bluuebunny/crossref_metadata_2025 huggingface dataset:
GABAergic Regulation of Astroglial Gliotransmission through Cx43 Hemichannels
Authors: Jiménez-Dinamarca Ivanka , Reyes-Lizana Rachel , Lemunao-Inostroza Yordan , Cárdenas Kevin , Castro-Lazo Raimundo , Peña Francisca , Lucero Claudia M. , Prieto-Villalobos Juan , Retamal Mauricio Antonio , Orellana Juan Andrés , Stehberg Jimmy
Published: November 2022

Gamma-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain. It is produced by interneurons and recycled by astrocytes. In neurons, GABA activates the influx of Cl- via the GABAA receptor or efflux or K+ via the GABAB receptor, inducing hyperpolarization and synaptic inhibition. In astrocytes, the activation of both GABAA and GABAB receptors induces an increase in intracellular Ca2+ and the release of glutamate and ATP. Connexin 43 (Cx43) hemichannels are among the main Ca2+-dependent cellular mechanisms for the astroglial release of glutamate and ATP. However, no study has evaluated the effect of GABA on astroglial Cx43 hemichannel activity and Cx43 hemichannel-mediated gliotransmission. Here we assessed the effects of GABA on Cx43 hemichannel activity in DI NCT1 rat astrocytes and hippocampal brain slices. We found that GABA induces a Ca2+-dependent increase in Cx43 hemichannel activity in astrocytes mediated by the GABAA receptor, as it was blunted by the GABAA receptor antagonist bicuculline but unaffected by GABAB receptor antagonist CGP55845. Moreover, GABA induced the Cx43 hemichannel-dependent release of glutamate and ATP, which was also prevented by bicuculline, but unaffected by CGP. Gliotransmission in response to GABA was also unaffected by pannexin 1 channel blockade. These results are discussed in terms of the possible role of astroglial Cx43 hemichannel-mediated glutamate and ATP release in regulating the excitatory/inhibitory balance in the brain and their possible contribution to psychiatric disorders.
Quantitative Analysis of Acetone in Transformer Oil Based on ZnO NPs@Ag NWs SERS Substrates Combined with a Stoichiometric Model
Authors: Zhang Xinyuan , Lei Yu , Song Ruimin , Chen Weigen , Wang Changding , Wang Ziyi , Yin Zhixian , Wan Fu
Published: November 2022

Acetone is an essential indicator for determining the aging of transformer insulation. Rapid, sensitive, and accurate quantification of acetone in transformer oil is highly significant in assessing the aging of oil-paper insulation systems. In this study, silver nanowires modified with small zinc oxide nanoparticles (ZnO NPs@Ag NWs) were excellent surface-enhanced Raman scattering (SERS) substrates and efficiently and sensitively detected acetone in transformer oil. Stoichiometric models such as multiple linear regression (MLR) models and partial least square regressions (PLS) were investigated to quantify acetone in transformer oil and compared with commonly used univariate linear regressions (ULR). PLS combined with a preprocessing algorithm provided the best prediction model, with a correlation coefficient of 0.998251 for the calibration set, 0.997678 for the predictive set, a root mean square error in the calibration set (RMSECV = 0.12596 mg/g), and a prediction set (RMSEP = 0.11408 mg/g). For an acetone solution of 0.003 mg/g, the mean absolute percentage error (MAPE) was the lowest among the three quantitative models. For a concentration of 7.29 mg/g, the MAPE was 1.60%. This method achieved limits of quantification and detections of 0.003 mg/g and 1 μg/g, respectively. In general, these results suggested that ZnO NPs@Ag NWs as SERS substrates coupled with PLS simply and accurately quantified trace acetone concentrations in transformer oil.
Magnetic Multi-Enzymatic System for Cladribine Manufacturing
Authors: Cruz Guillermo , Saiz Laura Pilar , Bilal Muhammad , Eltoukhy Lobna , Loderer Christoph , Fernández-Lucas Jesús
Published: November 2022

Enzyme-mediated processes have proven to be a valuable and sustainable alternative to traditional chemical methods. In this regard, the use of multi-enzymatic systems enables the realization of complex synthetic schemes, while also introducing a number of additional advantages, including the conversion of reversible reactions into irreversible processes, the partial or complete elimination of product inhibition problems, and the minimization of undesirable by-products. In addition, the immobilization of biocatalysts on magnetic supports allows for easy reusability and streamlines the downstream process. Herein we have developed a cascade system for cladribine synthesis based on the sequential action of two magnetic biocatalysts. For that purpose, purine 2′-deoxyribosyltransferase from Leishmania mexicana (LmPDT) and Escherichia coli hypoxanthine phosphoribosyltransferase (EcHPRT) were immobilized onto Ni2+-prechelated magnetic microspheres (MagReSyn®NTA). Among the resulting derivatives, MLmPDT3 (activity: 11,935 IU/gsupport, 63% retained activity, operational conditions: 40 °C and pH 5–7) and MEcHPRT3 (12,840 IU/gsupport, 45% retained activity, operational conditions: pH 5–8 and 40–60 °C) emerge as optimal catalysts for further synthetic application. Moreover, the MLmPDT3/MEcHPRT3 system was biochemically characterized and successfully applied to the one-pot synthesis of cladribine under various conditions. This methodology not only displayed a 1.67-fold improvement in cladribine synthesis (compared to MLmPDT3), but it also implied a practically complete transformation of the undesired by-product into a high-added-value product (90% conversion of Hyp into IMP). Finally, MLmPDT3/MEcHPRT3 was reused for 16 cycles, which displayed a 75% retained activity.
Effects of Biochar and Nitrogen Application on Rice Biomass Saccharification, Bioethanol Yield and Cell Wall Polymers Features
Authors: Ali Izhar , Adnan Muhammad , Iqbal Anas , Ullah Saif , Khan Muhammad , Yuan Pengli , Zhang Hua , Nasar Jamal , Gu Minghua , Jiang Ligeng
Published: November 2022

