bluuebunny/crossref_metadata_2025 huggingface dataset:
The THO/TREX Complex Active in Alternative Splicing Mediates Plant Responses to Salicylic Acid and Jasmonic Acid
Authors: Sun Nengxu , Kong Xiangjiu , Liu Yueyan , Gong Tingting , Gu Xiaoyong , Liu Lijing
Published: November 2021

Salicylic acid (SA) and jasmonic acid (JA) are essential plant immune hormones, which could induce plant resistance to multiple pathogens. However, whether common components are employed by both SA and JA to induce defense is largely unknown. In this study, we found that the enhanced disease susceptibility 8 (EDS8) mutant was compromised in plant defenses to hemibiotrophic pathogen Pseudomonas syringae pv. maculicola ES4326 and necrotrophic pathogen Botrytis cinerea, and was deficient in plant responses to both SA and JA. The EDS8 was identified to be THO1, which encodes a subunit of the THO/TREX complex, by using mapping-by-sequencing. To check whether the EDS8 itself or the THO/TREX complex mediates SA and JA signaling, the mutant of another subunit of the THO/TREX complex, THO3, was tested. THO3 mutation reduced both SA and JA induced defenses, indicating that the THO/TREX complex is critical for plant responses to these two hormones. We further proved that the THO/TREX interacting protein SERRATE, a factor regulating alternative splicing (AS), was involved in plant responses to SA and JA. Thus, the AS events in the eds8 mutant after SA or JA treatment were determined, and we found that the SA and JA induced different alternative splicing events were majorly modulated by EDS8. In summary, our study proves that the THO/TREX complex active in AS is involved in both SA and JA induced plant defenses.
Ets1 Promotes the Differentiation of Post-Selected iNKT Cells through Regulation of the Expression of Vα14Jα18 T Cell Receptor and PLZF
Authors: Chuang Ya-Ting , Chuang Wan-Chu , Liu Chih-Chun , Liu Chia-Wei , Huang Yu-Wen , Yang Huang-Yu , Ho I-Cheng , Tai Tzong-Shyuan
Published: November 2021

The transcription factor Ets1 is essential for the development/differentiation of invariant Natural Killer T (iNKT) cells at multiple stages. However, its mechanisms of action and target genes in iNKT cells are still elusive. Here, we show that Ets1 is required for the optimal expression of the Vα14Jα18 T cell receptor (TCR) in post-selected thymic iNKT cells and their immediate differentiation. Ets1 is also critical for maintaining the peripheral homeostasis of iNKT cells, which is a role independent of the expression of the Vα14Jα18 TCR. Genome-wide transcriptomic analyses of post-selected iNKT cells further reveal that Ets1 controls leukocytes activation, proliferation differentiation, and leukocyte-mediated immunity. In addition, Ets1 regulates the expression of ICOS and PLZF in iNKT cells. More importantly, restoring the expression of PLZF and the Vα14Jα18 TCR partially rescues the differentiation of iNKT cells in the absence of Ets1. Taken together, our results establish a detailed molecular picture of how Ets1 regulates the stepwise differentiation of iNKT cells.
Investigation of Ifosfamide Toxicity Induces Common Upstream Regulator in Liver and Kidney
Authors: Han Hyoung-Yun , Choi Mi-Sun , Yoon Seokjoo , Ko Je-Won , Kim Sang-Kyum , Kim Tae-Won
Published: November 2021

Ifosfamide is an alkylating agent, a synthetic analogue of cyclophosphamide, used to treat various solid cancers. In this study, the toxicity of ifosfamide was evaluated using single-and multiple-dose intraperitoneal administration in rats under Good Laboratory Practice guidelines, and an additional microarray experiment was followed to support toxicological findings. A single dose of ifosfamide (50 mg/kg) did not induce any pathological changes. Meanwhile, severe renal toxicity was observed in the 7 and 28 days consecutively administered groups, with significant increases in blood urea nitrogen and creatinine levels. In the tox-list analysis, cholesterol synthesis-related genes were mostly affected in the liver and renal failure-related genes were affected in the kidney after ifosfamide administration. Moreover, interferon regulatory factor 7 was selected as the main upstream regulator that changed in both the liver and kidney, and was found to interact with other target genes, such as ubiquitin specific peptidase 18, radical S-adenosyl methionine domain containing 2, and interferon-stimulated gene 15, which was further confirmed by real-time RT-PCR analysis. In conclusion, we confirmed kidney-biased ifosfamide organ toxicity and identified identically altered genes in both the liver and kidney. Further comprehensive toxicogenomic studies are required to reveal the exact relationship between ifosfamide-induced genes and organ toxicity.
A New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis
Authors: Adams James , Thornton Benjamin P. , Tabernero Lydia
Published: November 2021

The kinase interaction motif protein tyrosine phosphatases (KIM-PTPs), HePTP, PTPSL and STEP, are involved in the negative regulation of mitogen-activated protein kinase (MAPK) signalling pathways and are important therapeutic targets for a number of diseases. We have used VSpipe, a virtual screening pipeline, to identify a ligand cluster distribution that is unique to this subfamily of PTPs. Several clusters map onto KIM-PTP specific sequence motifs in contrast to the cluster distribution obtained for PTP1B, a classic PTP that mapped to general PTP motifs. Importantly, the ligand clusters coincide with previously reported functional and substrate binding sites in KIM-PTPs. Assessment of the KIM-PTP specific clusters, using ligand efficiency index (LEI) plots generated by the VSpipe, ascertained that the binders in these clusters reside in a more drug-like chemical–biological space than those at the active site. LEI analysis showed differences between clusters across all KIM-PTPs, highlighting a distinct and specific profile for each phosphatase. The most druggable cluster sites are unexplored allosteric functional sites unique to each target. Exploiting these sites may facilitate the delivery of inhibitors with improved drug-like properties, with selectivity amongst the KIM-PTPs and over other classical PTPs.
Eco-Friendly Ether and Ester-Urethane Prepolymer: Structure, Processing and Properties
Authors: Niesiobędzka Joanna , Głowińska Ewa , Datta Janusz
Published: November 2021

