bluuebunny/crossref_metadata_2025 huggingface dataset:
Skeletal Class III Malocclusion Is Associated with ADAMTS2 Variants and Reduced Expression in a Familial Case
Authors: Yao Siyue , Zhou Xi , Vona Barbara , Fan Liwen , Zhang Chengcheng , Li Dandan , Yuan Hua , Du Yifei , Ma Lan , Pan Yongchu
Published: September 2022

Skeletal Class III malocclusion with maxillary deficiency is a severe maxillofacial disease with unclear pathogenic mechanisms. We recruited a Han Chinese family who was clinically diagnosed with skeletal Class III malocclusion and maxillary deficiency. Using whole exome sequencing, a missense variant in ADAMTS2 (NM_014244: c.3506G>T: p.G1169V) was identified and predicted as deleterious by in silico tools. We also found ADAMTS2 variants associated with deficient maxillary development in a cohort. ADAMTS2 expression in HEK293 cells showed significant decrease due to the variant, which was also consistent in dental pulp stem cells from the proband and a healthy control. In the adamts2-knockdown zebrafish model, the length and width of the ethmoid plate, as well as the length of the palatoquadrate became significantly shorter than the control group (p < 0.001), while there was no significant difference in the length and width of the mandible. The expression of Sox3, which was required in early embryonic craniofacial development, was significantly downregulated in the adamts2-knockdown zebrafish embryos. Bioinformatic and cellular studies showed that the decreased expression of ADAMTS2 may inhibit downstream ErbB signaling pathway transduction and restrain subsequent osteogenesis in human adult mesenchymal stromal cells. Collectively, these data showed that ADAMTS2 (c.3506G>T: p.G1169V) may confer susceptibility to risk of skeletal Class III malocclusion with maxillary deficiency.
Transcriptome-Wide m6A Methylome Profiling in Sorghum following GA3 Treatment under Salt Stress
Authors: Wu Yanqing , Liu Jiao , Zhou Guisheng
Published: September 2022

Sorghum (“Jitian 3”) is a salt-tolerant seed cultivar used regularly in marginal lands, such as those with saline soils. Herein, we examined the potential of employing gibberellic acid (GA3) as an inducer of sorghum development during salt stress. Thus far, there have been no reports on the signaling network involved in the GA3-mediated regulation of sorghum development. In this study, we demonstrated that the stimulating properties of 50 mg/L GA3 on sorghum development was far superior to other GA3 concentrations under a 150 mM NaCl salinity condition. Furthermore, using methylated RNA immunoprecipitation sequencing (MeRIP-seq), we established an m6A methylation (m6A-M) profile in sorghum following exposure to 50 mg/L GA3. Overall, 23,363 m6A peaks and 16,200 m6A genes were screened among the GA3-treated and control leaves. These identified peaks were shown to be primarily enriched in the coding, as were the 3′- and 5′-untranslated regions. In addition, we employed m6A and transcript expression cross-analysis to identify 70 genes with differential transcript expression and simultaneous m6A-M. Intriguingly, the principal gene, LOC8066282, which is associated with LOC8084853, was shown to be intricately linked to the phosphatidylinositol signaling, which in turn regulates sorghum development and response to salt stress. This investigation presents a novel RNA m6A-M profile in sorghum, which may facilitate new insights into the underlying signaling behind salt stress resistance. This work will also benefit future investigations on foreign GA3 administration of sorghum.
Integrated Metabolites and Transcriptomics at Different Growth Stages Reveal Polysaccharide and Flavonoid Biosynthesis in Cynomorium songaricum
Authors: Wang Jie , Su Hongyan , Wu Zhibo , Wang Wenshu , Zhou Yubi , Li Mengfei
Published: September 2022

Cynomorium songaricum is a perennial parasitic herb, and its stem is widely used as a traditional Chinese medicine, which largely relies on bioactive compounds (e.g., polysaccharides, flavonoids, and triterpenes). To date, although the optimum harvest time of stems has been demonstrated at the unearthed stage (namely the early flowering stage, EFS), the accumulation mechanism of polysaccharides and flavonoids during growth stages is still limited. In this study, the physiological characteristics (stem fresh weight, contents of soluble sugar and flavonoids, and antioxidant capacity) at four different growth stages (germination stage (GS), vegetative growth stage (VGS), EFS, and flowering stage (FS)) were determined, transcriptomics were analyzed by illumina sequencing, and expression levels of key genes were validated by qRT-PCR at the GS, VGS, and EFS. The results show that the stem biomass, soluble sugar and total flavonoids contents, and antioxidant capacity peaked at EFS compared with GS, VGS, and FS. A total of 6098 and 13,023 differentially expressed genes (DEGs) were observed at VGS and EFS vs. GS, respectively, with 367 genes co-expressed. Based on their biological functions, 109 genes were directly involved in polysaccharide and flavonoid biosynthesis as well as growth and development. The expression levels of key genes involved in polysaccharides (e.g., GLCs, XTHs and PMEs), flavonoids (e.g., 4CLLs, CYPs and UGTs), growth and development (e.g., AC58, TCPs and AP1), hormones biosynthesis and signaling (e.g., YUC8, AIPT and ACO1), and transcription factors (e.g., MYBs, bHLHs and WRKYs) were in accordance with changes of physiological characteristics. The combinational analysis of metabolites with transcriptomics provides insight into the mechanism of polysaccharide and flavonoid biosynthesis in C. songaricum during growth stages.
Chidamide plus Tyrosine Kinase Inhibitor Remodel the Tumor Immune Microenvironment and Reduce Tumor Progression When Combined with Immune Checkpoint Inhibitor in Naïve and Anti-PD-1 Resistant CT26-Bearing Mice
Authors: Chen Jia-Shiong , Hsieh Yi-Chien , Chou Cheng-Han , Wu Yi-Hong , Yang Mu-Hsuan , Chu Sz-Hao , Chao Ye-Su , Chen Chia-Nan
Published: September 2022