Rice is a major food crop that produces abundant biomass wastes for biofuels. To improve rice biomass and yield, nitrogen (N) fertilizer is excessively used, which is not eco-friendly. Alternatively, biochar (B) application is favored to improve rice biomass and yield under low chemical fertilizers. To minimize the reliance on N fertilizer, we applied four B levels (0, 10, 20, and 30 t B ha−1) combined with two N rates (low-135 and high-180 kg ha−1) to improve biomass yield. Results showed that compared to control, the combined B at 20–30 t ha−1 with low N application significantly improved plant dry matter and arabinose (Ara%), while decreasing cellulose crystallinity (Crl), degree of polymerization (DP), and the ratio of xylose/arabinose (Xyl/Ara), resulting in high hexoses (% cellulose) and bioethanol yield (% dry matter). We concluded that B coupled with N can alter cell wall polymer features in paddy rice resulting in high biomass saccharification and bioethanol production.
Effects of Two Bacillus Velezensis Microbial Inoculants on the Growth and Rhizosphere Soil Environment of Prunus davidiana
Authors: Shi Huimin , Lu Lanxiang , Ye Jianren , Shi Lina
Published: November 2022

Microbial inoculants, as harmless, efficient, and environmentally friendly plant growth promoters and soil conditioners, are attracting increasing attention. In this study, the effects of Bacillus velezensis YH-18 and B. velezensis YH-20 on Prunus davidiana growth and rhizosphere soil bacterial community in continuously cropped soil were investigated by inoculation tests. The results showed that in a pot seedling experiment, inoculation with YH-18 and YH-20 resulted in a certain degree of increase in diameter growth, plant height, and leaf area at different time periods of 180 days compared with the control. Moreover, after 30 and 90 days of inoculation, the available nutrients in the soil were effectively improved, which protected the continuously cropped soil from acidification. In addition, high-throughput sequencing showed that inoculation with microbial inoculants effectively slowed the decrease in soil microbial richness and diversity over a one-month period. At the phylum level, Proteobacteria and Bacteroidetes were significantly enriched on the 30th day. At the genus level, Sphingomonas and Pseudomonas were significantly enriched at 15 and 30 days, respectively. These bacterial phyla and genera can effectively improve the soil nutrient utilization rate, antagonize plant pathogenic bacteria, and benefit the growth of plants. Furthermore, inoculation with YH-18 and inoculation with YH-20 resulted in similar changes in the rhizosphere microbiome. This study provides a basis for the short-term effect of microbial inoculants on the P. davidiana rhizosphere microbiome and has application value for promoting the cultivation and production of high-quality fruit trees.
E3 Ubiquitin Ligase FBXO3 Drives Neuroinflammation to Aggravate Cerebral Ischemia/Reperfusion Injury
Authors: Gao Yu , Xiao Xinyu , Luo Jing , Wang Jianwei , Peng Qiling , Zhao Jing , Jiang Ning , Zhao Yong
Published: November 2022

Ischemic stroke, one of the most universal causes of human mortality and morbidity, is pathologically characterized by inflammatory cascade, especially during the progression of ischemia/reperfusion (I/R) injury. F-Box Protein 3 (FBXO3), a substrate-recognition subunit of SKP1-cullin 1-F-box protein (SCF) E3 ligase complexes, has recently been proven to be severed as an underlying pro-inflammatory factor in pathological processes of diverse diseases. Given these considerations, the current study aims at investigating whether FBXO3 exerts impacts on inflammation in cerebral I/R injury. In this study, first, it was verified that FBXO3 protein expression increased after a middle cerebral artery occlusion/reperfusion (MCAO/R) model in Sprague–Dawley (SD) rats and was specifically expressed in neurons other than microglia or astrocytes. Meanwhile, in mouse hippocampal neuronal cell line HT22 cells, the elevation of FBXO3 protein was observed after oxygen and glucose deprivation/reoxygenation (OGD/R) treatment. It was also found that interference of FBXO3 with siRNA significantly alleviated neuronal damage via inhibiting the inflammatory response in I/R injury both in vivo and in vitro. The FBXO3 inhibitor BC-1215 was used to confirm the pro-inflammatory effect of FBXO3 in the OGD/R model as well. Furthermore, by administration of FBXO3 siRNA and BC-1215, FBXO3 was verified to reduce the protein level of Homeodomain-Interacting Protein Kinase 2 (HIPK2), likely through the ubiquitin–proteasome system (UPS), to aggravate cerebral I/R injury. Collectively, our results underline the detrimental effect FBXO3 has on cerebral I/R injury by accelerating inflammatory response, possibly through ubiquitylating and degrading HIPK2. Despite the specific interaction between FBXO3 and HIPK2 requiring further study, we believe that our data suggest the therapeutic relevance of FBXO3 to ischemic stroke and provide a new perspective on the mechanism of I/R injury.
Mitochondrial Effects of Common Cardiovascular Medications: The Good, the Bad and the Mixed
Authors: Bețiu Alina M. , Noveanu Lavinia , Hâncu Iasmina M. , Lascu Ana , Petrescu Lucian , Maack Christoph , Elmér Eskil , Muntean Danina M.
Published: November 2022

