bluuebunny/crossref_metadata_2025 huggingface dataset:
[18F]NOS PET Brain Imaging Suggests Elevated Neuroinflammation in Idiopathic Parkinson’s Disease
Authors: Doot Robert K. , Young Anthony J. , Nasrallah Ilya M. , Wetherill Reagan R. , Siderowf Andrew , Mach Robert H. , Dubroff Jacob G.
Published: October 2022

Neuroinflammation is implicated as a key pathologic mechanism in many neurodegenerative diseases and is thought to be mediated in large part by microglia, native phagocytic immune cells of the CNS. Abnormal aggregation of the protein α-synuclein after phagocytosis by microglia is one possible neuropathophysiological mechanism driving Parkinson’s disease (PD). We conducted a human pilot study to evaluate the feasibility of targeting the inducible isoform of nitric oxide synthase using the [18F]NOS radiotracer to measure neuroinflammation in idiopathic PD. Ten adults consisting of 6 PD patients and 4 healthy controls (HC) underwent one hour of dynamic [18F]NOS positron emission tomography (PET) brain imaging with arterial blood sampling. We observed increased [18F]NOS whole brain distribution volume (VT) in PD patients compared to age-matched healthy controls (p < 0.008) via a 1-tissue compartment (TC) model. The rate constant K1 for transport from blood into tissue did not differ between groups (p = 0.72). These findings suggest elevated oxidative stress, a surrogate marker of inflammation, is present in early-stage idiopathic PD and indicate that [18F]NOS PET imaging is a promising, non-invasive method to measure neuroinflammation.
Influence of Shear Stress, Inflammation and BRD4 Inhibition on Human Endothelial Cells: A Holistic Proteomic Approach
Authors: Jarausch Johannes , Neuenroth Lisa , Andag Reiner , Leha Andreas , Fischer Andreas , Asif Abdul R. , Lenz Christof , Eidizadeh Abass
Published: October 2022

Atherosclerosis is an important risk factor in the development of cardiovascular diseases. In addition to increased plasma lipid concentrations, irregular/oscillatory shear stress and inflammatory processes trigger atherosclerosis. Inhibitors of the transcription modulatory bromo- and extra-terminal domain (BET) protein family (BETi) could offer a possible therapeutic approach due to their epigenetic mechanism and anti-inflammatory properties. In this study, the influence of laminar shear stress, inflammation and BETi treatment on human endothelial cells was investigated using global protein expression profiling by ion mobility separation-enhanced data independent acquisition mass spectrometry (IMS-DIA-MS). For this purpose, primary human umbilical cord derived vascular endothelial cells were treated with TNFα to mimic inflammation and exposed to laminar shear stress in the presence or absence of the BRD4 inhibitor JQ1. IMS-DIA-MS detected over 4037 proteins expressed in endothelial cells. Inflammation, shear stress and BETi led to pronounced changes in protein expression patterns with JQ1 having the greatest effect. To our knowledge, this is the first proteomics study on primary endothelial cells, which provides an extensive database for the effects of shear stress, inflammation and BETi on the endothelial proteome.
Nose-to-Brain: The Next Step for Stem Cell and Biomaterial Therapy in Neurological Disorders
Authors: Villar-Gómez Natalia , Ojeda-Hernandez Doddy Denise , López-Muguruza Eneritz , García-Flores Silvia , Bonel-García Natalia , Benito-Martín María Soledad , Selma-Calvo Belen , Canales-Aguirre Alejandro Arturo , Mateos-Díaz Juan Carlos , Montero-Escribano Paloma , Matias-Guiu Jordi A. , Matías-Guiu Jorge , Gómez-Pinedo Ulises
Published: October 2022

Neurological disorders are a leading cause of morbidity worldwide, giving rise to a growing need to develop treatments to revert their symptoms. This review highlights the great potential of recent advances in cell therapy for the treatment of neurological disorders. Through the administration of pluripotent or stem cells, this novel therapy may promote neuroprotection, neuroplasticity, and neuroregeneration in lesion areas. The review also addresses the administration of these therapeutic molecules by the intranasal route, a promising, non-conventional route that allows for direct access to the central nervous system without crossing the blood–brain barrier, avoiding potential adverse reactions and enabling the administration of large quantities of therapeutic molecules to the brain. Finally, we focus on the need to use biomaterials, which play an important role as nutrient carriers, scaffolds, and immune modulators in the administration of non-autologous cells. Little research has been conducted into the integration of biomaterials alongside intranasally administered cell therapy, a highly promising approach for the treatment of neurological disorders.
Effects of Noonan Syndrome-Germline Mutations on Mitochondria and Energy Metabolism
Authors: Bajia Donald , Bottani Emanuela , Derwich Katarzyna
Published: October 2022

Noonan syndrome (NS) and related Noonan syndrome with multiple lentigines (NSML) contribute to the pathogenesis of human diseases in the RASopathy family. This family of genetic disorders constitute one of the largest groups of developmental disorders with variable penetrance and severity, associated with distinctive congenital disabilities, including facial features, cardiopathies, growth and skeletal abnormalities, developmental delay/mental retardation, and tumor predisposition. NS was first clinically described decades ago, and several genes have since been identified, providing a molecular foundation to understand their physiopathology and identify targets for therapeutic strategies. These genes encode proteins that participate in, or regulate, RAS/MAPK signalling. The RAS pathway regulates cellular metabolism by controlling mitochondrial homeostasis, dynamics, and energy production; however, little is known about the role of mitochondrial metabolism in NS and NSML. This manuscript comprehensively reviews the most frequently mutated genes responsible for NS and NSML, covering their role in the current knowledge of cellular signalling pathways, and focuses on the pathophysiological outcomes on mitochondria and energy metabolism.
Reprogramming T-Cell Metabolism for Better Anti-Tumor Immunity
Authors: Ping Yu , Shen Chunyi , Huang Bo , Zhang Yi
Published: October 2022