Combined inhibition of vascular endothelial growth factor receptor (VEGFR) and the programmed cell death protein 1 (PD-1) pathways has shown efficacy in multiple cancers; however, the clinical outcomes show limited benefits and the unmet clinical needs still remain and require improvement in efficacy. Using murine colon carcinoma (CT26) allograft models, we examined the efficacy and elucidated novel tumor microenvironment (TME) remodeling mechanisms underlying the combination of chidamide (a benzamide-based class l histone deacetylase inhibitor; brand name in Taiwan, Kepida®) with VEGF receptor tyrosine kinase inhibitor (TKIs; cabozantinib/regorafenib, etc.) and immune checkpoint inhibitors (ICIs; anti-PD-1/anti-PD-L1/anti-CTLA-4 antibodies). The TME was assessed using flow cytometry and RNA-sequencing to determine the novel mechanisms and their correlation with therapeutic effects in mice with significant treatment response. Compared with ICI alone or cabozantinib/regorafenib + ICI, combination of chidamide + cabozantinib/regorafenib + ICI increased the tumor response and survival benefits. In particular, treatment of CT26-bearing mice with chidamide + regorafenib + anti-PD-1 antibody showed a better objective response rate (ORR) and overall survival (OS). Similar results were observed in anti-PD-1 treatment-resistant mice. After treatment with this optimal combination, in the TME, RNA-sequencing revealed that downregulated mRNAs were correlated with leukocyte migration, cell chemotaxis, and macrophage gene sets, and flow cytometry analysis showed that the cell numbers of myeloid-derived polymorphonuclear suppressor cells and tumor-associated macrophages were decreased. Accordingly, chidamide + regorafenib + anti-PD-1 antibody combination therapy could trigger a novel TME remodeling mechanism by attenuating immunosuppressive cells, and restoring T-cell activation to enhance ORR and OS. Our studies also showed that the addition of Chidamide to the regorafenib + anti-PD-1 Ab combination could induce a durable tumor-specific response by attenuating immune suppression in the TME. In addition, this result suggests that TME remodeling, mediated by epigenetic immunomodulator combined with TKI and ICI, would be more advantageous for achieving a high objective response rate, when compared to TKI plus ICI or ICI alone, and maintaining long-lasting antitumor activity.
Successful i-GONAD in Mice at Early Zygote Stage through In Vivo Electroporation Three Min after Intraoviductal Instillation of CRISPR-Ribonucleoprotein
Authors: Takabayashi Shuji , Iijima Kenta , Tsujimura Masumi , Aoshima Takuya , Takagi Hisayoshi , Aoto Kazushi , Sato Masahiro
Published: September 2022

Improved genome editing via oviductal nucleic acids delivery (i-GONAD) is a new technology enabling in situ genome editing of mammalian zygotes exiting the oviductal lumen, which is now available in mice, rats, and hamsters. In this method, CRISPR/Cas9 genome-editing reagents are delivered directly to the oviducts of pregnant animals (corresponding to late zygote stage). After intraoviductal instillation, electric shock to the entire oviduct was provided with a specialized electroporation (EP) device to drive the genome editing reagents into the zygotes present in the oviductal lumen. i-GONAD toward early zygotes has been recognized as difficult, because they are tightly surrounded by a cumulus cell layer, which often hampers effective transfer of nucleic acids to zygotes. However, in vivo EP three min after intraoviductal instillation of the genome-editing reagents enabled genome editing of early zygotes with an efficiency of 70%, which was in contrast with the rate of 18% when in vivo EP was performed immediately after intraoviductal instillation at Day 0.5 of pregnancy (corresponding to 13:00–13:30 p.m. on the day when vaginal plug was recognized after natural mating). We also found that addition of hyaluronidase, an enzyme capable of removing cumulus cells from a zygote, slightly enhanced the efficiency of genome editing in early zygotes. These findings suggest that cumulus cells surrounding a zygote can be a barrier for efficient generation of genome-edited mouse embryos and indicate that a three-minute interval before in vivo EP is effective for achieving i-GONAD-mediated genome editing at the early zygote stage. These results are particularly beneficial for researchers who want to perform genome editing experiments targeting early zygotes.
Act Early and at the Right Location: SARS-CoV-2 T Cell Kinetics and Tissue Localization
Authors: Bertoletti Antonio , Le Bert Nina , Tan Anthony T.
Published: September 2022

The emergence of new SARS-CoV-2 lineages able to escape antibodies elicited by infection or vaccination based on the Spike protein of the Wuhan isolates has reduced the ability of Spike-specific antibodies to protect previously infected or vaccinated individuals from infection. Therefore, the role played by T cells in the containment of viral replication and spread after infection has taken a more central stage. In this brief review, we will discuss the role played by T cells in the protection from COVID-19, with a particular emphasis on the kinetics of the T cell response and its localization at the site of primary infection.
A Functional Network Driven by MicroRNA-125a Regulates Monocyte Trafficking in Acute Inflammation
Authors: Tomasi Stephanie , Li Lei , Hinske Ludwig Christian , Tomasi Roland , Amini Martina , Strauß Gabriele , Müller Martin Bernhard , Hirschberger Simon , Peterss Sven , Effinger David , Pogoda Kristin , Kreth Simone , Hübner Max
Published: September 2022