Mitochondria are central organelles in the homeostasis of the cardiovascular system via the integration of several physiological processes, such as ATP generation via oxidative phosphorylation, synthesis/exchange of metabolites, calcium sequestration, reactive oxygen species (ROS) production/buffering and control of cellular survival/death. Mitochondrial impairment has been widely recognized as a central pathomechanism of almost all cardiovascular diseases, rendering these organelles important therapeutic targets. Mitochondrial dysfunction has been reported to occur in the setting of drug-induced toxicity in several tissues and organs, including the heart. Members of the drug classes currently used in the therapeutics of cardiovascular pathologies have been reported to both support and undermine mitochondrial function. For the latter case, mitochondrial toxicity is the consequence of drug interference (direct or off-target effects) with mitochondrial respiration/energy conversion, DNA replication, ROS production and detoxification, cell death signaling and mitochondrial dynamics. The present narrative review aims to summarize the beneficial and deleterious mitochondrial effects of common cardiovascular medications as described in various experimental models and identify those for which evidence for both types of effects is available in the literature.
Preliminary Expression Analysis of the OSCA Gene Family in Maize and Their Involvement in Temperature Stress
Authors: Li Yuanyang , Zhang Yubin , Li Bin , Hou Liyuan , Yu Jianing , Jia Chengguo , Wang Zhe , Chen Siqi , Zhang Mingzhe , Qin Jianchun , Cao Ning , Cui Jinhu , Shi Wuliang
Published: November 2022

Hyperosmolality-gated calcium-permeable channels (OSCA) are characterized as an osmosensor in plants; they are able to recognize and respond to exogenous and endogenous osmotic changes, and play a vital role in plant growth and adaptability to environmental stress. To explore the potential biological functions of OSCAs in maize, we performed a bioinformatics and expression analysis of the ZmOSCA gene family. Using bioinformatics methods, we identified twelve OSCA genes from the genome database of maize. According to their sequence composition and phylogenetic relationship, the maize OSCA family was classified into four groups (Ⅰ, Ⅱ, Ⅲ, and Ⅳ). Multiple sequence alignment analysis revealed a conserved DUF221 domain in these members. We modeled the calcium binding sites of four OSCA families using the autodocking technique. The expression profiles of ZmOSCA genes were analyzed in different tissues and under diverse abiotic stresses such as drought, salt, high temperature, and chilling using quantitative real-time PCR (qRT-PCR). We found that the expression of twelve ZmOSCA genes is variant in different tissues of maize. Furthermore, abiotic stresses such as drought, salt, high temperature, and chilling differentially induced the expression of twelve ZmOSCA genes. We chose ZmOSCA2.2 and ZmOSCA2.3, which responded most strongly to temperature stress, for prediction of protein interactions. We modeled the calcium binding sites of four OSCA families using autodocking tools, obtaining a number of new results. These results are helpful in understanding the function of the plant OSCA gene family for study of the molecular mechanism of plant osmotic stress and response, as well as exploration of the interaction between osmotic stress, high-temperature stress, and low-temperature stress signal transduction mechanisms. As such, they can provide a theoretical basis for crop breeding.
De Novo Transcriptome Assembly and Analysis of Longevity Genes Using Subterranean Termite (Reticulitermes chinensis) Castes
Authors: Haroon  , Li Yu-Xin , Ye Chen-Xu , Su Jian , Nabi Ghulam , Su Xiao-Hong , Xing Lian-Xi
Published: November 2022

The longevity phenomenon is entirely controlled by the insulin signaling pathway (IIS-pathway). Both vertebrates and invertebrates have IIS-pathways that are comparable to one another, though no one has previously described de novo transcriptome assembly of IIS-pathway-associated genes in termites. In this research, we analyzed the transcriptomes of both reproductive (primary kings “PK” and queens “PQ”, secondary worker reproductive kings “SWRK” and queens “SWRQ”) and non-reproductive (male “WM” and female “WF” workers) castes of the subterranean termite Reticulitermes chinensis. The goal was to identify the genes responsible for longevity in the reproductive and non-reproductive castes. Through transcriptome analysis, we annotated 103,589,264 sequence reads and 184,436 (7G) unigenes were assembled, GC performance was measured at 43.02%, and 64,046 sequences were reported as CDs sequences. Of which 35 IIS-pathway-associated genes were identified, among 35 genes, we focused on the phosphoinositide-dependent kinase-1 (Pdk1), protein kinase B2 (akt2-a), tuberous sclerosis-2 (Tsc2), mammalian target of rapamycin (mTOR), eukaryotic translation initiation factor 4E (EIF4E) and ribosomal protein S6 (RPS6) genes. Previously these genes (Pdk1, akt2-a, mTOR, EIF4E, and RPS6) were investigated in various organisms, that regulate physiological effects, growth factors, protein translation, cell survival, proliferation, protein synthesis, cell metabolism and survival, autophagy, fecundity rate, egg size, and follicle number, although the critical reason for longevity is still unclear in the termite castes. However, based on transcriptome profiling, the IIS-pathway-associated genes could prolong the reproductive caste lifespan and health span. Therefore, the transcriptomic shreds of evidence related to IIS-pathway genes provide new insights into the maintenance and relationships between biomolecular homeostasis and remarkable longevity. Finally, we propose a strategy for future research to decrypt the hidden costs associated with termite aging in reproductive and non-reproductive castes.
Vitamin D-Related Genes and Thyroid Cancer—A Systematic Review
Authors: Maciejewski Adam , Lacka Katarzyna
Published: November 2022