This study concerns bio-based urethane prepolymers. The relationship between the chemical structure and the thermal and processing parameters of bio-based isocyanate-terminated ether and ester-urethane prepolymers was investigated. Bio-based prepolymers were obtained with the use of bio-monomers such as bio-based diisocyanate, bio-based polyether polyol or polyester polyols. In addition to their composition, the bio-based prepolymers were different in the content of iso-cyanate groups content (ca. 6 and 8%). The process of pre-polymerization and the obtained bio-based prepolymers were analyzed by determining the content of unreacted NCO groups, Fourier transform infrared spectroscopy, proton nuclear magnetic resonance, thermogravimetry, and rheological measurements. The research conducted facilitated the evaluation of the properties and processability of urethane prepolymers based on natural components. The results indicate that a significant impact on the processability has the origin the polyol ingredient as well as the NCO content. The thermal stability of all of the prepolymers is similar. A prepolymer based on a poly-ether polyol is characterized by a lower viscosity at a lower temperature than the prepolymer based on a polyester polyol. The viscosity value depends on the NCO content.
The Effects of Flavonoid Apigenin on Male Reproductive Health: Inhibition of Spermatogonial Proliferation through Downregulation of Prmt7/Akt3 Pathway
Authors: Wang Bingyuan , Zhang Mingrui , Guo Jiankang , Liu Zhiguo , Zhou Rong , Guo Fei , Li Kui , Mu Yulian
Published: November 2021

Apigenin, a common dietary flavonoid abundantly present in a variety of fruits and vegetables, has promising anticancer properties. As an effector of apigenin in myoblasts, protein arginine methyltransferase 7 (Prmt7) is required for male germ cell development. However, whether apigenin may influence male reproductive health through Prmt7 is still unclear. To this end, mouse spermatogonia were treated with different concentrations (2.5 to 50 μM) of apigenin for 48 h, which showed that apigenin could cause reduced cell proliferation in conjunction with longer S phase and G2/M phase (with concentrations of 10 and 20 μM, respectively), and increased apoptosis of spermatogonia (with concentration of 20 μM). Reduced Prmt7 expression was found in 20 μM apigenin-treated spermatogonia. Moreover, siRNA-induced Prmt7 knockdown exhibited similar influence on spermatogonia as that of apigenin treatment. In mechanistic terms, transcriptome analysis revealed 287 differentially expressed genes between Prmt7-downregulated and control spermatogonia. Furthermore, rescue experiments suggested that the effects of apigenin on spermatogonia might be mediated through the Prmt7/Akt3 pathway. Overall, our study supports that apigenin can interfere with mouse spermatogonial proliferation by way of the downregulated Prmt7/Akt3 pathway, which demonstrates that the concentration should be taken into account in future applications of apigenin for cancer therapy of men.
Quadruple and Truncated MEK3 Mutants Identified from Acute Lymphoblastic Leukemia Promote Degradation and Enhance Proliferation
Authors: Ayala-Marin Yoshira M. , Grant Alice H. , Rodriguez Georgialina , Kirken Robert A.
Published: November 2021

Compared to other ethnicities, Hispanic children incur the highest rates of leukemia, and most cases are diagnosed as Acute Lymphoblastic Leukemia (ALL). Despite improved treatment and survival for ALL, disproportionate health outcomes in Hispanics persist. Thus, it is essential to identify oncogenic mutations within this demographic to aid in the development of new strategies to diagnose and treat ALL. Using whole-exome sequencing, five single nucleotide polymorphisms within mitogen-activated protein kinase 3 (MAP2K3) were identified in an ALL cancer patient library from the U.S./Mexico border. MAP2K3 R26T and P11T are located near the substrate-binding site, while R65L and R67W localized to the kinase domain. Truncated-MAP2K3 mutant Q73* was also identified. Transfection in HEK293 cells showed that the quadruple-MEK3 mutant (4M-MEK3) impacted protein stability, inducing degradation and reducing expression. The expression of 4M-MEK3 could be rescued by cysteine/serine protease inhibition, and proteasomal degradation of truncated-MEK3 occurred in a ubiquitin-independent manner. MEK3 mutants displayed reduced auto-phosphorylation and enzymatic activity, as seen by decreases in p38 phosphorylation. Furthermore, uncoupling of the MEK3/p38 signaling pathway resulted in less suppressive activity on HEK293 cell viability. Thus, disruption of MEK3 activation may promote proliferative signals in ALL. These findings suggest that MEK3 represents a potential therapeutic target for treating ALL.
Differential Expression Patterns of TDP-43 in Single Moderate versus Repetitive Mild Traumatic Brain Injury in Mice
Authors: Janković Tamara , Dolenec Petra , Rajič Bumber Jelena , Gržeta Nika , Kriz Jasna , Župan Gordana , Pilipović Kristina
Published: November 2021