During the onset of acute inflammation, rapid trafficking of leukocytes is essential to mount appropriate immune responses towards an inflammatory insult. Monocytes are especially indispensable for counteracting the inflammatory stimulus, neutralising the noxa and reconstituting tissue homeostasis. Thus, monocyte trafficking to the inflammatory sites needs to be precisely orchestrated. In this study, we identify a regulatory network driven by miR-125a that affects monocyte adhesion and chemotaxis by the direct targeting of two adhesion molecules, i.e., junction adhesion molecule A (JAM-A), junction adhesion molecule-like (JAM-L) and the chemotaxis-mediating chemokine receptor CCR2. By investigating monocytes isolated from patients undergoing cardiac surgery, we found that acute yet sterile inflammation reduces miR-125a levels, concomitantly enhancing the expression of JAM-A, JAM-L and CCR2. In contrast, TLR-4-specific stimulation with the pathogen-associated molecular pattern (PAMP) LPS, usually present within the perivascular inflamed area, resulted in dramatically induced levels of miR-125a with concomitant repression of JAM-A, JAM-L and CCR2 as early as 3.5 h. Our study identifies miR-125a as an important regulator of monocyte trafficking and shows that the phenotype of human monocytes is strongly influenced by this miRNA, depending on the type of inflammatory stimulus.
The Perfect Match: Assessment of Sample Collection Efficiency for Immunological and Molecular Findings in Different Types of Fabrics
Authors: C. Zapico Sara , Dytso Alex , Rubio Leticia , Roca Gabriela
Published: September 2022

Body fluid identification at crime scenes can be crucial in retrieving the appropriate evidence that leads to the perpetrator and, in some cases, the victim. For this purpose, immunochromatographic tests are simple, fast and suitable for crime scenes. The potential sample is retrieved with a swab, normally a cotton swab, moistened in a specific buffer. Nonetheless, there are other swab types available, which have been proven to be efficient for DNA isolation and analysis. The aim of this study is to evaluate the efficiency of different swab types for body fluid identification as well as DNA isolation and characterization. Fifty microliters of human saliva were deposited in three different types of fabric (denim, cotton, and polyester). After 24 h at room temperature, samples were recovered by applying three different swab types, and the tests were performed. Subsequently, total DNA was recovered from the sample buffer. Cotton swabs performed worse in denim and cotton fabrics in both immunochromatography tests and DNA yield. No differences were observed for polyester. In contrast, and except for two replicates, it was possible to obtain a full DNA profile per fabric and swab type, and to identify the mtDNA haplogroup. In this paper, the impact of swab types on body fluid identification through the application of immunochromatographic tests is analyzed for the first time. This work corroborates previous research related to the influence of swab types in nuclear DNA isolation and characterization.
Crosstalk between Ca2+ Signaling and Cancer Stemness: The Link to Cisplatin Resistance
Authors: Kouba Sana , Hague Frédéric , Ahidouch Ahmed , Ouadid-Ahidouch Halima
Published: September 2022

In the fight against cancer, therapeutic strategies using cisplatin are severely limited by the appearance of a resistant phenotype. While cisplatin is usually efficient at the beginning of the treatment, several patients endure resistance to this agent and face relapse. One of the reasons for this resistant phenotype is the emergence of a cell subpopulation known as cancer stem cells (CSCs). Due to their quiescent phenotype and self-renewal abilities, these cells have recently been recognized as a crucial field of investigation in cancer and treatment resistance. Changes in intracellular calcium (Ca2+) through Ca2+ channel activity are essential for many cellular processes such as proliferation, migration, differentiation, and survival in various cell types. It is now proved that altered Ca2+ signaling is a hallmark of cancer, and several Ca2+ channels have been linked to CSC functions and therapy resistance. Moreover, cisplatin was shown to interfere with Ca2+ homeostasis; thus, it is considered likely that cisplatin-induced aberrant Ca2+ signaling is linked to CSCs biology and, therefore, therapy failure. The molecular signature defining the resistant phenotype varies between tumors, and the number of resistance mechanisms activated in response to a range of pressures dictates the global degree of cisplatin resistance. However, if we can understand the molecular mechanisms linking Ca2+ to cisplatin-induced resistance and CSC behaviors, alternative and novel therapeutic strategies could be considered. In this review, we examine how cisplatin interferes with Ca2+ homeostasis in tumor cells. We also summarize how cisplatin induces CSC markers in cancer. Finally, we highlight the role of Ca2+ in cancer stemness and focus on how they are involved in cisplatin-induced resistance through the increase of cancer stem cell populations and via specific pathways.
Molecular Characterization of MHC Class I Alpha 1 and 2 Domains in Asian Seabass (Lates calcarifer)
Authors: Loh Zhixuan , Huan Xuelu , Awate Sunita , Schrittwieser Markus , Renia Laurent , Ren Ee Chee
Published: September 2022

