bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Cannabidiol on Innate Immunity: Experimental Evidence and Clinical Relevance
Authors: Martini Stefano , Gemma Alessandra , Ferrari Marco , Cosentino Marco , Marino Franca
Published: February 2023

Cannabidiol (CBD) is the main non-psychotropic cannabinoid derived from cannabis (Cannabis sativa L., fam. Cannabaceae). CBD has received approval by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of seizures associated with Lennox–Gastaut syndrome or Dravet syndrome. However, CBD also has prominent anti-inflammatory and immunomodulatory effects; evidence exists that it could be beneficial in chronic inflammation, and even in acute inflammatory conditions, such as those due to SARS-CoV-2 infection. In this work, we review available evidence concerning CBD’s effects on the modulation of innate immunity. Despite the lack so far of clinical studies, extensive preclinical evidence in different models, including mice, rats, guinea pigs, and even ex vivo experiments on cells from human healthy subjects, shows that CBD exerts a wide range of inhibitory effects by decreasing cytokine production and tissue infiltration, and acting on a variety of other inflammation-related functions in several innate immune cells. Clinical studies are now warranted to establish the therapeutic role of CBD in diseases with a strong inflammatory component, such as multiple sclerosis and other autoimmune diseases, cancer, asthma, and cardiovascular diseases.
Monoclonal Antibodies: The Greatest Resource to Treat Multiple Myeloma
Authors: De Luca Fabiola , Allegra Alessandro , Di Chio Carla , Previti Santo , Zappalà Maria , Ettari Roberta
Published: February 2023

Multiple myeloma (MM) is a currently incurable hematologic cancer. This disease is characterized by immunological alterations of myeloid cells and lymphocytes. The first-line therapy involves the use of classic chemotherapy; however, many patients have a relapsed form that could evolve into a refractory MM. The new therapeutic frontiers involve the use of new monoclonal antibodies (Mab) such as daratumumab, isatuximab, and elotuzumab. In addition to monoclonal antibodies, new immunotherapies based on modern bispecific antibodies and chimeric antigen receptor (CAR) T cell therapy have been investigated. For this reason, immunotherapy represents the greatest hope for the treatment of MM. This review intends to focus the attention on the new approved antibody targets. The most important are: CD38 (daratumumab and isatuximab), SLAM7 (elotuzumab), and BCMA (belantamab mafodotin) for the treatment of MM currently used in clinical practice. Although the disease is still incurable, the future perspective is to find the best therapeutic combination among all available drugs.
Symbiotic Bacteria System of Locusta migratoria Showed Antifungal Capabilities against Beauveria bassiana
Authors: Tan Shuqian , Wei Hongshuang , Camara Ibrahima , Jia Haoran , Cao Kaili , Shi Wangpeng
Published: February 2023

The stability of symbiotic flora is an important indicator of the health of an organism. Symbiotic bacteria have been proven to be closely involved in the immune process of organisms. The pathogenicity of Beauveria bassiana was studied in relation to symbiotic bacteria on the surface and inside of the migratory locust (Locusta migratoria). The results showed that the surface disinfection of test locusts contributed to the pathogenicity of B. bassiana to locusts. Most of the surface bacteria of L. migratoria caused some inhibition of B. bassiana growth, and LM5-4 (Raoultella ornithinolytica), LM5-2 (Enterobacter aerogenes), and LM5-13 (Citrobacter freundii) showed the highest inhibitory effect on the growth of B. bassiana. The inoculation of locusts with additional surface symbiotic bacteria reduced the virulence of B. bassiana to L. migratoria. Infection by different strains of B. bassiana caused similar changes in the symbiotic flora of migratory locusts. The inoculation of locusts with additional intestinal symbiotic bacteria (Enterobacter sp.) reduced the virulence of B. bassiana to L. migratoria. These findings illustrate the effect of bacterial communities on fungal infections in L. migratoria when seen from the perspective of ecology in a microenvironment. The active antifungal substances of such bacteria and their mechanisms of action need further study.
An Injectable Engineered Cartilage Gel Improves Intervertebral Disc Repair in a Rat Nucleotomy Model
Authors: Bhujel Basanta , Yang Soon Shim , Kim Hwal Ran , Kim Sung Bum , Min Byoung-Hyun , Choi Byung Hyune , Han Inbo
Published: February 2023

Lower back pain is a major problem caused by intervertebral disc degeneration. A common surgical procedure is lumbar partial discectomy (excision of the herniated disc causing nerve root compression), which results in further disc degeneration, severe lower back pain, and disability after discectomy. Thus, the development of disc regenerative therapies for patients who require lumbar partial discectomy is crucial. Here, we investigated the effectiveness of an engineered cartilage gel utilizing human fetal cartilage-derived progenitor cells (hFCPCs) on intervertebral disc repair in a rat tail nucleotomy model. Eight-week-old female Sprague-Dawley rats were randomized into three groups to undergo intradiscal injection of (1) cartilage gel, (2) hFCPCs, or (3) decellularized extracellular matrix (ECM) (n = 10/each group). The treatment materials were injected immediately after nucleotomy of the coccygeal discs. The coccygeal discs were removed six weeks after implantation for radiologic and histological analysis. Implantation of the cartilage gel promoted degenerative disc repair compared to hFCPCs or hFCPC-derived ECM by increasing the cellularity and matrix integrity, promoting reconstruction of nucleus pulposus, restoring disc hydration, and downregulating inflammatory cytokines and pain. Our results demonstrate that cartilage gel has higher therapeutic potential than its cellular or ECM component alone, and support further translation to large animal models and human subjects.
Biomarkers in the Rat Hippocampus and Peripheral Blood for an Early Stage of Mental Disorders Induced by Water Immersion Stress
Authors: Suzuki Keisuke , Shibato Junko , Rakwal Randeep , Takaura Masahiko , Hotta Ryotaro , Masuo Yoshinori
Published: February 2023

