bluuebunny/crossref_metadata_2025 huggingface dataset:
The Next Frontier: Translational Development of Ubiquitination, SUMOylation, and NEDDylation in Cancer
Authors: Pellegrino Nicole E. , Guven Arcan , Gray Kayleigh , Shah Punit , Kasture Gargi , Nastke Maria-Dorothea , Thakurta Anjan , Gesta Stephane , Vishnudas Vivek K. , Narain Niven R. , Kiebish Michael A.
Published: March 2022

Post-translational modifications of proteins ensure optimized cellular processes, including proteostasis, regulated signaling, cell survival, and stress adaptation to maintain a balanced homeostatic state. Abnormal post-translational modifications are associated with cellular dysfunction and the occurrence of life-threatening diseases, such as cancer and neurodegenerative diseases. Therefore, some of the frequently seen protein modifications have been used as disease markers, while others are targeted for developing specific therapies. The ubiquitin and ubiquitin-like post-translational modifiers, namely, small ubiquitin-like modifier (SUMO) and neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8), share several features, such as protein structures, enzymatic cascades mediating the conjugation process, and targeted amino acid residues. Alterations in the regulatory mechanisms lead to aberrations in biological processes during tumorigenesis, including the regulation of tumor metabolism, immunological modulation of the tumor microenvironment, and cancer stem cell stemness, besides many more. Novel insights into ubiquitin and ubiquitin-like pathways involved in cancer biology reveal a potential interplay between ubiquitination, SUMOylation, and NEDDylation. This review outlines the current understandings of the regulatory mechanisms and assay capabilities of ubiquitination, SUMOylation, and NEDDylation. It will further highlight the role of ubiquitination, SUMOylation, and NEDDylation in tumorigenesis.
Targeting Protein Translation in Melanoma by Inhibiting EEF-2 Kinase Regulates Cholesterol Metabolism though SREBP2 to Inhibit Tumour Development
Authors: Dinavahi Saketh S. , Chen Yu-Chi , Gowda Raghavendra , Dhanyamraju Pavan Kumar , Punnath Kishore , Desai Dhimant , Berg Arthur , Kimball Scot R. , Amin Shantu , Yang Jin-Ming , Robertson Gavin P.
Published: March 2022

Decreasing the levels of certain proteins has been shown to be important for controlling cancer but it is currently unknown whether proteins could potentially be targeted by the inhibiting of protein synthesis. Under this circumstance, targeting protein translation could preferentially affect certain pathways, which could then be of therapeutic advantage when treating cancer. In this report, eukaryotic elongation factor-2 kinase (EEF2K), which is involved in protein translation, was shown to regulate cholesterol metabolism. Targeting EEF2K inhibited key parts of the cholesterol pathway in cancer cells, which could be rescued by the addition of exogenous cholesterol, suggesting that it is a potentially important pathway modulated by targeting this process. Specifically, targeting EEF2K significantly suppressed tumour cell growth by blocking mRNA translation of the cholesterol biosynthesis transcription factor, sterol regulatory element-binding protein (SREBP) 2, and the proteins it regulates. The process could be rescued by the addition of LDL cholesterol taken into the cells via non-receptor-mediated-uptake, which negated the need for SREBP2 protein. Thus, the levels of SREBP2 needed for cholesterol metabolism in cancer cells are therapeutically vulnerable by targeting protein translation. This is the first report to suggest that targeting EEF2K can be used to modulate cholesterol metabolism to treat cancer.
PARP Inhibitor Decreases Akt Phosphorylation and Induces Centrosome Amplification and Chromosomal Aneuploidy in CHO-K1 Cells
Authors: Tanaka Masakazu , Mushiake Masatoshi , Takahashi Jun , Sasaki Yuka , Yamashita Sachiko , Ida Chieri , Masutani Mitsuko , Miwa Masanao
Published: March 2022

Cancer cells are known to have chromosomal number abnormalities (aneuploidy), a hallmark of malignant tumors. Cancer cells also have an increased number of centrosomes (centrosome amplification). Paradoxically, cancer therapies, including γ-irradiation and some anticancer drugs, are carcinogenic and can induce centrosome amplification and chromosomal aneuploidy. Thus, the processes of carcinogenesis and killing cancer cells might have some mechanisms in common. Previously, we found that the inhibitors of polyADP-ribosylation, a post-translational modification of proteins, caused centrosome amplification. However, the mechanism of action of the inhibitors of polyADP-ribosylation is not fully understood. In this study, we found that an inhibitor of polyADP-ribosylation, 3-aminobenzamide, caused centrosome amplification, as well as aneuploidy of chromosomes in CHO-K1 cells. Moreover, inhibitors of polyADP-ribosylation inhibited AKT phosphorylation, and inhibitors of AKT phosphorylation inhibited polyADP-ribosylation, suggesting the involvement of polyADP-ribosylation in the PI3K/Akt/mTOR signaling pathway for controlling cell proliferation. Our data suggest a possibility for developing drugs that induce centrosome amplification and aneuploidy for therapeutic applications to clinical cancer.
miRNA Expression Profiling in Subcutaneous Adipose Tissue of Monozygotic Twins Discordant for HIV Infection: Validation of Differentially Expressed miRNA and Bioinformatic Analysis
Authors: Bresciani Elena , Squillace Nicola , Orsini Valentina , Piolini Roberta , Rizzi Laura , Molteni Laura , Meanti Ramona , Soria Alessandro , Lapadula Giuseppe , Bandera Alessandra , Gori Andrea , Bonfanti Paolo , Omeljaniuk Robert John , Locatelli Vittorio , Torsello Antonio
Published: March 2022