Traumatic brain injury (TBI) is a disabling disorder and a major cause of death and disability in the world. Both single and repetitive traumas affect the brain acutely but can also lead to chronic neurodegenerative changes. Clinical studies have shown some dissimilarities in transactive response DNA binding protein 43 (TDP-43) expression patterns following single versus repetitive TBI. We explored the acute cortical post-traumatic changes of TDP-43 using the lateral fluid percussion injury (LFPI) model of single moderate TBI in adult male mice and investigated the association of TDP-43 with post-traumatic neuroinflammation and synaptic plasticity. In the ipsilateral cortices of animals following LFPI, we found changes in the cytoplasmic and nuclear levels of TDP-43 and the decreased expression of postsynaptic protein 95 within the first 3 d post-injury. Subacute pathological changes of TDP-43 in the hippocampi of animals following LFPI and in mice exposed to repetitive mild TBI (rmTBI) were studied. Changes in the hippocampal TDP-43 expression patterns at 14 d following different brain trauma procedures showed pathological alterations only after single moderate, but not following rmTBI. Hippocampal LFPI-induced TDP-43 pathology was not accompanied by the microglial reaction, contrary to the findings after rmTBI, suggesting that different types of brain trauma may cause diverse pathophysiological changes in the brain, specifically related to the TDP-43 protein as well as to the microglial reaction. Taken together, our findings may contribute to a better understanding of the pathophysiological events following brain trauma.
Combination of Near-Infrared Photoimmunotherapy Using Trastuzumab and Small Protein Mimetic for HER2-Positive Breast Cancer
Authors: Yamaguchi Haruka , On Jotaro , Morita Takao , Suzuki Takamasa , Okada Yasuo , Ono Junya , Evdokiou Andreas
Published: November 2021

Near-infrared photoimmunotherapy (NIR-PIT) is a promising cancer therapy based on a monoclonal antibody conjugated to a photosensitizer (IR700Dye) that is activated by near-infrared light irradiation. We previously reported on the use of NIR-PIT with a small protein mimetic, the Affibody molecule (6–7 kDa), instead of a monoclonal antibody. In this study, we investigated a combination of NIR-PIT for HER2-positive breast cancer cells (SK-BR3, MDA-MB361, and JIMT1) with HER2 Affibody-IR700Dye conjugate and trastuzumab-IR700Dye conjugate. HER2 Affibody and trastuzumab target different epitopes of the HER2 protein and do not compete. In vitro, the combination of NIR-PIT using both HER2 Affibody-IR700Dye conjugate and trastuzumab-IR700Dye conjugate induced necrotic cell death of HER2-positive breast cancer cells without damage to HER2-negative breast cancer cells (MCF7). It was more efficient than NIR-PIT using either the HER2 Affibody-IR700Dye conjugate alone or the trastuzumab-IR700Dye conjugate alone. Additionally, this combination of NIR-PIT was significantly effective against HER2 low-expressing cancer cells, trastuzumab-resistant cells (JIMT1), and brain metastatic cells of breast cancer (MDA-MB361). Furthermore, in vivo imaging exhibited the strong fluorescence intensity of both HER2 Affibody-IR700Dye conjugates and trastuzumab-Alexa488 conjugates in HER2-positive tumor, indicating that both HER2 Affibody and trastuzumab specifically bind to HER2-positive tumors without competing with each other. In conclusion, the combination of NIR-PIT using both HER2 Affibody and trastuzumab expands the targeting scope of NIR-PIT for HER2-positive breast cancer.
Multifunctional Cyanine-Based Theranostic Probe for Cancer Imaging and Therapy
Authors: Peng Cheng-Liang , Shih Ying-Hsia , Chiang Ping-Fang , Chen Chun-Tang , Chang Ming-Cheng
Published: November 2021

Cancer is one of the leading causes of death in the world. A cancer-targeted multifunctional probe labeled with the radionuclide has been developed to provide multi-modalities for NIR fluorescence and nuclear imaging (PET, SPECT), for photothermal therapy (PTT), and targeted radionuclide therapy of cancer. In this study, synthesis, characterization, in vitro, and in vivo biological evaluation of the cyanine-based probe (DOTA-NIR790) were demonstrated. The use of cyanine dyes for the selective accumulation of cancer cells were used to achieve the characteristics of tumor markers. Therefore, all kinds of organ tumors can be targeted for diagnosis and treatment. The DOTA-NIR790 labeled with lutetium-111 could detect original or metastatic tumors by using SPECT imaging and quantify tumor accumulation. The β-emission of 177Lu-DOTA-NIR790 can be used for targeted radionuclide therapy of tumors. The DOTA-NIR790 enabled imaging by NIR fluorescence and by nuclear imaging (SPECT) to monitor in real-time the tumor accumulation and the situation of cancer therapy, and to guide the surgery or the photothermal therapy of the tumor. The radionuclide-labeled heptamethine cyanine based probe (DOTA-NIR790) offers multifunctional modalities for imaging and therapies of cancer.
The Epithelial-to-Mesenchymal Transition (EMT) in the Development and Metastasis of Malignant Pleural Mesothelioma
Authors: Ramundo Valeria , Zanirato Giada , Aldieri Elisabetta
Published: November 2021