It is difficult to evaluate the pre-symptomatic state of mental disorders and prevent its onset. Since stress could be a trigger of mental disorders, it may be helpful to identify stress-responsive biomarkers (stress markers) for the evaluation of stress levels. We have so far performed omics analyses of the rat brain and peripheral blood after various kinds of stress and have found numerous factors that respond to stress. In this study, we investigated the effects of relatively moderate stress on these factors in the rat to identify stress marker candidates. Adult male Wistar rats underwent water immersion stress for 12 h, 24 h, or 48 h. Stress caused weight loss and elevated serum corticosterone levels, and alterations regarded as anxiety and/or fear-like behaviors. Reverse-transcription PCR and Western blot analyses revealed significant alterations in the expressions of hippocampal genes and proteins by the stress for no longer than 24 h, such as mitogen-activated protein kinase phosphatase 1 (MKP-1), CCAAT/enhancer-binding protein delta (CEBPD), small ubiquitin-like modifier proteins 1/sentrin-specific peptidase 5 (SENP5), matrix metalloproteinase-8 (MMP-8), kinase suppressor of Ras 1 (KSR1), and MKP-1, MMP-8, nerve growth factor receptor (NGFR). Similar alterations were observed in three genes (MKP-1, CEBPD, MMP-8) in the peripheral blood. The present results strongly suggest that these factors may serve as stress markers. The correlation of these factors in the blood and brain may enable the evaluation of stress-induced changes in the brain by blood analysis, which will contribute to preventing the onset of mental disorders.
Computer-Aided Virtual Screening and In Vitro Validation of Biomimetic Tyrosinase Inhibitory Peptides from Abalone Peptidome
Authors: Kongsompong Sasikarn , E-kobon Teerasak , Taengphan Weerasak , Sangkhawasi Mattanun , Khongkow Mattaka , Chumnanpuen Pramote
Published: February 2023

Hyperpigmentation is a medical and cosmetic problem caused by an excess accumulation of melanin or the overexpression of the enzyme tyrosinase, leading to several skin disorders, i.e., freckles, melasma, and skin cancer. Tyrosinase is a key enzyme in melanogenesis and thus a target for reducing melanin production. Although abalone is a good source of bioactive peptides that have been used for several properties including depigmentation, the available information on the anti-tyrosinase property of abalone peptides remains insufficient. This study investigated the anti-tyrosinase properties of Haliotis diversicolor tyrosinase inhibitory peptides (hdTIPs) based on mushroom tyrosinase, cellular tyrosinase, and melanin content assays. The binding conformation between peptides and tyrosinase was also examined by molecular docking and dynamics study. KNN1 showed a high potent inhibitory effect on mushroom tyrosinase with an IC50 of 70.83 μM. Moreover, our selected hdTIPs could inhibit melanin production through the reductions in tyrosinase activity and reactive oxygen species (ROS) levels by enhancing the antioxidative enzymes. RF1 showed the highest activity on both cellular tyrosinase inhibition and ROS reduction. leading to the lower melanin content in B16F10 murine melanoma cells. Accordingly, it can be assumed that our selected peptides exhibited high potential in medical cosmetology applications.
Diagnostic Significance of hsa-miR-21-5p, hsa-miR-192-5p, hsa-miR-155-5p, hsa-miR-199a-5p Panel and Ratios in Hepatocellular Carcinoma on Top of Liver Cirrhosis in HCV-Infected Patients
Authors: Eldosoky Mona , Hammad Reham , Elmadbouly Asmaa , Aglan Reda , AbdelHamid Sherihan , Alboraie Mohamed , Hassan Donia , Shaheen Mohamed , Rushdi Areej , Ahmed Reem , Abdelbadea Alzahra , Abdelmageed Neamat , Elshafei Ahmed , Ali Elham , Abo-Elkheir Omaima , Zaky Samy , Hamdy Nadia , Lambert Claude
Published: February 2023

