bluuebunny/crossref_metadata_2025 huggingface dataset:
The Worldview Sources of Bashkir Theater
Authors:   Ufa State Institute of Arts named after Zagir Ismagilov, Sagitova Aisylu S.
Published: January 2021

The art of the Bashkir people, similarly to the art of all the peoples of the world, emerged in very early historical times and has its unique roots, which lead us into those remote times when the Bashkirs worshiped pagan gods, and all of their life was that of service to natural elements. These were the times when the great epos “Ural-batyr” was created, which in many ways has conditioned the worldview and world-perception of the Bashkir people during the course of many centuries. Particularly in the epic character of this work and in its pure, unadulterated, direct pathos lies the key to the romantically elevated Bashkir performing art. Frequently even presently, in the technological age of all-pervading mercenary self-interest, cold rationality and unlimited irony in national theater, in some performances a special style of pronunciation of the text as a type of epic singing is preserved. In any of the productions carried out by the Bashkir State Mazhit Gafuri Academic Theater of Drama — whether it be national, Russian or Western European classics or relevant contemporary dramaturgy — it always has the sound of the unusual, original, elevated, melodic, poetical intonation of speech, characteristic only to the Bashkir language. This peculiar intonation is an integral part (ancient, mythological, and archetypical) of the Bashkir consciousness and its product — the Bashkir language, in its sound and melody reminding heroic chants: strict, measured, not restless, maybe, at times harsh and at the same time soft. The language is an invaluable repository of people’s ancient culture and history. The Bashkir art of theatrical performance, which aspires towards capacious relief forms, parabolic, profound plot-generating meanings and epic melodiousness, is in many ways determined particularly by its mythological world perception. The latter is genetically intrinsic to the Bashkir people and is perceived by them as “a genuine and maximally concrete reality”. The worldview sources and folklore traditions make it possible for the Bashkir people to preserve their face and, keeping up with the time, to orient themselves on folklore traditions as the measure of things and the reference point in the constantly changing contemporary world. Therein is contained the unique sense of motion and development of the Bashkir theater: to be con-temporary (in tune with the times), but to base itself on the timeless and the eternal.
Specific Features of Festive Culture in Modern China
Authors:   School of Arts and Humanities of the Far Eastern Federal University, Artashkina Tamara A. , Shang Bofei ,   School of Arts and Humanities of the Far Eastern Federal University
Published: January 2021

The history of XX-century China can be divided into several periods that greatly altered the path of China’s historical development: Xinhai Revolution, Anti-Japanese war, civil war, establishment of PRC, Cultural Revolution, policy of reforms and openness. Uneven development of contemporary China has had its influence on Chinese holidays. The authors consider the concept of “national holidays of China” a basic category. In the Chinese language, a “holiday” is an unusual day or days connected with something. All national Chinese holidays fall into two categories: government and popular. Chinese government holidays include official holidays established by law; they are days-off for all Chinese citizens. Currently there are 7 government holidays in China and many popular holidays. Popular holidays include traditional holidays, occupational or social holidays, holidays of national minorities or others. Not all Chinese citizens have days-off during these popular holidays. There are two aspects of cultural problems in modern China: a big gap between urban culture and rural cultures; there is a problem of active borrowing and introduction of Western culture into the national culture of China. In particular, many western holidays have intervened into the tissue of Chinese culture. However, western holidays do not alter the cultural meaning of Chinese traditional holidays; they have acquired Chinese features and enriched the life of young Chinese people. Chinese festive culture is transformed within the following areas: traditional holidays are replaced with innovative ones; modern holidays are formed under the influence of new social and political conditions and cultural globalization; transformation of traditional holidays changes either their quantity or their content and cultural meaning. However, the authors have come to the conclusion that despite the transformational processes the cultural meaning and main cultural functions of traditional holidays are preserved: reunion of families and, hence, the reunion of the whole nation.
Gold Nanoparticles Combined Human β-Defensin 3 Gene-Modified Human Periodontal Ligament Cells Alleviate Periodontal Destruction via the p38 MAPK Pathway
Authors: Li Lingjun , Zhang Yangheng , Wang Min , Zhou Jing , Zhang Qian , Yang Wenrong , Li Yanfen , Yan Fuhua
Published: January 2021

Periodontitis is a chronic inflammatory disease with plaques as the initiating factor, which will induce the destruction of periodontal tissues. Numerous studies focused on how to obtain periodontal tissue regeneration in inflammatory environments. Previous studies have reported adenovirus-mediated human β-defensin 3 (hBD3) gene transfer could potentially enhance the osteogenic differentiation of human periodontal ligament cells (hPDLCs) and bone repair in periodontitis. Gold nanoparticles (AuNPs), the ideal inorganic nanomaterials in biomedicine applications, were proved to have synergetic effects with gene transfection. To further observe the potential promoting effects, AuNPs were added to the transfected cells. The results showed the positive effects of osteogenic differentiation while applying AuNPs into hPDLCs transfected by adenovirus encoding hBD3 gene. In vivo, after rat periodontal ligament cell (rPDLC) transplantation into SD rats with periodontitis, AuNPs combined hBD3 gene modification could also promote periodontal regeneration. The p38 mitogen-activated protein kinase (MAPK) pathway was demonstrated to potentially regulate both the in vitro and in vivo processes. In conclusion, AuNPs can promote the osteogenic differentiation of hBD3 gene-modified hPDLCs and periodontal regeneration via the p38 MAPK pathway.
Haspin Modulates the G2/M Transition Delay in Response to Polarization Failures in Budding Yeast
Authors: Galli Martina , Diani Laura , Quadri Roberto , Nespoli Alessandro , Galati Elena , Panigada Davide , Plevani Paolo , Muzi-Falconi Marco
Published: January 2021

