bluuebunny/crossref_metadata_2025 huggingface dataset:
Digital versus Traditional Workflow for Immediate Loading in Single-Implant Restoration: A Randomized Clinical Trial
Authors: Capparé Paolo , Ferrini Francesco , Ruscica Corrado , Pantaleo Giuseppe , Tetè Giulia , Gherlone Enrico Felice
Published: December 2021

The purpose of this randomized controlled trial was to compare the immediate-loading protocol, in single restorations in the esthetic zone, by comparing the digital workflow in a test group (TG) vs. the analogical workflow in a control group (CG). A total of 50 patients were enrolled, requiring single hopeless tooth extraction. Twenty-five patients (TG) were randomly assigned to the immediate-loading protocol using the digital workflow, and twenty-five patients (CG) were assigned to the conventional workflow. Clinical and radiographic parameters were evaluated at the time of implant insertion (baseline) and after 3, 6 and 12 months, respectively. A clinician blind to conditions measured the Pink Esthetic Score (PES), as well as patient satisfaction. At 12-month follow-up, a cumulative survival rate of 100% was reported for all implants. No failures or biological complications were observed. No statistically significant differences were detected in the mean values of marginal bone loss and PES between the TG (0.12 ± 0.66 mm for MBL, 7.75 ± 0.89 for PES) and the CG (0.15 ± 0.54 mm for MBL, 7.50 ± 0.89 for PES). In 11 cases of TG, and 10 cases of CG, a one-year follow-up period showed an increased marginal bone level. No statistically significant differences were found in the mean total PES between test (7.75 ± 0.89) and control (7.5 ± 0.81) conditions. Furthermore, a customer satisfaction survey showed that patients preferred the digital workflow over the conventional workflow procedure (97.6 ± 4.3 vs. 69.2 ± 13.8). Digital workflow was more time-efficient than conventional workflow (97.2 ± 7.3 vs. 81.2 ± 11.3). Within the limitations of this study, no statistically significant differences were found between digital and traditional workflow.
Which Properties Allow Ligands to Open and Bind to the Transient Binding Pocket of Human Aldose Reductase?
Authors: Sandner Anna , Ngo Khang , Sager Christoph , Scheer Frithjof , Daude Michael , Diederich Wibke , Heine Andreas , Klebe Gerhard
Published: December 2021

The transient specificity pocket of aldose reductase only opens in response to specific ligands. This pocket may offer an advantage for the development of novel, more selective ligands for proteins with similar topology that lack such an adaptive pocket. Our aim was to elucidate which properties allow an inhibitor to bind in the specificity pocket. A series of inhibitors that share the same parent scaffold but differ in their attached aromatic substituents were screened using ITC and X-ray crystallography for their ability to occupy the pocket. Additionally, we investigated the electrostatic potentials and charge distribution across the attached terminal aromatic groups with respect to their potential to bind to the transient pocket of the enzyme using ESP calculations. These methods allowed us to confirm the previously established hypothesis that an electron-deficient aromatic group is an important prerequisite for opening and occupying the specificity pocket. We also demonstrated from our crystal structures that a pH shift between 5 and 8 does not affect the binding position of the ligand in the specificity pocket. This allows for a comparison between thermodynamic and crystallographic data collected at different pH values.
A Proteomic Approach to Identify Zein Proteins upon Eco-Friendly Ultrasound-Based Extraction
Authors: Darie-Ion Laura , Jayathirtha Madhuri , Hitruc Gabriela Elena , Zaharia Marius-Mihai , Gradinaru Robert Vasile , Darie Costel C. , Pui Aurel , Petre Brindusa Alina
Published: December 2021

Zein is a type of prolamin storage protein that has a variety of biomedical and industrial applications. Due to the considerable genetic variability and polyploidity of the starting material, as well as the extraction methods used, the characterization of the protein composition of zein requires a combination of different analytical processes. Therefore, we combined modern analytical methods such as mass spectrometry (MS), Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), atomic force microscopy (AFM), or Fourier transform infrared spectroscopy–attenuated total reflectance (FTIR-ATR) for a better characterization of the extracted zein. In this study, we present an enhanced eco-friendly extraction method, including grinding and sieving corn seeds, for prolamins proteins using an ultrasonic extraction methodology. The use of an ultrasonic homogenizer, 65% ethanol extraction buffer, and 710 µm maize granulation yielded the highest protein extraction from all experimental conditions we employed. An SDS PAGE analysis of the extracted zein protein mainly revealed two intense bands of approximatively 20 and 23 kDa, suggesting that the extracted zein was mostly α-zein monomer. Additionally, MS analysis revealed as a main component the α-zein PMS2 (Uniprot accession no. P24450) type protein in the maize flour extract. Moreover, AFM studies show that extracting zein with a 65% ethanol and a 710 µm granulation yields a homogeneous content that could allow these proteins to be employed in future medical applications. This research leads to a better understanding of zeins content critical for developing new applications of zein in food and pharmaceutical industries, such as biocompatible medical vehicles based on polyplexes complex nanoparticles of zein with antimicrobial or drug delivery properties.
Identification and Validation of PLOD2 as an Adverse Prognostic Biomarker for Oral Squamous Cell Carcinoma
Authors: Sun Yawei , Wang Shuai , Zhang Xingwei , Wu Zhuhao , Li Zihui , Ding Zhuang , Huang Xiaofeng , Chen Sheng , Jing Yue , Zhang Xiaoxin , Ding Liang , Song Yuxian , Sun Guowen , Ni Yanhong
Published: December 2021