Early hepatocellular carcinoma (HCC) diagnosis is challenging. Moreover, for patients with alpha-fetoprotein (AFP)-negative HCC, this challenge is augmented. MicroRNAs (miRs) profiles may serve as potential HCC molecular markers. We aimed to assess plasma homo sapiens—(hsa)-miR-21-5p, hsa-miR-155-5p, hsa-miR-192-5p, and hsa-miR-199a-5p—expression levels as a panel of biomarkers for HCC in chronic hepatitis C virus (CHCV) patients with liver cirrhosis (LC), especially AFP-negative HCC cases, as a step toward non-protein coding (nc) RNA precision medicine. Subjects and methods: 79 patients enrolled with CHCV infection with LC, subclassified into an LC group without HCC (n = 40) and LC with HCC (n = 39). Real-time quantitative PCR was used to measure plasma hsa-miR-21-5p, hsa-miR-155-5p, hsa-miR-192-5p, and hsa-miR-199a-5p. Results: Plasma hsa-miR-21-5p and hsa-miR-155-5p demonstrated significant upregulation, while hsa-miR-199a-5p demonstrated significant downregulation in the HCC group (n = 39) when compared to the LC group (n = 40). hsa-miR-21-5p expression was positively correlated with serum AFP, insulin, and insulin resistance (r = 0.5, p < 0.001, r = 0.334, p = 0.01, and r = 0.303, p = 0.02, respectively). According to the ROC curves, for differentiating HCC from LC, combining AFP with each of hsa-miR-21-5p, hsa-miR-155-5p, and miR199a-5p improved the diagnostic sensitivity to 87%, 82%, and 84%, respectively, vs. 69% for AFP alone, with acceptable specificities of 77.5%, 77.5%, and 80%, respectively, and AUC = 0.89, 0.85, and 0.90, respectively vs. 0.85 for AFP alone. hsa-miR-21-5p/hsa-miR-199a-5p and hsa-miR-155-5p/hsa-miR-199a-5p ratios discriminated HCC from LC at AUC = 0.76 and 0.71, respectively, with sensitivities = 94% and 92% and specificities = 48% and 53%, respectively. Upregulation of plasma hsa-miR-21-5p was considered as an independent risk factor for HCC development [OR = 1.198(1.063–1.329), p = 0.002]. Conclusions: Combining each of hsa-miR-21-5p, hsa-miR-155-5p, and hsa-miR-199a-5p with AFP made it possible to identify HCC development in the LC patients’ cohort with higher sensitivity than using AFP alone. hsa-miR-21-5p/hsa-miR-199a-5p and hsa-miR-155-5p/hsa-miR-199a-5p ratios are potential HCC molecular markers for AFP-negative HCC patients. hsa-miR-21-5p was linked, clinically and via in silico proof, to insulin metabolism, inflammation, dyslipidemia, and tumorigenesis in the HCC patients’ group as well as for an upregulated independent risk factor for the emergence of HCC from LC in the CHCV patients.
Rodent Models of Dilated Cardiomyopathy and Heart Failure for Translational Investigations and Therapeutic Discovery
Authors: Ponzoni Matteo , Coles John G. , Maynes Jason T.
Published: February 2023

Even with modern therapy, patients with heart failure only have a 50% five-year survival rate. To improve the development of new therapeutic strategies, preclinical models of disease are needed to properly emulate the human condition. Determining the most appropriate model represents the first key step for reliable and translatable experimental research. Rodent models of heart failure provide a strategic compromise between human in vivo similarity and the ability to perform a larger number of experiments and explore many therapeutic candidates. We herein review the currently available rodent models of heart failure, summarizing their physiopathological basis, the timeline of the development of ventricular failure, and their specific clinical features. In order to facilitate the future planning of investigations in the field of heart failure, a detailed overview of the advantages and possible drawbacks of each model is provided.
Genetic and Clinical Characteristics of Korean Chronic Lymphocytic Leukemia Patients with High Frequencies of MYD88 Mutations
Authors: Ahn Ari , Kim Hoon Seok , Kim Tong-Yoon , Lee Jong-Mi , Kang Dain , Yu Haein , Lee Chae Yeon , Kim Yonggoo , Eom Ki-Seong , Kim Myungshin
Published: February 2023

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries. However, CLL is relatively rare in Asia; its genetic features are rarely studied. Here, we aimed to genetically characterize Korean CLL patients and to elucidate the genetic and clinical associations based on data obtained from 113 patients at a single Korean institute. We used next-generation sequencing to explore the multi-gene mutational data and immunoglobulin heavy chain variable gene clonality with somatic hypermutation (SHM). MYD88 (28.3%), including L265P (11.5%) and V217F (13.3%), was the most frequently mutated gene, followed by KMT2D (6.2%), NOTCH1 (5.3%), SF3B1 (5.3%), and TP53 (4.4%). MYD88-mutated CLL was characterized by SHM and atypical immunophenotype with fewer cytogenetic abnormalities. The 5-year time to treatment (TTT) of the overall cohort was 49.8% ± 8.2% (mean ± standard deviation) and the 5-year overall survival was 86.2% ± 5.8%. Patients with SHM, isolated del(13q), TP53-wild type, and NOTCH1-wild type showed better results than those without these conditions. In the subgroup analyses, patients with SHM and L265P presented shorter TTT than patients with SHM but not L265P. In contrast, V217F was associated with a higher SHM percentage and showed a favorable prognosis. Our study revealed the distinct characteristics of Korean CLL patients with high frequencies of MYD88 mutations and their clinical relevance.
Heat-Killed Staphylococcus aureus Induces Bone Mass Loss through Telomere Erosion
Authors: Deng Songyun , Yang Mankai , Su Jianwen , Cui Naiqian , Wu Siyuan , Zhang Guangyan , Wang Lei , Hou Yilong , Chai Yu , Yu Bin
Published: February 2023

The mechanism of systemic osteoporosis caused by chronic infection is not completely clear, and there is a lack of reasonable interventions for this disease. In this study, heat-killed S. aureus (HKSA) was applied to simulate the inflammation caused by the typical clinical pathogen and to explore the mechanism of systemic bone loss caused by it. In this study, we found that the systemic application of HKSA caused bone loss in mice. Further exploration found that HKSA caused cellular senescence, telomere length shortening, and telomere dysfunction-induced foci (TIF) in limb bones. As a well-known telomerase activator, cycloastragenol (CAG) significantly alleviated HKSA-induced telomere erosion and bone loss. These results suggested that telomere erosion in bone marrow cells is a possible mechanism of HKSA-induced bone loss. CAG may protect against HKSA-induced bone loss by alleviating telomere erosion in bone marrow cells.
Whole Transcriptome Analysis of Hypothalamus in Mice during Short-Term Starvation
Authors: Oh Eun-Young , Park Byong Seo , Yang Hye Rim , Lee Ho Gyun , Tu Thai Hien , Yang Sunggu , Han Mi-Ryung , Kim Jae Geun
Published: February 2023