Symmetry breaking by cellular polarization is an exquisite requirement for the cell-cycle of Saccharomyces cerevisiae cells, as it allows bud emergence and growth. This process is based on the formation of polarity clusters at the incipient bud site, first, and the bud tip later in the cell-cycle, that overall promote bud emission and growth. Given the extreme relevance of this process, a surveillance mechanism, known as the morphogenesis checkpoint, has evolved to coordinate the formation of the bud and cell cycle progression, delaying mitosis in the presence of morphogenetic problems. The atypical protein kinase haspin is responsible for histone H3-T3 phosphorylation and, in yeast, for resolution of polarity clusters in mitosis. Here, we report a novel role for haspin in the regulation of the morphogenesis checkpoint in response to polarity insults. Particularly, we show that cells lacking the haspin ortholog Alk1 fail to achieve sustained checkpoint activation and enter mitosis even in the absence of a bud. In alk1Δ cells, we report a reduced phosphorylation of Cdc28-Y19, which stems from a premature activation of the Mih1 phosphatase. Overall, the data presented in this work define yeast haspin as a novel regulator of the morphogenesis checkpoint in Saccharomyces cerevisiae, where it monitors polarity establishment and it couples bud emergence to the G2/M cell cycle transition.
The Role of TRP Channels and PMCA in Brain Disorders: Intracellular Calcium and pH Homeostasis
Authors: Hwang Sung-Min , Lee Ji Yeon , Park Chul-Kyu , Kim Yong Ho
Published: January 2021

Brain disorders include neurodegenerative diseases (NDs) with different conditions that primarily affect the neurons and glia in the brain. However, the risk factors and pathophysiological mechanisms of NDs have not been fully elucidated. Homeostasis of intracellular Ca2+ concentration and intracellular pH (pHi) is crucial for cell function. The regulatory processes of these ionic mechanisms may be absent or excessive in pathological conditions, leading to a loss of cell death in distinct regions of ND patients. Herein, we review the potential involvement of transient receptor potential (TRP) channels in NDs, where disrupted Ca2+ homeostasis leads to cell death. The capability of TRP channels to restore or excite the cell through Ca2+ regulation depending on the level of plasma membrane Ca2+ ATPase (PMCA) activity is discussed in detail. As PMCA simultaneously affects intracellular Ca2+ regulation as well as pHi, TRP channels and PMCA thus play vital roles in modulating ionic homeostasis in various cell types or specific regions of the brain where the TRP channels and PMCA are expressed. For this reason, the dysfunction of TRP channels and/or PMCA under pathological conditions disrupts neuronal homeostasis due to abnormal Ca2+ and pH levels in the brain, resulting in various NDs. This review addresses the function of TRP channels and PMCA in controlling intracellular Ca2+ and pH, which may provide novel targets for treating NDs.
Excessive All-Trans Retinoic Acid Inhibits Cell Proliferation Through Upregulated MicroRNA-4680-3p in Cultured Human Palate Cells
Authors: Yoshioka Hiroki , Ramakrishnan Sai Shankar , Shim Junbo , Suzuki Akiko , Iwata Junichi
Published: January 2021

Cleft palate is the second most common congenital birth defect, and both environmental and genetic factors are involved in the etiology of the disease. However, it remains largely unknown how environmental factors affect palate development. Our previous studies show that several microRNAs (miRs) suppress the expression of genes involved in cleft palate. Here we show thatmiR-4680-3pplays a crucial role in cleft palate pathogenesis. We found thatall-transretinoic acid (atRA) specifically inducesmiR-4680-3pin cultured human embryonic palatal mesenchymal (HEPM) cells. Overexpression ofmiR-4680-3pinhibited cell proliferation in a dose-dependent manner through the suppression of expression ofERBB2andJADE1, which are known cleft palate-related genes. Importantly, amiR-4680-3p-specific inhibitor normalized cell proliferation and altered expression ofERBB2andJADE1in cells treated withatRA. Taken together, our results suggest that upregulation ofmiR-4680-3pinduced byatRA may cause cleft palate through suppression ofERBB2andJADE1. Thus, miRs may be potential targets for the prevention and diagnosis of cleft palate.
Functional Non-coding RNA During Embryonic Myogenesis and Postnatal Muscle Development and Disease
Authors: Luo Hongmei , Lv Wei , Tong Qian , Jin Jianjun , Xu Zaiyan , Zuo Bo
Published: January 2021

Skeletal muscle is a highly heterogeneous tissue that plays a crucial role in mammalian metabolism and motion maintenance. Myogenesis is a complex biological process that includes embryonic and postnatal development, which is regulated by specific signaling pathways and transcription factors. Various non-coding RNAs (ncRNAs) account for the majority of total RNA in cells and have an important regulatory role in myogenesis. In this review, we introduced the research progress in miRNAs, circRNAs, and lncRNAs related to embryonic and postnatal muscle development. We mainly focused on ncRNAs that regulate myoblast proliferation, differentiation, and postnatal muscle development through multiple mechanisms. Finally, challenges and future perspectives related to the identification and verification of functional ncRNAs are discussed. The identification and elucidation of ncRNAs related to myogenesis will enrich the myogenic regulatory network, and the effective application of ncRNAs will enhance the function of skeletal muscle.
Arabidopsis ADF5 Acts as a Downstream Target Gene of CBFs in Response to Low-Temperature Stress
Authors: Zhang Pan , Qian Dong , Luo Changxin , Niu Yingzhi , Li Tian , Li Chengying , Xiang Yun , Wang Xinyu , Niu Yue
Published: January 2021