Background: Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2), a key enzyme that catalyzes the hydroxylation of lysine, plays a crucial role in the progression of several solid tumors. However, its spatial expression profile and prognostic significance in oral squamous cell carcinoma (OSCC) have not been revealed. Materials: Mass spectrometry was used to explore amino acid perturbations between OSCC tumor tissues and paired normal tissues of 28 patients. Then, PLOD2 mRNA and protein levels were assessed using several public databases and 18 pairs of OSCC patients’ tissues. Additionally, PLOD2 spatial expression profiles were investigated in 100 OSCC patients by immunohistochemistry and its diagnostic and prognostic values were also evaluated. Lastly, gene set enrichment analysis (GSEA) was used to investigate the potential functions of PLOD2 in OSCC. Results: Lysine was significantly elevated in OSCC tissues and could effectively distinguish tumor from normal tissues (AUC = 0.859, p = 0.0035). PLOD2 mRNA and protein levels were highly increased in tumor tissues of head and neck squamous cell carcinoma (HNSCC) (p < 0.001) and OSCC compared with those in nontumor tissues (p < 0.001). Histopathologically, PLOD2 was ubiquitously expressed in tumor cells (TCs) and fibroblast-like cells (FLCs) of OSCC patients but absent in tumor-infiltrating lymphocytes (TILs). Patients with highly expressed PLOD2 in TCs (PLOD2TCs) and FLCs (PLOD2FLCs) showed poor differentiation, a worse pattern of invasion (WPOI) and more lymph node metastasis (LNM), contributing to higher postoperative metastasis risk and poor survival time. However, PLOD2FLCs rather than PLOD2TCs was an independent risk factor for survival outcomes in OSCC patients. Molecularly, GSEA demonstrated highly expressed PLOD2 was mainly enriched in epithelial–mesenchymal transformation (EMT), TGF-beta signaling and hypoxia pathway, which are associated with poor clinical outcomes of OSCC patients. Conclusions: PLOD2 was a poor prognostic biomarker for OSCC patients and may affect the metastasis of OSCC through EMT pathway. These findings might shed novel sights for future research in PLOD2 targeted OSCC therapy.
On Demand Biosensors for Early Diagnosis of Cancer and Immune Checkpoints Blockade Therapy Monitoring from Liquid Biopsy
Authors: Mummareddy Sai , Pradhan Stuti , Narasimhan Ashwin , Natarajan Arutselvan
Published: December 2021

Recently, considerable interest has emerged in the development of biosensors to detect biomarkers and immune checkpoints to identify and measure cancer through liquid biopsies. The detection of cancer biomarkers from a small volume of blood is relatively fast compared to the gold standard of tissue biopsies. Traditional immuno-histochemistry (IHC) requires tissue samples obtained using invasive procedures and specific expertise as well as sophisticated instruments. Furthermore, the turnaround for IHC assays is usually several days. To overcome these challenges, on-demand biosensor-based assays were developed to provide more immediate prognostic information for clinicians. Novel rapid, highly precise, and sensitive approaches have been under investigation using physical and biochemical methods to sense biomarkers. Additionally, interest in understanding immune checkpoints has facilitated the rapid detection of cancer prognosis from liquid biopsies. Typically, these devices combine various classes of detectors with digital outputs for the measurement of soluble cancer or immune checkpoint (IC) markers from liquid biopsy samples. These sensor devices have two key advantages: (a) a small volume of blood drawn from the patient is sufficient for analysis, and (b) it could aid physicians in quickly selecting and deciding the appropriate therapy regime for the patients (e.g., immune checkpoint blockade (ICB) therapy). In this review, we will provide updates on potential cancer markers, various biosensors in cancer diagnosis, and the corresponding limits of detection, while focusing on biosensor development for IC marker detection.
Application of Tamm Plasmon Polaritons and Cavity Modes for Biosensing in the Combined Spectroscopic Ellipsometry and Quartz Crystal Microbalance Method
Authors: Plikusienė Ieva , Bužavaitė-Vertelienė Ernesta , Mačiulis Vincentas , Valavičius Audrius , Ramanavičienė Almira , Balevičius Zigmas
Published: December 2021

Low-cost 1D plasmonic photonic structures supporting Tamm plasmon polaritons and cavity modes were employed for optical signal enhancement, modifying the commercially available quartz crystal microbalance with dissipation (QCM-D) sensor chip in a combinatorial spectroscopic ellipsometry and quartz microbalance method. The Tamm plasmon optical state and cavity mode (CM) for the modified mQCM-D sample obtained sensitivity of ellipsometric parameters to RIU of ΨTPP = 126.78 RIU−1 and ΔTPP = 325 RIU−1, and ΨCM = 264 RIU−1 and ΔCM = 645 RIU−1, respectively. This study shows that Tamm plasmon and cavity modes exhibit about 23 and 49 times better performance of ellipsometric parameters, respectively, for refractive index sensing than standard spectroscopic ellipsometry on a QCM-D sensor chip. It should be noted that for the optical biosensing signal readout, the sensitivity of Tamm plasmon polaritons and cavity modes are comparable with and higher than the standard QCM-D sensor chip. The different origin of Tamm plasmon polaritons (TPP) and cavity mode (CM) provides further advances and can determine whether the surface (TPP) or bulk process (CM) is dominating. The dispersion relation feature of TPP, namely the direct excitation without an additional coupler, allows the possibility to enhance the optical signal on the sensing surface. To the best of our knowledge, this is the first study and application of the TPP and CM in the combinatorial SE-QCM-D method for the enhanced readout of ellipsometric parameters.
Quarantine Hotels: The Adaptation of Hotels for Quarantine Use in Australia
Authors: Dincer Demet , Gocer Ozgur
Published: December 2021