T cells play central roles in the anti-tumor immunity, whose activation and differentiation are profoundly regulated by intrinsic metabolic reprogramming. Emerging evidence has revealed that metabolic processes of T cells are generally altered by tumor cells or tumor released factors, leading to crippled anti-tumor immunity. Therefore, better understanding of T cell metabolic mechanism is crucial in developing the next generation of T cell-based anti-tumor immunotherapeutics. In this review, we discuss how metabolic pathways affect T cells to exert their anti-tumor effects and how to remodel the metabolic programs to improve T cell-mediated anti-tumor immune responses. We emphasize that glycolysis, carboxylic acid cycle, fatty acid oxidation, cholesterol metabolism, amino acid metabolism, and nucleotide metabolism work together to tune tumor-reactive T-cell activation and proliferation.
Prolonged Antiretroviral Treatment Induces Adipose Tissue Remodelling Associated with Mild Inflammation in SIV-Infected Macaques
Authors: Mausoléo Aude , Olivo Anaelle , Desjardins Delphine , Sáez-Cirión Asier , Barrail-Tran Aurélie , Avettand-Fenoel Véronique , Noël Nicolas , Lagathu Claire , Béréziat Véronique , Le Grand Roger , Lambotte Olivier , Bourgeois Christine
Published: October 2022

During chronic SIV/HIV infection, adipose tissue (AT) is the target of both antiretroviral treatment (ART) and the virus. AT might subsequently contribute to the low-grade systemic inflammation observed in patients on ART. To evaluate the inflammatory profile of AT during chronic SIV/HIV infection, we assayed subcutaneous and visceral abdominal AT from non-infected (SIV−, control), ART-naïve SIV-infected (SIV+) and ART-controlled SIV-infected (SIV+ART+) cynomolgus macaques for the mRNA expression of genes coding for factors related to inflammation. Significant differences were observed only when comparing the SIV+ART+ group with the SIV+ and/or SIV− groups. ART-treated infection impacted the metabolic fraction (with elevated expression of PPARγ and CEBPα), the extracellular matrix (with elevated expression of COL1A2 and HIF-1α), and the inflammatory profile. Both pro- and anti-inflammatory signatures were detected in AT, with greater mRNA expression of anti-inflammatory markers (adiponectin and CD163) and markers associated with inflammation (TNF-α, Mx1, CCL5 and CX3CL1). There were no intergroup differences in other markers (IL-6 and MCP-1). In conclusion, we observed marked differences in the immune and metabolic profiles of AT in the context of an ART-treated, chronic SIV infection; these differences were related more to ART than to SIV infection per se.
Application of Lacunarity for Quantification of Single Molecule Localization Microscopy Images
Authors: Kovács Bálint Barna H. , Varga Dániel , Sebők Dániel , Majoros Hajnalka , Polanek Róbert , Pankotai Tibor , Hideghéty Katalin , Kukovecz Ákos , Erdélyi Miklós
Published: October 2022

The quantitative analysis of datasets achieved by single molecule localization microscopy is vital for studying the structure of subcellular organizations. Cluster analysis has emerged as a multi-faceted tool in the structural analysis of localization datasets. However, the results it produces greatly depend on the set parameters, and the process can be computationally intensive. Here we present a new approach for structural analysis using lacunarity. Unlike cluster analysis, lacunarity can be calculated quickly while providing definitive information about the structure of the localizations. Using simulated data, we demonstrate how lacunarity results can be interpreted. We use these interpretations to compare our lacunarity analysis with our previous cluster analysis-based results in the field of DNA repair, showing the new algorithm’s efficiency.
Diverging Effects of Adolescent Ethanol Exposure on Tripartite Synaptic Development across Prefrontal Cortex Subregions
Authors: Walker Christopher Douglas , Sexton Hannah Gray , Hyde Jentre , Greene Brittani , Risher Mary-Louise
Published: October 2022

Adolescence is a developmental period that encompasses, but is not limited to, puberty and continues into early adulthood. During this period, maturation and refinement are observed across brain regions such as the prefrontal cortex (PFC), which is critical for cognitive function. Adolescence is also a time when excessive alcohol consumption in the form of binge drinking peaks, increasing the risk of long-term cognitive deficits and the risk of developing an alcohol use disorder later in life. Animal models have revealed that adolescent ethanol (EtOH) exposure results in protracted disruption of neuronal function and performance on PFC-dependent tasks that require higher-order decision-making. However, the role of astrocytes in EtOH-induced disruption of prefrontal cortex-dependent function has yet to be elucidated. Astrocytes have complex morphologies with an extensive network of peripheral astrocyte processes (PAPs) that ensheathe pre- and postsynaptic terminals to form the ‘tripartite synapse.’ At the tripartite synapse, astrocytes play several critical roles, including synaptic maintenance, dendritic spine maturation, and neurotransmitter clearance through proximity-dependent interactions. Here, we investigate the effects of adolescent binge EtOH exposure on astrocyte morphology, PAP-synaptic proximity, synaptic stabilization proteins, and dendritic spine morphology in subregions of the PFC that are important in the emergence of higher cognitive function. We found that adolescent binge EtOH exposure resulted in subregion specific changes in astrocyte morphology and astrocyte-neuronal interactions. While this did not correspond to a loss of astrocytes, synapses, or dendritic spines, there was a corresponding region-specific and EtOH-dependent shift in dendritic spine phenotype. Lastly, we found that changes in astrocyte-neuronal interactions were not a consequence of changes in the expression of key synaptic structural proteins neurexin, neuroligin 1, or neuroligin 3. These data demonstrate that adolescent EtOH exposure results in enduring effects on neuron-glia interactions that persist into adulthood in a subregion-specific PFC manner, suggesting selective vulnerability. Further work is necessary to understand the functional and behavioral implications.
Liquid Biopsy and the Translational Bridge from the TIME to the Clinic
Authors: Walker Paul
Published: October 2022