Low temperature is a major adverse environment that affects normal plant growth. Previous reports showed that the actin cytoskeleton plays an important role in the plant response to low-temperature stress, but the regulatory mechanism of the actin cytoskeleton in this process is not clear. C-repeat binding factors (CBFs) are the key molecular switches for plants to adapt to cold stress. However, whether CBFs are involved in the regulation of the actin cytoskeleton has not been reported. We found that Arabidopsis actin depolymerizing factor 5 (ADF5), an ADF that evolved F-actin bundling function, was up-regulated at low temperatures. We also demonstrated that CBFs bound to the ADF5 promoter directly in vivo and in vitro. The cold-induced expression of ADF5 was significantly inhibited in the cbfs triple mutant. The freezing resistance of the adf5 knockout mutant was weaker than that of wild type (WT) with or without cold acclimation. After low-temperature treatment, the actin cytoskeleton of WT was relatively stable, but the actin cytoskeletons of adf5, cbfs, and adf5 cbfs were disturbed to varying degrees. Compared to WT, the endocytosis rate of the amphiphilic styryl dye FM4-64 in adf5, cbfs, and adf5 cbfs at low temperature was significantly reduced. In conclusion, CBFs directly combine with the CRT/DRE DNA regulatory element of the ADF5 promoter after low-temperature stress to transcriptionally activate the expression of ADF5; ADF5 further regulates the actin cytoskeleton dynamics to participate in the regulation of plant adaptation to a low-temperature environment.
Tetradecanoic Acids With Anti-Virulence Properties Increase the Pathogenicity of Pseudomonas aeruginosa in a Murine Cutaneous Infection Model
Authors: Juárez-Rodríguez Martha María , Cortes-López Humberto , García-Contreras Rodolfo , González-Pedrajo Bertha , Díaz-Guerrero Miguel , Martínez-Vázquez Mariano , Rivera-Chávez José Alberto , Soto-Hernández Ramón Marcos , Castillo-Juárez Israel
Published: January 2021

Blocking virulence is a promising alternative to counteract Pseudomonas aeruginosa infections. In this regard, the phenomenon of cell-cell communication by quorum sensing (QS) is an important anti-virulence target. In this field, fatty acids (FA) have gained notoriety for their role as autoinducers, as well as anti-virulence molecules in vitro, like some saturated FA (SAFA). In this study, we analyzed the anti-virulence activity of SAFA with 12 to18 carbon atoms and compared their effect with the putative autoinducer cis-2-decenoic acid (CDA). The effect of SAFA on six QS-regulated virulence factors and on the secretion of the exoenzyme ExoU was evaluated. In addition, a murine cutaneous infection model was used to determine their influence on the establishment and damage caused by P. aeruginosa PA14. Dodecanoic (lauric, C12:0) and tetradecanoic (myristic, C14:0) acids (SAFA C12-14) reduced the production of pyocyanin by 35–58% at 40 and 1,000 µM, while CDA inhibited it 62% at a 3.1 µM concentration. Moreover, the SAFA C12-14 reduced swarming by 90% without affecting biofilm formation. In contrast, CDA reduced the biofilm by 57% at 3 µM but did not affect swarming. Furthermore, lauric and myristic acids abolished ExoU secretion at 100 and 50 µM respectively, while CDA reduced it by ≈ 92% at 100 µM. Remarkably, the coadministration of myristic acid (200 and 1,000 µM) with P. aeruginosa PA14 induced greater damage and reduced survival of the animals up to 50%, whereas CDA to 500 µM reduced the damage without affecting the viability of the PA14 strain. Hence, our results show that SAFA C12-14 and CDA have a role in regulation of P. aeruginosa virulence, although their inhibition/activation molecular mechanisms are different in complex environments such as in vivo systems.
Immunomodulatory Approaches in Diabetes-Induced Cardiorenal Syndromes
Authors: Ammar Lama A. , Nahlawi Mohamad I. , Shayya Nizar W. , Ghadieh Hilda E. , Azar Nadim S. , Harb Frédéric , Eid Assaad A.
Published: January 2021

Immunomodulatory approaches are defined as all interventions that modulate and curb the immune response of the host rather than targeting the disease itself with the aim of disease prevention or treatment. A better understanding of the immune system continues to offer innovative drug targets and methods for immunomodulatory interventions. Cardiorenal syndrome is a clinical condition that defines disorders of the heart and kidneys, both of which communicate with one another through multiple pathways in an interdependent relationship. Cardiorenal syndrome denotes the confluence of heart-kidney relationships across numerous interfaces. As such, a dysfunctional heart or kidney has the capacity to initiate disease in the other organ via common hemodynamic, neurohormonal, immunological, and/or biochemical feedback pathways. Understanding how immunomodulatory approaches are implemented in diabetes-induced cardiovascular and renal diseases is important for a promising regenerative medicine, which is the process of replacing cells, tissues or organs to establish normal function. In this article, after a brief introduction on the immunomodulatory approaches in diseases, we will be reviewing the epidemiology and classifications of cardiorenal syndrome. We will be emphasizing on the hemodynamic factors and non-hemodynamic factors linking the heart and the kidneys. In addition, we will be elaborating on the immunomodulatory pathways involved in diabetes-induced cardiorenal syndrome namely, RAS, JAK/STAT, and oxidative stress. Moreover, we will be addressing possible therapeutic approaches that target the former pathways in an attempt to modulate the immune system.
Clustering of Experimental Seismo-Acoustic Events Using Self-Organizing Map (SOM)
Authors: Giudicepietro Flora , Esposito Antonietta M. , Spina Laura , Cannata Andrea , Morgavi Daniele , Layer Lukas , Macedonio Giovanni
Published: January 2021