The Asian seabass is of importance both as a farmed and wild animal. With the emergence of infectious diseases, there is a need to understand and characterize the immune system. In humans, the highly polymorphic MHC class I (MHC-I) molecules play an important role in antigen presentation for the adaptive immune system. In the present study, we characterized a single MHC-I gene in Asian seabass (Lates calcarifer) by amplifying and sequencing the MHC-I alpha 1 and alpha 2 domains, followed by multi-sequence alignment analyses. The results indicated that the Asian seabass MHC-I α1 and α2 domain sequences showed an overall similarity within Asian seabass and retained the majority of the conserved binding residues of human leukocyte antigen-A2 (HLA-A2). Phylogenetic tree analysis revealed that the sequences belonged to the U lineage. Mapping the conserved binding residue positions on human HLA-A2 and grass carp crystal structure showed a high degree of similarity. In conclusion, the availability of MHC-I α1 and α2 sequences enhances the quality of MHC class I genetic information in Asian seabass, providing new tools to analyze fish immune responses to pathogen infections, and will be applicable in the study of the phylogeny and the evolution of antigen-specific receptors.
Raman Spectra and Ancient Life: Vibrational ID Profiles of Fossilized (Bone) Tissues
Authors: Jurašeková Zuzana , Fabriciová Gabriela , Silveira Luis F. , Lee Yuong-Nam , Gutak Jaroslav M. , Ataabadi Majid Mirzaie , Kundrát Martin
Published: September 2022

Raman micro-spectroscopy is a non-destructive and non-contact analytical technique that combines microscopy and spectroscopy, thus providing a potential for non-invasive and in situ molecular identification, even over heterogeneous and rare samples such as fossilized tissues. Recently, chemical imaging techniques have become an increasingly popular tool for characterizing trace elements, isotopic information, and organic markers in fossils. Raman spectroscopy also shows a growing potential in understanding bone microstructure, chemical composition, and mineral assemblance affected by diagenetic processes. In our lab, we have investigated a wide range of different fossil tissues, mainly of Mesozoic vertebrates (from Jurassic through Cretaceous). Besides standard spectra of sedimentary rocks, including pigment contamination, our Raman spectra also exhibit interesting spectral features in the 1200–1800 cm−1 spectral range, where Raman bands of proteins, nucleic acids, and other organic molecules can be identified. In the present study, we discuss both a possible origin of the observed bands of ancient organic residues and difficulties with definition of the specific spectral markers in fossilized soft and hard tissues.
Whole-Genome Metalloproteases in the Wheat Sharp Eyespot Pathogen Rhizoctonia cerealis and a Role in Fungal Virulence
Authors: Guo Feilong , Pan Lijun , Liu Hongwei , Lv Liangjie , Chen Xiyong , Liu Yuping , Li Hui , Ye Wenwu , Zhang Zengyan
Published: September 2022

Rhizoctonia cerealis is the causal agent of sharp eyespot, a devastating disease of cereal crops including wheat. Several metalloproteases have been implicated in pathogenic virulence, but little is known about whole-genome metalloproteases in R. cerealis. In this study, a total of 116 metalloproteases-encoding genes were identified and characterized from the R. cerealis Rc207 genome. The gene expression profiles and phylogenetic relationship of 11 MEP36/fungalysin metalloproteases were examined during the fungal infection to wheat, and function of an upregulated secretory MEP36 named RcFL1 was validated. Of 11 MEP36 family metalloproteases, ten, except RcFL5, were predicted to be secreted proteins and nine encoding genes, but not RcFL5 and RcFL2, were expressed during the R. cerealis infection process. Phylogenetic analysis suggested that MEP36 metalloproteases in R. cerealis were closely related to those of Rhizoctonia solani but were remote to those of Bipolaris sorokiniana, Fusarium graminearum, F. pseudograminearum, and Pyricularia oryzae. Expression of RcFL1 was significantly upregulated during the infection process and induced plant cell death in wheat to promote the virulence of the pathogen. The MEP36 domain was necessary for the activities of RcFL1. Furthermore, RcFL1 could repress the expression of wheat genes coding for the chitin elicitor receptor kinase TaCERK1 and chitinases. These results suggest that this MEP36 metalloprotease RcFL1 may function as a virulence factor of R. cerealis through inhibiting host chitin-triggered immunity and chitinases. This study provides insights on pathogenic mechanisms of R. cerealis. RcFL1 likely is an important gene resource for improving resistance of wheat to R. cerealis through host-induced gene silencing strategy.
Plasma Small Extracellular Vesicle Cathepsin D Dysregulation in GRN/C9orf72 and Sporadic Frontotemporal Lobar Degeneration
Authors: Bellini Sonia , Saraceno Claudia , Benussi Luisa , Geviti Andrea , Longobardi Antonio , Nicsanu Roland , Cimini Sara , Ricci Martina , Canafoglia Laura , Coppola Cinzia , Puoti Gianfranco , Binetti Giuliano , Rossi Giacomina , Ghidoni Roberta
Published: September 2022