Combined AntiRetroviral Treatments (cARTs) used for HIV infection may result in varied metabolic complications, which in some cases, may be related to patient genetic factors, particularly microRNAs. The use of monozygotic twins, differing only for HIV infection, presents a unique and powerful model for the controlled analysis of potential alterations of miRNAs regulation consequent to cART treatment. Profiling of 2578 mature miRNA in the subcutaneous (SC) adipose tissue and plasma of monozygotic twins was investigated by the GeneChip® miRNA 4.1 array. Real-time PCR and ddPCR experiments were performed in order to validate differentially expressed miRNAs. Target genes of deregulated miRNAs were predicted by the miRDB database (prediction score > 70) and enrichment analysis was carried out with g:Profiler. Processes in SC adipose tissue most greatly affected by miRNA up-regulation included (i) macromolecular metabolic processes, (ii) regulation of neurogenesis, and (iii) protein phosphorylation. Furthermore, KEGG analysis revealed miRNA up-regulation involvement in (i) insulin signaling pathways, (ii) neurotrophin signaling pathways, and (iii) pancreatic cancer. By contrast, miRNA up-regulation in plasma was involved in (i) melanoma, (ii) p53 signaling pathways, and (iii) focal adhesion. Our findings suggest a mechanism that may increase the predisposition of HIV+ patients to insulin resistance and cancer.
Spectral Dependence of the Energy Transfer from Photosynthetic Complexes to Monolayer Graphene
Authors: Szalkowski Marcin , Surrente Alessandro , Wiwatowski Kamil , Yang Zhuo , Zhang Nan , Olmos Julian D. Janna , Kargul Joanna , Plochocka Paulina , Maćkowski Sebastian
Published: March 2022

Fluorescence excitation spectroscopy at cryogenic temperatures carried out on hybrid assemblies composed of photosynthetic complexes deposited on a monolayer graphene revealed that the efficiency of energy transfer to graphene strongly depended on the excitation wavelength. The efficiency of this energy transfer was greatly enhanced in the blue-green spectral region. We observed clear resonance-like behavior for both a simple light-harvesting antenna containing only two chlorophyll molecules (PCP) and a large photochemically active reaction center associated with the light-harvesting antenna (PSI–LHCI), which pointed towards the general character of this effect.
Toward a Treatment of Cancer: Design and In Vitro/In Vivo Evaluation of Uncharged Pyrazoline Derivatives as a Series of Novel SHP2 Inhibitors
Authors: Dai Jiajia , Zhang Yiting , Gao Yanan , Bai Xiaoyi , Liu Fang , Li Shuo , Yu Yanyan , Hu Wenpeng , Shi Ting , Shi Dayong , Li Xiangqian
Published: March 2022

Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene, which is involved in the RAS/MAPK cell signaling transduction process. SHP2 has been shown to contribute to the progression of various cancers and is emerging as an important target for anti-tumor drug research. However, past efforts to develop SHP2 inhibitors into drugs have been unsuccessful owing to the positively charged nature of the active site pocket tending to bind negatively charged groups that are usually non-drug-like. Here, a series of uncharged pyrazoline derivatives were designed and developed as new SHP2 inhibitors using a structure-based strategy. Compound 4o, which exhibited the strongest SHP2 inhibitory activity, bound directly to the catalytic domain of SHP2 in a competitive manner through multiple hydrogen bonds. Compound 4o affected the RAS/MAPK signaling pathway by inhibiting SHP2, and subsequently induced apoptosis and growth inhibition of HCT116 cells in vitro and in vivo. Notably, the oral administration of compound 4o in large doses showed no obvious toxicity. In summary, our findings provide a basis for the further development of compound 4o as a safe, effective and anti-tumor SHP2 inhibitor.
The ATF3–OPG Axis Contributes to Bone Formation by Regulating the Differentiation of Osteoclasts, Osteoblasts, and Adipocytes
Authors: Kim Jung Ha , Kim Kabsun , Kim Inyoung , Seong Semun , Koh Jeong-Tae , Kim Nacksung
Published: March 2022

Activating transcription factor 3 (ATF3) has been identified as a negative regulator of osteoblast differentiation in in vitro study. However, it was not associated with osteoblast differentiation in in vivo study. To provide an understanding of the discrepancy between the in vivo and in vitro findings regarding the function of ATF3 in osteoblasts, we investigated the unidentified roles of ATF3 in osteoblast biology. ATF3 enhanced osteoprotegerin (OPG) production, not only in osteoblast precursor cells, but also during osteoblast differentiation and osteoblastic adipocyte differentiation. In addition, ATF3 increased nodule formation in immature osteoblasts and decreased osteoblast-dependent osteoclast formation, as well as the transdifferentiation of osteoblasts to adipocytes. However, all these effects were reversed by the OPG neutralizing antibody. Taken together, these results suggest that ATF3 contributes to bone homeostasis by regulating the differentiation of various cell types in the bone microenvironment, including osteoblasts, osteoclasts, and adipocytes via inducing OPG production.
Small Vessel Disease: Ancient Description, Novel Biomarkers
Authors: Moretti Rita , Caruso Paola
Published: March 2022