The analogue experiments that produce seismo-acoustic events are relevant for understanding the degassing processes of a volcanic system. The aim of this work is to design an unsupervised neural network for clustering experimental seismo-acoustic events in order to investigate the possible cause-effect relationships between the obtained signals and the processes. We focused on two tasks: 1) identify an appropriate strategy for parameterizing experimental seismo-acoustic events recorded during analogue experiments devoted to the study of degassing behavior at basaltic volcanoes; 2) define the set up of the selected neural network, the Self-Organizing Map (SOM), suitable for clustering the features extracted from the experimental events. The seismo-acoustic events were generated using an ad hoc experimental setup under different physical conditions of the analogue magma (variable viscosity), injected gas flux (variable flux velocity) and conduit surface (variable surface roughness). We tested the SOMs ability to group the experimental seismo-acoustic events generated under controlled conditions and conduit geometry of the analogue volcanic system. We used 616 seismo-acoustic events characterized by different analogue magma viscosity (10, 100, 1000 Pa s), gas flux (5, 10, 30, 60, 90, 120, 150, 180 × 10−3 l/s) and conduit roughness (i.e. different fractal dimension corresponding to 2, 2.18, 2.99). We parameterized the seismo-acoustic events in the frequency domain by applying the Linear Predictive Coding to both accelerometric and acoustic signals generated by the dynamics of various degassing regimes, and in the time domain, applying a waveform function. Then we applied the SOM algorithm to cluster the feature vectors extracted from the seismo-acoustic data through the parameterization phase, and identified four main clusters. The results were consistent with the experimental findings on the role of viscosity, flux velocity and conduit roughness on the degassing regime. The neural network is capable to separate events generated under different experimental conditions. This suggests that the SOM is appropriate for clustering natural events such as the seismo-acoustic transients accompanying Strombolian explosions and that the adopted parameterization strategy may be suitable to extract the significant features of the seismo-acoustic (and/or infrasound) signals linked to the physical conditions of the volcanic system.
Levothyroxine Therapy in Gastric Malabsorptive Disorders
Authors: Virili Camilla , Brusca Nunzia , Capriello Silvia , Centanni Marco
Published: January 2021

Oral levothyroxine sodium is absorbed in the small intestine, mainly in the jejunum and the ileum being lower the absorption rate at duodenal level. The time interval between the ingestion of oral thyroxine and its appearance in the plasma renders unlike a gastric absorption of the hormone. However, several evidence confirm the key role of the stomach as a prerequisite for an efficient absorption of oral levothyroxine. In the stomach, in fact, occur key steps leading to the dissolution of thyroxine from the solid form, the process bringing the active ingredient from the pharmaceutical preparation to the aqueous solution. In particular, gastric juice pH, volume, viscosity, as well as gastric emptying time seem to be the most important limiting factors. These hypotheses are confirmed by the detection of an increased need for levothyroxine in patients with Helicobacter pylori infection, chronic atrophic gastritis, gastroparesis, or in simultaneous treatment with drugs interfering with gastric acidic output. The aim of the present article is to focus on the knowledge of pathophysiologic events that determine the absorptive fate of traditional (tablet) and alternative thyroxine preparations (softgel capsule and liquid solution) in patients bearing gastric disorders.
Can Overgrazing Responses Be Disentangled by Above- and Below-Ground Traits?
Authors: Zhang Hui , He Qifang , Pandey Shree Prakash , Jiang Kai , Wang Chen
Published: January 2021

Understanding functional traits that capture species response to overgrazing can help optimize ecosystem functioning. However, most studies have ignored the effects of life-form on the response of above- and below-ground traits to overgrazing. Here, we determined whether the above- and below-ground traits respond similarly to overgrazing; and does the response of above- and below-ground traits to overgrazing vary between the species of annual vs. perennial life-forms. We compared common grassland species between fenced and overgrazed meadows at four elevations (from 3000 to 3600 m), spanning an area of ∼200 square kilometers on the Qinghai-Tibetan Plateau. We found overgrazing resulted in large removal of perennial species at all elevations, which forced perennial species to alter their above- and below-ground traits so that they could shift from resource conservation to resource acquisition to avoid overgrazing. In contrast, overgrazing promoted annual species at all elevation, thus annual species did not make any response to overgrazing. These findings bridge the gap in the literature for the influence of annual vs. perennial life-forms on species-specific response at both above-, and below-ground levels during overgrazing. More important, these results can facilitate selecting species for sustainable ecosystem managements and restoration from overgrazing.
Monitoring the Spread of Water Hyacinth (Pontederia crassipes): Challenges and Future Developments
Authors: Datta Aviraj , Maharaj Savitri , Prabhu G. Nagendra , Bhowmik Deepayan , Marino Armando , Akbari Vahid , Rupavatharam Srikanth , Sujeetha J. Alice R. P. , Anantrao Girish Gunjotikar , Poduvattil Vidhu Kampurath , Kumar Saurav , Kleczkowski Adam
Published: January 2021