Malignant pleural mesothelioma (MPM) is an aggressive tumor mainly associated with asbestos exposure and is characterized by a very difficult pharmacological approach. One of the molecular mechanisms associated with cancer onset and invasiveness is the epithelial-to-mesenchymal transition (EMT), an event induced by different types of inducers, such as transforming growth factor β (TGFβ), the main inducer of EMT, and oxidative stress. MPM development and metastasis have been correlated to EMT; On one hand, EMT mediates the effects exerted by asbestos fibers in the mesothelium, particularly via increased oxidative stress and TGFβ levels evoked by asbestos exposure, thus promoting a malignant phenotype, and on the other hand, MPM acquires invasiveness via the EMT event, as shown by an upregulation of mesenchymal markers or, although indirectly, some miRNAs or non-coding RNAs, all demonstrated to be involved in cancer onset and metastasis. This review aims to better describe how EMT is involved in driving the development and invasiveness of MPM, in an attempt to open new scenarios that are useful in the identification of predictive markers and to improve the pharmacological approach against this aggressive cancer.
Kinase-Inhibitors in Iodine-Refractory Differentiated Thyroid Cancer—Focus on Occurrence, Mechanisms, and Management of Treatment-Related Hypertension
Authors: Kaae Anne Christine , Kreissl Michael C. , Krüger Marcus , Infanger Manfred , Grimm Daniela , Wehland Markus
Published: November 2021

Differentiated thyroid cancer (DTC) usually has a good prognosis when treated conventionally with thyroidectomy, radioactive iodine (RAI) and thyroid-stimulating hormone suppression, but some tumors develop a resistance to RAI therapy, requiring alternative treatments. Sorafenib, lenvatinib and cabozantinib are multikinase inhibitors (MKIs) approved for the treatment of RAI-refractory DTC. The drugs have been shown to improve progression-free survival (PFS) and overall survival (OS) via the inhibition of different receptor tyrosine kinases (RTKs) that are involved in tumorigenesis and angiogenesis. Both sorafenib and lenvatinib have been approved irrespective of the line of therapy for the treatment of RAI-refractory DTC, whereas cabozantinib has only been approved as a second-line treatment. Adverse effects (AEs) such as hypertension are often seen with MKI treatment, but are generally well manageable. In this review, current clinical studies will be discussed, and the toxicity and safety of sorafenib, lenvatinib and cabozantinib treatment will be evaluated, with a focus on AE hypertension and its treatment options. In short, treatment-emergent hypertension (TE-HTN) occurs with all three drugs, but is usually well manageable and leads only to a few dose modifications or even discontinuations. This is emphasized by the fact that lenvatinib is widely considered the first-line drug of choice, despite its higher rate of TE-HTN.
OsABF1 Represses Gibberellin Biosynthesis to Regulate Plant Height and Seed Germination in Rice (Oryza sativa L.)
Authors: Tang Liqun , Xu Huayu , Wang Yifeng , Wang Huimei , Li Zhiyong , Liu Xixi , Shu Yazhou , Li Guan , Liu Wanning , Ying Jiezheng , Tong Xiaohong , Yao Jialing , Xiao Wenfei , Tang Shaoqing , Ni Shen , Zhang Jian
Published: November 2021

Gibberellins (GAs) are diterpenoid phytohormones regulating various aspects of plant growth and development, such as internode elongation and seed germination. Although the GA biosynthesis pathways have been identified, the transcriptional regulatory network of GA homeostasis still remains elusive. Here, we report the functional characterization of a GA-inducible OsABF1 in GA biosynthesis underpinning plant height and seed germination. Overexpression of OsABF1 produced a typical GA-deficient phenotype with semi-dwarf and retarded seed germination. Meanwhile, the phenotypes could be rescued by exogenous GA3, suggesting that OsABF1 is a key regulator of GA homeostasis. OsABF1 could directly suppress the transcription of green revolution gene SD1, thus reducing the endogenous GA level in rice. Moreover, OsABF1 interacts with and transcriptionally antagonizes to the polycomb repression complex component OsEMF2b, whose mutant showed as similar but more severe phenotype to OsABF1 overexpression lines. It is suggested that OsABF1 recruits RRC2-mediated H3K27me3 deposition on the SD1 promoter, thus epigenetically silencing SD1 to maintain the GA homeostasis for growth and seed germination. These findings shed new insight into the functions of OsABF1 and regulatory mechanism underlying GA homeostasis in rice.
Salivary Trefoil Factor Family (TFF) Peptides and Their Roles in Oral and Esophageal Protection: Therapeutic Potential
Authors: Hoffmann Werner
Published: November 2021

Human saliva is a complex body fluid with more than 3000 different identified proteins. Besides rheological and lubricating properties, saliva supports wound healing and acts as an antimicrobial barrier. TFF peptides are secreted from the mucous acini of the major and minor salivary glands and are typical constituents of normal saliva; TFF3 being the predominant peptide compared with TFF1 and TFF2. Only TFF3 is easily detectable by Western blotting. It occurs in two forms, a disulfide-linked homodimer (Mr: 13k) and a high-molecular-mass heterodimer with IgG Fc binding protein (FCGBP). TFF peptides are secretory lectins known for their protective effects in mucous epithelia; the TFF3 dimer probably has wound-healing properties due to its weak motogenic effect. There are multiple indications that FCGBP and TFF3-FCGBP play a key role in the innate immune defense of mucous epithelia. In addition, homodimeric TFF3 interacts in vitro with the salivary agglutinin DMBT1gp340. Here, the protective roles of TFF peptides, FCGBP, and DMBT1gp340 in saliva are discussed. TFF peptides are also used to reduce radiotherapy- or chemotherapy-induced oral mucositis. Thus, TFF peptides, FCGBP, and DMBT1gp340 are promising candidates for better formulations of artificial saliva, particularly improving wound healing and antimicrobial effects even in the esophagus.
Aging, Bone Marrow and Next-Generation Sequencing (NGS): Recent Advances and Future Perspectives
Authors: Ganguly Payal , Toghill Bradley , Pathak Shelly
Published: November 2021