Vitamin D, formerly known for its role in calcium-phosphorus homeostasis, was shown to exert a broad influence on immunity and on differentiation and proliferation processes in the last few years. In the field of endocrinology, there is proof of the potential role of vitamin D and vitamin D-related genes in the pathogenesis of thyroid cancer—the most prevalent endocrine malignancy. Therefore, the study aimed to systematically review the publications on the association between vitamin D-related gene variants (polymorphisms, mutations, etc.) and thyroid cancer. PubMed, EMBASE, Scopus, and Web of Science electronic databases were searched for relevant studies. A total of ten studies were found that met the inclusion criteria. Six vitamin D-related genes were analyzed (VDR—vitamin D receptor, CYP2R1—cytochrome P450 family 2 subfamily R member 1, CYP24A1—cytochrome P450 family 24 subfamily A member 1, CYP27B1—cytochrome P450 family 27 subfamily B member 1, DHCR7—7-dehydrocholesterol reductase and CUBN—cubilin). Moreover, a meta-analysis was conducted to summarize the data from the studies on VDR polymorphisms (rs2228570/FokI, rs1544410/BsmI, rs7975232/ApaI and rs731236/TaqI). Some associations between thyroid cancer risk (VDR, CYP24A1, DHCR7) or the clinical course of the disease (VDR) and vitamin D-related gene polymorphisms were described in the literature. However, these results seem inconclusive and need validation. A meta-analysis of the five studies of common VDR polymorphisms did not confirm their association with increased susceptibility to differentiated thyroid cancer. Further efforts are necessary to improve our understanding of thyroid cancer pathogenesis and implement targeted therapies for refractory cases.
The Amino Acid Permease MoGap1 Regulates TOR Activity and Autophagy in Magnaporthe oryzae
Authors: Huang Changli , Li Lin , Wang Lei , Bao Jiandong , Zhang Xiaozhi , Yan Jiongyi , Wu Jiaqi , Cao Na , Wang Jiaoyu , Zhao Lili , Liu Xiaohong , Yu Xiaoping , Zhu Xueming , Lin Fucheng
Published: November 2022

Rice is an important food crop all over the world. It can be infected by the rice blast fungus Magnaporthe oryzae, which results in a significant reduction in rice yield. The infection mechanism of M. oryzae has been an academic focus for a long time. It has been found that G protein, AMPK, cAMP-PKA, and MPS1-MAPK pathways play different roles in the infection process. Recently, the function of TOR signaling in regulating cell growth and autophagy by receiving nutritional signals generated by plant pathogenic fungi has been demonstrated, but its regulatory mechanism in response to the nutritional signals remains unclear. In this study, a yeast amino acid permease homologue MoGap1 was identified and a knockout mutant of MoGap1 was successfully obtained. Through a phenotypic analysis, a stress analysis, autophagy flux detection, and a TOR activity analysis, we found that the deletion of MoGap1 led to a sporulation reduction as well as increased sensitivity to cell wall stress and carbon source stress in M. oryzae. The ΔMogap1 mutant showed high sensitivity to the TOR inhibitor rapamycin. A Western blot analysis further confirmed that the TOR activity significantly decreased, which improved the level of autophagy. The results suggested that MoGap1, as an upstream regulator of TOR signaling, regulated autophagy and responded to adversities such as cell wall stress by regulating the TOR activity.
Episignature Mapping of TRIP12 Provides Functional Insight into Clark–Baraitser Syndrome
Authors: van der Laan Liselot , Rooney Kathleen , Alders Mariëlle , Relator Raissa , McConkey Haley , Kerkhof Jennifer , Levy Michael A. , Lauffer Peter , Aerden Mio , Theunis Miel , Legius Eric , Tedder Matthew L. , Vissers Lisenka E. L. M. , Koene Saskia , Ruivenkamp Claudia , Hoffer Mariette J. V. , Wieczorek Dagmar , Bramswig Nuria C. , Herget Theresia , González Vanesa López , Santos-Simarro Fernando , Tørring Pernille M. , Denomme-Pichon Anne-Sophie , Isidor Bertrand , Keren Boris , Julia Sophie , Schaefer Elise , Francannet Christine , Maillard Pierre-Yves , Misra-Isrie Mala , Van Esch Hilde , Mannens Marcel M. A. M. , Sadikovic Bekim , van Haelst Mieke M. , Henneman Peter
Published: November 2022

Clark–Baraitser syndrome is a rare autosomal dominant intellectual disability syndrome caused by pathogenic variants in the TRIP12 (Thyroid Hormone Receptor Interactor 12) gene. TRIP12 encodes an E3 ligase in the ubiquitin pathway. The ubiquitin pathway includes activating E1, conjugating E2 and ligating E3 enzymes which regulate the breakdown and sorting of proteins. This enzymatic pathway is crucial for physiological processes. A significant proportion of TRIP12 variants are currently classified as variants of unknown significance (VUS). Episignatures have been shown to represent a powerful diagnostic tool to resolve inconclusive genetic findings for Mendelian disorders and to re-classify VUSs. Here, we show the results of DNA methylation episignature analysis in 32 individuals with pathogenic, likely pathogenic and VUS variants in TRIP12. We identified a specific and sensitive DNA methylation (DNAm) episignature associated with pathogenic TRIP12 variants, establishing its utility as a clinical biomarker for Clark–Baraitser syndrome. In addition, we performed analysis of differentially methylated regions as well as functional correlation of the TRIP12 genome-wide methylation profile with the profiles of 56 additional neurodevelopmental disorders.
Selective Impact of MTMS-Based Xerogel Morphology on Boosted Proliferation and Enhanced Naphthoquinone Production in Cultures of Rindera graeca Transgenic Roots
Authors: Wierzchowski Kamil , Nowak Bartosz , Kawka Mateusz , Więckowicz Patryk , Dąbkowska-Susfał Katarzyna , Pietrosiuk Agnieszka , Sykłowska-Baranek Katarzyna , Pilarek Maciej
Published: November 2022