Water hyacinth (Pontederia crassipes, also referred to as Eichhornia crassipes) is one of the most invasive weed species in the world, causing significant adverse economic and ecological impacts, particularly in tropical and sub-tropical regions. Large scale real-time monitoring of areas of chronic infestation is critical to formulate effective control strategies for this fast spreading weed species. Assessment of revenue generation potential of the harvested water hyacinth biomass also requires enhanced understanding to estimate the biomass yield potential for a given water body. Modern remote sensing technologies can greatly enhance our capacity to understand, monitor, and estimate water hyacinth infestation within inland as well as coastal freshwater bodies. Readily available satellite imagery with high spectral, temporal, and spatial resolution, along with conventional and modern machine learning techniques for automated image analysis, can enable discrimination of water hyacinth infestation from other floating or submerged vegetation. Remote sensing can potentially be complemented with an array of other technology-based methods, including aerial surveys, ground-level sensors, and citizen science, to provide comprehensive, timely, and accurate monitoring. This review discusses the latest developments in the use of remote sensing and other technologies to monitor water hyacinth infestation, and proposes a novel, multi-modal approach that combines the strengths of the different methods.
Using Synthetically Engineered Guide RNAs to Enhance CRISPR Genome Editing Systems in Mammalian Cells
Authors: Allen Daniel , Rosenberg Michael , Hendel Ayal
Published: January 2021

CRISPR-Cas9 is quickly revolutionizing the way we approach gene therapy. CRISPR-Cas9 is a complexed, two-component system using a short guide RNA (gRNA) sequence to direct the Cas9 endonuclease to the target site. Modifying the gRNA independent of the Cas9 protein confers ease and flexibility to improve the CRISPR-Cas9 system as a genome-editing tool. gRNAs have been engineered to improve the CRISPR system's overall stability, specificity, safety, and versatility. gRNAs have been modified to increase their stability to guard against nuclease degradation, thereby enhancing their efficiency. Additionally, guide specificity has been improved by limiting off-target editing. Synthetic gRNA has been shown to ameliorate inflammatory signaling caused by the CRISPR system, thereby limiting immunogenicity and toxicity in edited mammalian cells. Furthermore, through conjugation with exogenous donor DNA, engineered gRNAs have been shown to improve homology-directed repair (HDR) efficiency by ensuring donor proximity to the edited site. Lastly, synthetic gRNAs attached to fluorescent labels have been developed to enable highly specific nuclear staining and imaging, enabling mechanistic studies of chromosomal dynamics and genomic mapping. Continued work on chemical modification and optimization of synthetic gRNAs will undoubtedly lead to clinical and therapeutic benefits and, ultimately, routinely performed CRISPR-based therapies.
Base and Prime Editing Technologies for Blood Disorders
Authors: Antoniou Panagiotis , Miccio Annarita , Brusson Mégane
Published: January 2021

Nuclease-based genome editing strategies hold great promise for the treatment of blood disorders. However, a major drawback of these approaches is the generation of potentially harmful double strand breaks (DSBs). Base editing is a CRISPR-Cas9-based genome editing technology that allows the introduction of point mutations in the DNA without generating DSBs. Two major classes of base editors have been developed: cytidine base editors or CBEs allowing C>T conversions and adenine base editors or ABEs allowing A>G conversions. The scope of base editing tools has been extensively broadened, allowing higher efficiency, specificity, accessibility to previously inaccessible genetic loci and multiplexing, while maintaining a low rate of Insertions and Deletions (InDels). Base editing is a promising therapeutic strategy for genetic diseases caused by point mutations, such as many blood disorders and might be more effective than approaches based on homology-directed repair, which is moderately efficient in hematopoietic stem cells, the target cell population of many gene therapy approaches. In this review, we describe the development and evolution of the base editing system and its potential to correct blood disorders. We also discuss challenges of base editing approaches–including the delivery of base editors and the off-target events–and the advantages and disadvantages of base editing compared to classical genome editing strategies. Finally, we summarize the recent technologies that have further expanded the potential to correct genetic mutations, such as the novel base editing system allowing base transversions and the more versatile prime editing strategy.
Enrichment of Circular RNA Expression Deregulation at the Transition to Recurrent Spontaneous Seizures in Experimental Temporal Lobe Epilepsy
Authors: Gomes-Duarte Andreia , Bauer Sebastian , Venø Morten T. , Norwood Braxton A. , Henshall David C. , Kjems Jørgen , Rosenow Felix , Vangoor Vamshidhar R. , Pasterkamp R. Jeroen
Published: January 2021