The COVID-19 global health crisis has spatial implications concerning social isolation to control the spread of the virus. The preventive measures require travelers to stay in mandatory quarantine for 14 days upon arrival from another country. Due to a shortage of government facilities, more hotels have started to function as quarantine facilities. This research focuses on quarantine hotels in Australia, as one of the first countries to implement an international border restriction, to evaluate the spatial needs of users and what see outcomes can be identified. By primarily focusing on hotel users’ well-being during the isolation period, this paper responds to an information gap regarding the quarantine hotel system by providing user opinions on the negative and positive factors affecting their well-being. A survey with multiple-choice and open-ended questionnaire items was conducted with 54 participants to investigate their experiences in quarantine hotels. Among the nine key sources of well-being, the three highest-scored responses were an operable window (4.7), ventilation (4.5), and natural lighting (4.3). Access to the outdoor environment via a balcony or operable window was an acute and fundamental requirement for guests. Additionally, participants mentioned that they are unwilling to return to the hotel where they spent their quarantine, which raises issues regarding the future of hotels.
Microdosing of Psychoactive Substances in Business Practice
Authors: Lehmert Karel , Ambrozova Eva , Pokorny Vratislav , Kolenak Jiri
Published: December 2021

Abusing psychoactive substances has been a popular sport in the business world since the mid-19th century. First, they were appreciated for their stimulating or tonic effects, but later with psychedelics on the scene, their importance in subculture matured. In the last decade, it has become very popular to use LSD and cocaine in subtle doses, which provides users with a high that is enough to feel their psychoactive potential, but not as high that significant behavioral changes can be seen. Unlike regular use, microdosing is usually sufficient to affect a few without undue finish and withdrawal symptoms. It allows for abuse in the regular mode of the working week with a rest phase on the weekend. The diametric difference between the abuse of standard dosing and micro-dosing is also in the decreasing tolerance of the organism. Over time, an organism permanently exposed to microdosing of stimulants is sufficient to achieve a gradually decreasing dose effect that psychedelics develop resistance to. Case studies of such prolonged use were described and analyzed to show the role of microdosing in the creative world and for business managers. Initial field research, funded by the Newton University internal grant, focused on contamination mapping in office spaces for employees in target positions. Further research continues on the investigation of microdosing in conditions of corporate reality.
Promising Antigens for the New Frontier of Targeted Immunotherapy in Multiple Myeloma
Authors: Cho Shih-Feng , Xing Lijie , Anderson Kenneth C. , Tai Yu-Tzu
Published: December 2021

The incorporation of novel agents in recent treatments in multiple myeloma (MM) has improved the clinical outcome of patients. Specifically, the approval of monoclonal antibody (MoAb) against CD38 (daratumumab) and SLAMF7 (elotuzumab) in relapsed and refractory MM (RRMM) represents an important milestone in the development of targeted immunotherapy in MM. These MoAb-based agents significantly induce cytotoxicity of MM cells via multiple effector-dependent mechanisms and can further induce immunomodulation to repair a dysfunctional tumor immune microenvironment. Recently, targeting B cell maturation antigen (BCMA), an even MM-specific antigen, has shown high therapeutic activities by chimeric antigen receptor T cells (CAR T), antibody-drug conjugate (ADC), bispecific T-cell engager (BiTE), as well as bispecific antibody (BiAb), with some already approved for heavily pretreated RRMM patients. New antigens, such as orphan G protein-coupled receptor class C group 5 member D (GPRC5D) and FcRH5, were identified and rapidly moved to ongoing clinical studies. We here summarized the pathobiological function of key MM antigens and the status of the corresponding immunotherapies. The potential challenges and emerging treatment strategies are also discussed.
Implementation and Effectiveness of Novel Therapeutic Substances for Advanced Malignant Melanoma in Saxony, Germany, 2010–2020—Cohort Study Based on Administrative Data
Authors: Datzmann Thomas , Schmitt Jochen , Fuhrmann Saskia , Roessler Martin , Meier Friedegund , Schoffer Olaf
Published: December 2021

(1) Background: Targeted (TT) and immune checkpoint inhibitor (ICI) therapies have become available in the routine care of metastatic melanoma in recent years. (2) Objective: We compared mortality in patients with metastatic melanoma and different systemic therapies. (3) Methods: A retrospective cohort study, based on pseudonymized health insurance data of about two million individuals from Saxony, Germany, was conducted for the years 2010 to 2020. Only patients with an advanced stage, i.e., distant metastases were considered for the main analysis. Relative survival since metastasis and predicted survivor curves derived from a Cox model were used to assess potential differences in mortality. (4) Results: Relative survival was highest in the subgroup with sequential use of ICI and TT. All treatments except interferon had significant hazard ratios (HR) in the Cox model with time-dependent effects indicating a protective effect after treatment initiation (HR 0.01–0.146) but decreasing over time (HR 1.351–2.310). The predicted survivor curves revealed best survival under ICI-TT treatment and worst survival under TT treatment alone. (5) Conclusions: We found real-world evidence for survival benefits of patients with metastatic melanoma who received sequential ICI and TT treatment. It is conceivable that the observed high survival differences were overestimated due to bias, such as confounding by indication.
Correction: Lin et al. Potent Anticancer Effects of Epidithiodiketopiperazine NT1721 in Cutaneous T Cell Lymphoma. Cancers 2021, 13, 3367
Authors: Lin Min , Kowolik Claudia M. , Xie Jun , Yadav Sushma , Overman Larry E. , Horne David A.
Published: December 2021