The aging of bone marrow (BM) remains a very imperative and alluring subject, with an ever-increasing interest among fellow scientists. A considerable amount of progress has been made in this field with the established ‘hallmarks of aging’ and continued efforts to investigate the age-related changes observed within the BM. Inflammaging is considered as a low-grade state of inflammation associated with aging, and whilst the possible mechanisms by which aging occurs are now largely understood, the processes leading to the underlying changes within aged BM remain elusive. The ability to identify these changes and detect such alterations at the genetic level are key to broadening the knowledgebase of aging BM. Next-generation sequencing (NGS) is an important molecular-level application presenting the ability to not only determine genomic base changes but provide transcriptional profiling (RNA-seq), as well as a high-throughput analysis of DNA–protein interactions (ChIP-seq). Utilising NGS to explore the genetic alterations occurring over the aging process within alterative cell types facilitates the comprehension of the molecular and cellular changes influencing the dynamics of aging BM. Thus, this review prospects the current landscape of BM aging and explores how NGS technology is currently being applied within this ever-expanding field of research.
Effect of EGFR on SQSTM1 Expression in Malignancy and Tumor Progression of Oral Squamous Cell Carcinoma
Authors: Tseng Yu-Kai , Chen Chun-Feng , Shu Chih-Wen , Lee Cheng-Hsin , Chou Yan-Ting , Li Yi-Jing , Liou Huei-Han , Cheng Jiin-Tsuey , Chen Chun-Lin , Ger Luo-Ping , Liu Pei-Feng
Published: November 2021

Oral squamous cell carcinoma (OSCC) is one of the most common types of malignant tumor. Sequestosome 1 (SQSTM1) serves as an adaptor of autophagy for degrading protein aggregates. The regulation of autophagy by EGFR and its clinical impacts are indicated in various types of cancer. However, the association of EGFR and SQSTM1 in OSCC is still unknown. Our results show that the expression levels of SQSTM1 and EGFR proteins are higher in tumor tissues than in the corresponding tumor-adjacent (CTAN) tissues of OSCC patients. The expression levels of SQSTM1 were positively associated with the EGFR expression level. High co-expression of SQSTM1 and EGFR is associated with poor prognosis in OSCC patients. Moreover, SQSTM1 expression is decreased in EGFR-knockdown cells. Cell growth and invasion/migration are also decreased in cells with single/combined knockdowns of EGFR and SQSTM1 or in SQSTM1-knockdown cells without EGFR kinase inhibitor Lapatinib treatment compared to that in scrambled cells. However, cell growth and invasion/metastasis were not significantly different between the scrambled cells and SQSTM1-knockdown cells in the presence of Lapatinib. This study is the first to indicate the biological roles and clinical significance of SQSTM1 regulation by EGFR in OSCC.
Loss of Function of Mutant IDS Due to Endoplasmic Reticulum-Associated Degradation: New Therapeutic Opportunities for Mucopolysaccharidosis Type II
Authors: Matsuhisa Koji , Imaizumi Kazunori
Published: November 2021

Mucopolysaccharidosis type II (MPS II) results from the dysfunction of a lysosomal enzyme, iduronate-2-sulfatase (IDS). Dysfunction of IDS triggers the lysosomal accumulation of its substrates, glycosaminoglycans, leading to mental retardation and systemic symptoms including skeletal deformities and valvular heart disease. Most patients with severe types of MPS II die before the age of 20. The administration of recombinant IDS and transplantation of hematopoietic stem cells are performed as therapies for MPS II. However, these therapies either cannot improve functions of the central nervous system or cause severe side effects, respectively. To date, 729 pathogenetic variants in the IDS gene have been reported. Most of these potentially cause misfolding of the encoded IDS protein. The misfolded IDS mutants accumulate in the endoplasmic reticulum (ER), followed by degradation via ER-associated degradation (ERAD). Inhibition of the ERAD pathway or refolding of IDS mutants by a molecular chaperone enables recovery of the lysosomal localization and enzyme activity of IDS mutants. In this review, we explain the IDS structure and mechanism of activation, and current findings about the mechanism of degradation-dependent loss of function caused by pathogenetic IDS mutation. We also provide a potential therapeutic approach for MPS II based on this loss-of-function mechanism.
Signaling at Physical Barriers during Pollen–Pistil Interactions
Authors: Robichaux Kayleigh J. , Wallace Ian S.
Published: November 2021

In angiosperms, double fertilization requires pollen tubes to transport non-motile sperm to distant egg cells housed in a specialized female structure known as the pistil, mediating the ultimate fusion between male and female gametes. During this journey, the pollen tube encounters numerous physical barriers that must be mechanically circumvented, including the penetration of the stigmatic papillae, style, transmitting tract, and synergid cells as well as the ultimate fusion of sperm cells to the egg or central cell. Additionally, the pollen tube must maintain structural integrity in these compact environments, while responding to positional guidance cues that lead the pollen tube to its destination. Here, we discuss the nature of these physical barriers as well as efforts to genetically and cellularly identify the factors that allow pollen tubes to successfully, specifically, and quickly circumnavigate them.
Multi-Omics Analysis Reveals Anti-Staphylococcus aureus Activity of Actinomycin D Originating from Streptomyces parvulus
Authors: Lin Yuqi , Huang Li , Zhang Xiaoyong , Yang Jiajia , Chen Xiaodan , Li Fengming , Liu Jun , Huang Riming
Published: November 2021