Mesial temporal lobe epilepsy (mTLE) is a common form of epilepsy and is characterized by recurrent spontaneous seizures originating from the temporal lobe. The majority of mTLE patients develop pharmacoresistance to available anti-epileptic drugs (AEDs) while exhibiting severe pathological changes that can include hippocampal atrophy, neuronal death, gliosis and chronic seizures. The molecular mechanisms leading to mTLE remain incompletely understood, but are known to include defects in post-transcriptional gene expression regulation, including in non-coding RNAs (ncRNAs). Circular RNAs (circRNAs) are a class of recently rediscovered ncRNAs with high levels of expression in the brain and proposed roles in diverse neuronal processes. To explore a potential role for circRNAs in epilepsy, RNA-sequencing (RNA-seq) was performed on hippocampal tissue from a rat perforant pathway stimulation (PPS) model of TLE at different post-stimulation time points. This analysis revealed 218 differentially expressed (DE) circRNAs. Remarkably, the majority of these circRNAs were changed at the time of the occurrence of the first spontaneous seizure (DOFS). The expression pattern of two circRNAs, circ_Arhgap4 and circ_Nav3, was further validated and linked to miR-6328 and miR-10b-3p target regulation, respectively. This is the first study to examine the regulation of circRNAs during the development of epilepsy. It reveals an intriguing link between circRNA deregulation and the transition of brain networks into the state of spontaneous seizure activity. Together, our results provide a molecular framework for further understanding the role and mechanism-of-action of circRNAs in TLE.
Helicobacter and the Potential Role in Neurological Disorders: There Is More Than Helicobacter pylori
Authors: Gorlé Nina , Bauwens Eva , Haesebrouck Freddy , Smet Annemieke , Vandenbroucke Roosmarijn E.
Published: January 2021

Trillions of symbiotic microbial cells colonize our body, of which the larger part is present in the human gut. These microbes play an essential role in our health and a shift in the microbiome is linked to several diseases. Recent studies also suggest a link between changes in gut microbiota and neurological disorders. Gut microbiota can communicate with the brain via several routes, together called the microbiome–gut–brain axis: the neuronal route, the endocrine route, the metabolic route and the immunological route. Helicobacter is a genus of Gram-negative bacteria colonizing the stomach, intestine and liver. Several papers show the role of H. pylori in the development and progression of neurological disorders, while hardly anything is known about other Helicobacter species and the brain. We recently reported a high prevalence of H. suis in patients with Parkinson’s disease and showed an effect of a gastric H. suis infection on the mouse brain homeostasis. Here, we discuss the potential role of H. suis in neurological disorders and how it may affect the brain via the microbiome–gut–brain axis.
Changes in the Immune Phenotype and Gene Expression Profile Driven by a Novel Tuberculosis Nanovaccine: Short and Long-Term Post-immunization
Authors: Martínez-Pérez Amparo , Igea Ana , Estévez Olivia , Ferreira Catarina M. , Torrado Egídio , Castro António Gil , Fernández Carmen , Spetz Anna-Lena , Adam Lucille , López González Moisés , Singh Mahavir , Reljic Rajko , González-Fernández África
Published: January 2021

Deciphering protection mechanisms againstMycobacterium tuberculosis(Mtb) remains a critical challenge for the development of new vaccines and therapies. We analyze the phenotypic and transcriptomic profile in lung of a novel tuberculosis (TB) nanoparticle-based boosting mucosal vaccine Nano-FP1, which combined to BCG priming conferred enhanced protection in mice challenged with low-doseMtb. We analyzed the vaccine profile and efficacy at short (2 weeks), medium (7 weeks) and long term (11 weeks) post-vaccination, and compared it to ineffective Nano-FP2 vaccine. We observed several changes in the mouse lung environment by both nanovaccines, which are lost shortly after boosting. Additional boosting at long-term (14 weeks) recovered partially cell populations and transcriptomic profile, but not enough to enhance protection to infection. An increase in both total and resident memory CD4 and CD8 T cells, but no pro-inflammatory cytokine levels, were correlated with better protection. A unique gene expression pattern with differentially expressed genes revealed potential pathways associated to the immune defense againstMtb. Our findings provide an insight into the critical immune responses that need to be considered when assessing the effectiveness of a novel TB vaccine.
The Severity of Neurological Dysfunction in Preschool Children, Secondary to Damage Generated During the Perinatal Period, is Associated With a Pro-Inflammatory Pattern of Serum Molecules
Authors: Madrid Miriam , Brianza-Padilla Malinalli , Echeverría Juan C. , Rivera-González Rolando , Bojalil Rafael
Published: January 2021

Disorders in the child’s neurological development caused by perinatal risks can lead to long-term altered neurological signs that begin at an early age and involve persistent functional disorders. Recent data suggest that tissue dysfunction, not just acute damage, may initiate or perpetuate an inflammatory response. The aim of this study was to find out if any neurological dysfunction in preschool children secondary to damage generated during the perinatal period is associated with the magnitude of perinatal risks and long-term modifications in the serum concentrations of inflammatory molecules. The participants, aged 1–4 years, were on neurodevelopmental follow-up and rehabilitation therapy from the first three months of life and had no acute disease data. We classified the children into three groups according to the importance of their perinatal risks: low, medium, and high. The results show that 1) the magnitude of perinatal risks correlated with the severity of neurological dysfunction; 2) the greatest changes in the concentrations of the molecules of the inflammatory process were associated with the most altered neurological signs. This suggests that persistent nervous system dysfunction keeps inflammatory responses active even in the absence of an acute process of infection or damage.
Probiotics, Anticipation Stress, and the Acute Immune Response to Night Shift
Authors: West Nicholas P. , Hughes Lily , Ramsey Rebecca , Zhang Ping , Martoni Christopher J. , Leyer Gregory J. , Cripps Allan W. , Cox Amanda J.
Published: January 2021

Introduction

Sleep disturbance and sleep disruption are associated with chronic, low grade inflammation and may underpin a range of chronic diseases in night shift workers. Through modulation of the intestinal microbiota, probiotic supplements may moderate the effects of sleep disruption on the immune system. The aim of this study was to examine 14 days of daily probiotic supplementation on the acute response of acute phase proteins and immune markers to sleep disruption associated with night shift work (Australia and New Zealand Clinical Trials Registry: 12617001552370).