In situ extraction is a method for separating plant secondary metabolites from in vitro systems of plant biomass cultures. The study aimed to investigate the MTMS-based xerogels morphology effect on the growth kinetics and deoxyshikonin productivity in xerogel-supported in vitro culture systems of Rindera graeca hairy root. Cultures were supplemented with three types of xerogel, i.e., mesoporous gel, microporous gel, and agglomerated precipitate, in the disintegrated or monolithic form. Structure, oil sorption capacity, and SEM analyses for xerogel-based additives were performed. Application of monolithic macroporous xerogel resulted in the highest biomass proliferation, i.e., 5.11-fold fresh biomass increase after four weeks of the screening culture. The highest deoxyshikonin production (i.e., 105.03 µg) was noted when hairy roots were maintained with particles of disintegrated mesoporous xerogel. The detailed kinetics investigations (6-week culture) revealed the highest growth of hairy root biomass and secondary metabolite production, equaling 9.46-fold fresh weight biomass and 204.08 µg deoxyshikonin, respectively. MTMS-based xerogels have been recognized as selective biocompatible scaffolds for boosting the proliferation of transgenic roots or for productivity enhancement of naphthoquinones without detrimental effects on biomass growth, and their successful applicability in in situ removal of secondary plant metabolites has been experimentally confirmed.
Rufinamide, a Triazole-Derived Antiepileptic Drug, Stimulates Ca2+-Activated K+ Currents While Inhibiting Voltage-Gated Na+ Currents
Authors: Lai Ming-Chi , Wu Sheng-Nan , Huang Chin-Wei
Published: November 2022

Rufinamide (RFM) is a clinically utilized antiepileptic drug that, as a triazole derivative, has a unique structure. The extent to which this drug affects membrane ionic currents remains incompletely understood. With the aid of patch clamp technology, we investigated the effects of RFM on the amplitude, gating, and hysteresis of ionic currents from pituitary GH3 lactotrophs. RFM increased the amplitude of Ca2+-activated K+ currents (IK(Ca)) in pituitary GH3 lactotrophs, and the increase was attenuated by the further addition of iberiotoxin or paxilline. The addition of RFM to the cytosolic surface of the detached patch of membrane resulted in the enhanced activity of large-conductance Ca2+-activated K+ channels (BKCa channels), and paxilline reversed this activity. RFM increased the strength of the hysteresis exhibited by the BKCa channels and induced by an inverted isosceles-triangular ramp pulse. The peak and late voltage-gated Na+ current (INa) evoked by rapid step depolarizations were differentially suppressed by RFM. The molecular docking approach suggested that RFM bound to the intracellular domain of KCa1.1 channels with amino acid residues, thereby functionally affecting BKCa channels’ activity. This study is the first to present evidence that, in addition to inhibiting the INa, RFM effectively modifies the IK(Ca), which suggests that it has an impact on neuronal function and excitability.
Ferroptosis Signaling in Pancreatic β-Cells: Novel Insights & Therapeutic Targeting
Authors: Elumalai Suma , Karunakaran Udayakumar , Moon Jun-Sung , Won Kyu-Chang
Published: November 2022

Metabolic stress impairs pancreatic β-cell survival and function in diabetes. Although the pathophysiology of metabolic stress is complex, aberrant tissue damage and β-cell death are brought on by an imbalance in redox equilibrium due to insufficient levels of endogenous antioxidant expression in β-cells. The vulnerability of β-cells to oxidative damage caused by iron accumulation has been linked to contributory β-cell ferroptotic-like malfunction under diabetogenic settings. Here, we take into account recent findings on how iron metabolism contributes to the deregulation of the redox response in diabetic conditions as well as the ferroptotic-like malfunction in the pancreatic β-cells, which may offer insights for deciphering the pathomechanisms and formulating plans for the treatment or prevention of metabolic stress brought on by β-cell failure.
New Drugs and Novel Cellular Targets against Tuberculosis
Authors: Degiacomi Giulia , Makarov Vadim , Pasca Maria Rosalia , Chiarelli Laurent Roberto
Published: November 2022

Mycobacterium tuberculosis (Mtb) is the etiological agent of tuberculosis (TB), one of the most life-threatening communicable diseases, which causes 10 million new cases each year and results in an estimated 1 [...]
Natural IgG against S-Protein and RBD of SARS-CoV-2 Do Not Bind and Hydrolyze DNA and Are Not Autoimmune
Authors: Timofeeva Anna M. , Sedykh Sergey E. , Ermakov Evgeny A. , Matveev Andrey L. , Odegova Eva I. , Sedykh Tatiana A. , Shcherbakov Dmitry N. , Merkuleva Iuliia A. , Volosnikova Ekaterina A. , Nesmeyanova Valentina S. , Tikunova Nina V. , Nevinsky Georgy A.
Published: November 2022

Since the onset of the COVID-19 pandemic, numerous publications have appeared describing autoimmune pathologies developing after a coronavirus infection, with several papers reporting autoantibody production during the acute period of the disease. Several viral diseases are known to trigger autoimmune processes, and the appearance of catalytic antibodies with DNase activity is one of the earliest markers of several autoimmune pathologies. Therefore, we analyzed whether IgG antibodies from blood plasma of SARS-CoV-2 patients after recovery could bind and hydrolyze DNA. We analyzed how vaccination of patients with adenovirus Sputnik V vaccine influences the production of abzymes with DNase activity. Four groups were selected for the analysis, each containing 25 patients according to their relative titers of antibodies to S-protein: with high and median titers, vaccinated with Sputnik V with high titers, and a control group of donors with negative titers. The relative titers of antibodies against DNA and the relative DNase activity of IgGs depended very much on the individual patient and the donor, and no significant correlation was found between the relative values of antibodies titers and their DNase activity. Our results indicate that COVID-19 disease and vaccination with adenoviral Sputnik V vaccine do not result in the development or enhancement of strong autoimmune reactions as in the typical autoimmune diseases associated with the production of anti-DNA and DNA hydrolyzing antibodies.
Post-COVID-19 Syndrome: Retinal Microcirculation as a Potential Marker for Chronic Fatigue
Authors: Schlick Sarah , Lucio Marianna , Wallukat Gerd , Bartsch Alexander , Skornia Adam , Hoffmanns Jakob , Szewczykowski Charlotte , Schröder Thora , Raith Franziska , Rogge Lennart , Heltmann Felix , Moritz Michael , Beitlich Lorenz , Schottenhamml Julia , Herrmann Martin , Harrer Thomas , Ganslmayer Marion , Kruse Friedrich E. , Lämmer Robert , Mardin Christian , Hohberger Bettina
Published: November 2022