Research and advancing understanding of the tumor immune microenvironment (TIME) is vital to optimize and direct more effective cancer immune therapy. Pre-clinical bench research is vital to better understand the genomic interplay of the TIME and immune therapy responsiveness. However, a vital key to effective translational cancer research is having a bridge of translation to bring that understanding from the bench to the bedside. Without that bridge, research into the TIME will lack an efficient and effective translation into the clinic and cancer treatment decision making. As a clinical oncologist, the purpose of this commentary is to emphasize the importance of researching and improving clinical utility of the bridge, as well as the TIME research itself.
Blood Endothelial-Cell Extracellular Vesicles as Potential Biomarkers for the Selection of Plasma in COVID-19 Convalescent Plasma Therapy
Authors: Amri Nada , Tessier Nolwenn , Bégin Rémi , Vachon Laurent , Bégin Philippe , Bazin Renée , Loubaki Lionel , Martel Catherine
Published: October 2022

Despite the advancement of vaccination and therapies currently available, deaths due to the coronavirus disease 2019 (COVID-19) are still heavily documented. Severely infected individuals experience a generalized inflammatory storm, caused by massive secretion of pro-inflammatory cytokines that can lead to endothelial dysfunction, cardiovascular disease, multi-organ failure, and even death. COVID-19 convalescent plasma (CCP) therapy, selected primarily based on anti-SARS-CoV-2 antibody levels, has not been as convincing as expected in the fight against COVID-19. Given the consequences of a dysfunctional endothelium on the progression of the disease, we propose that the selection of plasma for CCP therapy should be based on more specific parameters that take into consideration the effect on vascular inflammation. Thus, in the present study, we have characterized a subset of CCP that have been used for CCP therapy and measured their anti- or pro-inflammatory effect on human coronary artery endothelial cells (HCAECs). Our data revealed that the longer the time lapse between the onset of symptoms and the plasma donation, the more mitochondrial dysfunction can be evidenced. The concentration of blood endothelial cell extracellular vesicles (BEC-EVs) was increased in the plasma of young individuals with mild symptoms. This type of selected convalescent plasma promoted the activation of the blood vascular endothelium, as reflected by the overexpression of ICAM1 and NFκB1 and the downregulation of VE-Cadherin. We propose this mechanism is a warning signal sent by the injured endothelium to trigger self-defense of peripheral blood vessels against excessive inflammation. Therefore, these results are in line with our previous data. They suggest that a more specific selection of COVID-19 convalescent plasma should be based on the time of donation following the onset of the clinical symptoms of the donor, the severity of the symptoms, and the age of the donor. These characteristics are relatively easy to identify in any hospital and would reflect the concentration of plasma BEC-EVs and be optimal in CCP therapy.
Single Cell Transcriptomics to Understand HSC Heterogeneity and Its Evolution upon Aging
Authors: Hérault Léonard , Poplineau Mathilde , Remy Elisabeth , Duprez Estelle
Published: October 2022

Single-cell transcriptomic technologies enable the uncovering and characterization of cellular heterogeneity and pave the way for studies aiming at understanding the origin and consequences of it. The hematopoietic system is in essence a very well adapted model system to benefit from this technological advance because it is characterized by different cellular states. Each cellular state, and its interconnection, may be defined by a specific location in the global transcriptional landscape sustained by a complex regulatory network. This transcriptomic signature is not fixed and evolved over time to give rise to less efficient hematopoietic stem cells (HSC), leading to a well-documented hematopoietic aging. Here, we review the advance of single-cell transcriptomic approaches for the understanding of HSC heterogeneity to grasp HSC deregulations upon aging. We also discuss the new bioinformatics tools developed for the analysis of the resulting large and complex datasets. Finally, since hematopoiesis is driven by fine-tuned and complex networks that must be interconnected to each other, we highlight how mathematical modeling is beneficial for doing such interconnection between multilayered information and to predict how HSC behave while aging.
Of Flies and Men—The Discovery of TLRs
Authors: Weiss Hauke Johannes , O’Neill Luke Anthony John
Published: October 2022