Methods

Individuals (mean age 41 ± 11 yrs; 74% female) performing routine night shift were randomly assigned to a probiotic group (1 × 1010 colony forming units (CFU) Lactobacillus acidophilus DDS-1 or 1 × 1010 CFU Bifidobacterium animalis subsp. lactis UABla-12) or placebo (n= 29 per group). Participants undertook a 14-day supplementation period that coincided with a period of no night shifts followed by two consecutive night shifts. Blood samples were collected prior to the start of supplementation (V1), prior to commencing the first night shift (V2), after the first night shift (V3) and after the second night shift (V4). Serum was assessed for markers of stress (cortisol), acute phase response (C reactive protein (CRP), erythrocyte sedimentation rate, pentraxin), adhesion markers (serum E-selectin, mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), and serum cytokines (interleukin (IL)-1ra, IL-1β, IL-6, tumor necrosis factor (TNF)-α, IL-10). Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and a Fitbit activity tracker.

Results

The groups were well balanced on key markers and the probiotic strains were well tolerated. The 14-day supplementation period that coincided with typical night-day sleep-wake cycles leading up to night shift (V1 to V2) was associated with significant changes in the placebo group in the concentration of serum cortisol (p = 0.01), pentraxin (p = 0.001), MAdCAM-1 (p = 0.001), and IL-1ra (p=0.03). In contrast, probiotic supplementation moderated changes in these serum markers from V1 to V2. No significant interaction effects (time by group) were observed for the serum markers prior to and after night shift work following probiotic supplementation due to the substantial changes in the serum markers that occurred during the normal sleep period from V1 to V2.

Conclusions

Probiotics may moderate the effects of anticipatory stress on the immune system in the lead up to night shift.
CD8+ T Lymphocytes: Crucial Players in Sjögren’s Syndrome
Authors: Zhou Huimin , Yang Jun , Tian Jie , Wang Shengjun
Published: January 2021

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease associated with damage to multiple organs and glands. The most common clinical manifestations are dry eyes, dry mouth, and enlarged salivary glands. Currently, CD4+ T lymphocytes are considered to be key factors in the immunopathogenesis of pSS, but various studies have shown that CD8+ T lymphocytes contribute to acinar injury in the exocrine glands. Therefore, in this review, we discussed the classification and features of CD8+ T lymphocytes, specifically describing the role of CD8+ T lymphocytes in disease pathophysiology. Furthermore, we presented treatment strategies targeting CD8+ T cells to capitalize on the pathogenic and regulatory potential of CD8+ T lymphocytes in SS to provide promising new strategies for this inflammatory disease.
TFH Cells Induced by Vaccination and Following SIV Challenge Support Env-Specific Humoral Immunity in the Rectal-Genital Tract and Circulation of Female Rhesus Macaques
Authors: Helmold Hait Sabrina , Hogge Christopher James , Rahman Mohammad Arif , Hunegnaw Ruth , Mushtaq Zuena , Hoang Tanya , Robert-Guroff Marjorie
Published: January 2021

T follicular helper (TFH) cells are pivotal in lymph node (LN) germinal center (GC) B cell affinity maturation. Circulating CXCR5+ CD4+ T (cTFH) cells have supported memory B cell activation and broadly neutralizing antibodies in HIV controllers. We investigated the contribution of LN SIV-specific TFH and cTFH cells to Env-specific humoral immunity in female rhesus macaques following a mucosal Ad5hr-SIV recombinant priming and SIV gp120 intramuscular boosting vaccine regimen and following SIV vaginal challenge. TFH and B cells were characterized by flow cytometry. B cell help was evaluated in TFH-B cell co-cultures and by real-time PCR. Vaccination induced Env-specific TFH and Env-specific memory (ESM) B cells in LNs. LN Env-specific TFH cells post-priming and GC ESM B cells post-boosting correlated with rectal Env-specific IgA titers, and GC B cells at the same timepoints correlated with vaginal Env-specific IgG titers. Vaccination expanded cTFH cell responses, including CD25+ Env-specific cTFH cells that correlated negatively with vaginal Env-specific IgG titers but positively with rectal Env-specific IgA titers. Although cTFH cells post-2nd boost positively correlated with viral-loads following SIV challenge, cTFH cells of SIV-infected and protected macaques supported maturation of circulating B cells into plasma cells and IgA release in co-culture. Additionally, cTFH cells of naïve macaques promoted upregulation of genes associated with B cell proliferation, BCR engagement, plasma cell maturation, and antibody production, highlighting the role of cTFH cells in blood B cell maturation. Vaccine-induced LN TFH and GC B cells supported anti-viral mucosal immunity while cTFH cells provided B cell help in the periphery during immunization and after SIV challenge. Induction of TFH responses in blood and secondary lymphoid organs is likely desirable for protective efficacy of HIV vaccines.
Spatio-Temporal Assessment of the European Hake (Merluccius merluccius) Recruits in the Northern Iberian Peninsula
Authors: Izquierdo Francisco , Paradinas Iosu , Cerviño Santiago , Conesa David , Alonso-Fernández Alexandre , Velasco Francisco , Preciado Izaskun , Punzón Antonio , Saborido-Rey Fran , Pennino Maria Grazia
Published: January 2021