Small vessel disease (SVD) is one of the most frequent pathological conditions which lead to dementia. Biochemical and neuroimaging might help correctly identify the clinical diagnosis of this relevant brain disease. The microvascular alterations which underlie SVD have common origins, similar cognitive outcomes, and common vascular risk factors. Nevertheless, the arteriolosclerosis process, which underlines SVD development, is based on different mechanisms, not all completely understood, which start from a chronic hypoperfusion state and pass through a chronic brain inflammatory condition, inducing a significant endothelium activation and a consequent tissue remodeling action. In a recent review, we focused on the pathophysiology of SVD, which is complex, involving genetic conditions and different co-morbidities (i.e., diabetes, chronic hypoxia condition, and obesity). Currently, many points still remain unclear and discordant. In this paper, we wanted to focus on new biomarkers, which can be the expression of the endothelial dysfunction, or of the oxidative damage, which could be employed as markers of disease progression or for future targets of therapies. Therefore, we described the altered response to the endothelium-derived nitric oxide-vasodilators (ENOV), prostacyclin, C-reactive proteins, and endothelium-derived hyperpolarizing factors (EDHF). At the same time, due to the concomitant endothelial activation and chronic neuroinflammatory status, we described hypoxia-endothelial-related markers, such as HIF 1 alpha, VEGFR2, and neuroglobin, and MMPs. We also described blood–brain barrier disruption biomarkers and imaging techniques, which can also describe perivascular spaces enlargement and dysfunction. More studies should be necessary, in order to implement these results and give them a clinical benefit.
Immunometabolism of Myeloid-Derived Suppressor Cells: Implications for Mycobacterium tuberculosis Infection and Insights from Tumor Biology
Authors: Munansangu Brian S. M. , Kenyon Colin , Walzl Gerhard , Loxton André G. , Kotze Leigh A. , du Plessis Nelita
Published: March 2022

The field of immunometabolism seeks to decipher the complex interplay between the immune system and the associated metabolic pathways. The role of small molecules that can target specific metabolic pathways and subsequently alter the immune landscape provides a desirable platform for new therapeutic interventions. Immunotherapeutic targeting of suppressive cell populations, such as myeloid-derived suppressor cells (MDSC), by small molecules has shown promise in pathologies such as cancer and support testing of similar host-directed therapeutic approaches in MDSC-inducing conditions such as tuberculosis (TB). MDSC exhibit a remarkable ability to suppress T-cell responses in those with TB disease. In tumors, MDSC exhibit considerable plasticity and can undergo metabolic reprogramming from glycolysis to fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) to facilitate their immunosuppressive functions. In this review we look at the role of MDSC during M. tb infection and how their metabolic reprogramming aids in the exacerbation of active disease and highlight the possible MDSC-targeted metabolic pathways utilized during M. tb infection, suggesting ways to manipulate these cells in search of novel insights for anti-TB therapies.
Validation of a Novel Stereo Vibrometry Technique for Spiderweb Signal Analysis
Authors: Justus Nathan , Krugner Rodrigo , Hatton Ross L.
Published: March 2022

From courtship rituals, to prey identification, to displays of rivalry, a spider’s web vibrates with a symphony of information. Examining the modality of information being transmitted and how spiders interact with this information could lead to new understanding how spiders perceive the world around them through their webs, and new biological and engineering techniques that leverage this understanding. Spiders interact with their webs through a variety of body motions, including abdominal tremors, bounces, and limb jerks along threads of the web. These signals often create a large enough visual signature that the web vibrations can be analyzed using video vibrometry on high-speed video of the communication exchange. Using video vibrometry to examine these signals has numerous benefits over the conventional method of laser vibrometry, such as the ability to analyze three-dimensional vibrations and the ability to take measurements from anywhere in the web, including directly from the body of the spider itself. In this study, we developed a method of three-dimensional vibration analysis that combines video vibrometry with stereo vision, and verified this method against laser vibrometry on a black widow spiderweb that was experiencing rivalry signals from two female spiders.
The Addition of Sterols and Cryoprotectants to Optimize a Diet Developed for Eldana saccharina Walker (Lepidoptera: Pyralidae) Using the Carcass Milling Technique
Authors: Ngomane Nomalizo C. , Terblanche John S. , Conlong Des E.
Published: March 2022

Various combinations and concentrations of cholesterol (C) and stigmasterol (S) were added into a base diet developed for Eldana saccharina. Survival of inoculated neonate was high on all diets (>92% at day 20 and >95% at day 27). Fastest larval development occurred on the minimum specification (MS) (+1.0 gS) and MS (+0.2 gC: 0.2 gS) diets (72 and 70% pupation respectively at day 20). Significantly slower development (15% pupation) occurred on the control diet at day 20. Female pupal weight increased when larvae fed on the MS (+0.1 gC), (+0.1 gS) and (+0.2 gC:0.2 gS) diets (0.2143 ± 0.00 g, 0.2271 ± 0.01 g and 0.2252 ± 0.01 g, respectively) as compared with the control diet (0.1886 ± 0.00 g). Adult emergence was significantly higher (100%) from the MS (+0.1 gS) and MS (+0.2 gC:0.2 gS) diets, as compared with the remaining sterol (95%) and control diets (97%). To potentially increase E. saccharina’s cold tolerance, inclusion of cryoprotectants L-proline (P) and trehalose (T) into the MS diet was investigated. Males from the MS (0.2 gP:0.2 gT), MS (0.5 gP:0.5 gT) and MS (1.0 gT) diets recovered fastest from chill coma treatment (204 ± 44 s, 215 ± 7 s and 215 ± 9 s, respectively) than those from the remaining cryoprotectant diets (305 ± 22 s). The addition of cryoprotectants severely reduced female fertility (<44%) when mated with non-chill coma exposed males. In contrast, eggs from females not exposed to chilling treatment were 84% fertile when mated with males from the same source. The MS (0.2 gC:0.2 gS) diet is the preferred choice to replace the currently used diet, reducing the larval growth period by 60% without negative effects on key life cycle parameters of E. saccharina.
Consequences of Thermal Variation during Development and Transport on Flight and Low-Temperature Performance in False Codling Moth (Thaumatotibia leucotreta): Fine-Tuning Protocols for Improved Field Performance in a Sterile Insect Programme
Authors: Huisamen Elizabeth J. , Karsten Minette , Terblanche John S.
Published: March 2022