Staphylococcus aureus (S. aureus) is a common pathogen that causes various serious diseases, including chronic infections. Discovering new antibacterial agents is an important aspect of the pharmaceutical field because of the lack of effective antibacterial drugs. In our research, we found that one anti-S. aureus substance is actinomycin D, originating from Streptomyces parvulus (S. parvulus); then, we further focused on the anti-S. aureus ability and the omics profile of S. aureus in response to actinomycin D. The results revealed that actinomycin D had a significant inhibitory activity on S. aureus with a minimum inhibitory concentration (MIC) of 2 μg/mL and a minimum bactericidal concentration (MBC) of 64 μg/mL. Bacterial reactive oxygen species (ROS) increased 3.5-fold upon treatment with actinomycin D, as was measured with the oxidation-sensitive fluorescent probe DCFH-DA, and H2O2 increased 3.5 times with treatment by actinomycin D. Proteomics and metabolomics, respectively, identified differentially expressed proteins in control and treatment groups, and the co-mapped correlation network of proteomics and metabolomics annotated five major pathways that were potentially related to disrupting the energy metabolism and oxidative stress of S. aureus. All findings contributed to providing new insight into the mechanisms of the anti-S. aureus effects of actinomycin D originating from S. parvulus.
Ferroptosis Induction in Multiple Myeloma Cells Triggers DNA Methylation and Histone Modification Changes Associated with Cellular Senescence
Authors: Logie Emilie , Van Puyvelde Bart , Cuypers Bart , Schepers Anne , Berghmans Herald , Verdonck Jelle , Laukens Kris , Godderis Lode , Dhaenens Maarten , Deforce Dieter , Vanden Berghe Wim
Published: November 2021

Disease relapse and therapy resistance remain key challenges in treating multiple myeloma. Underlying (epi-)mutational events can promote myelomagenesis and contribute to multi-drug and apoptosis resistance. Therefore, compounds inducing ferroptosis, a form of iron and lipid peroxidation-regulated cell death, are appealing alternative treatment strategies for multiple myeloma and other malignancies. Both ferroptosis and the epigenetic machinery are heavily influenced by oxidative stress and iron metabolism changes. Yet, only a limited number of epigenetic enzymes and modifications have been identified as ferroptosis regulators. In this study, we found that MM1 multiple myeloma cells are sensitive to ferroptosis induction and epigenetic reprogramming by RSL3, irrespective of their glucocorticoid-sensitivity status. LC-MS/MS analysis revealed the formation of non-heme iron-histone complexes and altered expression of histone modifications associated with DNA repair and cellular senescence. In line with this observation, EPIC BeadChip measurements of significant DNA methylation changes in ferroptotic myeloma cells demonstrated an enrichment of CpG probes located in genes associated with cell cycle progression and senescence, such as Nuclear Receptor Subfamily 4 Group A member 2 (NR4A2). Overall, our data show that ferroptotic cell death is associated with an epigenomic stress response that might advance the therapeutic applicability of ferroptotic compounds.
Optimizing the Aspect Ratio of Nanopatterned Mesoporous TiO2 Thin-Film Layer to Improve Energy Conversion Efficiency of Perovskite Solar Cells
Authors: Yang Hwa-Young , Chuquer Ana , Han Seung-Hee , Gaudel Gangasagar Sharma , Pham Xuan-Hung , Kim Hyung-Mo , Yun Won-Ju , Jun Bong-Hyun , Rho Won-Yeop
Published: November 2021

The energy conversion efficiency (ECE) (η), current density (Jsc), open-circuit voltage (Voc), and fill factor (ff) of perovskite solar cells were studied by using the transmittance of a nanopatterned mesoporous TiO2 (mp-TiO2) thin-film layer. To improve the ECE of perovskite solar cells, a mp-TiO2 thin-film layer was prepared to be used as an electron transport layer (ETL) via the nanoimprinting method for nanopatterning, which was controlled by the aspect ratio. The nanopatterned mp-TiO2 thin-film layer had a uniform and well-designed structure, and the diameter of nanopatterning was 280 nm. The aspect ratio was controlled at the depths of 75, 97, 127, and 167 nm, and the perovskite solar cell was fabricated with different depths. The ECE of the perovskite solar cells with the nanopatterned mp-TiO2 thin-film layer was 14.50%, 15.30%, 15.83%, or 14.24%, which is higher than that of a non-nanopatterned mp-TiO2 thin-film layer (14.07%). The enhancement of ECE was attributed to the transmittance of the nanopatterned mp-TiO2 thin-film layer that is due to the improvement of the electron generation. As a result, better electron generation affected the electron density, and Jsc increased the Voc, and ff of perovskite solar cells.
Crabp1 Modulates HPA Axis Homeostasis and Anxiety-like Behaviors by Altering FKBP5 Expression
Authors: Lin Yu-Lung , Wei Chin-Wen , Lerdall Thomas A. , Nhieu Jennifer , Wei Li-Na
Published: November 2021

Retinoic acid (RA), the principal active metabolite of vitamin A, is known to be involved in stress-related disorders. However, its mechanism of action in this regard remains unclear. This study reports that, in mice, endogenous cellular RA binding protein 1 (Crabp1) is highly expressed in the hypothalamus and pituitary glands. Crabp1 knockout (CKO) mice exhibit reduced anxiety-like behaviors accompanied by a lowered stress induced-corticosterone level. Furthermore, CRH/DEX tests show an increased sensitivity (hypersensitivity) of their feedback inhibition in the hypothalamic–pituitary–adrenal (HPA) axis. Gene expression studies show reduced FKBP5 expression in CKO mice; this would decrease the suppression of glucocorticoid receptor (GR) signaling thereby enhancing their feedback inhibition, consistent with their dampened corticosterone level and anxiety-like behaviors upon stress induction. In AtT20, a pituitary gland adenoma cell line elevating or reducing Crabp1 level correspondingly increases or decreases FKBP5 expression, and its endogenous Crabp1 level is elevated by GR agonist dexamethasone or RA treatment. This study shows, for the first time, that Crabp1 regulates feedback inhibition of the the HPA axis by modulating FKBP5 expression. Furthermore, RA and stress can increase Crabp1 level, which would up-regulate FKBP5 thereby de-sensitizing feedback inhibition of HPA axis (by decreasing GR signaling) and increasing the risk of stress-related disorders.
Role of Cell-Free DNA and Deoxyribonucleases in Tumor Progression
Authors: Alekseeva Ludmila , Mironova Nadezhda
Published: November 2021

