bluuebunny/crossref_metadata_2025 huggingface dataset:
A Classification-Based Blockchain Architecture for Smart Home with Hierarchical PoW Mechanism
Authors: Lv Weilu , Wang Ning , Xie Xianwang , Hong Zhen
Published: August 2022

Smart home, as a typical Internet of Things (IoT) application, provides people with a variety of conveniences. Unfortunately, it may suffer from security and privacy issues. Currently, blockchain theory is considered as one of the potential solutions to the IoT security problem. However, according to the rules of blockchain, it requires large storage to store distributed ledgers and undertakes long latency caused by proof of work (PoW), which cannot be performed by resource-constrained IoT devices. To address the issue, we propose a classification-based blockchain architecture with a hierarchical PoW mechanism, which can reduce the storage consumption and decrease the latency. In our architecture, we divide IoT devices into several child nodes by data classification and convert the data storage into partial network storage. Furthermore, we try to set the moderate-cost security grades (SG) to adjust the difficulty of PoW for reduction of latency. Finally, comparing the performance of our scheme with the traditional method and current technology, the proposed architecture not only takes up less storage (i.e., almost 90% reduction) but also increases efficiency (i.e., almost 50% running time saving) while ensuring safety.
Reversing PD-1 Resistance in B16F10 Cells and Recovering Tumour Immunity Using a COX2 Inhibitor
Authors: Pi Chenyu , Jing Ping , Li Bingyu , Feng Yan , Xu Lijun , Xie Kun , Huang Tao , Xu Xiaoqing , Gu Hua , Fang Jianmin
Published: August 2022

Immunotherapy is an effective method for tumour treatment. Anti-programmed cell death protein 1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) monoclonal antibodies play a significant role in immunotherapy of most tumours; however, some patients develop drug resistance to PD-1/PD-L1 therapy. Cyclooxygenase-2 (COX2) is expressed in various solid tumours, and prostaglandin E2 (PGE2) drives the development of malignant tumours. We developed a drug-resistant B16F10 (B16F10-R) tumour mouse model through four rounds of selection in vivo. Subsequently, we investigated changes in PD-L1 expression and lymphocyte infiltration in B16F10-NR and B16F10-R tumours. Additionally, we explored the role of COX2 in acquired resistance to pembrolizumab, an anti-PD-1 treatment. Immune cell infiltration was significantly decreased in resistant tumours compared to B16F10-NR tumours; however, ptgs2 gene expression was significantly elevated in resistant tumours. Aspirin or celecoxib combined with pembrolizumab can effectively reverse tumour drug resistance. In addition, ptgs2 knockout or the use of the EP4 inhibitor E7046 abrogated drug resistance to anti-PD-1 treatment in B16F10-R tumour cells. Our study showed that inhibition of the COX2/PGE2/EP4 axis could increase the number of immune cells infiltrating the tumour microenvironment and recover drug-resistant tumour sensitivity to pembrolizumab. Thus, we highlight COX2 inhibition as a promising therapeutic target for drug-resistant tumours for future consideration.
Circulating Tumour Cells, Cell Free DNA and Tumour-Educated Platelets as Reliable Prognostic and Management Biomarkers for the Liquid Biopsy in Multiple Myeloma
Authors: Allegra Alessandro , Cancemi Gabriella , Mirabile Giuseppe , Tonacci Alessandro , Musolino Caterina , Gangemi Sebastiano
Published: August 2022

Liquid biopsy is one of the fastest emerging fields in cancer evaluation. Circulating tumour cells and tumour-originated DNA in plasma have become the new targets for their possible employ in tumour diagnosis, and liquid biopsy can define tumour burden without invasive procedures. Multiple Myeloma, one of the most frequent hematologic tumors, has been the target of therapeutic progresses in the last few years. Bone marrow aspirate is the traditional tool for diagnosis, prognosis, and genetic evaluation in multiple myeloma patients. However, this painful procedure presents a relevant drawback for regular disease examination as it requires an invasive practice. Moreover, new data demonstrated that a sole bone marrow aspirate is incapable of expressing the multifaceted multiple myeloma genetic heterogeneity. In this review, we report the emerging usefulness of the assessment of circulating tumour cells, cell-free DNA, extracellular RNA, cell-free proteins, extracellular vesicles, and tumour-educated platelets to evaluate the changing mutational profile of multiple myeloma, as early markers of disease, reliable predictors of prognosis, and as useful tools to perform less invasive monitoring in multiple myeloma.
TROP2 Represents a Negative Prognostic Factor in Colorectal Adenocarcinoma and Its Expression Is Associated with Features of Epithelial–Mesenchymal Transition and Invasiveness
Authors: Švec Jiří , Šťastná Monika , Janečková Lucie , Hrčkulák Dušan , Vojtěchová Martina , Onhajzer Jakub , Kříž Vítězslav , Galušková Kateřina , Šloncová Eva , Kubovčiak Jan , Pfeiferová Lucie , Hrudka Jan , Matěj Radoslav , Waldauf Petr , Havlůj Lukáš , Kolář Michal , Kořínek Vladimír
Published: August 2022