Emerging data suggest the roles of endo-lysosomal dysfunctions in frontotemporal lobar degeneration (FTLD) and in other dementias. Cathepsin D is one of the major lysosomal proteases, mediating the degradation of unfolded protein aggregates. In this retrospective study, we investigated cathepsin D levels in human plasma and in the plasma small extracellular vesicles (sEVs) of 161 subjects (40 sporadic FTLD, 33 intermediate/pathological C9orf72 expansion carriers, 45 heterozygous/homozygous GRN mutation carriers, and 43 controls). Cathepsin D was quantified by ELISA, and nanoparticle tracking analysis data (sEV concentration for the cathepsin D level normalization) were extracted from our previously published dataset or were newly generated. First, we revealed a positive correlation of the cathepsin D levels with the age of the patients and controls. Even if no significant differences were found in the cathepsin D plasma levels, we observed a progressive reduction in plasma cathepsin D moving from the intermediate to C9orf72 pathological expansion carriers. Observing the sEVs nano-compartment, we observed increased cathepsin D sEV cargo (ng/sEV) levels in genetic/sporadic FTLD. The diagnostic performance of this biomarker was fairly high (AUC = 0.85). Moreover, sEV and plasma cathepsin D levels were positively correlated with age at onset. In conclusion, our study further emphasizes the common occurrence of endo-lysosomal dysregulation in GRN/C9orf72 and sporadic FTLD.
Brain Neurons during Physiological Aging: Morphological Features, Autophagic and Mitochondrial Contribution
Authors: Sukhorukov Vladimir , Magnaeva Alina , Baranich Tatiana , Gofman Anna , Voronkov Dmitry , Gulevskaya Tatiana , Glinkina Valeria , Illarioshkin Sergey
Published: September 2022

Accumulating data suggest that the brain undergoes various changes during aging. Among them are loss of both white and gray matter, neurons and synapses degeneration, as well as oxidative, inflammatory, and biochemical changes. The above-mentioned age-related features are closely related to autophagy and mitochondria. Therefore, we aimed to reveal the most peculiar morphological features of brain nervous tissue and to characterize the expression of autophagy and mitochondrial immunohistochemical biomarkers in neurons of different human brain zones during aging. Counting the number of neurons as well as Microtubule-associated proteins 1A/1B light chain 3B (LC3B), Heat shock protein 70 (HSP70), Lysosome-associated membrane protein type 2A (LAMP2A), Alpha subunit of ATP synthase (ATP5A), and Parkinson disease protein 7 (DJ1) immunohistochemical staining were performed on FFPE samples of human prefrontal cortex, corpus striatum, and hippocampus obtained from autopsy. Statistical analysis revealed a loss of neurons in the studied elderly group in comparison to the young group. When the expression of macroautophagy (LC3B), chaperon-mediated autophagy (HSP70, LAMP2A), and mitochondrial respiratory chain complex V (ATP5A) markers for the young and elderly groups were compared, the latter was found to have a significantly higher rate of optical density, whilst there was no significance in DJ1 expression. These findings, while preliminary, suggest that both autophagy and mitochondria are involved in neuronal maintenance during aging and could indicate their potential role in adaptive mechanisms that occur in aging.
Activation of Inflammatory Networks in the Lungs Caused by Chronic Cold Stress Is Moderately Attenuated by Glucose Supplementation
Authors: Teng Teng , Yang Hao , Xu Tianqi , Sun Guodong , Song Xin , Bai Guangdong , Shi Baoming
Published: September 2022

Mammals that live in cold climates endure months of exposure to low temperature in the winter. The incidence of respiratory diseases has increased. The goal of this study was to investigate the effects of chronic cold stress on lung inflammatory networks, apoptosis, and mitochondrial function via Yorkshire pig models, as well as the ameliorative effect of glucose as energy supplements. Here, two trials were conducted (chronic cold stress and glucose supplementation). The results showed that chronic cold stress induced obvious inflammatory cell infiltration in the lungs and damaged the lung tissue structure. Compared with the Y-Con group, the expression of toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), high mobility group box 1 (HMGB1), nucleotide-binding domain, and leucine-rich repeat protein 3 (NLRP3), IL-1β, IL-2, IL-6, and IFN-γ in the lungs of the Y-CS group was enhanced by chronic cold stress (p < 0.05). Moreover, chronic cold stress promoted the expression of the Bax and Mfn2 in lungs of Y-CS group (p < 0.05). Interestingly, dietary glucose supplementation significantly reduced inflammatory cell infiltration in the lungs. Moreover, glucose supplementation inhibited the expression of TLR4, MyD88, HMGB1, NLRP3, IL-1β, IL-2, IL-6, IFN-γ, and Bax during chronic cold stress. In conclusion, chronic cold stress promoted inflammatory networks, apoptosis, and mitochondrial fusion in the lungs. Dietary glucose supplementation inhibited the inflammatory network during chronic cold stress.
Identification of NHLRC1 as a Novel AKT Activator from a Lung Cancer Epigenome-Wide Association Study (EWAS)
Authors: Faltus Christian , Lahnsteiner Angelika , Barrdahl Myrto , Assenov Yassen , Hüsing Anika , Bogatyrova Olga , Laplana Marina , Johnson Theron , Muley Thomas , Meister Michael , Warth Arne , Thomas Michael , Plass Christoph , Kaaks Rudolf , Risch Angela
Published: September 2022