In 2011, the Nobel Prize in Physiology or Medicine was awarded to three immunologists: Bruce A. Beutler, Jules A. Hoffmann, and Ralph M. Steinman. While Steinman was honored for his work on dendritic cells and adaptive immunity, Beutler and Hoffman received the prize for their contributions to discoveries in innate immunity. In 1996, Hoffmann found the toll gene to be crucial for mounting antimicrobial responses in fruit flies, first implicating this developmental gene in immune signaling. Two years later, Beutler built on this observation by describing a Toll-like gene, tlr4, as the receptor for the bacterial product LPS, representing a crucial step in innate immune activation and protection from bacterial infections in mammals. These publications spearheaded research in innate immune sensing and sparked a huge interest regarding innate defense mechanisms in the following years and decades. Today, Beutler and Hoffmann’s research has not only resulted in the discovery of the role of multiple TLRs in innate immunity but also in a much broader understanding of the molecular components of the innate immune system. In this review, we aim to collect the discoveries leading up to the publications of Beutler and Hoffmann, taking a close look at how early advances in both developmental biology and immunology converged into the research awarded with the Nobel Prize. We will also discuss how these discoveries influenced future research and highlight the importance they hold today.
STAT3 and Its Targeting Inhibitors in Oral Squamous Cell Carcinoma
Authors: Jiang Mingjing , Li Bo
Published: October 2022

Oral squamous cell carcinoma (OSCC) usually originates from the precancerous lesions of oral mucosa and accounts for approximately 90% of oral cancers. Current therapeutic approaches do not yet meet the needs of patients, and the 5-year survival rate of patients with OSCC is only 50%. Recent studies have revealed that the signal transducer and activator of transcription 3 (STAT3) plays a key role in the development and progression of OSCC. STAT3 is overexpressed and constitutively activated in OSCC cells, and promotes cancer cell proliferation and anti-apoptosis, migration and invasion, angiogenesis, radiotherapy resistance, and immune escape, as well as stem cell self-renewal and differentiation by regulating the transcription of its downstream target genes. Inhibitors of the STAT3 signaling pathway have shown the promising anticancer effects in vitro and in vivo, and STAT3 is expected to be a molecular target for the treatment of OSCC. In this review, we highlight the oncogenic significance of STAT3 in OSCC with an emphasis on the therapeutic approaches and effective small molecule inhibitors targeting STAT3. Finally, we also propose the potential research directions in the expectation of developing more specific STAT3 inhibitors for OSCC treatment.
Sleep Alterations in a Mouse Model of Spinocerebellar Ataxia Type 3
Authors: Tsimpanouli Maria-Efstratia , Ghimire Anjesh , Barget Anna J. , Weston Ridge , Paulson Henry L. , Costa Maria do Carmo , Watson Brendon O.
Published: October 2022

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder showing progressive neuronal loss in several brain areas and a broad spectrum of motor and non-motor symptoms, including ataxia and altered sleep. While sleep disturbances are known to play pathophysiologic roles in other neurodegenerative disorders, their impact on SCA3 is unknown. Using spectrographic measurements, we sought to quantitatively characterize sleep electroencephalography (EEG) in SCA3 transgenic mice with confirmed disease phenotype. We first measured motor phenotypes in 18–31-week-old homozygous SCA3 YACMJD84.2 mice and non-transgenic wild-type littermate mice during lights-on and lights-off periods. We next implanted electrodes to obtain 12-h (zeitgeber time 0-12) EEG recordings for three consecutive days when the mice were 26–36 weeks old. EEG-based spectroscopy showed that compared to wild-type littermates, SCA3 homozygous mice display: (i) increased duration of rapid-eye movement sleep (REM) and fragmentation in all sleep and wake states; (ii) higher beta power oscillations during REM and non-REM (NREM); and (iii) additional spectral power band alterations during REM and wake. Our data show that sleep architecture and EEG spectral power are dysregulated in homozygous SCA3 mice, indicating that common sleep-related etiologic factors may underlie mouse and human SCA3 phenotypes.
Direct Differentiation of Human Embryonic Stem Cells to 3D Functional Hepatocyte-like Cells in Alginate Microencapsulation Sphere
Authors: Xie Xiaoling , Zhou Xiaoling , Liu Tingdang , Zhong Zhiqian , Zhou Qi , Iqbal Waqas , Xie Qingdong , Wei Chiju , Zhang Xin , Chang Thomas Ming Swi , Sun Pingnan
Published: October 2022

Background: The lack of a stable source of hepatocytes is one of major limitations in hepatocyte transplantation and clinical applications of a bioartificial liver. Human embryonic stem cells (hESCs) with a high degree of self-renewal and totipotency are a potentially limitless source of a variety of cell lineages, including hepatocytes. Many techniques have been developed for effective differentiation of hESCs into functional hepatocyte-like cells. However, the application of hESC-derived hepatocyte-like cells (hESC-Heps) in the clinic has been constrained by the low yield of fully differentiated cells, small-scale culture, difficulties in harvesting, and immunologic graft rejection. To resolve these shortcomings, we developed a novel 3D differentiation system involving alginate-microencapsulated spheres to improve current hepatic differentiation, providing ready-to-use hESC-Heps. Methods: In this study, we used alginate microencapsulation technology to differentiate human embryonic stem cells into hepatocyte-like cells (hESC-Heps). Hepatic markers of hESC-Heps were examined by qPCR and Western blotting, and hepatic functions of hESC-Heps were evaluated by indocyanine-green uptake and release, and ammonia removal. Results: The maturity and hepatic functions of the hESC-Heps derived from this 3D system were better than those derived from 2D culture. Hepatocyte-enriched genes, such as HNF4α, AFP, and ALB, were expressed at higher levels in 3D hESC-Heps than in 2D hESC-Heps. 3D hESC-Heps could metabolize indocyanine green and had better capacity to scavenge ammonia. In addition, the 3D sodium alginate hydrogel microspheres could block viral entry into the microspheres, and thus protect hESC-Heps in 3D microspheres from viral infection. Conclusion: We developed a novel 3D differentiation system for differentiating hESCs into hepatocyte-like cells by using alginate microcapsules.
The Toll-like Receptor 4 Polymorphism Asp299Gly Is Associated with an Increased Risk of Ovarian Cancer
Authors: Kania Katarzyna D. , Haręża Daria , Wilczyński Jacek R. , Wilczyński Miłosz , Jarych Dariusz , Malinowski Andrzej , Paradowska Edyta
Published: October 2022