Trophoblastic cell surface antigen 2 (TROP2) is a membrane glycoprotein overexpressed in many solid tumors with a poor prognosis, including intestinal neoplasms. In our study, we show that TROP2 is expressed in preneoplastic lesions, and its expression is maintained in most colorectal cancers (CRC). High TROP2 positivity correlated with lymph node metastases and poor tumor differentiation and was a negative prognostic factor. To investigate the role of TROP2 in intestinal tumors, we analyzed two mouse models with conditional disruption of the adenomatous polyposis coli (Apc) tumor-suppressor gene, human adenocarcinoma samples, patient-derived organoids, and TROP2-deficient tumor cells. We found that Trop2 is produced early after Apc inactivation and its expression is associated with the transcription of genes involved in epithelial–mesenchymal transition, the regulation of migration, invasiveness, and extracellular matrix remodeling. A functionally similar group of genes was also enriched in TROP2-positive cells from human CRC samples. To decipher the driving mechanism of TROP2 expression, we analyzed its promoter. In human cells, this promoter was activated by β-catenin and additionally by the Yes1-associated transcriptional regulator (YAP). The regulation of TROP2 expression by active YAP was verified by YAP knockdown in CRC cells. Our results suggest a possible link between aberrantly activated Wnt/β-catenin signaling, YAP, and TROP2 expression.
Molecular Testing for Thyroid Nodules: The Experience at McGill University Teaching Hospitals in Canada
Authors: Rajab Mohannad , Payne Richard J. , Forest Véronique-Isabelle , Pusztaszeri Marc
Published: August 2022

In the past few decades, molecular characterization of thyroid cancer has made significant progress and is able to identify thyroid-cancer-related molecular markers that can then be applied clinically for improved decision making. The aim of this review is to provide a general overview about the molecular markers (mutations and alterations) of thyroid cancers, present several molecular tests, and discuss the clinical applications of identifying these markers supported by the clinical experience of several high-volume thyroid cancer specialists at the McGill university hospitals in Montreal, Canada. Our group experience showed that molecular testing can reclassify more than half of the patients with indeterminate thyroid nodules (Bethesda III and IV) into benign and spare these patients from unnecessary diagnostic surgery. Furthermore, it can help optimize the initial management in thyroid cancers with no evidence of high risk of recurrence of disease preoperatively. While routine molecular testing is not firmly established for thyroid FNA specimens that are suspicious or positive for malignancy (Bethesda V and VI), knowledge of a thyroid nodule’s molecular risk group profile in such cases, together with its clinical and radiologic features, can help select the optimal surgical options (lobectomy versus upfront total thyroidectomy and central neck dissection), as demonstrated by our studies.
Investigating the Retained Inhibitory Effect of Cobimetinib against p.P124L Mutated MEK1: A Combined Liquid Biopsy and in Silico Approach
Authors: Catoni Cristina , Poggiana Cristina , Facchinetti Antonella , Pigozzo Jacopo , Piccin Luisa , Chiarion-Sileni Vanna , Rosato Antonio , Minervini Giovanni , Scaini Maria Chiara
Published: August 2022

The systemic treatment of metastatic melanoma has radically changed, due to an improvement in the understanding of its genetic landscape and the advent of targeted therapy. However, the response to BRAF/MEK inhibitors is transitory, and big efforts were made to identify the mechanisms underlying the resistance. We exploited a combined approach, encompassing liquid biopsy analysis and molecular dynamics simulation, for tracking tumor evolution, and in parallel defining the best treatment option. The samples at different time points were collected from a BRAF-mutant melanoma patient who developed an early resistance to dabrafenib/trametinib. The analysis of the circulating tumor DNA (ctDNA) identified the MEK1 p.P124L mutation that confers resistance to trametinib. With an in silico modeling, we identified cobimetinib as an alternative MEK inhibitor, and consequently suggested a therapy switch to vemurafenib/cobimetinib. The patient response was followed by ctDNA tracking and circulating melanoma cell (CMC) count. The cobimetinib administration led to an important reduction in the BRAF p.V600E and MEK1 p.P124L allele fractions and in the CMC number, features suggestive of a putative response. In summary, this study emphasizes the usefulness of a liquid biopsy-based approach combined with in silico simulation, to track real-time tumor evolution while assessing the best treatment option.
Physical Activity and Cancer Care—A Review
Authors: Misiąg Weronika , Piszczyk Anna , Szymańska-Chabowska Anna , Chabowski Mariusz
Published: August 2022

In 2020, 19.3 million new cancer cases were diagnosed, and almost 10 million deaths from cancer were recorded. Cancer patients may experience fatigue, depression, anxiety, reduced quality of life and sleep problems. Cancer treatments cause numerous side effects and have a negative impact on all body systems. Physical activity is important for cancer patients. The aim of this review is to analyse recent studies on the role of physical activity in cancer patients and emphasize its importance. The review included 36 papers published in English between 2017 and 2021. The findings from these studies show that physical activity decreases the severity of side effects of cancer treatment, reduces fatigue, improves quality of life, has a positive impact on mental health and improves aerobic fitness in cancer patients. Moreover, it reduces the risk of cancer recurrence and death. Physical activity is recommended for patients with any type of cancer and at all stages of treatment. The type of physical activity should depend on the condition of the individual patient. It is extremely difficult to determine what type, intensity and duration of physical activity is likely to have the greatest effect.
The Prognostic Value of a Single, Randomly Timed Circulating Tumor DNA Measurement in Patients with Metastatic Melanoma
Authors: Boerlin Aurelio , Bellini Elisa , Turko Patrick , Cheng Phil F. , Levesque Mitchell P. , Dummer Reinhard , Ramelyte Egle
Published: August 2022