Here we aimed to assess whether variation in (1) developmental temperature and (2) transport conditions influenced the low-temperature performance and flight ability of false codling moth (FCM) adults in an SIT programme. To achieve the first aim, larvae were exposed to either a (control) (constant 25 °C), a cold treatment (constant 15 °C) or a fluctuating thermal regime (FTR) (25 °C for 12 h to 15 °C for 12 h) for 5 days, whereafter larvae were returned to 25 °C to pupate and emerge. After adult emergence, critical thermal minimum, chill coma recovery time, life history traits and laboratory flight ability were scored. For the second aim, adult FCM were exposed to 4 or 25 °C with or without vibrations to simulate road transportation. After the pre-treatments, flight ability, spontaneous behaviour (i.e., muscle coordination by monitoring whether the moth moved out of a defined circle or not) and chill coma recovery time were determined. The first experiment showed that FTR led to enhanced cold tolerance, increased flight performance and high egg-laying capacity with minimal costs. The second experiment showed that transport conditions currently in use did not appear to adversely affect flight and low-temperature performance of FCM. These results are important for refining conditions prior to and during release for maximum field efficacy in an SIT programme for FCM.
Formulation of Artificial Diets for Mass-Rearing Eldana saccharina Walker (Lepidoptera: Pyralidae) Using the Carcass Milling Technique
Authors: Ngomane Nomalizo C. , Pieterse Elsje , Woods Michael J. , Conlong Des E.
Published: March 2022

The carcass milling technique (CMT) formulates specific diets from nutrient analyses of species to be reared and their natural host plants. The first of four diets developed used the minimum ingredient specifications (MS) of published diets for Eldana saccharina. The remaining were based on the ideal amino acid composition and profile (IAAP) of its second (IAAP2), third/fourth (IAAP3/4) and fifth/sixth (IAAP5/6) instar larvae. The control was a modified Ostrinia nubilalis diet. Survival to pupae of inoculated E saccharina neonates was high on all CMT formulations (>92% at day 20 and >97% at day 27). Larvae developed fastest on the IAAP3/4 and MS diets (25% and 17% prepupae and pupae on day 20, respectively). Pupal weights were not significantly influenced by CMT diets (0.1121 g male; 0.1864 g female). The control group produced heavier male and female pupae (0.1204 g; 0.2085 g, respectively). Adult emergence was highest from the MS (98%), then the IAAP3/4 (97%) and control (96%) diets. Sex ratio of adults from all diets was close to one. Males from the IAAP5/6 diet mated with significantly more females (six), and females from the MS diet mated with more males (three) than those from remaining formulations. All females produced in excess of 870 eggs, more than 90% were fertile after mating. The pH (4.79); moisture content (81.43%) and water activity (0.92 aw) of the diets were not significantly different, maintaining quality and stability throughout the larval period, ensuring optimal growth and development. The MS diet formulation was the preferred choice to replace the current E. saccharina diet.
Biochemical and Morphological Mechanisms Underlying the Performance and Preference of Fall Armyworm (Spodoptera frugiperda) on Wheat and Faba Bean Plants
Authors: Liu Huan , Cheng Yumeng , Wang Xiaoqing , Francis Frédéric , Wang Qian , Liu Xiaobei , Zhang Yong , Chen Julian
Published: March 2022

Spodoptera frugiperda (J. E. Smith), which attacked China in 2019, remains a significant threat to wheat production. Wheat–faba bean intercropping systems prevent damage caused by wheat aphids; however, the potential role in S. frugiperda control remains unclear. Here, the adaptability and preferences of S. frugiperda to wheat and its common intercropped plant, faba bean, were evaluated to implement an eco-friendly approach for S. frugiperda management. Their adaptability showed that both hosts could support S. frugiperda to complete their life cycle; however, the larvae performed worse on faba bean compared with on wheat. The biochemical analysis revealed that faba bean plants had lower contents of soluble sugars and total proteins but higher levels of phenolics and tannins than in wheat leaves. The gravid S. frugiperda preferred (during the preference assays) to oviposit on wheat rather than on faba bean plants in cage tests. The wheat odor was preferred over the faba bean odor in the Y-tube olfactometer bioassays. The morphological scanning electron microscopy (SEM) showed increased trichome density on wheat leaves. Therefore, the faba bean plants displayed antibiosis on larvae and were repellent to female moths, thus, suggesting that faba bean plants could serve as a push crop to be intercropped with wheat for S. frugiperda control for wheat fields.
Can We Trust Trust Management Systems?
Authors: Marche Claudio , Nitti Michele
Published: March 2022