Many studies have reported an increase in the level of circulating cell-free DNA (cfDNA) in the blood of patients with cancer. cfDNA mainly comes from tumor cells and, therefore, carries features of its genomic profile. Moreover, tumor-derived cfDNA can act like oncoviruses, entering the cells of vulnerable organs, transforming them and forming metastatic nodes. Another source of cfDNA is immune cells, including neutrophils that generate neutrophil extracellular traps (NETs). Despite the potential eliminative effect of NETs on tumors, in some cases, their excessive generation provokes tumor growth as well as invasion. Considering both possible pathological contributions of cfDNA, as an agent of oncotransformation and the main component of NETs, the study of deoxyribonucleases (DNases) as anticancer and antimetastatic agents is important and promising. This review considers the pathological role of cfDNA in cancer development and the role of DNases as agents to prevent and/or prohibit tumor progression and the development of metastases.
Literature Review of Machine-Learning Algorithms for Pressure Ulcer Prevention: Challenges and Opportunities
Authors: Ribeiro Fernando , Fidalgo Filipe , Silva Arlindo , Metrôlho José , Santos Osvaldo , Dionisio Rogério
Published: November 2021

Pressure ulcers are associated with significant morbidity, resulting in a decreased quality of life for the patient, and contributing to healthcare professional burnout, as well as an increase of health service costs. Their prompt diagnosis and treatment are important, and several studies have proposed solutions to help healthcare professionals in this process. This work analyzes studies that use machine-learning algorithms for risk assessment and management of preventive treatments for pressure ulcers. More specifically, it focuses on the use of machine-learning algorithms that combine information from intrinsic and extrinsic pressure-ulcer predisposing factors to produce recommendations/alerts to healthcare professionals. The review includes articles published from January 2010 to June 2021. From 60 records screened, seven articles were analyzed in full-text form. The results show that most of the proposed algorithms do not use information related to both intrinsic and extrinsic predisposing factors and that many of the approaches separately address one of the following three components: data acquisition; data analysis, and production of complementary support to well-informed clinical decision-making. Additionally, only a few studies describe in detail the outputs of the algorithm, such as alerts and recommendations, without assessing their impacts on healthcare professionals’ activities.
A Novel True Random Number Generator in Near Field Communication as Memristive Wireless Power Transmission
Authors: Kuka Colin Sokol , Hu Yihua , Xu Quan , Chandler James , Alkahtani Mohammed
Published: November 2021

The security of powering systems has been a major problem over the last decade, leading to an increased interest in wireless power and data transfer. In this research paper, a new inductive Wireless Power Transfer (WPT) circuit topology has been used. In traditional WPT circuits, the inverters are used to produce an oscillation for the transmitter coils. The classic WPT system includes intrinsic energy dissipation sources due to the use of switches, necessitating the need of an extra control circuit to ensure proper switching time. Furthermore, they have limited data encryption capabilities. As a result, an unique WPT system based on memristors has been developed, eliminating the need for switches. Furthermore, because this novel topology communicates a synchronised chaotic behaviour, it becomes highly beneficial. This circuit may be used in Near Field Communication (NFC), where chaotic true random numbers (TRNG) can be generated to increase security. The results of simulations indicate the functioning of the Memristor-based WPT (M-WPT) and its ability to generate random numbers. We experimentally proved the chaotic behaviour of the circuit and statistically demonstrated the development of the TRNG, using an Arduino board and the Chua circuit to build the M-WPT circuit.
Real-Life Outcomes of Coronary Bifurcation Stenting in Acute Myocardial Infarction (Zabrze–Opole Registry)
Authors: Milejski Wojciech , Sacha Jerzy , Feusette Piotr , Cisowski Marek , Muzyk Piotr , Tomasik Andrzej , Gierlotka Marek , Morawiec Beata , Kawecki Damian
Published: November 2021

Percutaneous coronary intervention (PCI) of bifurcation lesions is a technical challenge associated with high risk of adverse events, especially in primary PCI. The aim of the study is to analyze long-term outcomes after PCI for coronary bifurcation in acute myocardial infarction (AMI). The outcome was defined as the rate of major adverse cardiac event related to target lesion failure (MACE-TLF) (death-TLF, nonfatal myocardial infarction-TLF and target lesion revascularization (TLR)) and the rate of stent thrombosis (ST). From 306 patients enrolled to the registry, 113 were diagnosed with AMI. In the long term, AMI was not a risk factor for MACE-TLF. The risk of MACE-TLF was dependent on the culprit lesion, especially in the right coronary artery (RCA) and side branch (SB) with a diameter >3 mm. When PCI was performed in the SB, the inflation pressure in SB remained the single risk factor of poor prognosis. The rate of cumulative ST driven by late ST in AMI was dependent on the inflation pressure in the main branch (MB). In conclusion, PCI of bifurcation culprit lesions should be performed carefully in case of RCA and large SB diameter and attention should be paid to high inflation pressure in the SB. On the contrary, the lower the inflation pressure in the MB, the higher the risk of ST.
Association of Plasma Branched-Chain and Aromatic Amino Acids with Reduction in Kidney Function Evaluated in Apparently Healthy Adults
Authors: Mahbub MH , Yamaguchi Natsu , Nakagami Yuki , Hase Ryosuke , Takahashi Hidekazu , Ishimaru Yasutaka , Watanabe Rie , Saito Hiroyuki , Shimokawa Junki , Yamamoto Hiroshi , Kikuchi Shinya , Tanabe Tsuyoshi
Published: November 2021