Changes in DNA methylation identified by epigenome-wide association studies (EWAS) have been recently linked to increased lung cancer risk. However, the cellular effects of these differentially methylated positions (DMPs) are often unclear. Therefore, we investigated top differentially methylated positions identified from an EWAS study. This included a putative regulatory region of NHLRC1. Hypomethylation of this gene was recently linked with decreased survival rates in lung cancer patients. HumanMethylation450 BeadChip array (450K) analysis was performed on 66 lung cancer case-control pairs from the European Prospective Investigation into Cancer and Nutrition Heidelberg lung cancer EWAS (EPIC HD) cohort. DMPs identified in these pre-diagnostic blood samples were then investigated for differential DNA methylation in lung tumor versus adjacent normal lung tissue from The Cancer Genome Atlas (TCGA) and replicated in two independent lung tumor versus adjacent normal tissue replication sets with MassARRAY. The EPIC HD top hypermethylated DMP cg06646708 was found to be a hypomethylated region in multiple data sets of lung tumor versus adjacent normal tissue. Hypomethylation within this region caused increased mRNA transcription of the closest gene NHLRC1 in lung tumors. In functional assays, we demonstrate attenuated proliferation, viability, migration, and invasion upon NHLRC1 knock-down in lung cancer cells. Furthermore, diminished AKT phosphorylation at serine 473 causing expression of pro-apoptotic AKT-repressed genes was detected in these knock-down experiments. In conclusion, this study demonstrates the powerful potential for discovery of novel functional mechanisms in oncogenesis based on EWAS DNA methylation data. NHLRC1 holds promise as a new prognostic biomarker for lung cancer survival and prognosis, as well as a target for novel treatment strategies in lung cancer patients.
Modulating Activity Evaluation of Gut Microbiota with Versatile Toluquinol
Authors: Zhang Long-Long , Liu Ya-Jun , Chen Yong-Hong , Wu Zhuang , Liu Bo-Ran , Cheng Qian-Yi , Zhang Ke-Qin , Niu Xue-Mei
Published: September 2022

Gut microbiota have important implications for health by affecting the metabolism of diet and drugs. However, the specific microbial mediators and their mechanisms in modulating specific key intermediate metabolites from fungal origins still remain largely unclear. Toluquinol, as a key versatile precursor metabolite, is commonly distributed in many fungi, including Penicillium species and their strains for food production. The common 17 gut microbes were cultivated and fed with and without toluquinol. Metabolic analysis revealed that four strains, including the predominant Enterococcus species, could metabolize toluquinol and produce different metabolites. Chemical investigation on large-scale cultures led to isolation of four targeted metabolites and their structures were characterized with NMR, MS, and X-ray diffraction analysis, as four toluquinol derivatives (1–4) through O1/O4-acetyl and C5/C6-methylsulfonyl substitutions, respectively. The four metabolites were first synthesized in living organisms. Further experiments suggested that the rare methylsulfonyl groups in 3–4 were donated from solvent DMSO through Fenton’s reaction. Metabolite 1 displayed the strongest inhibitory effect on cancer cells A549, A2780, and G401 with IC50 values at 0.224, 0.204, and 0.597 μM, respectively, while metabolite 3 displayed no effect. Our results suggest that the dominant Enterococcus species could modulate potential precursors of fungal origin and change their biological activity.
Interleukin-10 Protects against Ureteral Obstruction-Induced Kidney Fibrosis by Suppressing Endoplasmic Reticulum Stress and Apoptosis
Authors: Jung Kyongjin , Lee Taejin , Kim Jooyoung , Sung Eongi , Song Inhwan
Published: September 2022

Fibrosis is a common final pathway of chronic kidney disease, which is a major incurable disease. Although fibrosis has an irreversible pathophysiology, the molecular and cellular mechanisms responsible remain unclear and no specific treatment is available to halt the progress of renal fibrosis. Thus, an improved understanding of the cellular mechanism involved and a novel therapeutic approach are urgently required for end-stage renal disease (ESRD). We investigated the role played by interleukin-10 (IL-10, a potent anti-inflammatory cytokine) in kidney fibrosis and the mechanisms involved using IL-10−/− mice and TCMK-1 cells (mouse kidney tubular epithelial cell line). Endoplasmic reticulum stress (ERS), apoptosis, and fibrosis in IL-10−/− mice were more severe than in IL-10+/+ mice after unilateral ureteral obstruction (UUO). The 4-Phenylbutyrate (an ERS inhibitor) treatment induced dramatic reductions in ERS, apoptosis, and fibrosis-associated factors in the renal tissues of IL-10−/− mice, compared to wild-type controls after UUO. On the other hand, in cultured TCMK-1 cells, the ERS inducers (tunicamycin, thapsigargin, or brefeldin A) enhanced the expressions of proapoptotic and profibrotic factors, though these effects were mitigated by IL-10. These results were supported by the observation that IL-10 siRNA transfection aggravated tunicamycin-induced CHOP and a-SMA expressions in TCMK-1 cells. We conclude that the anti-fibrotic effects of IL-10 were attributable to the inhibition of ERS-mediated apoptosis and believe that the results of this study improve the understanding of the cellular mechanism responsible for fibrosis and aid in the development of novel therapeutic approaches.
Modulation of Immune Cells as a Therapy for Cutaneous Lupus Erythematosus
Authors: Soto Jorge A. , Melo-González Felipe , Riedel Claudia A. , Bueno Susan M. , Kalergis Alexis M.
Published: September 2022

Cutaneous lupus erythematosus (CLE) is an autoimmune disorder like systemic lupus erythematosus (SLE). Both SLE and CLE characterize autoantibody secretion and immune cell recruitment. In particular, CLE can be divided into three more frequent types, varying in the severity of the skin lesions they present. The role of type I IFN was shown to be one of the leading causes of the development of this pathology in the skin. Different treatments have been developed and tested against these different variants of CLE to decrease the increasing levels of CLE in humans. In this article, a literature revision discussing the similarities between SLE and CLE is carried out. In addition, new advances in understanding the development of CLE and the leading treatments being evaluated in animal models and clinical trials are reviewed.
Overexpression of PagERF072 from Poplar Improves Salt Tolerance
Authors: Zhang Xuemei , Cheng Zihan , Yao Wenjing , Gao Yuan , Fan Gaofeng , Guo Qing , Zhou Boru , Jiang Tingbo
Published: September 2022