Molecular profiling of the hypothalamus in response to metabolic shifts is a critical cue to better understand the principle of the central control of whole-body energy metabolism. The transcriptional responses of the rodent hypothalamus to short-term calorie restriction have been documented. However, studies on the identification of hypothalamic secretory factors that potentially contribute to the control of appetite are lacking. In this study, we analyzed the differential expression of hypothalamic genes and compared the selected secretory factors from the fasted mice with those of fed control mice using bulk RNA-sequencing. We verified seven secretory genes that were significantly altered in the hypothalamus of fasted mice. In addition, we determined the response of secretory genes in cultured hypothalamic cells to treatment with ghrelin and leptin. The current study provides further insights into the neuronal response to food restriction at the molecular level and may be useful for understanding the hypothalamic control of appetite.
Thyroid Hormone Transporters MCT8 and OATP1C1 Are Expressed in Pyramidal Neurons and Interneurons in the Adult Motor Cortex of Human and Macaque Brain
Authors: Wang Yu , Wang Ting , Montero-Pedrazuela Ana , Guadaño-Ferraz Ana , Rausell Estrella
Published: February 2023

Monocarboxylate transporter 8 (MCT8) and organic anion transporter polypeptide 1C1 (OATP1C1) are thyroid hormone (TH) transmembrane transporters that play an important role in the availability of TH for neural cells, allowing their proper development and function. It is important to define which cortical cellular subpopulations express those transporters to explain why MCT8 and OATP1C1 deficiency in humans leads to dramatic alterations in the motor system. By means of immunohistochemistry and double/multiple labeling immunofluorescence in adult human and monkey motor cortices, we demonstrate the presence of both transporters in long-projection pyramidal neurons and in several types of short-projection GABAergic interneurons in both species, suggesting a critical position of these transporters for modulating the efferent motor system. MCT8 is present at the neurovascular unit, but OATP1C1 is only present in some of the large vessels. Both transporters are expressed in astrocytes. OATP1C1 was unexpectedly found, only in the human motor cortex, inside the Corpora amylacea complexes, aggregates linked to substance evacuation towards the subpial system. On the basis of our findings, we propose an etiopathogenic model that emphasizes these transporters’ role in controlling excitatory/inhibitory motor cortex circuits in order to understand some of the severe motor disturbances observed in TH transporter deficiency syndromes.
Neutral and Pectic Heteropolysaccharides Isolated from Opuntia joconostle Mucilage: Composition, Molecular Dimensions and Prebiotic Potential
Authors: Cruz-Rubio José Manuel , Riva Alessandra , Cybulska Justyna , Zdunek Artur , Berry David , Loeppert Renate , Viernstein Helmut , Praznik Werner , Maghuly Fatemeh
Published: February 2023

Opuntia joconostle is a semi-wild cactus cultivated for its fruit. However, the cladodes are often discarded, wasting the potentially useful mucilage in them. The mucilage is composed primarily of heteropolysaccharides, characterized by their molar mass distribution, monosaccharide composition, structural features (by vibrational spectroscopy, FT IR, and atomic force microscopy, AFM), and fermentability by known saccharolytic commensal members of the gut microbiota. After fractionation with ion exchange chromatography, four polysaccharides were found: one neutral (composed mainly of galactose, arabinose, and xylose) and three acidic, with a galacturonic acid content from 10 to 35%mol. Their average molar masses ranged from 1.8 × 105 to 2.8 × 105 g·mol−1. Distinct structural features such as galactan, arabinan, xylan, and galacturonan motifs were present in the FT IR spectra. The intra- and intermolecular interactions of the polysaccharides, and their effect on the aggregation behavior, were shown by AFM. The composition and structural features of these polysaccharides were reflected in their prebiotic potential. Lactobacilli and Bifidobacteria were not able to utilize them, whereas members of Bacteroidetes showed utilization capacity. The obtained data suggest a high economic potential for this Opuntia species, with potential uses such as animal feed in arid areas, precise prebiotic, and symbiotic formulations, or as the carbon skeleton source in a green refinery. Our methodology can be used to evaluate the saccharides as the phenotype of interest, helping to guide the breeding strategy.
EverAnalyzer: A Self-Adjustable Big Data Management Platform Exploiting the Hadoop Ecosystem
Authors: Karamolegkos Panagiotis , Mavrogiorgou Argyro , Kiourtis Athanasios , Kyriazis Dimosthenis
Published: February 2023

Big Data is a phenomenon that affects today’s world, with new data being generated every second. Today’s enterprises face major challenges from the increasingly diverse data, as well as from indexing, searching, and analyzing such enormous amounts of data. In this context, several frameworks and libraries for processing and analyzing Big Data exist. Among those frameworks Hadoop MapReduce, Mahout, Spark, and MLlib appear to be the most popular, although it is unclear which of them best suits and performs in various data processing and analysis scenarios. This paper proposes EverAnalyzer, a self-adjustable Big Data management platform built to fill this gap by exploiting all of these frameworks. The platform is able to collect data both in a streaming and in a batch manner, utilizing the metadata obtained from its users’ processing and analytical processes applied to the collected data. Based on this metadata, the platform recommends the optimum framework for the data processing/analytical activities that the users aim to execute. To verify the platform’s efficiency, numerous experiments were carried out using 30 diverse datasets related to various diseases. The results revealed that EverAnalyzer correctly suggested the optimum framework in 80% of the cases, indicating that the platform made the best selections in the majority of the experiments.
Educational Breakout Based on Star Wars for Learning the History of Spanish Sign Language
Authors: Moreno-Rodriguez Ricardo , Lopez-Bastias José Luis , Diaz-Vega Miriam , Espada-Chavarria Rosa
Published: February 2023