Ovarian cancer (OC) is one of the most common cancers threatening women’s lives around the world. Epithelial ovarian tumors represent the most common ovarian neoplasms. Most OC patients are diagnosed at the advanced stage, and there is an urgent need to identify novel biomarkers of the disease. Single-nucleotide polymorphisms (SNPs) in TLR genes may serve as crucial markers of cancer susceptibility. We investigated the frequency of TLR polymorphisms in a group of 200 women, including 70 with OC. Four SNPs, two each in TLR4 (rs4986790 and rs4986791) and TLR9 (rs187084 and rs5743836), were analyzed using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). The digested fragments were separated and identified by multicapillary electrophoresis. The load quantification of human papillomavirus (HPV) types 16/18 was determined using a digital droplet PCR method. We found an increased frequency of heterozygous genotype and minor allele of the TLR4 rs4986790 SNP in women with OC compared with healthy controls, and this result remained highly significant after Bonferroni’s correction for multiple testing (p < 0.0001). No evidence of linkage disequilibrium was found with any of the examined TLR SNPs. The findings suggest that the TLR4 Asp299Gly polymorphism could be a genetic risk factor for the development of OC.
Genetic Association between Farrowing Rates and Swine Leukocyte Antigen Alleles or Haplotypes in Microminipigs
Authors: Ando Asako , Matsubara Tatsuya , Suzuki Shingo , Imaeda Noriaki , Takasu Masaki , Shigenari Atsuko , Miyamoto Asuka , Ohshima Shino , Kametani Yoshie , Shiina Takashi , Kulski Jerzy K. , Kitagawa Hitoshi
Published: October 2022

We have previously reported specific swine leukocyte antigen (SLA) haplotype associations with significant effects on several reproduction performance traits in a highly inbred miniature pig population of Microminipigs (MMPs). In this study, to clarify the effects on farrowing rates of SLA similarity between mating partners in the MMP population, we compared the farrowing rates as a measure of reproductive success after 1063-cumulative matings among the following three groups of mating partners: (1) completely sharing SLA class I or class II haplotypes or alleles between partners (CS), (2) only one sharing the haplotypes or alleles (OS), and (3) non-sharing the haplotypes or alleles (NS). Average farrowing rates in CS groups consisting of completely sharing SLA class II haplotypes or DRBI and DQB1 alleles were lowest in the three groups. Moreover, lower farrowing rates were indicated in mating pairs with smaller amino acid pairwise genetic distances of SLA-1, SLA-3, DRB1 and DQB1 alleles between the pairs. These results suggested that the dissimilarity of SLA class I and class II alleles between mating partners markedly improved reproductive performance; therefore, SLA alleles or haplotypes are potentially useful genetic markers for the selection of mating pairs in breeding programs and epistatic studies of reproductive traits of MMPs.
Necrostatin-1 Alleviates Lung Ischemia-Reperfusion Injury via Inhibiting Necroptosis and Apoptosis of Lung Epithelial Cells
Authors: Dong Lingjun , Liang Fuxiang , Lou Zhiling , Li Yangfan , Li Jinsheng , Chen Yaling , Ding Jingjing , Jiang Bin , Wu Chuanqiang , Yu Huan , Liu Yafei , Zhang Weiping , Lu Yunbi , Wu Ming
Published: October 2022

Lung ischemia-reperfusion injury (LIRI) is associated with many diseases, including primary graft dysfunction after lung transplantation, and has no specific and effective therapies. Necroptosis contributes to the pathogenesis of ischemia-reperfusion injury. Necrostatin-1 (Nec-1), the necroptosis inhibitor targeting RIPK1, has been reported to alleviate ischemia-reperfusion injury in various organs. However, the underlying mechanism of Nec-1 in LIRI remains unclear. In this paper, an in vivo LIRI model was built up by left lung hilar clamping in mice, and an in vitro cold ischemia-reperfusion (CI/R) model using BEAS-2B cells was applied to mimic the lung transplantation setting. We found Nec-1 significantly alleviated ischemia-reperfusion-induced lung injury, cytokine releasing, and necroptosis of epithelial cells in mouse lungs. In vitro, Nec-1 also mitigated CI/R-induced cell death and inflammatory responses in BEAS-2B cells, and these protective effects were achieved by simultaneously inhibiting the formation of necrosome and RIPK1-dependent apoptosis. However, Nec-1 decreased the necrosome number but increased the apoptosis level in lung tissues after ischemia reperfusion. We further clarified that Nec-1 could also attenuate lung injury by promoting neutrophil apoptosis from flow cytometry. In conclusion, Nec-1 alleviated lung ischemia-reperfusion injury by inhibiting necroptosis and apoptosis of epithelial cells and promoting the apoptosis of neutrophils. Thus, Nec-1 could be a promising medication against primary graft dysfunction after lung transplantation.
Axon Guidance Molecules and Pain
Authors: Damo Elisa , Simonetti Manuela
Published: October 2022