The protection of fish nurseries has been recognized as a useful tool to efficiently manage fisheries given that protected areas enhance the recruitment of target species. To identify and locate potential nursery areas, a solid understanding of species-environment relationships and their spatio-temporal dynamics is needed. Within this context, in this study we assess where European hake (Merluccius merluccius) recruits persistently aggregate in the northern continental shelf of the Iberian Peninsula. Hake recruit data collected during scientific trawl surveys between 2005 and 2016 were analyzed using Bayesian hurdle hierarchical spatio-temporal models, considering the environmental variables bathymetry, sea bottom temperature and salinity. Additionally, three different spatio-temporal structures (i.e., persistent, progressive, or opportunistic) were compared to assess the temporal persistence of nurseries over time. Among all the environmental variables analyzed, bathymetry was the most important. The preferential habitat of recruits was found to be within a bathymetric range of 120–200 m. Our findings clearly show that there is a temporally persistent main nursery located along the continental shelf of the Artabrian gulf (off La Coruña) in addition to several areas with high aggregations of hake recruits but with strong inter-annual variability. We argue that the analytical framework applied in this study allowed us to identify European hake nurseries in the northern continental shelf of the Iberian Peninsula, as well as their spatio-temporal fluctuations throughout the study period (2005–2016), and to assess which environmental factors, among bathymetry, sea bottom temperature and salinity, influence the occurrence and abundance of recruits in the study area. Results of our models also produce a new abundance index that could be useful for improving traditional stock assessment models.
Marine Oil Snow, a Microbial Perspective
Authors: Gregson Benjamin H. , McKew Boyd A. , Holland Robert D. , Nedwed Timothy J. , Prince Roger C. , McGenity Terry J.
Published: January 2021

Under certain conditions, dispersed crude oil in the sea combines with organisms, organic matter, and minerals to form marine oil snow (MOS), thereby contributing to the sinking of oil to the seafloor. Marine microbes are the main players in MOS formation, particularly via the production of extracellular polymeric substances. Distinct groups of microbes also consume the majority of the hydrocarbons during descent, leading to enrichment of the less bioavailable hydrocarbons and asphaltenes in the residue. Here we discuss the dynamics of microbial communities in MOS together with their impacts on MOS evolution. We explore the effects of dispersant application on MOS formation, and consider ways in which laboratory experiments investigating MOS formation can be more representative of the situation in the marine environment, which in turn will improve our understanding of the contribution of MOS to the fate of spilled oil.
Investigating the Effect of Structure to Structure Separation Distance on Firebrand Accumulation
Authors: Suzuki Sayaka , Manzello Samuel L.
Published: January 2021

Wind plays an important role in the built environment. Large outdoor fires in the built environment are no exception. Under strong wind, firebrands fly far, which leads to quick fire spread. In this study, the effect of structure to structure separation distance on firebrand accumulation was investigated by using a custom designed firebrand generator installed in a real scale wind tunnel. Firebrands accumulated at 4 and 6 m s−1, but no firebrand accumulation zone was observed at 8 and 10 m s−1, regardless of separation distance (SD). Experimental results were compared with a simple CFD flow simulation (no firebrands included). The size of firebrand accumulation zone as well as distance from the structure front was compared with SD in the cases of 4 and 6 m s−1 wind speeds. It was found that firebrands behave differently from SD = 1 to 2 m, to that of SD = 2 to 3 m. The results of this study are the first to explore these important interactions between firebrands and structure separation distances. The results of this work will help develop and design sustainable communities that may better resist the destruction of increasing large outdoor fire outbreaks worldwide, as well as help develop the next generation of CFD models needed to grasp the important large outdoor fire problem and associated firebrand processes.
Low Soluble Receptor for Advanced Glycation End Products Precedes and Predicts Cardiometabolic Events in Women With Rheumatoid Arthritis
Authors: Nadali Mitra , Lyngfelt Lovisa , Erlandsson Malin C. , Silfverswärd Sofia Töyrä , Andersson Karin M. E. , Bokarewa Maria I. , Pullerits Rille
Published: January 2021

Background: Cardiovascular disease (CVD) causes premature mortality in rheumatoid arthritis (RA). Levels of soluble (s)RAGE change with aging, hypertension and hypercholesterolemia. We assessed whether sRAGE was associated with increased risk of CVD in RA patients.

Methods: Serum sRAGE was measured in 184 female RA patients and analyzed with respect to CVD risk estimated by the Framingham algorithm (eCVR), metabolic profile and inflammation. Levels of sRAGE in 13 patients with known cardio-metabolic morbidity defined the cut-off for low sRAGE. Prospective 5-year follow-up of new CV and metabolic events was completed.

Results: Low sRAGE was significantly associated with previous history and with new imminent cardiometabolic events in the prospective follow-up of RA patients. In both cases, low sRAGE reflected higher estimation of CVR in those patients. Low sRAGE was attributed to adverse metabolic parameters including high fasting plasma glucose and body fat content rather than inflammation. The association of sRAGE and poor metabolic profile was prominent in patients younger than 50 years.

Conclusions: This study points at low sRAGE as a marker of metabolic failure developed during chronic inflammation. It highlights the importance for monitoring metabolic health in female RA patients for timely prevention of CVD.

Trial registration:ClinicalTrials.gov with ID NCT03449589. Registered 28, February 2018.