Melanoma currently lacks validated blood-based biomarkers for monitoring and predicting treatment efficacy. Circulating tumor DNA (ctDNA), originating from tumor cells and detectable in plasma, has emerged as a possible biomarker in patients with metastatic melanoma. In this retrospective, single-center study, we collected 129 plasma samples from 79 patients with stage IIIB–IV melanoma as determined by the American Joint Committee on Cancer (AJCC, 8th edition). For the determination of ctDNA levels, we used eight different assays of droplet digital polymerase chain reaction (ddPCR) to detect the most common hotspot mutations in the BRAF and NRAS genes. The aim of the study was to investigate the association of the detectability of ctDNA at a non-prespecified time point in a patient’s treatment with tumor progression, and to correlate ctDNA with commonly used biomarkers (protein S100, LDH, and CRP). Patients with detectable ctDNA progressed more frequently in PET-CT within 12 months than those without detectable ctDNA. Detectability of ctDNA was associated with shorter OS in univariate and multivariate analyses. ctDNA was detectable in a statistically significantly larger proportion of patients with distant metastases (79%) than in patients with no distant metastases or only intracranial metastases (32%). Elevated protein S100 and CRP correlated better with detectable ctDNA than LDH. This study supports the potential of ctDNA as a prognostic biomarker in patients with metastatic melanoma. However, additional prospective longitudinal studies with quantitative assessments of ctDNA are necessary to investigate the limitations and strengths of ctDNA as a biomarker.
PARP1: Liaison of Chromatin Remodeling and Transcription
Authors: Zong Wen , Gong Yamin , Sun Wenli , Li Tangliang , Wang Zhao-Qi
Published: August 2022

Poly(ADP-ribosyl)ation (PARylation) is a covalent post-translational modification and plays a key role in the immediate response of cells to stress signals. Poly(ADP-ribose) polymerase 1 (PARP1), the founding member of the PARP superfamily, synthesizes long and branched polymers of ADP-ribose (PAR) onto acceptor proteins, thereby modulating their function and their local surrounding. PARP1 is the most prominent of the PARPs and is responsible for the production of about 90% of PAR in the cell. Therefore, PARP1 and PARylation play a pleotropic role in a wide range of cellular processes, such as DNA repair and genomic stability, cell death, chromatin remodeling, inflammatory response and gene transcription. PARP1 has DNA-binding and catalytic activities that are important for DNA repair, yet also modulate chromatin conformation and gene transcription, which can be independent of DNA damage response. PARP1 and PARylation homeostasis have also been implicated in multiple diseases, including inflammation, stroke, diabetes and cancer. Studies of the molecular action and biological function of PARP1 and PARylation provide a basis for the development of pharmaceutic strategies for clinical applications. This review focuses primarily on the role of PARP1 in the regulation of chromatin remodeling and transcriptional activation.
A Focus on Intermediate-Risk Acute Myeloid Leukemia: Sub-Classification Updates and Therapeutic Challenges
Authors: Awada Hassan , Mustafa Ali Moaath K. , Thapa Bicky , Awada Hussein , Seymour Leroy , Liu Louisa , Gurnari Carmelo , Kishtagari Ashwin , Wang Eunice , Baer Maria R.
Published: August 2022

Acute myeloid leukemia (AML) represents a heterogeneous group of hematopoietic neoplasms deriving from the abnormal proliferation of myeloid progenitors in the bone marrow. Patients with AML may have highly variable outcomes, which are generally dictated by individual clinical and genomic characteristics. As such, the European LeukemiaNet 2017 and 2022 guidelines categorize newly diagnosed AML into favorable-, intermediate-, and adverse-risk groups, based on their molecular and cytogenetic profiles. Nevertheless, the intermediate-risk category remains poorly defined, as many patients fall into this group as a result of their exclusion from the other two. Moreover, further genomic data with potential prognostic and therapeutic influences continue to emerge, though they are yet to be integrated into the diagnostic and prognostic models of AML. This review highlights the latest therapeutic advances and challenges that warrant refining the prognostic classification of intermediate-risk AML.
Hsp70–Bag3 Module Regulates Macrophage Motility and Tumor Infiltration via Transcription Factor LITAF and CSF1
Authors: Avinery Lena , Gahramanov Valid , Hesin Arkadi , Sherman Michael Y.
Published: August 2022

The molecular chaperone Hsp70 has been implicated in multiple stages of cancer development. In these processes, a co-chaperone Bag3 links Hsp70 with signaling pathways that control cancer development. Recently, we showed that besides affecting cancer cells, Hsp70 can also regulate the motility of macrophages and their tumor infiltration. However, the mechanisms of these effects have not been explored. Here, we demonstrated that the Hsp70-bound co-chaperone Bag3 associates with a transcription factor LITAF that can regulate the expression of inflammatory cytokines and chemokines in macrophages. Via this interaction, the Hsp70–Bag3 complex regulates expression levels of LITAF by controlling its proteasome-dependent and chaperone-mediated autophagy-dependent degradation. In turn, LITAF regulates the expression of the major chemokine CSF1, and adding this chemokine to the culture medium reversed the effects of Bag3 or LITAF silencing on the macrophage motility. Together, these findings uncover the Hsp70–Bag3–LITAF–CSF1 pathway that controls macrophage motility and tumor infiltration.
Properties and Recyclability of Abandoned Fishing Net-Based Plastic Debris
Authors: Kozioł Anna , Paso Kristofer Gunnar , Kuciel Stanisław
Published: August 2022