There is an omission in the Institutional Review Board Statement and Conflict of Interest statements of the paper [...]
Molecular Targeted Positron Emission Tomography Imaging and Radionuclide Therapy of Pancreatic Ductal Adenocarcinoma
Authors: Poels Thomas T. , Vuijk Floris A. , de Geus-Oei Lioe-Fee , Vahrmeijer Alexander L. , Oprea-Lager Daniela E. , Swijnenburg Rutger-Jan
Published: December 2021

Pancreatic ductal adenocarcinoma (PDAC) has an inauspicious prognosis, mainly due to difficulty in early detection of the disease by the current imaging modalities. The upcoming development of tumour-specific tracers provides an alternative solution for more accurate diagnostic imaging techniques for staging and therapy response monitoring. The future goal to strive for, in a patient with PDAC, should definitely be first to receive a diagnostic dose of an antibody labelled with a radionuclide and to subsequently receive a therapeutic dose of the same labelled antibody with curative intent. In the first part of this paper, we summarise the available evidence on tumour-targeted diagnostic tracers for molecular positron emission tomography (PET) imaging that have been tested in humans, together with their clinical indications. Tracers such as radiolabelled prostate-specific membrane antigen (PSMA)—in particular, 18F-labelled PSMA—already validated and successfully implemented in clinical practice for prostate cancer, also seem promising for PDAC. In the second part, we discuss the theranostic applications of these tumour-specific tracers. Although targeted radionuclide therapy is still in its infancy, lessons can already be learned from early publications focusing on dose fractioning and adding a radiosensitiser, such as gemcitabine.
Transcriptional Regulation of Amino Acid Transport in Glioblastoma Multiforme
Authors: Umans Robyn A. , Martin Joelle , Harrigan Megan E. , Patel Dipan C. , Chaunsali Lata , Roshandel Aarash , Iyer Kavya , Powell Michael D. , Oestreich Ken , Sontheimer Harald
Published: December 2021

Glioblastoma multiforme (GBM) is a deadly brain tumor with a large unmet therapeutic need. Here, we tested the hypothesis that wild-type p53 is a negative transcriptional regulator of SLC7A11, the gene encoding the System xc- (SXC) catalytic subunit, xCT, in GBM. We demonstrate that xCT expression is inversely correlated with p53 expression in patient tissue. Using representative patient derived (PDX) tumor xenolines with wild-type, null, and mutant p53 we show that p53 expression negatively correlates with xCT expression. Using chromatin immunoprecipitation studies, we present a molecular interaction whereby p53 binds to the SLC7A11 promoter, suppressing gene expression in PDX GBM cells. Accordingly, genetic knockdown of p53 increases SLC7A11 transcript levels; conversely, over-expressing p53 in p53-null GBM cells downregulates xCT expression and glutamate release. Proof of principal studies in mice with flank gliomas demonstrate that daily treatment with the mutant p53 reactivator, PRIMA-1Met, results in reduced tumor growth associated with reduced xCT expression. These findings suggest that p53 is a molecular switch for GBM glutamate biology, with potential therapeutic utility.
Kinetics of Grape Seed Oil Epoxidation in Supercritical CO2
Authors: Catalá Juan , García-Vargas Jesús Manuel , Ramos María Jesús , Rodríguez Juan Francisco , García María Teresa
Published: December 2021

The epoxidation of grape seed oil in supercritical CO2, to the best of our knowledge, has been only superficially described in the literature, apart from a short communication and our own previous published work on the topic. In this work, a thorough study of the performance of the supercritical epoxidation of grape seed oil is performed in a wide range of conditions, and the kinetic parameters of the supercritical epoxidation of vegetable oils are reported for the first time in the literature. The experimental work has covered a 40–60 °C temperature range at 150 bar, sampling during a period of 48 h. The nature and extent of the side reactions and secondary products obtained have been evaluated, being hydrolysis products and their oligomerization derivatives the major by-products. Reaction rate constants (10−2 h−1 order) and activation energy parameters were finally calculated from the experimental conversion and epoxy yield data to establish the effect of temperature on the kinetics of the process.
Electrocatalysts for Energy Conversion and Storage Devices
Authors: Baglio Vincenzo
Published: December 2021

Energy’s efficient conversion and storage are closely correlated to the development of electrochemical energy technologies, such as fuel cells, batteries, electrolyzers, etc [...]
Giardia duodenalis and Its Secreted PPIB Trigger Inflammasome Activation and Pyroptosis in Macrophages through TLR4-Induced ROS Signaling and A20-Mediated NLRP3 Deubiquitination
Authors: Liu Lin , Yang Yongwu , Fang Rui , Zhu Weining , Wu Jingxue , Li Xiaoyun , Patankar Jay V. , Li Wei
Published: December 2021

The extracellular protozoan parasite Giardia duodenalis is a well-known and important causative agent of diarrhea on a global scale. Macrophage pyroptosis has been recognized as an important innate immune effector mechanism against intracellular pathogens. Yet, the effects of noninvasive Giardia infection on macrophage pyroptosis and the associated molecular triggers and regulators remain poorly defined. Here we initially observed that NLRP3 inflammasome-mediated pyroptosis was activated in Giardia-treated macrophages, and inhibition of ROS, NLRP3, or caspase-1 could block GSDMD cleavage, IL-1β, IL-18 and LDH release, and the cell viability reduction. We also confirmed that Giardia-induced NLRP3 inflammasome activation was involved in its K63 deubiquitination. Thus, six candidate deubiquitinases were screened, among which A20 was identified as an effective regulator. We then screened TLRs on macrophage membranes and found that upon stimulation TLR4 was tightly correlated to ROS enhancement, A20-mediated NLRP3 deubiquitination, and pyroptotic signaling. In addition, several Giardia-secreted proteins were predicted as trigger factors via secretome analysis, of which peptidyl-prolyl cis-trans isomerase B (PPIB) independently induced macrophage pyroptosis. This was similar to the findings from the trophozoite treatment, and also led to the TLR4-mediated activation of NLRP3 through K63 deubiquitination by A20. Collectively, the results of this study have significant implications for expanding our understanding of host defense mechanisms after infection with G. duodenalis.
Molecular Biomarkers for Adrenoleukodystrophy: An Unmet Need
Authors: Honey Madison I. J. , Jaspers Yorrick R. J. , Engelen Marc , Kemp Stephan , Huffnagel Irene C.
Published: December 2021