Post-COVID-19 syndrome (PCS) is characterized by persisting sequelae after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). PCS can affect patients with all COVID-19 disease severities. As previous studies have revealed impaired blood flow as a provoking factor triggering PCS, it was the aim of the present study to investigate the potential association between self-reported chronic fatigue and retinal microcirculation in patients with PCS, potentially indicating an objective biomarker. A prospective study was performed, including 201 subjects: 173 patients with PCS and 28 controls. Retinal microcirculation was visualized by OCT angiography (OCT-A) and quantified using the Erlangen-Angio-Tool as macula and peripapillary vessel density (VD). Chronic fatigue (CF) was assessed according to the variables of Bell’s score, age and gender. VDs in the superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) were analyzed, considering the repetitions (12 times). Seropositivity for autoantibodies targeting G protein-coupled receptors (GPCR-AAbs) was determined by an established cardiomyocyte bioassay. Taking account of the repetitions, a mixed model was performed to detect possible differences in the least square means between the different groups included in the analysis. An age effect in relation to VD was observed between patients and controls (p < 0.0001). Gender analysis showed that women with PCS showed lower VD levels in the SVP compared to male patients (p = 0.0015). The PCS patients showed significantly lower VDs in the ICP as compared to the controls (p = 0.0001 (CI: 0.32; 1)). Moreover, considering PCS patients, the mixed model revealed a significant difference between those with chronic fatigue (CF) and those without CF with respect to VDs in the SVP (p = 0.0033 (CI: −4.5; −0.92)). The model included variables of age, gender and Bell’s score, representing a subjective marker for CF. Consequently, retinal microcirculation might serve as an objective biomarker in subjectively reported chronic fatigue in patients with PCS.
Neural Crest Development in Health and Disease
Authors: Pilon Nicolas
Published: November 2022

The first volume of this Special Issue met its goal of covering several aspects regarding both the normal and abnormal development of neural crest cells, which form a truly unique multipotent and highly migratory cell population that only exists in vertebrates [...]
Nanobodies for the Early Detection of Ovarian Cancer
Authors: Tran Lan-Huong , Graulus Geert-Jan , Vincke Cécile , Smiejkowska Natalia , Kindt Anne , Devoogdt Nick , Muyldermans Serge , Adriaensens Peter , Guedens Wanda
Published: November 2022

Ovarian cancer ranks fifth in cancer-related deaths among women. Since ovarian cancer patients are often asymptomatic, most patients are diagnosed only at an advanced stage of disease. This results in a 5-year survival rate below 50%, which is in strong contrast to a survival rate as high as 94% if detected and treated at an early stage. Monitoring serum biomarkers offers new possibilities to diagnose ovarian cancer at an early stage. In this study, nanobodies targeting the ovarian cancer biomarkers human epididymis protein 4 (HE4), secretory leukocyte protease inhibitor (SLPI), and progranulin (PGRN) were evaluated regarding their expression levels in bacterial systems, epitope binning, and antigen-binding affinity by enzyme-linked immunosorbent assay and surface plasmon resonance. The selected nanobodies possess strong binding affinities for their cognate antigens (KD~0.1–10 nM) and therefore have a pronounced potential to detect ovarian cancer at an early stage. Moreover, it is of utmost importance that the limits of detection (LOD) for these biomarkers are in the pM range, implying high specificity and sensitivity, as demonstrated by values in human serum of 37 pM for HE4, 163 pM for SLPI, and 195 pM for PGRN. These nanobody candidates could thus pave the way towards multiplexed biosensors.
Insights into the Orchestration of Gene Transcription Regulators in Helicobacter pylori
Authors: Vannini Andrea , Roncarati Davide , D’Agostino Federico , Antoniciello Federico , Scarlato Vincenzo
Published: November 2022

Bacterial pathogens employ a general strategy to overcome host defenses by coordinating the virulence gene expression using dedicated regulatory systems that could raise intricate networks. During the last twenty years, many studies of Helicobacter pylori, a human pathogen responsible for various stomach diseases, have mainly focused on elucidating the mechanisms and functions of virulence factors. In parallel, numerous studies have focused on the molecular mechanisms that regulate gene transcription to attempt to understand the physiological changes of the bacterium during infection and adaptation to the environmental conditions it encounters. The number of regulatory proteins deduced from the genome sequence analyses responsible for the correct orchestration of gene transcription appears limited to 14 regulators and three sigma factors. Furthermore, evidence is accumulating for new and complex circuits regulating gene transcription and H. pylori virulence. Here, we focus on the molecular mechanisms used by H. pylori to control gene transcription as a function of the principal environmental changes.
Deciphering the Roles & Regulation of Estradiol Signaling during Female Mini-Puberty: Insights from Mouse Models
Authors: Devillers Marie M. , Mhaouty-Kodja Sakina , Guigon Céline J.
Published: November 2022