Plastics in marine environments undergo molecular degradation via biocatalytic and photocatalytic mechanisms. Abandoned, lost, or discarded fishing gear (ALDFG) damages marine and coastal environments as well as plant and animal species. This article reviews ghost fishing, ecological damage from marine plastics, recommended recycling practices and alternative usages of derelict fishing gear. Material mixing techniques are proposed to counteract the effect of biocatalytic and photocatalytic biodegradation within the context of plastic fish net recycling. There is a need for a new and rapid “multidimensional molecular characterization” technology to quantify, at a batch level, the extent of photocatalytic or biocatalytic degradation experienced on each recovered fishing net, comprising molecular weight alteration, chemical functional group polydispersity and contaminant presence. Rapid multidimensional molecular characterization enables optimized conventional material mixing of recovered fishing nets. In this way, economically attractive social return schemes can be introduced for used fishing nets, providing an economic incentive for fishers to return conventional fishing nets for recycling.
Interventions to the Spontaneous Fabrication of Hierarchical ZSM-5 Zeolites by Fluorination-Alkaline Treatment
Authors: Guo Zifeng , Hong Meihua , Yu Yonghua , Liu Guanfeng , Zang Jiazong , Zhang Dazhi , Gong Huimin , Yang Keyu , Huang Shengjun
Published: August 2022

The sequential fluorination-alkaline treatment protocol has been applied for the tailoring of siliceous ZSM-5 zeolite. The original spontaneous growth of mesoporosity in alkaline medium is altered due to the antecedent fluorination step. The outcome is demonstrated by the apparent delay in the mesoporosity growth, whose essential duration for the well-defined mesoporosity is therefore extended from 30 min to 60 min. A low fluorination level decelerates the mesoporosity growth, whereas a high fluorination level enables the achievement of the mesoporosity. These impacts are closely linked with the alteration to the states of Al sites as the function of fluorination level. Compared to the states of Al sites in the pristine and steamed zeolites, the electronic and steric consequences on the environment of Al species by fluorination is proposed for the interplay with the alkaline medium for the mesoporosity growth.
Small Nucleolar RNAs and Their Comprehensive Biological Functions in Hepatocellular Carcinoma
Authors: Liu Xiaoyu , Xie Wan , Meng Silu , Kang Xiaoyan , Liu Yuhuan , Guo Lili , Wang Changyu
Published: August 2022

Small nucleolar RNAs (snoRNAs) are a class of highly conserved, stable non-coding RNAs involved in both post-transcriptional modification of RNA and in ribosome biogenesis. Recent research shows that the dysfunction of snoRNAs plays a pivotal role in hepatocellular carcinoma (HCC) and related etiologies, such as hepatitis B virus (HBV), hepatitis C virus (HCV), and non-alcoholic fatty liver disease (NAFLD). Growing evidence suggests that snoRNAs act as oncogenes or tumor suppressors in hepatocellular carcinoma (HCC) through multiple mechanisms. Furthermore, snoRNAs are characterized by their stability in body fluids and their clinical relevance and represent promising tools as diagnostic and prognostic biomarkers. SnoRNAs represent an emerging area of cancer research. In this review, we summarize the classification, biogenesis, activity, and functions of snoRNAs, as well as highlight the mechanism and roles of snoRNAs in HCC and related diseases. Our findings will aid in the understanding of complex processes of tumor occurrence and development, as well as suggest potential diagnostic markers and treatment targets. Furthermore, we discuss several limitations and suggest future research and application directions.
Glutamate Signaling and Filopodiagenesis of Astrocytoma Cells in Brain Cancers: Survey and Questions
Authors: Tabatabaee Mitra , Menard Frederic
Published: August 2022

Astrocytes are non-excitable cells in the CNS that can cause life-threatening astrocytoma tumors when they transform to cancerous cells. Perturbed homeostasis of the neurotransmitter glutamate is associated with astrocytoma tumor onset and progression, but the factors that govern this phenomenon are less known. Herein, we review possible mechanisms by which glutamate may act in facilitating the growth of projections in astrocytic cells. This review discusses the similarities and differences between the morphology of astrocytes and astrocytoma cells, and the role that dysregulation in glutamate and calcium signaling plays in the aberrant morphology of astrocytoma cells. Converging reports suggest that ionotropic glutamate receptors and voltage-gated calcium channels expressed in astrocytes may be responsible for the abnormal filopodiagenesis or process extension leading to astrocytoma cells’ infiltration throughout the brain.
A Combination Therapy of Urolithin A+EGCG Has Stronger Protective Effects than Single Drug Urolithin A in a Humanized Amyloid Beta Knockin Mice for Late-Onset Alzheimer’s Disease
Authors: Kshirsagar Sudhir , Alvir Rainier Vladlen , Pradeepkiran Jangampalli Adi , Hindle Ashly , Vijayan Murali , Ramasubramaniam Bhagavathi , Kumar Subodh , Reddy Arubala P. , Reddy P. Hemachandra
Published: August 2022

In the current study, for the first time, we study mitophagy enhancer urolithin A and a combination of urolithin A+green tea extract EGCG against human Aβ peptide-induced mitochondrial and synaptic, dendritic, inflammatory toxicities and behavioral changes in humanized homozygous amyloid beta knockin (hAbKI) mice of late-onset Alzheimer’s disease (AD). Our findings reveal significantly increased positive effects of urolithin A and a combination treatment of urolithin A+EGCG in hAbKI mice for phenotypic behavioral changes including motor coordination, locomotion/exploratory activity, spatial learning and working memory. mRNA and protein levels of mitochondrial fusion, synaptic, mitophagy and autophagy genes were upregulated, and mitochondrial fission genes are downregulated in urolithin A and combine treatment in hAbKI mice; however, the effect is stronger in combined treatment. Immunofluorescence analysis of hippocampal brain sections shows similar findings of mRNA and protein levels. Mitochondrial dysfunction is significantly reduced in both treatment groups, but a stronger reduction is observed in combined treatment. Dendritic spines and lengths are significantly increased in both treatment groups, but the effect is stronger in combined treatment. The fragmented number of mitochondria is reduced, and mitochondrial length is increased, and mitophagosomal formations are increased in both the groups, but the effect is stronger in the combined treatment. The levels of amyloid beta (Aβ) 40 and Aβ42 are reduced in both treatments, however, the reduction is higher for combined treatment. These observations suggest that urolithin A is protective against human Aβ peptide-induced toxicities; however, combined treatment of urolithin A+EGCG is effective and stronger, indicating that combined therapy is promising to treat late-onset AD patients.
High Fat Diet Multigenerationally Affects Hippocampal Neural Stem Cell Proliferation via Epigenetic Mechanisms
Authors: Natale Francesca , Spinelli Matteo , Barbati Saviana Antonella , Leone Lucia , Fusco Salvatore , Grassi Claudio
Published: August 2022