X-linked adrenoleukodystrophy (ALD) is an inherited progressive neurometabolic disease caused by mutations in the ABCD1 gene and the accumulation of very long-chain fatty acids in plasma and tissues. Patients present with heterogeneous clinical manifestations which can include adrenal insufficiency, myelopathy, and/or cerebral demyelination. In the absence of a genotype-phenotype correlation, the clinical outcome of an individual cannot be predicted and currently there are no molecular markers available to quantify disease severity. Therefore, there is an unmet clinical need for sensitive biomarkers to monitor and/or predict disease progression and evaluate therapy efficacy. The increasing amount of biological sample repositories (‘biobanking’) as well as the introduction of newborn screening creates a unique opportunity for identification and evaluation of new or existing biomarkers. Here we summarize and review the many studies that have been performed to identify and improve knowledge surrounding candidate molecular biomarkers for ALD. We also highlight several shortcomings of ALD biomarker studies, which often include a limited sample size, no collection of longitudinal data, and no validation of findings in an external cohort. Nonetheless, these studies have generated a list of interesting biomarker candidates and this review aspires to direct future biomarker research.
Fragment-Sized and Bidentate (Immuno)Proteasome Inhibitors Derived from Cysteine and Threonine Targeting Warheads
Authors: Kollár Levente , Gobec Martina , Proj Matic , Smrdel Lara , Knez Damijan , Imre Tímea , Gömöry Ágnes , Petri László , Ábrányi-Balogh Péter , Csányi Dorottya , Ferenczy György G. , Gobec Stanislav , Sosič Izidor , Keserű György M.
Published: December 2021

Constitutive- and immunoproteasomes are part of the ubiquitin–proteasome system (UPS), which is responsible for the protein homeostasis. Selective inhibition of the immunoproteasome offers opportunities for the treatment of numerous diseases, including inflammation, autoimmune diseases, and hematologic malignancies. Although several inhibitors have been reported, selective nonpeptidic inhibitors are sparse. Here, we describe two series of compounds that target both proteasomes. First, benzoxazole-2-carbonitriles as fragment-sized covalent immunoproteasome inhibitors are reported. Systematic substituent scans around the fragment core of benzoxazole-2-carbonitrile led to compounds with single digit micromolar inhibition of the β5i subunit. Experimental and computational reactivity studies revealed that the substituents do not affect the covalent reactivity of the carbonitrile warhead, but mainly influence the non-covalent recognition. Considering the small size of the inhibitors, this finding emphasizes the importance of the non-covalent recognition step in the covalent mechanism of action. As a follow-up series, bidentate inhibitors are disclosed, in which electrophilic heterocyclic fragments, i.e., 2-vinylthiazole, benzoxazole-2-carbonitrile, and benzimidazole-2-carbonitrile were linked to threonine-targeting (R)-boroleucine moieties. These compounds were designed to bind both the Thr1 and β5i-subunit-specific residue Cys48. However, inhibitory activities against (immuno)proteasome subunits showed that bidentate compounds inhibit the β5, β5i, β1, and β1i subunits with submicromolar to low-micromolar IC50 values. Inhibitory assays against unrelated enzymes showed that compounds from both series are selective for proteasomes. The presented nonpeptidic and covalent derivatives are suitable hit compounds for the development of either β5i-selective immunoproteasome inhibitors or compounds targeting multiple subunits of both proteasomes.
TGF-β Induction of miR-143/145 Is Associated to Exercise Response by Influencing Differentiation and Insulin Signaling Molecules in Human Skeletal Muscle
Authors: Dreher Simon I. , Höckele Selina , Huypens Peter , Irmler Martin , Hoffmann Christoph , Jeske Tim , Hastreiter Maximilian , Moller Anja , Birkenfeld Andreas L. , Häring Hans-Ulrich , Peter Andreas , Beckers Johannes , Hrabě de Angelis Martin , Weigert Cora
Published: December 2021