Extreme environments, especially drought and high salt conditions, seriously affect plant growth and development. Ethylene-responsive factor (ERF) transcription factors play an important role in salt stress response. In this study, a significantly upregulated ERF gene was identified in 84K (Populus alba × P. glandulosa), which was named PagERF072. PagERF072 was confirmed to be a nuclear-localized protein. The results of yeast two-hybrid (Y2H) assay showed that PagERF072 protein exhibited no self-activating activity, and yeast one-hybrid (Y1H) demonstrated that PagERF072 could specifically bind to GCC-box element. Under salt stress, the transgenic poplar lines overexpressing PagERF072 showed improved salt tolerance. The activities of peroxidase (POD), superoxide dismutase (SOD) and catalase (CAT) in transgenic poplars were significantly increased relative to those of wild-type (WT) plants, whereas malondialdehyde (MDA) content showed an opposite trend. In addition, reactive oxygen species (ROS) was significantly reduced, and the expression levels of POD- and SOD-related genes were significantly increased in transgenic poplars under salt stress compared with WT. All results indicate that overexpression of the PagERF072 gene can improve the salt tolerance of transgenic poplars.
Anti-Inflammatory Activity of Soluble Epoxide Hydrolase Inhibitors Based on Selenoureas Bearing an Adamantane Moiety
Authors: Burmistrov Vladimir , Morisseau Christophe , Babkov Denis A. , Golubeva Tatiana , Pitushkin Dmitry , Sokolova Elena V. , Vasipov Vladimir , Kuznetsov Yaroslav , Bazhenov Sergey V. , Novoyatlova Uliana S. , Bondarev Nikolay A. , Manukhov Ilya V. , Osipova Victoria , Berberova Nadezhda , Spasov Alexander A. , Butov Gennady M. , Hammock Bruce D.
Published: September 2022

The inhibitory potency of the series of inhibitors of the soluble epoxide hydrolase (sEH) based on the selenourea moiety and containing adamantane and aromatic lipophilic groups ranges from 34.3 nM to 1.2 μM. The most active compound 5d possesses aliphatic spacers between the selenourea group and lipophilic fragments. Synthesized compounds were tested against the LPS-induced activation of primary murine macrophages. The most prominent anti-inflammatory activity, defined as a suppression of nitric oxide synthesis by LPS-stimulated macrophages, was demonstrated for compounds 4a and 5b. The cytotoxicity of the obtained substances was studied using human neuroblastoma and fibroblast cell cultures. Using these cell assays, the cytotoxic concentration for 4a was 4.7–18.4 times higher than the effective anti-inflammatory concentration. The genotoxicity and the ability to induce oxidative stress was studied using bacterial lux-biosensors. Substance 4a does not exhibit genotoxic properties, but it can cause oxidative stress at concentrations above 50 µM. Put together, the data showed the efficacy and safety of compound 4a.
Machine Learning for Property Prediction and Optimization of Polymeric Nanocomposites: A State-of-the-Art
Authors: Champa-Bujaico Elizabeth , García-Díaz Pilar , Díez-Pascual Ana M.
Published: September 2022

Recently, the field of polymer nanocomposites has been an area of high scientific and industrial attention due to noteworthy improvements attained in these materials, arising from the synergetic combination of properties of a polymeric matrix and an organic or inorganic nanomaterial. The enhanced performance of those materials typically involves superior mechanical strength, toughness and stiffness, electrical and thermal conductivity, better flame retardancy and a higher barrier to moisture and gases. Nanocomposites can also display unique design possibilities, which provide exceptional advantages in developing multifunctional materials with desired properties for specific applications. On the other hand, machine learning (ML) has been recognized as a powerful predictive tool for data-driven multi-physical modelling, leading to unprecedented insights and an exploration of the system’s properties beyond the capability of traditional computational and experimental analyses. This article aims to provide a brief overview of the most important findings related to the application of ML for the rational design of polymeric nanocomposites. Prediction, optimization, feature identification and uncertainty quantification are presented along with different ML algorithms used in the field of polymeric nanocomposites for property prediction, and selected examples are discussed. Finally, conclusions and future perspectives are highlighted.
Green Tea Catechins: Nature’s Way of Preventing and Treating Cancer
Authors: Farhan Mohd
Published: September 2022

Green tea’s (Camellia sinensis) anticancer and anti-inflammatory effects are well-known. Catechins are the most effective antioxidants among the physiologically active compounds found in Camellia sinesis. Recent research demonstrates that the number of hydroxyl groups and the presence of specific structural groups have a substantial impact on the antioxidant activity of catechins. Unfermented green tea is the finest source of these chemicals. Catechins have the ability to effectively neutralize reactive oxygen species. The catechin derivatives of green tea include epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG) and epigallocatechin gallate (EGCG). EGCG has the greatest anti-inflammatory and anticancer potential. Notably, catechins in green tea have been explored for their ability to prevent a variety of cancers. Literature evidence, based on epidemiological and laboratory studies, indicates that green tea catechins have certain properties that can serve as the basis for their consideration as lead molecules in the synthesis of novel anticancer drugs and for further exploration of their role as pharmacologically active natural adjuvants to standard chemotherapeutics. The various sections of the article will focus on how catechins affect the survival, proliferation, invasion, angiogenesis, and metastasis of tumors by modulating cellular pathways.
Toll-like Receptor Mediation in SARS-CoV-2: A Therapeutic Approach
Authors: Manan Abdul , Pirzada Rameez Hassan , Haseeb Muhammad , Choi Sangdun
Published: September 2022