Early-life metabolic stress has been demonstrated to affect brain development, persistently influence brain plasticity and to exert multigenerational effects on cognitive functions. However, the impact of an ancestor’s diet on the adult neurogenesis of their descendants has not yet been investigated. Here, we studied the effects of maternal high fat diet (HFD) on hippocampal adult neurogenesis and the proliferation of neural stem and progenitor cells (NSPCs) derived from the hippocampus of both the second and the third generations of progeny (F2HFD and F3HFD). Maternal HFD caused a multigenerational depletion of neurogenic niche in F2HFD and F3HFD mice. Moreover, NSPCs derived from HFD descendants showed altered expression of genes regulating stem cell proliferation and neurodifferentiation (i.e., Hes1, NeuroD1, Bdnf). Finally, ancestor HFD-related hyper-activation of both STAT3 and STAT5 induced enhancement of their binding on the regulatory sequences of Gfap gene and an epigenetic switch from permissive to repressive chromatin on the promoter of the NeuroD1 gene. Collectively, our data indicate that maternal HFD multigenerationally affects hippocampal adult neurogenesis via an epigenetic derangement of pro-neurogenic gene expression in NSPCs.
Contribution of Oxidative Stress (OS) in Calcific Aortic Valve Disease (CAVD): From Pathophysiology to Therapeutic Targets
Authors: Tanase Daniela Maria , Valasciuc Emilia , Gosav Evelina Maria , Floria Mariana , Costea Claudia Florida , Dima Nicoleta , Tudorancea Ionut , Maranduca Minela Aida , Serban Ionela Lacramioara
Published: August 2022

Calcific aortic valve disease (CAVD) is a major cause of cardiovascular mortality and morbidity, with increased prevalence and incidence. The underlying mechanisms behind CAVD are complex, and are mainly illustrated by inflammation, mechanical stress (which induces prolonged aortic valve endothelial dysfunction), increased oxidative stress (OS) (which trigger fibrosis), and calcification of valve leaflets. To date, besides aortic valve replacement, there are no specific pharmacological treatments for CAVD. In this review, we describe the mechanisms behind aortic valvular disease, the involvement of OS as a fundamental element in disease progression with predilection in AS, and its two most frequent etiologies (calcific aortic valve disease and bicuspid aortic valve); moreover, we highlight the potential of OS as a future therapeutic target.
TcpC Inhibits M1 but Promotes M2 Macrophage Polarization via Regulation of the MAPK/NF-κB and Akt/STAT6 Pathways in Urinary Tract Infection
Authors: Fang Jiaqi , Ou Qian , Wu Boheng , Li Sisi , Wu Mian , Qiu Jialing , Cen Nuo , Hu Kaixin , Che Yangfei , Ma Yuan , Pan Jianping
Published: August 2022

TcpC is a multifunctional virulence factor of Uropathogenic Escherichia coli (UPEC). Macrophages can differentiate into two different subsets M1 and M2 that play distinct roles in anti-infection immunity. Here, we investigate the influence of TcpC on M1/M2 polarization and the potential mechanisms. Our data showed that M1 markers CD86 and iNOS were significantly inhibited, while the M2 markers CD163, CD206 and Arg-1 were enhanced in macrophages in kidneys from the TcpC-secreting wild-type CFT073 (CFT073wt)-infected pyelonephritis mouse model, compared with those in macrophages in kidneys from TcpC knockout CFT073 mutant (CFT073Δtcpc)-infected mice. CFT073wt or recombinant TcpC (rTcpC) treatment inhibits LPS + IFN-γ-induced CD80, CD86, TNF-α and iNOS expression, but promotes IL-4-induced CD163, CD206, Arg-1 and IL-10 expression in both human and mouse macrophage cell lines THP-1 and J774A.1. Moreover, rTcpC significantly attenuated LPS + IFN-γ-induced phosphorylation of p38, ERK, p50 and p65 but enhanced IL-4-induced phosphorylation of Akt and STAT6. These data suggest that TcpC inhibits M1 but promotes M2 macrophage polarization by down-regulation of p38, ERK/NF-κB and up-regulation of the Akt/STAT6 signaling pathway, respectively. Our findings not only illuminate the regulatory effects of TcpC on macrophage M1/M2 polarization and its related signaling pathways, but also provide a novel mechanism underlying TcpC-mediated immune evasion of macrophage-mediated innate immunity.
Heterogeneity of the NIH3T3 Fibroblast Cell Line
Authors: Rahimi Amir Mohammad , Cai Mingfang , Hoyer-Fender Sigrid
Published: August 2022