Physical training improves insulin sensitivity and can prevent type 2 diabetes (T2D). However, approximately 20% of individuals lack a beneficial outcome in glycemic control. TGF-β, identified as a possible upstream regulator involved in this low response, is also a potent regulator of microRNAs (miRNAs). The aim of this study was to elucidate the potential impact of TGF-β-driven miRNAs on individual exercise response. Non-targeted long and sncRNA sequencing analyses of TGF-β1-treated human skeletal muscle cells corroborated the effects of TGF-β1 on muscle cell differentiation, the induction of extracellular matrix components, and identified several TGF-β1-regulated miRNAs. qPCR validated a potent upregulation of miR-143-3p/145-5p and miR-181a2-5p by TGF-β1 in both human myoblasts and differentiated myotubes. Healthy subjects who were overweight or obese participated in a supervised 8-week endurance training intervention (n = 40) and were categorized as responder or low responder in glycemic control based on fold change ISIMats (≥+1.1 or <+1.1, respectively). In skeletal muscle biopsies of low responders, TGF-β signaling and miR-143/145 cluster levels were induced by training at much higher rates than among responders. Target-mining revealed HDACs, MYHs, and insulin signaling components INSR and IRS1 as potential miR-143/145 cluster targets. All these targets were down-regulated in TGF-β1-treated myotubes. Transfection of miR-143-3p/145-5p mimics in differentiated myotubes validated MYH1, MYH4, and IRS1 as miR-143/145 cluster targets. Elevated TGF-β signaling and miR-143/145 cluster induction in skeletal muscle of low responders might obstruct improvements in insulin sensitivity by training in two ways: by a negative impact of miR-143-3p on muscle cell fusion and myofiber functionality and by directly impairing insulin signaling via a reduction in INSR by TGF-β and finetuned IRS1 suppression by miR-143-3p.
Tolerance Induced by Antigen-Loaded PLG Nanoparticles Affects the Phenotype and Trafficking of Transgenic CD4+ and CD8+ T Cells
Authors: Neef Tobias , Ifergan Igal , Beddow Sara , Penaloza-MacMaster Pablo , Haskins Kathryn , Shea Lonnie D. , Podojil Joseph R. , Miller Stephen D.
Published: December 2021

We have shown that PLG nanoparticles loaded with peptide antigen can reduce disease in animal models of autoimmunity and in a phase 1/2a clinical trial in celiac patients. Clarifying the mechanisms by which antigen-loaded nanoparticles establish tolerance is key to further adapting them to clinical use. The mechanisms underlying tolerance induction include the expansion of antigen-specific CD4+ regulatory T cells and sequestration of autoreactive cells in the spleen. In this study, we employed nanoparticles loaded with two model peptides, GP33–41 (a CD8 T cell epitope derived from lymphocytic choriomeningitis virus) and OVA323–339 (a CD4 T cell epitope derived from ovalbumin), to modulate the CD8+ and CD4+ T cells from two transgenic mouse strains, P14 and DO11.10, respectively. Firstly, it was found that the injection of P14 mice with particles bearing the MHC I-restricted GP33–41 peptide resulted in the expansion of CD8+ T cells with a regulatory cell phenotype. This correlated with reduced CD4+ T cell viability in ex vivo co-cultures. Secondly, both nanoparticle types were able to sequester transgenic T cells in secondary lymphoid tissue. Flow cytometric analyses showed a reduction in the surface expression of chemokine receptors. Such an effect was more prominently observed in the CD4+ cells rather than the CD8+ cells.
Clinical Characteristics, Treatment, and Short-Term Outcome in Patients with Heart Failure and Cancer
Authors: Piotrowski Jędrzej , Timler Małgorzata , Kozłowski Remigiusz , Stasiak Arkadiusz , Stasiak Joanna , Bissinger Andrzej , Timler Dariusz , Timler Wojciech , Marczak Michał , Załuska Roman , Piotrowski Grzegorz
Published: December 2021

(1) Our study aimed to look at the clinical characteristics, treatment and short-term outcomes of patients hospitalized due to heart failure with coexisting cancer. (2) Methods: Seventy one cancer (Ca) patients and a randomly selected 70 patients without Ca, hospitalized due to heart failure exacerbation in the same time period constituted the study group (Ca patient group) and controls (non-Ca group), respectively. Data on clinical characteristics were collected retrospectively for both groups. (3) Results: Cancer patients presented with a less advanced NYHA class, had more frequent HFpEF, a higher peak troponin T level, and smaller left atrium size, as compared with controls. The in-hospital deaths of Ca patients were associated with: a higher New York Heart Association (NYHA) class, lower HgB level, worse renal function, higher K and AST levels, presence of diabetes mellitus, and HFpEF. By multivariate logistic regression analysis, impaired renal function was the only independent predictor of in-hospital death in Ca patients (OR-1.15; CI 1.05; 1.27); p = 0.017). The following covariates entered the regression: NYHA class, HgB, GFR, K+, AST, diabetes mellitus t.2, and HFpEF. (4) Conclusions: The clinical picture and the course of heart failure in patients with and without cancer are different.
Nitrogen and Bromide Co-Doped Hydroxyapatite Thin Films with Antimicrobial Properties
Authors: Iconaru Simona Liliana , Ciobanu Carmen Steluta , Predoi Daniela , Motelica-Heino Mikael , Negrilă Constantin Cătălin , Badea Monica Luminita , Predoi Mihai Valentin , Chifiriuc Carmen Mariana , Popa Marcela
Published: December 2021

Hydroxyapatite (Ca10(PO4)6(OH)2, HAp), due to its high biocompatibility, is widely used as biomaterial. Doping with various ions of hydroxyapatite is performed to acquire properties as close as possible to the biological apatite present in bones and teeth. In this research the results of a study performed on thin films of hydroxyapatite co-doped with nitrogen and bromine (NBrHAp) are presented for the first time. The NBrHAp suspension was obtained by performing the adapted co-precipitation method using cetyltrimethylammonium bromide (CTAB). The thin layers of NBrHAp were obtained by spin-coating. The stability of the NBrHAp suspension was examined by ultrasound measurements. The thin layers obtained by the spin-coating method were examined by scanning electron microscopy (SEM), optical microscopy (OM), and metallographic microscopy (MM). The presence of nitrogen and bromine were highlighted by energy-dispersive X-ray spectroscopy (EDS) and X-ray photoelectron spectroscopy (XPS) studies. Fourier transform infrared spectroscopy (FTIR) was used to highlight the chemical status of nitrogen and bromine. In addition, the powder obtained from the NBrHAp suspension was analyzed by XRD. Moreover, the in vitro antimicrobial activity of the NBrHAp suspensions and coatings was investigated using the reference microbial strains Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, and Candida albicans ATCC 10231. The results highlighted the successful obtainment of N and Br co-doped hydroxyapatite suspension for the first time by an adapted co-precipitation method. The obtained suspension was used to produce pure NBrHAp composite thin films with superior morphological properties. The NBrHAp suspensions and coatings exhibited in vitro antimicrobial activity against bacterial and fungal strains and revealed their good antimicrobial activity.
Recent Advances in Hollow Cathode Technology for Plasma-Enhanced ALD—Plasma Surface Modifications for Aluminum and Stainless-Steel Cathodes
Authors: Butcher Kenneth Scott Alexander , Georgiev Vasil , Georgieva Dimka
Published: December 2021