The Internet of Things is enriching our life with an ecosystem of interconnected devices. Object cooperation allows us to develop complex applications in which each node contributes one or more services. Therefore, the information moves from a provider to a requester node in a peer-to-peer network. In that scenario, trust management systems (TMSs) have been developed to prevent the manipulation of data by unauthorized entities and guarantee the detection of malicious behaviour. The community concentrates effort on designing complex trust techniques to increase their effectiveness; however, two strong assumptions have been overlooked. First, nodes could provide the wrong services due to malicious behaviours or malfunctions and insufficient accuracy. Second, the requester nodes usually cannot evaluate the received service perfectly. For this reason, a trust system should distinguish attackers from objects with poor performance and consider service evaluation errors. Simulation results prove that advanced trust algorithms are unnecessary for such scenarios with these deficiencies.
Introduction to Special Issue “Leaders in Cardiovascular Research, Dedicated to the Memory of Professor Adriana Gittenberger-de Groot”
Authors: Gittenberger Edi , Poelmann Robert E. , Jongbloed Monique R. M.
Published: March 2022

This Introduction provides both a short reflection on the scientific career of Adriana Gittenberger-de Groot and an overview of the papers that form the basis of this Special Issue giving them a proper perspective. The papers have as a central focus the outflow tract, and include contributions on development and pathology of the ventricles including AV valves, as well as developmental and pathomorphological aspects of the great arteries including semilunar valves and coronary arteries.
Porcine Models of Heart Regeneration
Authors: Velayutham Nivedhitha , Yutzey Katherine E.
Published: March 2022

Swine are popular large mammals for cardiac preclinical testing due to their similarities with humans in terms of organ size and physiology. Recent studies indicate an early neonatal regenerative capacity for swine hearts similar to small mammal laboratory models such as rodents, inspiring exciting possibilities for studying cardiac regeneration with the goal of improved clinical translation to humans. However, while swine hearts are anatomically similar to humans, fundamental differences exist in growth mechanisms, nucleation, and the maturation of pig cardiomyocytes, which could present difficulties for the translation of preclinical findings in swine to human therapeutics. In this review, we discuss the maturational dynamics of pig cardiomyocytes and their capacity for proliferative cardiac regeneration during early neonatal development to provide a perspective on swine as a preclinical model for developing cardiac gene- and cell-based regenerative therapeutics.
Impaired Terminal Erythroid Maturation in β0-Thalassemia/HbE Patients with Different Clinical Severity
Authors: Suriyun Thunwarat , Winichagoon Pranee , Fucharoen Suthat , Sripichai Orapan
Published: March 2022

Anemia in β-thalassemia is associated with ineffective erythropoiesis and a shortened lifespan of erythroid cells. The limited differentiation of β-thalassemic erythroblasts has been documented, but the characteristic feature of terminal erythroid maturation and its physiological relevance are not clearly described in β-thalassemias. Here, the red blood cell and reticulocyte cellular characteristics were determined in patients with β0-thalassemia/HbE in comparison to patients with iron deficiency anemia and healthy normal subjects. Severely affected β0-thalassemia/HbE patients showed the highest increase in immature reticulocytes, but the number of total erythrocytes was the lowest. Despite similar ranges of hemoglobin levels, β0-thalassemia/HbE patients had a higher number of reticulocytes and a greater proportion of immature fraction than patients with iron deficiency anemia did. In vitro CD34+ hematopoietic progenitor cells’ culture and flow cytometry analysis were conducted to investigate the erythroid maturation and mitochondrial clearance in β0-thalassemia/HbE erythroid cells as compared to normal cells. The delayed erythroid maturation and evidence of impaired mitochondria clearance were observed in β0-thalassemia/HbE cells at the terminal stage of differentiation. Additionally, increased transcript levels of genes related to erythroid mitophagy, BNIP3L and PINK1, were revealed in β0-thalassemia/HbE erythroblasts. The findings indicate that the erythroid maturation is physiologically relevant, and that the restoration of terminal maturation represents a potential therapeutic target for β-thalassemias.
Aberrant Structural Connectivity of the Triple Network System in Borderline Personality Disorder Is Associated with Behavioral Dysregulation
Authors: Quattrini Giulia , Magni Laura Rosa , Lanfredi Mariangela , Pedrini Laura , Carcione Antonino , Riccardi Ilaria , Corbo Daniele , Gasparotti Roberto , Rossi Roberta , Pievani Michela ,   the CLIMAMITHE Study Group
Published: March 2022

Background: Core symptoms of Borderline Personality Disorder (BPD) are associated to aberrant connectivity of the triple network system (salience network [SN], default mode network [DMN], executive control network [ECN]). While functional abnormalities are widely reported, structural connectivity (SC) and anatomical changes have not yet been investigated. Here, we explored the triple network’s SC, structure, and its association with BPD clinical features. Methods: A total of 60 BPD and 26 healthy controls (HC) underwent a multidomain neuropsychological and multimodal MRI (diffusion- and T1-weighted imaging) assessment. Metrics (fractional anisotropy [FA], mean diffusivity [MD], cortical thickness) were extracted from SN, DMN, ECN (triple network), and visual network (control network) using established atlases. Multivariate general linear models were conducted to assess group differences in metrics and associations with clinical features. Results: Patients showed increased MD in the anterior SN, dorsal DMN, and right ECN compared to HC. Diffusivity increases were more pronounced in patients with higher behavioral dysregulation, i.e., suicidal attempting, self-harm, and aggressiveness. No differences were detected in network structure. Conclusions: These results indicate that the triple network system is impaired in BPD at the microstructural level. The preferential involvement of anterior and right-lateralized subsystems and their clinical association suggests that these abnormalities could contribute to behavioral dysregulation.
Cardiac Glycosides Lower C-Reactive Protein Plasma Levels in Patients with Decompensated Heart Failure: Results from the Single-Center C-Reactive Protein-Digoxin Observational Study (C-DOS)
Authors: Zaczkiewicz Myron , Kostenzer Katharina , Graf Matthias , Mayer Benjamin , Zimmermann Oliver , Torzewski Jan
Published: March 2022