The embryonic mouse fibroblast cell line NIH3T3 is widely used in life science research, including the study of cell cycle control and primary cilia. Fibroblasts are the most important cell type in connective tissue, as they produce components of the extracellular matrix and determine tissue architecture. However, they are very heterogeneous and consist of subtypes specific to their organ of residence, among others. The NIH3T3 cell line was derived from whole mouse embryos that developed to pre-birth and is therefore most likely composed of different fibroblast subtypes. Furthermore, prolonged proliferation may have influenced their cellular composition. A heterogeneous cell population is unsuitable for any sophisticated research project. We found that the proportion of ciliated cells in the total NIH3T3 cell population was highly variable and asked whether this was a consequence of cellular heterogeneity and what molecular signatures were associated with it. We have established sub-cell lines by clonal expansion of single cells and characterized them morphologically and molecularly. Eventually, a myofibroblast-like and a fibroblast-like cell line were generated that differ in ciliation and proliferation. These homogeneous cell lines are valuable for a more detailed study of their molecular signatures, not least to uncover further the molecular pathways that contribute to the formation of the primary cilium.
Structure of an Intranucleosomal DNA Loop That Senses DNA Damage during Transcription
Authors: Gerasimova Nadezhda S. , Volokh Olesya I. , Pestov Nikolay A. , Armeev Grigory A. , Kirpichnikov Mikhail P. , Shaytan Alexey K. , Sokolova Olga S. , Studitsky Vasily M.
Published: August 2022

Transcription through chromatin by RNA polymerase II (Pol II) is accompanied by the formation of small intranucleosomal DNA loops containing the enzyme (i-loops) that are involved in survival of core histones on the DNA and arrest of Pol II during the transcription of damaged DNA. However, the structures of i-loops have not been determined. Here, the structures of the intermediates formed during transcription through a nucleosome containing intact or damaged DNA were studied using biochemical approaches and electron microscopy. After RNA polymerase reaches position +24 from the nucleosomal boundary, the enzyme can backtrack to position +20, where DNA behind the enzyme recoils on the surface of the histone octamer, forming an i-loop that locks Pol II in the arrested state. Since the i-loop is formed more efficiently in the presence of SSBs positioned behind the transcribing enzyme, the loop could play a role in the transcription-coupled repair of DNA damage hidden in the chromatin structure.
Axin2/Conductin Is Required for Normal Haematopoiesis and T Lymphopoiesis
Authors: de Roo Jolanda J. D. , Chhatta Amiet , Garcia-Perez Laura , Naber Brigitta A. E. , Vloemans Sandra A. , Salvatori Daniela C. F. , Pike-Overzet Karin , Mikkers Harald , Staal Frank J. T.
Published: August 2022

The development of T lymphocytes in the thymus and their stem cell precursors in the bone marrow is controlled by Wnt signaling in strictly regulated, cell-type specific dosages. In this study, we investigated levels of canonical Wnt signaling during hematopoiesis and T cell development within the Axin2-mTurquoise2 reporter. We demonstrate active Wnt signaling in hematopoietic stem cells (HSCs) and early thymocytes, but also in more mature thymic subsets and peripheral T lymphocytes. Thymic epithelial cells displayed particularly high Wnt signaling, suggesting an interesting crosstalk between thymocytes and thymic epithelial cells (TECs). Additionally, reporter mice allowed us to investigate the loss of Axin2 function, demonstrating decreased HSC repopulation upon transplantation and the partial arrest of early thymocyte development in Axin2Tg/Tg full mutant mice. Mechanistically, loss of Axin2 leads to supraphysiological Wnt levels that disrupt HSC differentiation and thymocyte development.
Effects of Novel Photosynthetic Inhibitor [CuL2]Br2 Complex on Photosystem II Activity in Spinach
Authors: Zharmukhamedov Sergey K. , Shabanova Mehriban S. , Rodionova Margarita V. , Huseynova Irada M. , Karacan Mehmet Sayım , Karacan Nurcan , Aşık Kübra Begüm , Kreslavski Vladimir D. , Alwasel Saleh , Allakhverdiev Suleyman I.
Published: August 2022

The effects of the novel [CuL2]Br2 complex (L = bis{4H-1,3,5-triazino [2,1-b]benzothiazole-2-amine,4-(2-imidazole)}copper(II) bromide complex) on the photosystem II (PSII) activity of PSII membranes isolated from spinach were studied. The absence of photosynthetic oxygen evolution by PSII membranes without artificial electron acceptors, but in the presence of [CuL2]Br2, has shown that it is not able to act as a PSII electron acceptor. In the presence of artificial electron acceptors, [CuL2]Br2 inhibits photosynthetic oxygen evolution. [CuL2]Br2 also suppresses the photoinduced changes of the PSII chlorophyll fluorescence yield (FV) related to the photoreduction of the primary quinone electron acceptor, QA. The inhibition of both characteristic PSII reactions depends on [CuL2]Br2 concentration. At all studied concentrations of [CuL2]Br2, the decrease in the FM level occurs exclusively due to a decrease in Fv. [CuL2]Br2 causes neither changes in the F0 level nor the retardation of the photoinduced rise in FM, which characterizes the efficiency of the electron supply from the donor-side components to QA through the PSII reaction center (RC). Artificial electron donors (sodium ascorbate, DPC, Mn2+) do not cancel the inhibitory effect of [CuL2]Br2. The dependences of the inhibitory efficiency of the studied reactions of PSII on [CuL2]Br2 complex concentration practically coincide. The inhibition constant Ki is about 16 µM, and logKi is 4.8. As [CuL2]Br2 does not change the aromatic amino acids’ intrinsic fluorescence of the PSII protein components, it can be proposed that [CuL2]Br2 has no significant effect on the native state of PSII proteins. The results obtained in the present study are compared to the literature data concerning the inhibitory effects of PSII Cu(II) aqua ions and Cu(II)-organic complexes.
Structural Entities Associated with Different Lipid Phases of Plant Thylakoid Membranes—Selective Susceptibilities to Different Lipases and Proteases
Authors: Dlouhý Ondřej , Karlický Václav , Javornik Uroš , Kurasová Irena , Zsiros Ottó , Šket Primož , Kanna Sai Divya , Böde Kinga , Večeřová Kristýna , Urban Otmar , Gasanoff Edward S. , Plavec Janez , Špunda Vladimír , Ughy Bettina , Garab Győző
Published: August 2022