Chronic pain is a debilitating condition that influences the social, economic, and psychological aspects of patients’ lives. Hence, the need for better treatment is drawing extensive interest from the research community. Developmental molecules such as Wnt, ephrins, and semaphorins are acknowledged as central players in the proper growth of a biological system. Their receptors and ligands are expressed in a wide variety in both neurons and glial cells, which are implicated in pain development, maintenance, and resolution. Thereby, it is not surprising that the impairment of those pathways affects the activities and functions of the entire cell. Evidence indicates aberrant activation of their pathways in the nervous system in rodent models of chronic pain. In those conditions, Wnt, ephrin, and semaphorin signaling participate in enhancing neuronal excitability, peripheral sensitization, synaptic plasticity, and the production and release of inflammatory cytokines. This review summarizes the current knowledge on three main developmental pathways and their mechanisms linked with the pathogenesis and progression of pain, considering their impacts on neuronal and glial cells in experimental animal models. Elucidations of the downstream pathways may provide a new mechanism for the involvement of Wnt, ephrin, and semaphorin pathways in pain chronicity.
Global Transcriptional and Epigenetic Reconfiguration during Chemical Reprogramming of Human Retinal Pigment Epithelial Cells into Photoreceptor-like Cells
Authors: Deng Xiaoqian , Lee Ryan , Lim Sin Yee , Zhong Zheng , Wang Jing , Liu Yizhi , Fan Guoping
Published: October 2022

Retinal degenerative diseases are frequently caused by the loss of retinal neural cells such as photoreceptors. Cell replacement is regarded as one of the most promising therapies. Multiple types of stem and somatic cells have been tested for photoreceptor conversion. However, current induction efficiencies are still low and the molecular mechanisms underlying reprogramming remain to be clarified. In this work, by combining treatment with small molecules, we directly reprogrammed human fetal retinal pigment epithelial (RPE) cells into chemically induced photoreceptor-like cells (CiPCs) in vitro. Bulk and single-cell RNA sequencing, as well as methylation sequencing, were performed to understand the transcriptional and epigenetic changes during CiPCs conversion. A multi-omics analysis showed that the direct reprogramming process partly resembled events of early retina development. We also found that the efficiency of CiPCs conversion from RPE is much better than that from human dermal fibroblasts (HDF). The small molecules effectively induced RPE cells into CiPCs via suppression of the epithelial-to-mesenchymal transition (EMT). Among the signaling pathways involved in CiPCs conversion, glutamate receptor activation is prominent. In summary, RPE cells can be efficiently reprogrammed into photoreceptor-like cells through defined pharmacological modulations, providing a useful cell source for photoreceptor generation in cell replacement therapy for retinal degenerative diseases.
The Adhesion G-Protein-Coupled Receptor GPR115/ADGRF4 Regulates Epidermal Differentiation and Associates with Cytoskeletal KRT1
Authors: Winkler Romy , Quaas Marianne , Glasmacher Stefan , Wolfrum Uwe , Thalheim Torsten , Galle Jörg , Krohn Knut , Magin Thomas M. , Aust Gabriela
Published: October 2022

Among the 33 human adhesion G-protein-coupled receptors (aGPCRs), a unique subfamily of GPCRs, only ADGRF4, encoding GPR115, shows an obvious skin-dominated transcriptomic profile, but its expression and function in skin is largely unknown. Here, we report that GPR115 is present in a small subset of basal and in most suprabasal, noncornified keratinocytes of the stratified epidermis, supporting epidermal transcriptomic data. In psoriatic skin, characterized by hyperproliferation and delayed differentiation, the expression of GPR115 and KRT1/10, the fundamental suprabasal keratin dimer, is delayed. The deletion of ADGRF4 in HaCaT keratinocytes grown in an organotypic mode abrogates KRT1 and reduces keratinocyte stratification, indicating a role of GPR115 in epidermal differentiation. Unexpectedly, endogenous GPR115, which is not glycosylated and is likely not proteolytically processed, localizes intracellularly along KRT1/10-positive keratin filaments in a regular pattern. Our data demonstrate a hitherto unknown function of GPR115 in the regulation of epidermal differentiation and KRT1.
Immunomodulatory Effect and Bone Homeostasis Regulation in Osteoblasts Differentiated from hADMSCs via the PD-1/PD-L1 Axis
Authors: Lee Seung-Cheol , Shin Min Kyoung , Jang Bo-Young , Lee Seung-Ho , Kim Min , Sung Jung-Suk
Published: October 2022

Human mesenchymal stem cells (hMSCs) are promising candidates for stem cell therapy and are known to secrete programmed death-1 (PD-1) ligand 1 (PD-L1) regulating T cell-mediated immunosuppression. Given the limitations of current stem cell therapy approaches, improvements in immunomodulatory capacity and stem cell differentiation efficacy are needed. In this study, we propose novel strategies to overcome the challenges that remain in hMSC-mediated bone regeneration. We found that PD-1 is highly expressed in osteoblasts, and the PD-1/PD-L1 axis mediated the decreased proinflammatory cytokine expressions in differentiated osteoblasts cocultured with human adipose derived mesenchymal stem cells (hADMSCs). Moreover, the decrease was attenuated by PD-1/PD-L1 pathway inhibition. Osteogenic properties including osteogenic gene expression and calcium deposits were increased in osteoblasts cocultured with hADMSCs compared with those that were monocultured. Osteoblasts treated with PD-L1 and exosomes from hADMSCs also exhibited enhanced osteogenic properties, including calcium deposits and osteogenic gene expression. In our cocultured system that mimics the physiological conditions of the bone matrix, the PD-1/PD-L1 axis mediated the increased expression of osteogenic genes, thereby enhancing the osteogenic properties, while the calcium deposits of osteoblasts were maintained. Our results provide the therapeutic potentials and novel roles of the PD-1/PD-L1 axis in bone matrix for modulating the bone properties and immunosuppressive potentials that can aid in the prevention of bone diseases via maintaining bone homeostasis.
A “Red-and-Green Porcelain” Figurine from a Jin Period Archaeological Site in the Primor’ye Region, Southern Russian Far East
Authors: Zhushchikhovskaya Irina S. , Buravlev Igor Yu
Published: October 2022