Recent randomized controlled multi-center trials JUPITER, CANTOS and COLCOT impressively demonstrated the effect of anti-inflammatory therapy on secondary prevention of cardiovascular events. These studies also rapidly re-vitalized the question of whether the C-reactive protein (CRP), the prototype human acute phase protein, is actively involved in atherosclerosis and its sequelae. Direct CRP inhibition may indeed improve the specificity and effectiveness of anti-inflammatory intervention. In the present paper, we report on the final results of our single-center C-reactive protein-Digoxin Observational Study (C-DOS). Methods and Results: Based on the experimental finding that cardiac glycosides potently inhibit hepatic CRP synthesis on the transcriptional level in vitro, 60 patients with decompensated heart failure, NYHA III–IV, severely reduced Left Ventricular Ejection Fraction (LVEF < 40%), and elevated CRP plasma levels were treated by either digoxin + conventional heart failure therapy (30 patients) or by conventional heart failure therapy alone (30 patients). Plasma CRP levels in both groups were assessed for 21 d. Plasma CRP levels on d1, d3 and d21 were compared by regression analysis. CRP levels d21–d1 significantly declined in both groups. Notably, comparative CRP reduction d21–d3 in digoxin versus the control group also revealed borderline significance (p = 0.051). Conclusions: This small observational trial provides the first piece of evidence that cardiac glycosides may inhibit CRP synthesis in humans. In case of further pharmacological developments, cardiac glycosides may emerge as lead compounds for chemical modification in order to improve the potency, selectivity and pharmacokinetics of CRP synthesis inhibition in cardiovascular disease.
Engineering 3D Printed Scaffolds with Tunable Hydroxyapatite
Authors: Kim Yoontae , Lee Eun-Jin , Kotula Anthony P. , Takagi Shozo , Chow Laurence , Alimperti Stella
Published: March 2022

Orthopedic and craniofacial surgical procedures require the reconstruction of bone defects caused by trauma, diseases, and tumor resection. Successful bone restoration entails the development and use of bone grafts with structural, functional, and biological features similar to native tissues. Herein, we developed three-dimensional (3D) printed fine-tuned hydroxyapatite (HA) biomimetic bone structures, which can be applied as grafts, by using calcium phosphate cement (CPC) bioink, which is composed of tetracalcium phosphate (TTCP), dicalcium phosphate anhydrous (DCPA), and a liquid [Polyvinyl butyral (PVB) dissolved in ethanol (EtOH)]. The ink was ejected through a high-resolution syringe nozzle (210 µm) at room temperature into three different concentrations (0.01, 0.1, and 0.5) mol/L of the aqueous sodium phosphate dibasic (Na2HPO4) bath that serves as a hardening accelerator for HA formation. Raman spectrometer, X-ray diffraction (XRD), and scanning electron microscopy (SEM) demonstrated the real-time HA formation in (0.01, 0.1, and 0.5) mol/L Na2HPO4 baths. Under those conditions, HA was formed at different amounts, which tuned the scaffolds’ mechanical properties, porosity, and osteoclast activity. Overall, this method may pave the way to engineer 3D bone scaffolds with controlled HA composition and pre-defined properties, which will enhance graft-host integration in various anatomic locations.
Improving Scene Text Recognition for Indian Languages with Transfer Learning and Font Diversity
Authors: Gunna Sanjana , Saluja Rohit , Jawahar Cheerakkuzhi Veluthemana
Published: March 2022

Reading Indian scene texts is complex due to the use of regional vocabulary, multiple fonts/scripts, and text size. This work investigates the significant differences in Indian and Latin Scene Text Recognition (STR) systems. Recent STR works rely on synthetic generators that involve diverse fonts to ensure robust reading solutions. We present utilizing additional non-Unicode fonts with generally employed Unicode fonts to cover font diversity in such synthesizers for Indian languages. We also perform experiments on transfer learning among six different Indian languages. Our transfer learning experiments on synthetic images with common backgrounds provide an exciting insight that Indian scripts can benefit from each other than from the extensive English datasets. Our evaluations for the real settings help us achieve significant improvements over previous methods on four Indian languages from standard datasets like IIIT-ILST, MLT-17, and the new dataset (we release) containing 440 scene images with 500 Gujarati and 2535 Tamil words. Further enriching the synthetic dataset with non-Unicode fonts and multiple augmentations helps us achieve a remarkable Word Recognition Rate gain of over 33% on the IIIT-ILST Hindi dataset. We also present the results of lexicon-based transcription approaches for all six languages.
Ultrahigh-Throughput Screening of High-β-Xylosidase-Producing Penicillium piceum and Investigation of the Novel β-Xylosidase Characteristics
Authors: Zhang Zhaokun , Ge Mingyue , Guo Qi , Jiang Yi , Jia Wendi , Gao Le , Hu Jianhua
Published: March 2022