It is well established that plant thylakoid membranes (TMs), in addition to a bilayer, contain two isotropic lipid phases and an inverted hexagonal (HII) phase. To elucidate the origin of non-bilayer lipid phases, we recorded the 31P-NMR spectra of isolated spinach plastoglobuli and TMs and tested their susceptibilities to lipases and proteases; the structural and functional characteristics of TMs were monitored using biophysical techniques and CN-PAGE. Phospholipase-A1 gradually destroyed all 31P-NMR-detectable lipid phases of isolated TMs, but the weak signal of isolated plastoglobuli was not affected. Parallel with the destabilization of their lamellar phase, TMs lost their impermeability; other effects, mainly on Photosystem-II, lagged behind the destruction of the original phases. Wheat-germ lipase selectively eliminated the isotropic phases but exerted little or no effect on the structural and functional parameters of TMs—indicating that the isotropic phases are located outside the protein-rich regions and might be involved in membrane fusion. Trypsin and Proteinase K selectively suppressed the HII phase—suggesting that a large fraction of TM lipids encapsulate stroma-side proteins or polypeptides. We conclude that—in line with the Dynamic Exchange Model—the non-bilayer lipid phases of TMs are found in subdomains separated from but interconnected with the bilayer accommodating the main components of the photosynthetic machinery.
Highly Photostable and pH−Sensitive Nanosensors
Authors: Lin Zhenzhen , Hu Fang , He Gang , Yang Youjun , Liao Yujun , Luo Xiao , Wang Xu-Dong
Published: August 2022

Determination of pH values has a vital influence in many chemical and biological processes. To accurately determine pH values, we fabricated a highly photostable ratiometric fluorescent pH−sensitive nanosensor by staining the core of mesoporous silica nanoparticle with a rhodol dye and chemically labelling its outer shell with a rhodamine derivative dye. The two dyes possess opposite pH−responding directions, which increases the band of the signal change. There is a nine−fold change in fluorescence intensity ratios when the solution pH changes from 3.0 and 9.0. Meanwhile, the nanosensors displayed yellowish emission in low pH value, orange emission in mid pH value, and reddish emission in high pH value, which can be readily inspected by bare eyes. Last but not least, excellent photostability and reversibility features make the nanosensors useful for the continuous measuring of pH with high accuracy.
Comparison of Amblyopia Treatment Effect with Dichoptic Method Using Polarizing Film and Occlusion Therapy Using an Eye Patch
Authors: Iwata Yo , Handa Tomoya , Ishikawa Hitoshi
Published: August 2022

We developed a novel, low-cost, easily administered method that uses a polarizing film to enable dichoptic treatment for amblyopia. In this study, we compared its effects with occlusion therapy using an eye patch. Fifty-eight patients (aged 4.7 ± 1.0 years) diagnosed with anisometric amblyopia were included and instructed to wear complete refractive correction glasses with either occlusion therapy using an eye patch (eye patch group) or dichoptic treatment using polarizing film (polarizing film group) for 2 h per day. We examined the improvement in the visual acuity and compliance rate of the patients 2 months after treatment initiation. After treatment, the polarizing film group showed significant improvement in visual acuity compared with the eye patch group. Moreover, the compliance rate was significantly better in the polarizing film group than in the eye patch group. In both groups, there was a significant correlation between the improvement in visual acuity and compliance rate. This new dichoptic treatment using a polarizing film was shown to be effective for anisometropic amblyopia.
Parental Views of Social Worker and Chaplain Involvement in Care and Decision Making for Critically Ill Children with Cancer
Authors: Michelson Kelly , Arenson Melanie , Charleston Elizabeth , Clayman Marla , Brazg Tracy , Rychlik Karen , Rosenberg Abby , Frader Joel
Published: August 2022

Background: Social workers (SWs) and chaplains are trained to support families facing challenges associated with critical illness and potential end-of-life issues. Little is known about how parents view SW/chaplain involvement in care for critically ill children with cancer. Methods: We studied parent perceptions of SW/chaplain involvement in care for pediatric intensive care unit (PICU) patients with cancer or who had a hematopoietic cell transplant. English- and Spanish-speaking parents completed surveys within 7 days of PICU admission and at discharge. Some parents participated in an optional interview. Results: Twenty-four parents of 18 patients completed both surveys, and six parents were interviewed. Of the survey respondents, 66.7% and 75% interacted with SWs or chaplains, respectively. Most parents described SW/chaplain interactions as helpful (81.3% and 72.2%, respectively), but few reported their help with decision making (18.8% and 12.4%, respectively). Parents described SW/chaplain roles related to emotional, spiritual, instrumental, and holistic support. Few parents expressed awareness about SW/chaplain interactions with other healthcare team members. Conclusions: Future work is needed to determine SWs’/chaplains’ contributions to and impact on parental decision making, improve parent awareness about SW/chaplain roles and engagement with the healthcare team, and understand why some PICU parents do not interact with SWs/chaplains.
Pregnancy Outcomes of Non-Visualization of the Fetal Gallbladder from a Chinese Tertiary Single Centre and Literature Review
Authors: Zhang Huijing , Zhu Xiaoying , Kang Jinling , Sun Yu , Yang Huixia
Published: August 2022