This paper considers the results of an examination of a polychrome glazed anthropomorphic ceramic figurine from the Prmor’ye region (southern Russian Far East) discovered at one of the Jin period (1115–1234 CE) archaeological sites. The study attests to the hypothesis about the attribution of this unique art object to the “red-and-green porcelain” produced in Northern China since the mid-Jin period. At present “the red-and-green porcelain” is the object of certain research interest as an important stage of Chinese ceramics history preceding the invention of famous porcelains with overglazed enamel decoration. The main technological features and material properties of the studied object were determined using analytical methods of optical and electron (SEM) microscopy with the use of X-ray elemental composition analysis (EDS, pXRF). The main result of the study presented in the paper includes evidence that the polychrome ceramic figurine found at the Anan’evka walled town in Primor’ey in the south of the Russian Far East belongs to the category of “red-and-green porcelain”, or “red-green ware”. As supposed, the figurine portrays Zen monk Budai—a person popular in Chinese arts and spiritual culture of the Song and Jin periods. Therefore, the polychrome ceramics figurine from the Primor’ye region may be considered today as the most northeastern case of “red-and-green porcelain” discovered in an archaeological context.
Structure and Electrical Properties of Carbon-Rich Polymer Derived Silicon Carbonitride (SiCN)
Authors: Adigun Oluwole Daniel , Ricohermoso Emmanuel , Daniyan Ayodele Abeeb , Umoru Lasisi Ejibunu , Ionescu Emanuel
Published: October 2022

This article reports on the structure and electronic properties of carbon-rich polysilazane polymer-derived silicon carbonitride (C/SiCN) corresponding to pyrolysis temperatures between 1100 and 1600 °C in an argon atmosphere. Raman spectroscopy, X-ray diffraction (XRD), energy dispersive X-ray spectroscopy (EDX), Scanning Electron Microscopy (SEM) and Hall measurements were used to support the structural and electronic properties characterization of the prepared C/SiCN nanocomposites. A structural analysis using Raman spectroscopy showed the evolution of sp2 hybridized carbon phase that resulted from the growth in the lateral crystallite size (La), average continuous graphene length including tortuosity (Leq) and inter-defects distance (LD) with an increase in pyrolysis temperature. The prepared C/SiCN monoliths showed a record high room temperature (RT) electrical conductivity of 9.6 S/cm for the sample prepared at 1600 °C. The electronic properties of the nanocomposites determined using Hall measurement revealed an anomalous change in the predominant charge carriers from n-type in the samples pyrolyzed at 1100 °C to predominantly p-type in the samples prepared at 1400 and 1600 °C. According to this outcome, tailor-made carbon-rich SiCN polymer-derived ceramics could be developed to produce n-type and p-type semiconductors for development of the next generation of electronic systems for applications in extreme temperature environments.
Preventing the Next Pandemic through a Planetary Health Approach: A Focus on Key Drivers of Zoonosis
Authors: Tajudeen Yusuf Amuda , Oladipo Habeebullah Jayeola , Oladunjoye Iyiola Olatunji , Mustapha Mutiat Oluwakemi , Mustapha Sheriff Taye , Abdullahi Adam Aberi , Yusuf Rashidat Onyinoyi , Abimbola Samuel Olushola , Adebayo Aminat Olaitan , Ikebuaso Joy Ginika , Adesuyi Damilola Samuel , Okereke Blessed , Omotosho Abass Olawale , Ahmed Abdulhakeem Funsho , El-Sherbini Mona Said
Published: October 2022

The ever-increasing global health impact of SARS-CoV-2—the etiological agent of coronavirus disease 2019 (COVID-19)—coupled with its socio-economic burden, has not only revealed the vulnerability of humanity to zoonotic pathogens of pandemic potential but also serves as a wake-up call for global health communities to rethink sustainable approaches towards preventing future pandemics. However, since the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES) convened experts have declared that future pandemics are likely to be zoonotic in origin, it is imperative that we understand the key drivers of zoonosis such as biodiversity loss, climate change, wildlife consumption, and population mobility, as well as the scientific evidence underpinning them. In this article, we underscore the correlations of these drivers with the emergence and re-emergence of zoonosis. Consequently, we highlighted the need for multidisciplinary collaboration under the planetary health approach between researchers across the fields of environmental and human health to fill the knowledge and research gaps on key drivers of zoonosis. This is to prevent or limit future pandemics by protecting the natural systems of the Earth and its resources and safeguarding human and animal health.
Study of Tube Pretension Effects on the Strength of the Flat-Round Tubesheet in a Quench Boiler
Authors: Zhao Guangrui , Qin Guomin , Liu Bin , Xing Fang , Qian Caifu
Published: October 2022