Mini-puberty of infancy is a short developmental phase occurring in humans and other mammals after birth. In females, it corresponds to transient and robust activation of the hypothalamo-pituitary-ovarian (HPO) axis revealed by high levels of gonadotropin hormones, follicular growth, and increased estradiol production by the ovary. The roles of estradiol signaling during this intriguing developmental phase are not yet well known, but accumulating data support the idea that it aids in the implementation of reproductive function. This review aims to provide in-depth information on HPO activity during this particular developmental phase in several mammal species, including humans, and to propose emerging hypotheses on the putative effect of estradiol signaling on the development and function of organs involved in female reproduction.
Recruiting Immunity for the Fight against Colorectal Cancer: Current Status and Challenges
Authors: Al-Hujaily Ensaf M. , Al-Sowayan Batla S. , Alyousef Zeyad , Uddin Shahab , Alammari Farah
Published: November 2022

Cancer immunotherapies have changed the landscape of cancer management and improved the standard treatment protocols used in multiple tumors. This has led to significant improvements in progression-free survival and overall survival rates. In this review article, we provide an insight into the major immunotherapeutic methods that are currently under investigation for colorectal cancer (CRC) and their clinical implementations. We emphasize therapies that are based on monoclonal antibodies (mAbs) and adoptive cell therapy, their mechanisms of action, their advantages, and their potential in combination therapy. We also highlight the clinical trials that have demonstrated both the therapeutic efficacy and the toxicities associated with each method. In addition, we summarize emerging targets that are now being evaluated as potential interventions for CRC. Finally, we discuss current challenges and future direction for the cancer immunotherapy field.
Synthesis of an Anti-CD7 Recombinant Immunotoxin Based on PE24 in CHO and E. coli Cell-Free Systems
Authors: Krebs Simon K. , Stech Marlitt , Jorde Felix , Rakotoarinoro Nathanaël , Ramm Franziska , Marinoff Sophie , Bahrke Sven , Danielczyk Antje , Wüstenhagen Doreen A. , Kubick Stefan
Published: November 2022

Recombinant immunotoxins (RITs) are an effective class of agents for targeted therapy in cancer treatment. In this article, we demonstrate the straight-forward production and testing of an anti-CD7 RIT based on PE24 in a prokaryotic and a eukaryotic cell-free system. The prokaryotic cell-free system was derived from Escherichia coli BL21 StarTM (DE3) cells transformed with a plasmid encoding the chaperones groEL/groES. The eukaryotic cell-free system was prepared from Chinese hamster ovary (CHO) cells that leave intact endoplasmic reticulum-derived microsomes in the cell-free reaction mix from which the RIT was extracted. The investigated RIT was built by fusing an anti-CD7 single-chain variable fragment (scFv) with the toxin domain PE24, a shortened variant of Pseudomonas Exotoxin A. The RIT was produced in both cell-free systems and tested for antigen binding against CD7 and cell killing on CD7-positive Jurkat, HSB-2, and ALL-SIL cells. CD7-positive cells were effectively killed by the anti-CD7 scFv-PE24 RIT with an IC50 value of 15 pM to 40 pM for CHO and 42 pM to 156 pM for E. coli cell-free-produced RIT. CD7-negative Raji cells were unaffected by the RIT. Toxin and antibody domain alone did not show cytotoxic effects on either CD7-positive or CD7-negative cells. To our knowledge, this report describes the production of an active RIT in E. coli and CHO cell-free systems for the first time. We provide the proof-of-concept that cell-free protein synthesis allows for on-demand testing of antibody–toxin conjugate activity in a time-efficient workflow without cell lysis or purification required.
Antipsychotic Drug-Mediated Adverse Effects on Rat Testicles May Be Caused by Altered Redox and Hormonal Homeostasis
Authors: Nikolić-Kokić Aleksandra , Tatalović Nikola , Brkljačić Jelena , Mijović Milica , Nestorović Vojkan , Mijušković Ana , Oreščanin-Dušić Zorana , Vidonja Uzelac Teodora , Nikolić Milan , Spasić Snežana , Blagojević Duško , Miljević Čedo
Published: November 2022

Sexual dysfunction, as a noticeable adverse effect of atypical antipsychotic drugs (APDs) for the treatment of schizophrenia, has not been investigated in detail. A study was undertaken to investigate whether 28-day long treatment with clozapine, ziprasidone or sertindole (using a recommended daily dose for atypical antipsychotic therapy), induced histopathological changes both in rat testicles and prostate, changed the activity of the antioxidant defence system and altered blood testosterone and prolactin. Clozapine, ziprasidone and sertindole induced histopathological changes in rat testicular tissue, which could be attributed to a disturbed testicular antioxidant defence system in addition to an altered prolactin to testosterone ratio. None of the APD treatments induced histopathological changes in prostate. Our results demonstrate that APDs have the capacity to change both redox and endocrinological balance. One or both outcomes could underline testicular degeneration and disturbed spermatogenesis.
Myostatin Knockout Affects Mitochondrial Function by Inhibiting the AMPK/SIRT1/PGC1α Pathway in Skeletal Muscle
Authors: Gu Mingjuan , Wei Zhuying , Wang Xueqiao , Gao Yang , Wang Dong , Liu Xuefei , Bai Chunling , Su Guanghua , Yang Lei , Li Guangpeng
Published: November 2022