Although educational breakout has been implemented in pre-university stages, there is little evidence in subjects related to history in postsecondary levels. The aim of this paper was to present the results obtained after implementing an educational breakout, under the premises of Universal Design for Learning, in a history subject that belongs to the university degree in Spanish Sign Language and Deaf Community. A descriptive and comparative ex post facto study (N = 59) was developed to quantify the impact of an educational breakout activity on the students’ commitment, establishing a pre- and post-comparison. Significant differences were found with respect to the perception of the speed of the passage of time and with respect to sustained attention, where there was a statistically significant difference between the time before and the time after the educational breakout. The predisposition of university students to participate in gamified or game-based activities was positive and in subjects such as history, and offers good results, both attitudinal and learning.
Efficacy of the 4F Feedback Model: A Game-Based Assessment in University Education
Authors: Freitas Sara de , Uren Victoria , Kiili Kristian , Ninaus Manuel , Petridis Panagiotis , Lameras Petros , Dunwell Ian , Arnab Sylvester , Jarvis Stephen , Star Kam
Published: February 2023

Feedback is a critical aspect of optimised learning design, but there are few, if any, feedback models that map different types of feedback and how they may assist students to increase performance and enhance their learning experience. This research paper outlines a feedback model as an extension of the four-dimensional framework which includes a consideration of the type, the content, the format, and the frequency of feedback, as well as the agent which delivers it. This model is based upon an understanding of learning in the context of designing learning experiences and utilises a game-based model of learning to understand the importance of motivation and autonomy in learners to enhance and accelerate learning. The framework is developed and reflected upon by analysing two cases: a medical triage case in which the timing and frequency of feedback proved critical, and a business simulation which illuminated the need for a range of types of feedback and to be aware of the possibility of different agents (instructor peer and game) that can deliver feedback. The extended model may help game and learning designers alike to discern different types of feedback, both in games and more generally, in more explicit and nuanced ways.
Gamma Knife Radiosurgery for Cushing’s Disease: Evaluation of Biological Effective Dose from a Single-Center Experience
Authors: Gao Yuan , Wang Mengqi , Wu Yang , Deng Hao , Xu Yangyang , Ren Yan , Wang Chun , Wang Wei
Published: February 2023

Objective: Gamma knife radiosurgery (GKRS) has served as an adjunctive treatment in Cushing’s disease (CD) for decades and has become a vital part of therapy in the management of CD. Biological effective dose (BED) is a radiobiological parameter with time correction, considering the cellular deoxyribonucleic acid repairment. We aimed to investigate the safety and efficacy of GKRS for CD and evaluate the association of BED and treatment outcome. Methods: A cohort study of 31 patients with CD received GKRS in West China Hospital between June 2010 and December 2021. Endocrine remission was defined as normalization of 24 h urinary free cortisol (UFC) or serum cortisol ≤ 50 nmol/L after a 1 mg dexamethasone suppression test. Result: The mean age was 38.6 years old, and females accounted for 77.4%. GKRS was the initial treatment for 21 patients (67.7%), and 32.3% of patients underwent GKRS after surgery due to residual disease and recurrence. The mean endocrine follow-up duration was 22 months. The median marginal dose was 28.0 Gy, and the median BED was 221.5 Gy2.47. Fourteen patients (45.1%) experienced control of hypercortisolism in the absence of pharmacological treatment, and the median duration to remission was 20.0 months. The cumulative rates of endocrine remission at 1, 2, and 3 years after GKRS were 18.9%, 55.3%, and 72.21%, respectively. The total complication rate was 25.8%, and the mean duration from GKRS to hypopituitary was 17.5 months. The new hypopituitary rate at 1, 2, and 3 years were 7.1%, 30.3%, and 48.4%, respectively. A high BED level (BED > 205 Gy2.47) was associated with better endocrine remission than a low BED level (BED ≤ 205 Gy2.47), while no significant differences were found between the BED level and hypopituitarism. Conclusions: GKRS was a second-line therapeutic option for CD with satisfactory safety and efficacy. BED should be considered during GKRS treatment planning, and optimization of BED is a potentially impactful avenue toward improving the efficacy of GKRS.
Transfer-Learning-Based Estimation of the Remaining Useful Life of Heterogeneous Bearing Types Using Low-Frequency Accelerometers
Authors: Schwendemann Sebastian , Sikora Axel
Published: February 2023

Deep learning approaches are becoming increasingly important for the estimation of the Remaining Useful Life (RUL) of mechanical elements such as bearings. This paper proposes and evaluates a novel transfer learning-based approach for RUL estimations of different bearing types with small datasets and low sampling rates. The approach is based on an intermediate domain that abstracts features of the bearings based on their fault frequencies. The features are processed by convolutional layers. Finally, the RUL estimation is performed using a Long Short-Term Memory (LSTM) network. The transfer learning relies on a fixed-feature extraction. This novel deep learning approach successfully uses data of a low-frequency range, which is a precondition to use low-cost sensors. It is validated against the IEEE PHM 2012 Data Challenge, where it outperforms the winning approach. The results show its suitability for low-frequency sensor data and for efficient and effective transfer learning between different bearing types.
Functional Analysis of the P-Type ATPases Apt2-4 from Cryptococcus neoformans by Heterologous Expression in Saccharomyces cerevisiae
Authors: Veit Sarina , Laerbusch Sabine , López-Marqués Rosa L. , Günther Pomorski Thomas
Published: February 2023