The innate immune system facilitates defense mechanisms against pathogen invasion and cell damage. Toll-like receptors (TLRs) assist in the activation of the innate immune system by binding to pathogenic ligands. This leads to the generation of intracellular signaling cascades including the biosynthesis of molecular mediators. TLRs on cell membranes are adept at recognizing viral components. Viruses can modulate the innate immune response with the help of proteins and RNAs that downregulate or upregulate the expression of various TLRs. In the case of COVID-19, molecular modulators such as type 1 interferons interfere with signaling pathways in the host cells, leading to an inflammatory response. Coronaviruses are responsible for an enhanced immune signature of inflammatory chemokines and cytokines. TLRs have been employed as therapeutic agents in viral infections as numerous antiviral Food and Drug Administration-approved drugs are TLR agonists. This review highlights the therapeutic approaches associated with SARS-CoV-2 and the TLRs involved in COVID-19 infection.
Malignant Transformation of Giant Cell Tumour of Bone: A Review of Literature and the Experience of a Referral Centre
Authors: Vari Sabrina , Riva Federica , Onesti Concetta Elisa , Cosimati Antonella , Renna Davide , Biagini Roberto , Baldi Jacopo , Zoccali Carmine , Anelli Vincenzo , Annovazzi Alessio , Covello Renato , Ascione Andrea , Casini Beatrice , Ferraresi Virginia
Published: September 2022

Giant cell tumour of bone (GCTB) is a benign, locally aggressive primary bone neoplasm that represents 5% of all bone tumours. The principal treatment approach is surgery. Although generally GCTB is considered only a locally aggressive disease, it can metastasise, and lung metastases occur in 1–9% of patients. To date, only the use of denosumab has been approved as medical treatment for GCTB. Even more rarely, GCTB undergoes sarcomatous transformation into a malignant tumour (4% of all GCTB), but history of this malignant transformation is unclear and unpredictable. Considering the rarity of the event, the data in the literature are few. In this review, we summarise published data of GCTB malignant transformation and we analyse three cases of malignant transformation of GCTB, evaluating histopathology, genetics, and radiological aspects. Despite the rarity of this event, we conclude that a strict follow up is recommended to detect early malignant transformation.
Higher Na+-Ca2+ Exchanger Function and Triggered Activity Contribute to Male Predisposition to Atrial Fibrillation
Authors: Thibault Simon , Long Valérie , Fiset Céline
Published: September 2022

Male sex is one of the most important risk factors of atrial fibrillation (AF), with the incidence in men being almost double that in women. However, the reasons for this sex difference are unknown. Accordingly, in this study, we sought to determine whether there are sex differences in intracellular Ca2+ homeostasis in mouse atrial myocytes that might help explain male predisposition to AF. AF susceptibility was assessed in male (M) and female (F) mice (4–5 months old) using programmed electrical stimulation (EPS) protocols. Males were 50% more likely to develop AF. The Ca2+ transient amplitude was 28% higher in male atrial myocytes. Spontaneous systolic and diastolic Ca2+ releases, which are known sources of triggered activity, were significantly more frequent in males than females. The time to 90% decay of Ca2+ transient was faster in males. Males had 54% higher Na+-Ca2+ exchanger (NCX1) current density, and its expression was also more abundant. L-type Ca2+ current (ICaL) was recorded with and without BAPTA, a Ca2+ chelator. ICaL density was lower in males only in the absence of BAPTA, suggesting stronger Ca2+-dependent inactivation in males. CaV1.2 expression was similar between sexes. This study reports major sex differences in Ca2+ homeostasis in mouse atria, with larger Ca2+ transients and enhanced NCX1 function and expression in males resulting in more spontaneous Ca2+ releases. These sex differences may contribute to male susceptibility to AF by promoting triggered activity.
Role of the Cysteine in R3 Tau Peptide in Copper Binding and Reactivity
Authors: Bacchella Chiara , Gentili Silvia , Mozzi Sara Ida , Monzani Enrico , Casella Luigi , Tegoni Matteo , Dell’Acqua Simone
Published: September 2022

Tau is a widespread neuroprotein that regulates the cytoskeleton assembly. In some neurological disorders, known as tauopathies, tau is dissociated from the microtubule and forms insoluble neurofibrillary tangles. Tau comprises four pseudorepeats (R1–R4), containing one (R1, R2, R4) or two (R3) histidines, that potentially act as metal binding sites. Moreover, Cys291 and Cys322 in R2 and R3, respectively, might have an important role in protein aggregation, through possible disulfide bond formation, and/or affecting the binding and reactivity of redox-active metal ions, as copper. We, therefore, compare the interaction of copper with octadeca-R3-peptide (R3C) and with the mutant containing an alanine residue (R3A) to assess the role of thiol group. Spectrophotometric titrations allow to calculate the formation constant of the copper(I) complexes, showing a remarkable stronger interaction in the case of R3C (log Kf = 13.4 and 10.5 for copper(I)-R3C and copper(I)-R3A, respectively). We also evaluate the oxidative reactivity associated to these copper complexes in the presence of dopamine and ascorbate. Both R3A and R3C peptides increase the capability of copper to oxidize catechols, but copper-R3C displays a peculiar mechanism due to the presence of cysteine. HPLC-MS analysis shows that cysteine can form disulfide bonds and dopamine-Cys covalent adducts, with potential implication in tau aggregation process.