Objection: To explore the clinical features and prognosis of non-visualization of the fetal gallbladder (NVFGB). Methods: Sixty-five cases diagnosed with NVFGB in the Peking University First Hospital were collected retrospectively from January 2019 to December 2020. Results: Forty-nine cases were successfully followed up. Among them, the gallbladder of 21 fetuses (42.9%) was present in the later pregnancy. In the rest 28 cases (57.1%), the gallbladders were absent during the whole pregnancy. Eleven of twenty-eight fetuses (39.3%) with NVFGB were complicated with other structural anomalies. In the remaining 17 cases of isolated NVFGB (60.7%) during the whole pregnancy, there was one case of congenital biliary atresia, three cases of a small gallbladder, one case of gallstone and one case of the gallbladder with several septa inside. A total of nine cases (18.4%) underwent prenatal diagnosis, four of which revealed abnormal copy number variant (CNV) results. Conclusion: Nearly half of NVFGB could be noted during the later pregnancy. The persistent NVFGB during the pregnancy has a higher risk to complicate gallbladder abnormality, other structural anomalies and abnormal CNV results. Other structures, especially the heart, gastrointestinal and urinary system, should be carefully examined when NVFGB is suspected.
Noninvasive Ventilation in Preterm Infants: Factors Influencing Weaning Decisions and the Role of the Silverman-Andersen Score
Authors: Nussbaum Claudia , Lengauer Maximilian , Puchwein-Schwepcke Alexandra F. , Weiss Veronique B. N. , Spielberger Benedikt , Genzel-Boroviczény Orsolya
Published: August 2022

The factors influencing weaning of preterm infants from noninvasive ventilation (NIV) are poorly defined and the weaning decisions are often driven by subjective judgement rather than objective measures. To standardize quantification of respiratory effort, the Silverman-Andersen Score (SAS) was included in our nursing routine. We investigated the factors that steer the weaning process and whether the inclusion of the SAS would lead to more stringent weaning. Following SAS implementation, we prospectively evaluated 33 neonates born ≤ 32 + 0 weeks gestational age. Age-, weight- and sex-matched infants born before routine SAS evaluation served as historic control. In 173 of 575 patient days, NIV was not weaned despite little respiratory distress (SAS ≤ 2), mainly due to bradycardias (60% of days without weaning), occurring alone (40%) or in combination with other factors such as apnea/desaturations. In addition, “soft factors” that are harder to grasp impact on weaning decisions, whereas the SAS overall played a minor role. Consequently, ventilation times did not differ between the groups. In conclusion, NIV weaning is influenced by various factors that override the absence of respiratory distress limiting the predictive value of the SAS. An awareness of the factors that influence weaning decisions is important as prolonged use of NIV has been associated with adverse outcome. Guidelines are necessary to standardize NIV weaning practice.
Residence with a Person Who Used Substances and Childhood Anxiety and Depression: A Cross-Sectional Analysis of the 2019 National Health Interview Survey
Authors: Jafry Zarena , Chui Kenneth , Stopka Thomas J. , Corlin Laura
Published: August 2022

Background: Children who live with a parent with a substance use disorder (SUD) are more likely to experience adverse health outcomes, including mental health disorders. We assessed whether residing with anyone who used substances was associated with children’s anxiety and/or depression, and whether these associations differed by the children’s age or sex. Methods: We analyzed nationally representative cross-sectional data from the 2019 National Health Interview Survey (n = 6642). The associations between ever residing with someone who used substances and caregiver-reported children’s anxiety and depression frequency (never/a few times a year/monthly/weekly/daily) were estimated using multinomial logistic regression models, adjusted for children’s age, children’s sex, children’s race/ethnicity, annual household income, and highest educational attainment by an adult in the household. We assessed whether the associations differed based on the children’s age (5–11/12–17 years) or sex. Results: Children who had resided with someone who used substances were more likely to be reported by their caregiver as having daily anxiety (risk ratio (RR) = 2.84; 95% confidence interval (CI) = 2.04, 3.95; referent = never anxious) and daily depression (RR = 3.35; 95% CI = 1.98, 5.67; referent = never depressed). Associations with more frequent anxiety were stronger among adolescents than younger children. Associations between residing with someone who used substances and depression frequency differed based on children’s age and sex. Conclusions: Our results suggest that residing with someone who used substances is associated with children’s anxiety and depression. Our findings can help inform screening and treatment efforts for anxiety and depression among children, as well as for the person using substances.
Rehabilitation of a Child with Neonatal Brachial Plexus Palsy: Case Report Described by Parents
Authors: Frade Fátima , Neves Lurdes , Florindo-Silva Fátima , Gómez-Salgado Juan , Jacobsohn Lia , Frade João
Published: August 2022

This paper presents a case report of a child with Neonatal Brachial Plexus Palsy on the right arm, with C5, C6, and C7 nerve injuries. The symptoms presented at birth and at the time of diagnosis were absence of movement in the right arm but with mobility of the fingers; internal rotation of the injured limb with elbow extension; active flexion of the wrist and fingers; and ulnar deviation of the hand. The rehabilitation plan followed the conservative approach and included different intervention strategies (passive and active mobilisation, kinesio tape, use of splints, bimanual stimulation, etc.) carried out by the occupational therapist and the physical therapist. The rehabilitation allowed the child to have a functional limb for daily activities, with bimanual motor integration and coordination; passive and active range of motion in the different joints except for pronation, sensibility, and maintained strength. In conclusion, it can be said that this case report describes a set of rehabilitation strategies that were used in the conservative treatment of a child with NBPP and the functional gains they allowed. Early intervention, parental involvement in the rehabilitation process, and continuous follow-up of the child favoured the prognosis and allowed the prevention of functional sequelae of the limb.