Lipid flippases of the P4-ATPase family actively transport phospholipids across cell membranes, an activity essential for key cellular processes such as vesicle budding and membrane trafficking. Members of this transporter family have also been implicated in the development of drug resistance in fungi. The encapsulated fungal pathogen Cryptococcus neoformans contains four P4-ATPases, among which Apt2-4p are poorly characterized. Using heterologous expression in the flippase-deficient S. cerevisiae strain dnf1Δdnf2Δdrs2Δ, we tested their lipid flippase activity in comparison to Apt1p using complementation tests and fluorescent lipid uptake assays. Apt2p and Apt3p required the co-expression of the C. neoformans Cdc50 protein for activity. Apt2p/Cdc50p displayed a narrow substrate specificity, limited to phosphatidylethanolamine and –choline. Despite its inability to transport fluorescent lipids, the Apt3p/Cdc50p complex still rescued the cold-sensitive phenotype of dnf1Δdnf2Δdrs2Δ, suggesting a functional role for the flippase in the secretory pathway. Apt4p, the closest homolog to Saccharomyces Neo1p, which does not require a Cdc50 protein, was unable to complement several flippase-deficient mutant phenotypes, neither in the presence nor absence of a β-subunit. These results identify C. neoformans Cdc50 as an essential subunit for Apt1-3p and provide a first insight into the molecular mechanisms underlying their physiological functions.
Population Pharmacokinetics of Isavuconazole in Critical Care Patients with COVID-19-Associated Pulmonary Aspergillosis and Monte Carlo Simulations of High Off-Label Doses
Authors: Perez Lucas , Corne Philippe , Pasquier Grégoire , Konecki Céline , Sadek Meriem , Le Bihan Clément , Klouche Kada , Mathieu Olivier , Reynes Jacques , Cazaubon Yoann
Published: February 2023

Isavuconazole is a triazole antifungal agent recently recommended as first-line therapy for invasive pulmonary aspergillosis. With the COVID-19 pandemic, cases of COVID-19-associated pulmonary aspergillosis (CAPA) have been described with a prevalence ranging from 5 to 30%. We developed and validated a population pharmacokinetic (PKpop) model of isavuconazole plasma concentrations in intensive care unit patients with CAPA. Nonlinear mixed-effect modeling Monolix software were used for PK analysis of 65 plasma trough concentrations from 18 patients. PK parameters were best estimated with a one-compartment model. The mean of ISA plasma concentrations was 1.87 [1.29–2.25] mg/L despite prolonged loading dose (72 h for one-third) and a mean maintenance dose of 300 mg per day. Pharmacokinetics (PK) modeling showed that renal replacement therapy (RRT) was significantly associated with under exposure, explaining a part of clearance variability. The Monte Carlo simulations suggested that the recommended dosing regimen did not achieve the trough target of 2 mg/L in a timely manner (72 h). This is the first isavuconazole PKpop model developed for CAPA critical care patients underlying the need of therapeutic drug monitoring, especially for patients under RRT.
Plastic Deformation Mechanism of High Strength and Toughness ZK61 Magnesium Alloy Plate by Multipass Horizontal Continuous Rolling
Authors: Chen Ming , Ma Cong , Liu Qingjie , Cheng Ming , Wang Haolei , Hu Xiaodong
Published: February 2023

ZK61 magnesium-alloy plate with high tensile strength and elongation is obtained by combined multipass symmetric hot rolling and asymmetric warm rolling. Deformation history considering varying strain rate obtained from the macro-finite element analysis of the selected passes are introduced into the viscoplastic self-consistent model (VPSC) as initial boundary conditions for macro- multiscale and micro-multiscale coupling analysis. VPSC simulation results show that in the initial stage of rolling deformation, the basal  slip is the dominated deformation mode, supplemented by prismatic  slip and pyramidal  slip. With increased rolling strain, the pyramidal  slip presents competitive relationship with basal  slip, and the activation amount of {101—1} compression twins is limited. During asymmetric rolling, the basal  slip is dominant, followed by the pyramidal  slip. Experimental results show that the basal texture is gradually strengthened after symmetric rolling, and grain size is refined due to the activation and recrystallization of twins. Asymmetric rolling makes the basal texture deflect 10° to the rolling direction and further refine the grain size. With the ongoing of symmetric rolling, the mechanical anisotropy of the plate weakens, and the yield strength, tensile strength, and plasticity of the material improves. In particular, after asymmetric rolling, the tensile strength in the RD and TD directions of the plate reaches 391.2 MPa and 398.9 MPa, whereas the elongation reaches 19.8% and 25.5%.
Synthesis of a Room-Temperature Curable Acrylic-Urethane Polymer Binder for Road Markings with High Transmittance
Authors: Lim Won-Bin , Kim Ju-Won , Lee Ju-Hong , Bae Ji-Hong , Min Jin-Gyu , Huh PilHo
Published: February 2023