A droplet-based microfluidic ultrahigh-throughput screening technology has been developed for the selection of high-β-xylosidase-producing Penicillium piceum W6 from the atmospheric and room-temperature plasma-mutated library of P. piceum. β-xylosidase hyperproducers filamentous fungi, P. piceum W6, exhibited an increase in β-xylosidase activity by 7.1-fold. A novel β-D-xylosidase was purified from the extracellular proteins of P. piceum W6 and designated as PpBXL. The optimal pH and temperature of PpBXL were 4.0 and 70 °C, respectively. PpBXL had high stability an acidic pH range of 3.0–5.0 and exhibited good thermostability with a thermal denaturation half-life of 10 days at 70 °C. Moreover, PpBXL showed the bifunctional activities of α-L-arabinofuranosidase and β-xylosidase. Supplementation with low-dose PpBXL (100 μg/g substrate) improved the yields of glucose and xylose generated from delignified biomass by 36–45%. The synergism between PpBXL and lignocellulolytic enzymes enhanced delignified biomass saccharification, increased the Xyl/Ara ratio, and decreased the strength of hydrogen bonds.
Immunomodulating Activity of Pleurotus eryngii Mushrooms Following Their In Vitro Fermentation by Human Fecal Microbiota
Authors: Vlassopoulou Marigoula , Paschalidis Nikolaos , Savvides Alexandros L. , Saxami Georgia , Mitsou Evdokia K. , Kerezoudi Evangelia N. , Koutrotsios Georgios , Zervakis Georgios I. , Georgiadis Panagiotis , Kyriacou Adamantini , Pletsa Vasiliki
Published: March 2022

Recent studies have revealed the crucial role of several edible mushrooms and fungal compounds, mainly polysaccharides, in human health and disease. The investigation of the immunomodulating effects of mushroom polysaccharides, especially β-glucans, and the link between their anticancer and immunomodulatory properties with their possible prebiotic activity on gut micro-organisms has been the subject of intense research over the last decade. We investigated the immunomodulating effects of Pleurotus eryngii mushrooms, selected due to their high β-glucan content, strong lactogenic effect, and potent geno-protective properties, following in vitro fermentation by fecal inocula from healthy elderly volunteers (>60 years old). The immunomodulating properties of the fermentation supernatants (FSs) were initially investigated in U937-derived human macrophages. Gene expression as well as pro- (TNF-α, IL-1β) and anti-inflammatory cytokines (IL-10, IL-1Rα) were assessed and correlated with the fermentation process. The presence of P. eryngii in the fermentation process led to modifications in immune response, as indicated by the altered gene expression and levels of the cytokines examined, a finding consistent for all volunteers. The FSs immunomodulating effect on the volunteers’ peripheral blood mononuclear cells (PBMCs) was verified through the use of cytometry by time of flight (CyTOF) analysis.
Promising Effects of Digital Chest Tube Drainage System for Pulmonary Resection: A Systematic Review and Network Meta-Analysis
Authors: Chang Po-Chih , Chen Kai-Hua , Jhou Hong-Jie , Lee Cho-Hao , Chou Shah-Hwa , Chen Po-Huang , Chang Ting-Wei
Published: March 2022

Objective: The chest tube drainage system (CTDS) of choice for the pleural cavity after pulmonary resection remains controversial. This systematic review and network meta-analysis (NMA) aimed to assess the length of hospital stay, chest tube placement duration, and prolonged air leak among different types of CTDS. Methods: This systemic review and NMA included 21 randomized controlled trials (3399 patients) in PubMed and Embase until 1 June 2021. We performed a frequentist random effect in our NMA, and a P-score was adopted to determine the best treatment. We assessed the clinical efficacy of different CTDSs (digital/suction/non-suction) using the length of hospital stay, chest tube placement duration, and presence of prolonged air leak. Results: Based on the NMA, digital CTDS was the most beneficial intervention for the length of hospital stay, being 1.4 days less than that of suction CTDS (mean difference (MD): −1.40; 95% confidence interval (CI): −2.20 to −0.60). Digital CTDS also had significantly reduced chest tube placement duration, being 0.68 days less than that of suction CTDSs (MD: −0.68; 95% CI: −1.32 to −0.04). Neither digital nor non-suction CTDS significantly reduced the risk of prolonged air leak. Conclusions: Digital CTDS is associated with better outcomes than suction and non-suction CTDS for patients undergoing pulmonary resections, specifically 0.68 days shorter chest tube duration and 1.4 days shorter hospital stay than suction CTDS.
The Challenge and Importance of Integrating Drug–Nutrient–Genome Interactions in Personalized Cardiovascular Healthcare
Authors: Stouras Ioannis , Papaioannou Theodore , Tsioufis Konstantinos , Eliopoulos Aristides , Sanoudou Despina
Published: March 2022

Despite the rich armamentarium of available drugs against different forms of cardiovascular disease (CVD), major challenges persist in their safe and effective use. These include high rates of adverse drug reactions, increased heterogeneity in patient responses, suboptimal drug efficacy, and in some cases limited compliance. Dietary elements (including food, beverages, and supplements) can modulate drug absorption, distribution, metabolism, excretion, and action, with significant implications for drug efficacy and safety. Genetic variation can further modulate the response to diet, to a drug, and to the interaction of the two. These interactions represent a largely unexplored territory that holds considerable promise in the field of personalized medicine in CVD. Herein, we highlight examples of clinically relevant drug–nutrient–genome interactions, map the challenges faced to date, and discuss their future perspectives in personalized cardiovascular healthcare in light of the rapid technological advances.
In Situ Tungsten Carbide Formation in Nanostructured Copper Matrix Composite Using Mechanical Alloying and Sintering
Authors: Yusoff Mahani , Zuhailawati Hussain
Published: March 2022