Recent designs have allowed hollow cathode gas plasma sources to be adopted for use in plasma-enhanced atomic layer deposition with the benefit of lower oxygen contamination for non-oxide films (a brief review of this is provided). From a design perspective, the cathode metal is of particular interest since—for a given set of conditions—the metal work function should determine the density of electron emission that drives the hollow cathode effect. However, we found that relatively rapid surface modification of the metal cathodes in the first hour or more of operation has a stronger influence. Langmuir probe measurements and hollow cathode electrical characteristics were used to study nitrogen and oxygen plasma surface modification of aluminum and stainless-steel hollow cathodes. It was found that the nitridation and oxidation of these metal cathodes resulted in higher plasma densities, in some cases by more than an order of magnitude, and a wider range of pressure operation. Moreover, it was initially thought that the use of aluminum cathodes would not be practical for gas plasma applications, as aluminum is extremely soft and susceptible to sputtering; however, it was found that oxide and nitride modification of the surface could protect the cathodes from such problems, possibly making them viable.
A Descriptive Analysis of the Impact of COVID-19 on Emergency Department Attendance and Visit Characteristics in Singapore
Authors: Lim Mei Qiu , Saffari Seyed Ehsan , Ho Andrew Fu Wah , Liew Johannes Nathaniel Min Hui , Tan Boon Kiat Kenneth , Sim Nicole Simin , Shen Yuzeng , Siddiqui Fahad Javaid , Ong Marcus Eng Hock
Published: December 2021

Background: The coronavirus disease 2019 (COVID-19) has impacted the utilisation of Emergency Department (ED) services worldwide. This study aims to describe the changes in attendance at a single ED and corresponding patient visit characteristics before and during the COVID-19 period. Methods: In a single-centre retrospective cohort study, we used descriptive statistics to compare ED attendance, patient demographics and visit characteristics during the COVID-19 period (1 January–28 June 2020) and its corresponding historical period in 2019 (2 January–30 June 2019). Results: The mean ED attendance decreased from 342 visits/day in the pre-COVID-19 period to 297 visits/day in the COVID-19 period. This was accompanied by a decline in presentations in nearly every ICD-10-CM diagnosis category except for respiratory-related diseases. Notably, we observed reductions in visits by critically ill patients and severe disease presentations during the COVID-19 period. We also noted a shift in the ED patient case-mix from ‘Non-fever’ cases to ‘Fever’ cases, likely giving rise to two distinct trough-to-peak visit patterns during the pre-Circuit Breaker and Circuit Breaker period. Conclusions: This descriptive study revealed distinct ED visit trends across different time periods. The COVID-19 pandemic caused a reduction in ED attendances amongst patients with low-acuity conditions and those with highest priority for emergency care. This raises concern about treatment-seeking delays and the possible impact on health outcomes. The downward trend in low-acuity presentations also presents learning opportunities for ED crowd management planning in a post-COVID-19 era.
Efficient Ag-Doped Perovskite Solar Cells Fabricated in Ambient Air
Authors: Hao Jiabin , Wang Zeming , Hao Huiying , Wang Guanlei , Gao Hongcheng , Wang Jianyu , Pan Bing , Qi Qiang
Published: December 2021

So far, it is still a great challenge to prepare high efficiency organic–inorganic perovskite solar cells in ambient air. Specifically, moisture is easily combined with the perovskite material during the spin-coating process, which result in porous perovskite films with poor surface morphology. In this study, we investigated crystalline Ag-doped perovskite films by a one-step spin-coating method in air with 30–40% relative humidity (RH), in which ethyl acetate (EA) was used as antisolvent can absorb moisture in air to reduced nucleation density. More significantly, EA is a feasible and environmentally friendly solvent to replace highly toxic solvent. Moreover, 1.0% Ag-doped device shows a highest power conversion efficiency (PCE) of 14.36%. The improved performance is not only ascribed to the superior CH3NH3PbI3 film with high crystallinity but to the versatile tunability of energy band structure.
Cathodoluminescence of Diamond: Features of Visualization
Authors: Vasilev Evgeny , Zedgenizov Dmitry , Zamyatin Dmitry , Klepikov Igor , Antonov Anton
Published: December 2021