Triol acrylic-urethane (t-AU) was synthesized from an addition reaction using trimethylolpropane, hexamethylene diisocyanate, and 2-hydroxyethyl methacrylate. The novel acrylic-urethane polymer was applied to a high-performance binder to prepare a reliable road marking paint. Acrylic-urethane polymer binder formulations were designed to optimize the effect of t-AU on the physical properties. The t-AU content in the formulation affected the adhesion and optical properties. The improvement in the adhesive performance and transparency ability for road markings was attributed to the optimal chemical structure or design of the acrylic-urethane polymer. The synthesis of t-AU was confirmed by Fourier transform infrared spectroscopy, and molecular weight and polydispersity index (PDI; PDI = Mw/Mn) measurements. The tensile and shear strength, hardness, gel fraction, crosslink density, contact angle, and transmittance of the acrylic-urethane polymer binder (AUP) were evaluated by curing at room temperature using a redox initiator system. An optimized AUP by adding 5 wt.% t-AU provides a viable alternative to high-performance binders in road marking paints.
Investigating the Impact of Fly Ash on the Strength and Micro-Structure of Concrete during Steam Curing and Subsequent Stages
Authors: Duan Yun , Wang Qicai , Long Zhaofei , Wang Xiaoping
Published: February 2023

Steam curing, a common way of curing precast concrete, can greatly improve its 1-day strength. However, the thermal effect of prolonged high-temperature curing can negatively impact the concrete’s performance, thus compromising production of precast products in cold regions. Fly ash (FA) is used as a supplementary cementitious material to improve part of the properties of concrete. In this paper, we investigated the effect of FA (10~30%) on the compressive strength and microstructure of manufactured sand concrete at the steam curing and later stages. Specifically, we analyzed the behavior of FA in the constant temperature phase under steam curing. Results indicated that the pozzolanic reaction of FA started to occur at 24 h of constant temperature curing. Early hydration under steam curing produces a large amount of Ca(OH)2, causing the pozzolanic reaction of FA to occur significantly earlier, and the high pH value of the solution and the fibrous mesh structure of the FA surface promote the pozzolanic reaction. The addition of 30% FA to manufactured sand concrete causes a significant reduction in early strength under steam curing, which is not beneficial to the formwork removal and tensioning of precast members. Notably, manufactured sand concrete with 20% FA under steam curing had the highest late strength. The filling effect of FA and the additional gel produced by the pozzolanic reaction would result in the reduction in large pore content, refinement of pore size, improvement of microstructural compactness, and increase in gel system strength. Therefore, the addition of 20% FA to the manufactured sand concrete can improve the long-term strength, which is beneficial to the production of precast beams in cold regions.
Thermal Stability and Mechanical Behavior of Ultrafine-Grained Titanium with Different Impurity Content
Authors: Majchrowicz Kamil , Sotniczuk Agata , Malicka Joanna , Choińska Emilia , Garbacz Halina
Published: February 2023

Ultrafine-grained (UFG) commercially pure (Ti Grade 2) and high-purity (Ti 99.99%) titanium can be a good alternative to less biocompatible Ti alloys in many biomedical applications. Their severe plastic deformation may lead to a substantial increase of strength, but their highly refined microstructure show a lower thermal stability which may limit their range of applications. The purpose of this study was to investigate the effect of interstitial elements on the thermal stability of UFG Ti Grade 2 and high-purity Ti 99.99% processed by a multi-pass cold rolling to the total thickness reduction of 90%. The severely cold rolled Ti sheets were annealed at temperature in the range of 100–600 °C for 1 h and, subsequently, they were evaluated in terms of microstructure stability, mechanical performance as well as heat effects measured by differential scanning calorimetry (DSC). It was found that the microstructure and mechanical properties were relatively stable up to 200 and 400 °C in the case of UFG Ti 99.99% and Ti Grade 2, respectively. DSC measurements confirmed the aforementioned results about lower temperature of recovery and recrystallization processes in the high-purity titanium. Surprisingly, the discontinuous yielding phenomenon occurred in both investigated materials after annealing above their thermal stability range, which was further discussed based on their microstructural characteristics. Additionally, the so-called hardening by annealing effect was observed within their thermal stability range (i.e., at 100–400 °C for UFG Ti Grade 2 and 100 °C for UFG Ti 99.99%).
In-Situ TEM Investigation of Helium Implantation in Ni-SiOC Nanocomposites
Authors: Wei Bingqiang , Wu Wenqian , Wang Jian
Published: February 2023

Ni-SiOC nanocomposites maintain crystal-amorphous dual-phase nanostructures after high-temperature annealing at different temperatures (600 °C, 800 °C and 1000 °C), while the feature sizes of crystal Ni and amorphous SiOC increase with the annealing temperature. Corresponding to the dual-phase nanostructures, Ni-SiOC nanocomposites exhibit a high strength and good plastic flow stability. In this study, we conducted a He implantation in Ni-SiOC nanocomposites at 300 °C by in-situ transmission electron microscope (TEM) irradiation test. In-situ TEM irradiation revealed that both crystal Ni and amorphous SiOC maintain stability under He irradiation. The 600 °C annealed sample presents a better He irradiation resistance, as manifested by a smaller He-bubble size and lower density. Both the grain boundary and crystal-amorphous phase boundary act as a sink to absorb He and irradiation-induced defects in the Ni matrix. More importantly, amorphous SiOC ceramic is immune to He irradiation damage, contributing to the He irradiation resistance of Ni alloy.
Destructive Effect of High-Temperature Heat Flow of Solid Slow-Release Energetic Materials on a Steel Target
Authors: Qiao Bingxü , Liang Zengyou , Liang Fudi
Published: February 2023