In this study, an in situ nanostructured copper tungsten carbide composite was synthesized by mechanical alloying (MA) and the powder metallurgy route. The microstructure and phase changes of the composite were characterized by X-ray diffraction, scanning electron microscopy and X-ray photoelectron spectroscopy. Tungsten carbide phases (WC and W2C) were only present after MA and combination of sintering. Higher energy associated with a longer milling time was beneficial for the formation of WC. Formation of W2C and WC resulted from internal refinement due to heavy plastic deformation in the composite. The solubility of the phases in the as-milled and sintered composite was described by the changes of the lattice parameter of Cu. Chemical analysis of the surface of a composite of W 4f and C 1s revealed that the increased defects introduced by MA affect the atomic binding of the W-C interaction.
Self-Centering Shape Memory Alloy-Viscoelastic Hybrid Braces for Seismic Resilience
Authors: Zhang Zhe-Xi , Ping Yiwei , He Xiuzhang
Published: March 2022

This paper presents a novel type of hybrid self-centering braces incorporating tension-only superelastic NiTi shape memory alloy (SMA) cables and integrated viscoelastic dampers (VEDs). One of our reasons for proposing this new SMA-viscoelastic hybrid brace (SCVEB) is to provide enhanced energy-dissipation ability whilst promoting increased self-centering tendency compared with the existing SMA-based self-centering solutions, where upgrading behavior is mainly benefited from the participation of the VEDs. The configuration and the working principle, along with theoretical equations describing the mechanical behavior of the SCVEB, are described in detail firstly. Experimental verification of individual elements in this SCVEB system, namely the NiTi SMA cables and VEDs, was performed to obtain a basic understanding of their mechanical properties. A proof-of-concept SCVEB specimen was then manufactured, and its cyclic performance was further investigated. Followed by this, a system-level analysis on a series of steel frames equipped with or without SCVEB was conducted. The results showed that the SCVEB system exhibited a moderate damping ratio and a more efficient controlled behavior in terms of its post-event residual deformation and floor acceleration when compared with those of the non-SCVEB system.
On the Comparative Analysis of Different Phase Coexistences in Mesoporous Materials
Authors: Enninful Henry R. N. B. , Enke Dirk , Valiullin Rustem
Published: March 2022

Alterations of fluid phase transitions in porous materials are conventionally employed for the characterization of mesoporous solids. In the first approximation, this may be based on the application of the Kelvin equation for gas–liquid and the Gibbs–Thomson equation for solid–liquid phase equilibria for obtaining pore size distributions. Herein, we provide a comparative analysis of different phase coexistences measured in mesoporous silica solids with different pore sizes and morphology. Instead of comparing the resulting pore size distributions, we rather compare the transitions directly by using a common coordinate for varying the experiment’s thermodynamic parameters based on the two equations mentioned. Both phase transitions in these coordinates produce comparable results for mesoporous solids of relatively large pore sizes. In contrast, marked differences are found for materials with smaller pore sizes. This illuminates the fact that, with reducing confinement sizes, thermodynamic fluctuations become increasingly important and different for different equilibria considered. In addition, we show that in the coordinate used for analysis, mercury intrusion matches perfectly with desorption and freezing transitions.
Improved Anti-Vulcanization and Bonding Performance of a Silver Alloy Bonding Wire by a Cathodic Passivation Treatment with Palladium
Authors: Yang Guannan , Zhou Zhiqiang , Zhang Haide , Zhang Yu , Peng Zhen , Gong Pan , Wang Xin , Cui Chengqiang
Published: March 2022

As a traditional interconnect material, silver alloy bonding wires are widely used in electronic packaging, but their propensity to vulcanize quickly has not been sufficiently addressed. The current surface anti-oxidation and anti-sulfidation treatments are often accompanied by a decline in bonding performance, which hinders the use of silver alloy bonding wires in new applications. In the present paper, we develop a new cathodic passivation treatment in a Pd-containing solution for silver bonding wires, which not only significantly improves their vulcanization resistance, but also maintains their bonding performance. The surface of the treated wires remains unaffected after vulcanization in 0.3 μg/m3 of ammonium sulfide for 60 min. Compared to a Pd-free passivation treatment, the bonding strength of the wire passivated with the Pd-containing solution improves from 0.20 to 0.27 N. XPS analysis confirms the existence of Pd on the surface of the wire. The solder ball formed an obtuse angle instead of a sharp angle on the pad, which is beneficial for bonding strength.
Efficient Flexible Multibody Models for Tilting Pad Journal Bearings
Authors: Giannetti Guglielmo , Meli Enrico , Rindi Andrea
Published: March 2022

Tilting pad journal bearings (TPJBs) are key components in modern rotating machines. They require accurate modeling to describe their behavior, and we considered the thermo-elasto-hydrodynamic approach. Thermo-elasto-hydrodynamic (TEHD) models are a powerful tool for machine design and analysis, but they have to assure a good compromise between accuracy and numerical efficiency. Current multi-physics TEHD models of TPJBs are very accurate; however, their numerical efficiency is still far from being satisfying for industrial applications. To partially fill this gap, we propose an innovative modeling approach based on efficient flexible multibody techniques, such as the Floating Frame of Reference Formulation (FFRF) and some extensions that can be easily coupled with different fluid dynamic models to describe the whole TPJB. The model was tested on a real TPJB geometry and validated through experimental tests. The results are encouraging and show the effectiveness of the proposed approach. Finally, the model proposed can be applied in different engineering fields, such as Oil & Gas and aeronautics, where TPJBs are typically used, where it is fundamental to always reach better performance with low energy consumption and where it is particularly important to have an efficient and accurate model to simulate long period times with brief simulation times.