A quench boiler is the key equipment in ethylene production for the rapid cooling of high-temperature cracking gas. In the boiler, heat transfer is occurs between the hot cracking gas passing through the inner heat exchange tubes with an average temperature of 385 °C and cold water (or boiler water) passing through the inner heat exchange tubes with an average temperature of 350 °C. Required for double-pipe heat transfer, special tubesheets formed by welding flat-round tubes side by side are difficult to design, as no suitable design code is available. The thermal expansion difference between the inner heat exchange tubes and the jacketed tubes could lead to high thermal stress on the tubesheet. In this study, we investigated the effects of pretension or prestretching of the heat exchange tubes on stress distribution and strength assessment of the flat-round tubesheet in a quench boiler under two dangerous load conditions. Results show that without prestretching the heat exchange tubes, the flat-round tubesheet cannot pass the strength assessment. Prestretching the heat exchange tubes is necessary, and a pretension of 9 mm is most suitable. The magnitude of the pretension of the heat exchange tubes should be determined based on the thermal expansion difference between the inner heat exchange tubes and the jacketed tubes, with consideration of the strength improvement of the flat-round tubesheet.
Efficiency of Mechanochemical Ball Milling Technique in the Preparation of Fe/TiO2 Photocatalysts
Authors: Taghipour Shabnam , Yeung King-Lun , Ataie-Ashtiani Behzad
Published: October 2022

Rapid population growth and widespread industrialization are the main contributing factors to the increasing contamination of the world’s diminishing freshwater resources. This work investigates Fe/TiO2 as an efficient and sustainable photocatalyst for treating organic micropollutants in water. The photocatalysts prepared by these mechanochemical methods used a high-energy ball milling technique to manipulate Fe/TiO2’s structural, optical, and catalytic properties for the photo-oxidation of 2,4-Dichlorophenol (2,4-DCP). Doping with iron effectively reduced the band gap of rutile TiO2 from 3 to 2.22 eV. By reducing the ball/powder ratio from 34 to 7, the removal efficiency of 2,4-DCP increased from 65.2 to 84.7%. Measuring the TOC indicated 63.5 and 49.4% mineralization by Fe/TiO2-7 and rutile TiO2, respectively, after 24 h. The energy yields for the Fe/TiO2 and rutile TiO2 were 0.13 and 0.06 g 2,4-DCP/kW h, respectively.
Non-Inferiority of Point-of-Care Ultrasound Compared to Radiography to Diagnose Upper Extremity Fractures in Children
Authors: Troxler David , Sanchez Carlos , de Trey Thierry , Mayr Johannes , Walther Michael
Published: October 2022

Conventional X-ray imaging for fracture diagnosis is time-consuming and exposes patients to ionizing radiation. Additionally, the positioning of the injured limb for standardized X-ray imaging is painful. Point-of-care ultrasound (POCUS) is increasingly available in medical offices and emergency rooms. This study aimed to prove the non-inferiority of POCUS compared to X-ray imaging with respect to diagnostic sensitivity, pain, and investigation time in the diagnosis of long-bone fractures of the upper extremity in children. Children and adolescents (1–18 years old) presenting to the UKBB emergency service between May 2020 and May 2021 with suspected upper extremity fracture were included in the study. Before obtaining X-ray images, we conducted a POCUS examination of the injured limb. Pain scores at inclusion as well as maximum pain scores during X-ray and ultrasound examinations were documented. The duration of POCUS and X-ray examinations was compared. We examined 403 children with POCUS and plain X-ray imaging. The mean age (±SD) of the children was 10.6 (±3.5) years. The non-inferiority of POCUS compared to X-ray was confirmed with an estimated sensitivity of 0.95 and a lower confidence interval of 0.93. Maximum pain during POCUS was significantly lower compared to pain at inclusion (p = 0.002) or maximum pain during radiographic examination (p = 0.03). POCUS examination took 3.9 (±2.9) min in the mean whilst the mean duration for obtaining the X-ray images was 16 (±37) min (p < 0.001). POCUS for diagnosing upper extremity fractures in children proved as sensitive as standard X-ray imaging and was significantly faster and less painful. Future prospective studies are required to confirm our findings.
Influence of Different Antiseizure Medications on Vascular Risk Factors in Children with Epilepsy
Authors: Mahrous Doaa M. , Moustafa Asmaa N. , Higazi Mahmoud M. , Higazi Aliaa M. , AbdelAziz Reem A.
Published: October 2022

Many studies have proposed that plasma homocysteine levels are increased as a side effect with the prolonged use of antiseizure medications. This is associated with an increase in carotid intima media thickness; hence, it increases the threat of atherosclerosis at a young age. We aimed to assess serum levels of homocysteine in epileptic children on long-standing antiseizure medications and its association with increased occurrence of cardiovascular disease. The study included 60 epileptic children aged between 2 and 15 years old who visited our pediatric neurology outpatient clinic and 25 apparently healthy children served as a control group. All included children were subjected to careful history taking, clinical examination, anthropometric measures, laboratory investigations including serum homocysteine levels and lipid profile, along with radiological assessment involving carotid intima media thickness and carotid stiffness. Results demonstrated a significant increase in the serum levels of homocysteine, carotid intima media thickness, and carotid stiffness in children on monotherapy of old generation antiseizure medications and polytherapy than that in children on monotherapy of new generation antiseizure medications and control children. Epileptic children on old generation and polytherapy antiseizure medications have an increased risk for cardiovascular diseases and need follow up for early intervention when needed.