To investigate the high-temperature heat flow’s destructive effect of solid slow-release energetic materials on a steel target, we prepared a sample of solid slow-release energetic materials, eruption devices, and a complete test system to conduct the destruction of high-temperature heat flow on the steel target. In addition, we proposed the energy density to characterise the high-temperature heat flow performance and numerically simulated the destructive effect of the high-temperature heat flow on the steel target. The numerical simulation results were in good agreement with the test results, and the error between them was under 8.5%. Based on the test and simulation results, the steady-state melting model of the steel target was established under the action of high-temperature heat flow. Moreover, a time-varying model of the melting hole shape was found. The results showed that the model of destroying the steel target with the high-temperature heat flow of solid slow-release energetic materials was highly accurate. Therefore, the model could provide theoretical guidance for designing and applying solid slow-release energetic materials in ammunition destruction, metal cutting, the simulation of the laser thermal effect, etc.
Antinociceptive Effects of Aaptamine, a Sponge Component, on Peripheral Neuropathy in Rats
Authors: Sung Chun-Sung , Cheng Hao-Jung , Chen Nan-Fu , Tang Shih-Hsuan , Kuo Hsiao-Mei , Sung Ping-Jyun , Chen Wu-Fu , Wen Zhi-Hong
Published: February 2023

Aaptamine, a natural marine compound isolated from the sea sponge, has various biological activities, including delta-opioid agonist properties. However, the effects of aaptamine in neuropathic pain remain unclear. In the present study, we used a chronic constriction injury (CCI)-induced peripheral neuropathic rat model to explore the analgesic effects of intrathecal aaptamine administration. We also investigated cellular angiogenesis and lactate dehydrogenase A (LDHA) expression in the ipsilateral lumbar spinal cord after aaptamine administration in CCI rats by immunohistofluorescence. The results showed that aaptamine alleviates CCI-induced nociceptive sensitization, allodynia, and hyperalgesia. Moreover, aaptamine significantly downregulated CCI-induced vascular endothelial growth factor (VEGF), cluster of differentiation 31 (CD31), and LDHA expression in the spinal cord. Double immunofluorescent staining showed that the spinal VEGF and LDHA majorly expressed on astrocytes and neurons, respectively, in CCI rats and inhibited by aaptamine. Collectively, our results indicate aaptamine’s potential as an analgesic agent for neuropathic pain. Furthermore, inhibition of astrocyte-derived angiogenesis and neuronal LDHA expression might be beneficial in neuropathy.
Ambiental Factors in Parkinson’s Disease Progression: A Systematic Review
Authors: Bougea Anastasia , Papagiannakis Nikolas , Simitsi Athina-Maria , Panagiotounakou Elpida , Chrysovitsanou Chrysa , Angelopoulou Efthalia , Koros Christos , Stefanis Leonidas
Published: February 2023

Background and Objectives: So far, there is little evidence of the ambient effect on motor and non-motor symptoms of Parkinson’s Disease (PD). This systematic review aimed to determine the association between ambiental factors and the progression of PD. Materials and Methods: A systematic literature search of PubMed, Cochrane, Embase, and Web of Science was conducted up to 21 December 2021 according the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: Eight articles were used in the analyses. Long-term exposure to fine particles (particulate matter ≤ 2.5 μm; PM2.5) was positively associated with disease aggravation in two studies. Short-term PM2.5 exposure was positively associated with disease aggravation in three studies. Significant associations were found between PD aggravation and NO2, SO2, CO, nitrate and organic matter (OM) concentrations in two studies. Associations were more pronounced, without reaching statistical significance however, in women, patients over 65 years old and cold temperatures. A 1% increase in temperature was associated with a significant 0.18% increase in Levodopa Equivalent Dose (LED). Ultraviolet light and humidity were not significantly associated with an increase in LED. There was no difference in hallucination severity with changing seasons. There was no evidence for seasonal fluctuation in Unified Parkinson’s Disease Rating Scale (UPDRS) scores. Conclusions: There is a link between air pollutants and temperature for PD progression, but this has yet to be proven. More longitudinal studies are warranted to confirm these findings.
Decreased Survival and Lung Function in Progressive Pulmonary Fibrosis
Authors: Platenburg Mark G. J. P. , van der Vis Joanne J. , Grutters Jan C. , van Moorsel Coline H. M.
Published: February 2023

Background and Objectives: Progressive pulmonary fibrosis (PPF) is a recently described term reserved for patients with fibrotic ILD other than idiopathic pulmonary fibrosis (IPF) with fast clinical deterioration. Here, survival and prognostic biomarkers at the time of diagnosis for PPF are investigated in a fibrotic ILD other than IPF cohort (non-IPF). Materials and Methods: Patients diagnosed during the period of 2012–2018 at the ILD Center of Excellence (St. Antonius Hospital, Nieuwegein, The Netherlands) with a fibrotic ILD were included in this study. The presence of PPF was investigated using the criteria from the updated IPF/PPF guideline during the first year after diagnosis. Logistic regression analysis was used to determine risk factors for PPF. A Kaplan–Meier survival analysis with log-rank test was conducted to analyze survival in patients with and without PPF. Results: This study included 304 non-IPF patients and, for comparison, 379 IPF patients. In non-IPF patients, 146 (46%) fulfilled ≥2 criteria for PPF. These patients had a median transplant-free survival rate of 2.9 ± 0.4 years, which was worse than non-IPF patients without PPF (10.1 ± 1.8 years, p < 0.001). The risk for PPF was increased in patients with FVC < 50% (odds ratio (OR) of 2.50, 95% CI = 1.01–6.17, p = 0.047) or DLCOc ≤ 35% (OR = 2.57, 95% CI = 1.24–5.35, p = 0.011). In the first 3 years after diagnosis, survival in PPF and IPF is the same, while in the following years IPF has a significantly worse survival. Conclusions: The non-IPF cohort with PPF had a significantly worse transplant-free survival compared with the non-IPF cohort without PPF. Independent risk factors for PPF in non-IPF were FVC < 50% and DLCOc ≤ 35%.