Myostatin (Mstn) is a major negative regulator of skeletal muscle mass and initiates multiple metabolic changes. The deletion of the Mstn gene in mice leads to reduced mitochondrial functions. However, the underlying regulatory mechanisms remain unclear. In this study, we used CRISPR/Cas9 to generate myostatin-knockout (Mstn-KO) mice via pronuclear microinjection. Mstn-KO mice exhibited significantly larger skeletal muscles. Meanwhile, Mstn knockout regulated the organ weights of mice. Moreover, we found that Mstn knockout reduced the basal metabolic rate, muscle adenosine triphosphate (ATP) synthesis, activities of mitochondrial respiration chain complexes, tricarboxylic acid cycle (TCA) cycle, and thermogenesis. Mechanistically, expressions of silent information regulator 1 (SIRT1) and phosphorylated adenosine monophosphate-activated protein kinase (pAMPK) were down-regulated, while peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) acetylation modification increased in the Mstn-KO mice. Skeletal muscle cells from Mstn-KO and WT were treated with AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR), and the AMPK inhibitor Compound C, respectively. Compared with the wild-type (WT) group, Compound C treatment further down-regulated the expression or activity of pAMPK, SIRT1, citrate synthase (CS), isocitrate dehydrogenase (ICDHm), and α-ketoglutarate acid dehydrogenase (α-KGDH) in Mstn-KO mice, while Mstn knockout inhibited the AICAR activation effect. Therefore, Mstn knockout affects mitochondrial function by inhibiting the AMPK/SIRT1/PGC1α signaling pathway. The present study reveals a new mechanism for Mstn knockout in regulating energy homeostasis.
Therapeutic and Metagenomic Potential of the Biomolecular Therapies against Periodontitis and the Oral Microbiome: Current Evidence and Future Perspectives
Authors: Santonocito Simona , Ferlito Salvatore , Polizzi Alessandro , Ronsivalle Vincenzo , Sclafani Rossana , Valletta Alessandra , Lo Giudice Antonino , Cavalcanti Raffaele , Spagnuolo Gianrico , Isola Gaetano
Published: November 2022

The principles of periodontal therapy are based on the control of microbial pathogens and host factors that contribute to biofilm dysbiosis, with the aim of modulating the progression of periodontitis and periodontal tissue destruction. It is currently known how differently each individual responds to periodontal treatment, depending on both the bacterial subtypes that make up the dysbiotic biofilm and interindividual variations in the host inflammatory response. This has allowed the current variety of approaches for the management of periodontitis to be updated by defining the goals of target strategies, which consist of reducing the periodontopathogenic microbial flora and/or modulating the host-mediated response. Therefore, this review aims to update the current variety of approaches for the management of periodontitis based on recent target therapies. Recently, encouraging results have been obtained from several studies exploring the effects of some targeted therapies in the medium- and long-term. Among the most promising target therapies analyzed and explored in this review include: cell-based periodontal regeneration, mediators against bone resorption, emdogain (EMD), platelet-rich plasma, and growth factors. The reviewed evidence supports the hypothesis that the therapeutic combination of epigenetic modifications of periodontal tissues, interacting with the dysbiotic biofilm, is a key step in significantly reducing the development and progression of disease in periodontal patients and improving the therapeutic response of periodontal patients. However, although studies indicate promising results, these need to be further expanded and studied to truly realize the benefits that targeted therapies could bring in the treatment of periodontitis.
Design of Hierarchically Tailored Hybrids Based on Nickle Nanocrystal-Decorated Manganese Dioxides for Enhanced Fire Safety of Epoxy Resin
Authors: Yuan Yao , Liang Chen , Yuen Anthony Chun Yin , Xu Lulu , Yu Bin , Cao Chengfei , Wang Wei
Published: November 2022

A novel and hierarchical hybrid composite (MnO2@CHS@SA@Ni) was synthesized utilizing manganese dioxide (MnO2) nanosheets as the core structure, self-assembly chitosan (CHS), sodium alginate (SA) and nickel species (Ni) as surface layers, and it was further incorporated into an epoxy matrix for achieving fire hazard suppression via surface self-assembly technology. Herein, the resultant hybrid epoxy composite possessed an exceptional nano-barrier and synergistic charring effect to aid the formation of a compact layered structure that enhanced its fire-resistive effectiveness. As a result, the addition of only 2 wt% MnO2@CHS@SA@Ni hybrids led to a dramatic reduction in the peak heat release rate and total heat release values (by ca. 33% and 27.8%) of the epoxy matrix. Notably, the peak smoke production rate and total smoke production values of EP/MnO2@CHS@SA@Ni 2% were decreased by ca. 16.9 and 38.4% compared to the corresponding data of pristine EP. This was accompanied by the suppression of toxic CO, NO release and the diffusion of thermal pyrolysis gases during combustion through TG-IR results. Overall, a significant fire-testing outcome of the proposed hierarchical structure was proven to be effective for epoxy composites in terms of flammability, smoke and toxicity reductions, optimizing their prospects in other polymeric materials in the respective fields.
Genome-Wide Comparison of Structural Variations and Transposon Alterations in Soybean Cultivars Induced by Spaceflight
Authors: Jin Hangxia , Fu Xujun , Yu Xiaomin , Zhu Longming , Yang Qinghua , Yuan Fengjie
Published: November 2022

Space mutation causes genetic and phenotypic changes in biological materials. Transposon activation is an adaptive mechanism for organisms to cope with changes in the external environment, such as space mutation. Although transposon alterations have been widely reported in diverse plant species, few studies have assessed the global transposon alterations in plants exposed to the space environment. In this study, for the first time, the effects of transposon alterations in soybean caused by space mutation were considered. A new vegetable soybean variety, ‘Zhexian 9’ (Z9), derived from space mutation treatment of ‘Taiwan 75’ (T75), was genetically analyzed. Comparative analyses of these two soybean genomes uncovered surprising structural differences, especially with respect to translocation breakends, deletions, and inversions. In total, 12,028 structural variations (SVs) and 29,063 transposable elements (TEs) between T75 and Z9 were detected. In addition, 1336 potential genes were variable between T75 and Z9 in terms of SVs and TEs. These differential genes were enriched in functions such as defense response, cell wall-related processes, epigenetics, auxin metabolism and transport, signal transduction, and especially methylation, which implied that regulation of epigenetic mechanisms and TE activity are important in the space environment. These results are helpful for understanding the role of TEs in response to the space environment and provide a theoretical basis for the selection of wild plant materials suitable for space breeding.