Zonal and sectorial heterogeneities in natural diamonds provide information on the growth conditions and post-growth changes. Cathodoluminescence (CL) microscopy revealed these heterogeneities in a very detailed manner with high spatial resolution. In this study, factors affecting the CL images of two natural diamonds were analyzed and the results of cathodoluminescence studies in steady-state (SS-CL) and scanning modes were compared. SS-CL was observed using an optical microscope, and scanning mode was evaluated via SEM (SEM-CL). It was demonstrated that the relative brightness of the <111> and <100> growth sectors in diamond crystals depends on the nature of defects in them and on the method of image detection (steady-state/scanning versus color/panchromatic). The differences between SS-CL and SEM-CL images can be attributed to the kinetics of luminescence and spectral sensitivity of the detectors. It was established that the nature of lattice defects around small inclusions can be changed (e.g., the intensity of blue luminescence from nitrogen-vacancy defects (N3V) decreases due to their transformation into nitrogen–hydrogen defects (N3VH). The hydrogen disproportion between the sectors is caused by different growth mechanisms. Hydrogen atoms in the diamond matrix can affect the kinetics of transformation of the defects by transforming a part of N3V to N3VH.
An Analytical Study of Internal Heating and Chemical Reaction Effects on MHD Flow of Nanofluid with Convective Conditions
Authors: Rasheed Haroon Ur , Islam Saeed , Helmi Maha M. , Alsallami Shami A. M. , Khan Zeeshan , Khan Ilyas
Published: December 2021

This research investigates the influence of the combined effect of the chemically reactive and thermal radiation on electrically conductive stagnation point flow of nanofluid flow in the presence of a stationary magnetic field. Furthermore, the effect of Newtonian heating, thermal dissipation, and activation energy are considered. The boundary layer theory developed the constitutive partial differential momentum, energy, and diffusion balance equations. The fundamental flow model is changed to a system of coupled ordinary differential equations (ODEs) via proper transformations. These nonlinear-coupled equations are addressed analytically by implementing an efficient analytical method, in which a Mathematica 11.0 programming code is developed for numerical simulation. For optimizing system accuracy, stability and convergence analyses are carried out. The consequences of dimensionless parameters on flow fields are investigated to gain insight into the physical parameters. The result of these physical constraints on momentum and thermal boundary layers, along with concentration profiles, are discussed and demonstrated via plotted graphs. The computational outcomes of skin friction coefficient, mass, and heat transfer rate under the influence of appropriate parameters are demonstrated graphically.
Sex and Age Effects on Monk Parakeet Home-Range Variation in the Urban Habitat
Authors: Senar Juan Carlos , Moyà Aura , Pujol Jorge , Tomas Xavier , Hatchwell Ben J.
Published: December 2021

Home-range size is a key aspect of space-use, and variation in home-range size and structure may have profound consequences for the potential impact of damage and control strategies for invasive species. However, knowledge on home-range structure of naturalized parrot species is very limited. The aim of this study was to quantify patterns of home-range variation according to sex and age of the monk parakeet Myiopsitta monachus, an invasive parakeet in Europe. Mean kernel home-range size was 12.4 ± 1.22 ha (range 1.7–74.1 ha; N = 73 birds). Juveniles had a larger home-range size than adults, but sexes did not differ in kernel home-range size. The mean maximum distance moved by monk parakeets was 727 ± 37.0 m (range: 150–1581 m), and it was not dependent on either the sex or age of the birds. Having a small home range is one of the conditions for the feasible eradication of an invasive species; hence, the small home range of urban monk parakeets that we report here is good news for pest managers. However, this small home-range size can limit the effectiveness of culling operations with traps or feeders with contraceptives or poison, and other alternatives, such as funnel nets or traps, should be used.
Low Represented Mutation Clustering in SARS-CoV-2 B.1.1.7 Sublineage Group with Synonymous Mutations in the E Gene
Authors: Bonacci Paolo Giuseppe , Bivona Dalida Angela , Bongiorno Dafne , Stracquadanio Stefano , Massimino Mariacristina , Bonomo Carmelo , Stracuzzi Alessia , Pennisi Paolo , Musso Nicolò , Stefani Stefania
Published: December 2021

Starting in 2019, the COVID-19 pandemic is a global threat that is difficult to monitor. SARS-CoV-2 is known to undergo frequent mutations, including SNPs and deletions, which seem to be transmitted together, forming clusters that define specific lineages. Reverse-Transcription quantitative PCR (RT-qPCR) has been used for SARS-CoV-2 diagnosis and is still considered the gold standard method. Our Eukaryotic Host Pathogens Interaction (EHPI) laboratory received six SARS-CoV-2-positive samples from a Sicilian private analysis laboratory, four of which showed a dropout of the E gene. Our sequencing data revealed the presence of a synonymous mutation (c.26415 C > T, TAC > TAT) in the E gene of all four samples showing the dropout in RT-qPCR. Interestingly, these samples also harbored three other mutations (S137L—Orf1ab; N439K—S gene; A156S—N gene), which had a very low diffusion rate worldwide. This combination suggested that these mutations may be linked to each other and more common in a specific area than in the rest of the world. Thus, we decided to analyze the 103 sequences in our internal database in order to confirm or disprove our “mutation cluster hypothesis”. Within our database, one sample showed the synonymous mutation (c.26415 C > T, TAC > TAT) in the E gene. This work underlines the importance of territorial epidemiological surveillance by means of NGS and the sequencing of samples with clinical and or technical particularities, e.g., post-vaccine infections or RT-qPCR amplification failures, to allow for the early identification of these SNPs. This approach may be an effective method to detect new mutational clusters and thus to predict new emerging SARS-CoV-2 lineages before they spread globally.
Diagnosis of Multidrug-Resistant Pathogens of Pneumonia
Authors: Sfeir Maroun M.
Published: December 2021

Hospital-acquired pneumonia and ventilator-associated pneumonia that are caused by multidrug resistant (MDR) pathogens represent a common and severe problem with increased mortality. Accurate diagnosis is essential to initiate appropriate antimicrobial therapy promptly while simultaneously avoiding antibiotic overuse and subsequent antibiotic resistance. Here, we discuss the main conventional phenotypic diagnostic tests and the advanced molecular tests that are currently available to diagnose the primary MDR pathogens and the resistance genes causing pneumonia.