to 2 slm of He filament plasma, the etch depth and etch rate increased, but there was little change in the etch width as the NF3 mixing amount increased. The increment of the NF3 mixing also suppressed the surface roughening of plasma etching. The addition of O2 to the He-NF3 filament plasma slightly increased the SiC wafer etch rate. When the NF3 mixing amount was 2 sccm, the roughness of the etched surface increased sharply by O2 addition. On the contrary, the NF3 mixing amount was 1 sccm; the addition of O2 reduced the roughness more than that of the pristine. The roughness of the pristine SiC wafer specimens is in the range of Ra 0.7–0.8 nm. After 30 min of etching on a 6 mm by 6 mm square area, the roughness of the etched surface reduced to Ra 0.587 nm, while the etch rate was 2.74 μm/h with a He:NF3:O2 of 2:1:3 (slm:sccm:sccm) filament plasma and 3 mm/s speed of raster scan etch of the optimized roughening suppression etching recipe.
An Integrated Mobile Augmented Reality Digital Twin Monitoring System
Authors: He F. , Ong S. K. , Nee A. Y. C.
Published: August 2021

The increasing digitalization and advancement in information communication technologies has greatly changed how humans interact with digital information. Nowadays, it is not sufficient to only display relevant data in production activities, as the enormous amount of data generated from smart devices can overwhelm operators without being fully utilized. Operators often require extensive knowledge of the machines in use to make informed decisions during processes such as maintenance and production. To enable novice operators to access such knowledge, it is important to reinvent the way of interacting with digitally enhanced smart devices. In this research, a mobile augmented reality remote monitoring system is proposed to help operators with low knowledge and experience level comprehend digital twin data of a device and interact with the device. It analyses both historic logs as well as real-time data through a cloud server and enriches 2D data with 3D models and animations in the 3D physical space. A cloud-based machine learning algorithm is applied to transform learned knowledge into live presentations on a mobile device for users to interact with. A scaled-down case study is conducted using a tower crane model to demonstrate the potential benefits as well as implications when the system is deployed in industrial environments. This user study verifies that the proposed solution yields consistent measurable improvements for novice users in human-device interaction that is statistically significant.
Pharmacists’ Insights and Behaviors in Preventing the Misuse of Topical Corticosteroids in Pakistan: A Mixed-Method Study
Authors: Shakeel Sadia , Nesar Shagufta , Iffat Wajiha , Rehman Hina , Aziz Samreen , Mumtaz Tayyaba , Hadi Hazrina , Jamshed Shazia
Published: August 2021

Topical corticosteroids (TCs) misuse has become a common issue for healthcare professionals and patients, particularly in Pakistan, as no stringent laws or rules are prohibiting the selling of over-the-counter medicines. The present study was designed to examine pharmacists’ insights and behaviors regarding TCs and their potential role in preventing the misuse of TCs in Pakistan. The study was a cross-sectional mixed-methods research design (phase 1, quantitative; and phase 2, qualitative) conducted from January to June 2021. The pharmacists working in various settings in Karachi were approached through different social media platforms. Data were collected through a web link of an online questionnaire with 30 closed-ended questions. Different statistical methods were employed for tabulating the quantitative data, while inductive thematic analysis was directed to classify themes from the qualitative data and to conclude findings. The mean cumulative knowledge score was 10.59 ± 1.63. The community pharmacists knew more about the available over-the-counter TCs (p = 0.041). The experienced pharmacists were more conversant than fresh pharmacists, regarding the mode of action (p = 0.008), choice of TC potency (p = 0.001), and most common local and systemic adverse effects of TCs (p = 0.001). Overall, respondents had a favorable attitude, with more than 80% agreeing that pharmacists could ensure that important safety issues are communicated with patients, and assist considerably in avoiding TC misuse. Analysis of data has produced 7 themes, 10 sub-themes, and 30 categories. Major themes included: use and misuse of TCs, adverse drug events due to TCs, cosmeto-vigilance, patient education, referral to a physician, and future perspectives for preventing TC misuse. The respondents were well versed with the dilemma of TCs misuse, and they considered patient characteristics, free availability of TCs, and lack of physician-pharmacist coordination as the major reasons. The major barriers for patient education stated by nearly all the respondents were a lack of time and lack of material/information for counseling. They emphasized the need for stringent legal strategies and the enforcement of current drug-control regulations, so that TCs are not supplied without appropriate prescriptions. The present findings indicate that pharmacists had appropriate knowledge and a positive attitude towards their potential role in preventing the misuse of TCs. Further education and sensitization in areas of deprived knowledge will undoubtedly aid in the prevention of TCs misuse by the community.
Surface Passivation Using N-Type Organic Semiconductor by One-Step Method in Two-Dimensional Perovskite Solar Cells
Authors: Wang Helong , Liu Guanchen , Xu Chongyang , Zeng Fanming , Xie Xiaoyin , Wu Sheng
Published: August 2021

Surface passivation, which has been intensively studied recently, is essential for the perovskite solar cells (PSCs), due to the intrinsic defects in perovskite crystal. A series of chemical or physical methods have been published for passivating the defects of perovskites, which effectively suppressed the charge recombination and enhanced the photovoltaic performance. In this study, the n-type semiconductor of [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) is dissolved in chlorobenzene (CB) for the surface passivation during the spin-coating process for depositing the two-dimensional (2D) perovskite film. This approach simplifies the fabrication process of 2D PSCs and benefits the film quality. As a result, the defects of perovskite film are effectively passivated by this method. A better perovskite/PCBM heterojunction is generated, exhibiting an increased film coverage and improved film morphology of PCBM. It is found that this technology results in an improved electron transporting performance as well as suppressed charge recombination for electron transport layer. As a result, PSCs based on the one-step formed perovskite/PCBM heterojunctions exhibit the optimized power conversion efficiency of 15.69% which is about 37% higher than that of regular perovskite devices. The device environmental stability is also enhanced due to the quality improved electron transport layer.