The published literature on the association of circulatory branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) with reduced kidney function is inconsistent or conflicting. Clarification of it might help to better understand the underlying pathophysiology and to determine potential biomarkers for early detection and evaluation of kidney function decline. Our main purpose was to explore and clarify the potential relationships of individual BCAAs and AAAs with estimated glomerular filtration rate (eGFR) decline. We included the data from 2804 healthy subjects and categorized them into three groups based on eGFR tertiles. The associations between individual amino acids and eGFR were explored by covariate-adjusted logistic regression models. There was a progressive increase in the concentrations of BCAAs and AAAs from the upper to the lower tertiles. We revealed significant positive associations of isoleucine, leucine, and phenylalanine with lower tertiles of eGFR in the adjusted models (p < 0.01–0.001). The findings hold a promising potential of using plasma isoleucine, leucine, and phenylalanine levels for evaluation of kidney function decline. Future longitudinal studies should investigate the causal association between altered levels of these amino acids and impaired kidney function and also the utility of the former as potential biomarkers for evaluating the risk and early detection of the latter.
Mitochondrial Medicine in the COVID-19 Era
Authors: Orsucci Daniele
Published: November 2021

Mitochondrial disorders are a remarkably complex group of diseases caused by impairment of the mitochondrial respiratory chain (or electron transport chain) [...]
Prevalence and Clinical Characteristics of Subclavian Steal Phenomenon/Syndrome in Patients with Acute Ischemic Stroke
Authors: Bajko Zoltan , Motataianu Anca , Stoian Adina , Barcutean Laura , Andone Sebastian , Maier Smaranda , Drăghici Iulia-Adela , Cioban Andrada , Balasa Rodica
Published: November 2021

There are no published clinical studies regarding the prevalence of subclavian steal among acute ischemic stroke patients. The aim of this study was to evaluate the prevalence and clinical significance of subclavian steal among a large number of consecutive ischemic stroke patients. Materials and methods: We reviewed the medical records of 2192 consecutive cases of acute ischemic stroke at a tertiary neurology clinic in Targu Mures, Romania, between 2018 and 2020. In total, 47 patients (2.2%) were diagnosed with subclavian steal phenomenon/syndrome. Results: Stroke patients with associated steal phenomenon were significantly younger (64.2 ± 11.1 versus 70.2 ± 12.8, p = 0.005) and predominantly male (68.1%). From among the 47 patients with subclavian steal phenomenon, nine (19.1%) presented stroke symptomatology in the vertebrobasilar territory. Overall, 83.3% of the stroke patients with associated steal phenomenon presented cerebral infarction and 16.7% presented TIA. There was no difference between groups regarding the affected vascular territory (VB versus carotid). Large artery atherosclerosis was more frequent in the stroke group with associated steal phenomenon (81.3% versus 43.5%, p = 0.0033). The NIHSS score at admission was higher in the patient group with associated steal phenomenon, but there was no difference in mRS at discharge. Associated carotid artery occlusion was more frequent in the stroke group with steal phenomenon (p < 0.01). Smoking and peripheral arteriopathy were more frequent in the patient group with associated steal phenomenon. Of the nine symptomatic patients, five underwent revascularization treatment. Conclusions: The prevalence of subclavian steal phenomenon among acute ischemic stroke patients was not higher than in other cohorts with heterogenous peripheral vascular pathologies. Similar to the general population, in acute ischemic stroke patients, the associated subclavian steal behaved like a benign hemodynamical condition, without severe consequences.
Injuries during Laparoscopic Cholecystectomy: A Scoping Review of the Claims and Civil Action Judgements
Authors: Cirocchi Roberto , Panata Laura , Griffiths Ewen A. , Tebala Giovanni D. , Lancia Massimo , Fedeli Piergiorgio , Lauro Augusto , Anania Gabriele , Avenia Stefano , Di Saverio Salomone , Burini Gloria , De Sol Angelo , Verdelli Anna Maria
Published: November 2021

Background. To define what type of injuries are more frequently related to medicolegal claims and civil action judgments. Methods. We performed a scoping review on 14 studies and 2406 patients, analyzing medicolegal claims related to laparoscopic cholecystectomy injuries. We have focalized on three phases associated with claims: phase of care, location of injuries, type of injuries. Results. The most common phase of care associated with litigation was the improper intraoperative surgical performance (47.6% ± 28.3%), related to a “poor” visualization, and the improper post-operative management (29.3% ± 31.6%). The highest rate of defense verdicts was reported for the improper post-operative management of the injury (69.3% ± 23%). A lower rate was reported in the incorrect presurgical assessment (39.7% ± 24.4%) and in the improper intraoperative surgical performance (21.39% ± 21.09%). A defense verdict was more common in cystic duct injuries (100%), lower in hepatic bile duct (42.9%) and common bile duct (10%) injuries. Conclusions. During laparoscopic cholecystectomy, the most common cause of claims, associated with lower rate of defense verdict, was the improper intraoperative surgical performance. The decision to take legal action was determined often for poor communication after the original incident.