bluuebunny/crossref_metadata_2025 huggingface dataset:
Aposiopesen und Ellipsen
Authors: Höfler Günther A.
Published: June 2021

The article examines the rhetorical devices of aposiopesis (broken-off speech) and ellipsis (omission of words) in dramatic texts of the »Sturm und Drang« movement as well as in examples of 21st-century drama. The main focus is on what is spoken in the mode of ›silent language‹. The analysis of 18th-century dramatic texts (Lenz and Goethe) draws on the anthropological and poetological writings of the time, which show that the presence of the unspeakable in dramatic language is primarily a matter of the »excitation of the soul« (Herder). In contemporary drama, on the other hand, no generalisable function for the abruption of speech or the effect of standing still can be determined; the lack of movement in these dramatic texts serves to highlight alienated human relationships (Thomas Arzt) and displays existential dissolutions of meaning (Ewald Palmetshofer).
Schreiben mit Licht
Authors: Bohn Ralf
Published: June 2021

In the 19th century, the stillness of movement during a photographic exposure required a staging based on academic traditions. Staging is the »spatialization« of a present absence – comparable to »writing« in the sense of Derrida. With the increasing mobility of camera techniques from the 20th century onwards, the focus is no longer on the reproduction of a moment, but instead on its performative invention.With the digital photography of the 21st century, a transformation from theatrical to functional staging takes place. The history of the writing scene of photography illustrates the interplay between concealment through technology and re-aestheticization, which with increasing oscillation turns into motor dizziness.
Die Bewegung des Anderen in den Schreibszenen von Hélène Cixous
Authors: Gritzner Karoline
Published: June 2021

This essay explores the significance of movement and alterity in Hélène Cixous’s practice of writing, which she defines as an »exposure« to the other and as a sensitization to the present moment. The focus is on Cixous’s presentation of different modalities of being that are indissociable from the materiality of ‚écriture féminine‘. These range from the necessity for blindness in the act of writing and the discovery of imaginary worlds, to experiences of flight, sexual difference and modes of »de-selfing« in the process of writing. The transformative event-character of Cixous’s writing is foregrounded in her short story ‚Savoir‘, where the relationship between seeing and not-seeing, presence and absence, knowledge and desire is captured in the fleeting traces of the written word.
Green recovery investments and entrepreneurship
Authors: Todd Iain , Cordero Lorena , Andrijevic Marina , McMongle Rob , Schmidt Silke
Published: June 2021

In this session, we will hear speakers from across Europe presenting their research, followed by discussion on investing in resilient and sustainable infrastructure and how decarbonisation fits with post-pandemic fiscal and monetary frameworks.
Climate law & governance
Authors: Phillips Freedom-Kai , Rao Tejas , Cordonier Segger Marie-Claire , Voigt Christina , Shinde Mrinalini , Byron Chantalle , Khan Hafij , Cherkaoui Ayman , Janusz-Pawletta Barbara , Leys Douglas , Atapattu Sumudu , Fawad Anusheh , Sindico Francesco , Harrington Alexandra
Published: June 2021

The session will focus on introducing the audience to new ways of thinking and understanding climate law and highlight how legal innovation can lead to the implementation of the Paris Agreement, and raising ambition globally. The CISDL is currently engaged in a research project culminating in the book “Courage, Contributions & Compliance: Advancing Climate Law and Governance Innovation” which seeks to highlight innovative approaches within climate law. The session will feature discussion by authors.
Place-based solutions
Authors: Georgi Birgit , Moore Henrietta , Mylan Jo , Wookey Lynda , Taylor Peter
Published: June 2021

This session will showcase four case studies from the UK, followed by a discussion on the lessons learned and their application globally.
Anther-Feeding-Induced RNAi in Brassicogethes aeneus Larvae
Authors: Willow Jonathan , Soonvald Liina , Sulg Silva , Kaasik Riina , Silva Ana Isabel , Taning Clauvis Nji Tizi , Christiaens Olivier , Smagghe Guy , Veromann Eve
Published: June 2021

The biosafety aspect of applying double-stranded RNA (dsRNA) in crop pest management is rooted in dsRNA's mode of action, which displays nucleotide sequence-specificity to a particular region of a messenger RNA (mRNA), against which the insecticidal dsRNA is designed. This prominent and promising class of insecticides therefore has the potential to target a single pest species while conferring negligible effect on non-target organisms. Recent studies examining the effect of target-specific dsRNA in adults of the pollen beetle Brassicogethes aeneus, a major pest of oilseed rape (Brassica napus) crops in Europe, suggest the potential for developing a gene-silencing approach within integrated B. aeneus management. The present study examines the efficacy of target-specific dsRNA on target-mRNA silencing, and subsequent gene-silencing-induced mortality, in B. aeneus larvae, as this life stage represents a critical target for achieving optimal integrated B. aeneus control. Treatment applications occurred via feeding on dsRNA-treated anthers for 3 d. We observed variable gene-silencing efficacy, all target treatments having a significant or marginally significant effect after 3 d of dsRNA feeding, with greater variability at 6 d. These results further validated significant gene-silencing-induced mortality observed for one of the target treatments. Moreover, gene-silencing-induced mortality occurred at a quicker rate in B. aeneus larvae compared to what has been previously observed in B. aeneus adults. Finally, we consider refinements that must be made to B. aeneus larval bioassay setups to promote and strengthen future larval studies regarding this important crop pest species.
In vitro–In vivo Hybrid Approach for Studying Modulation of NRF2 in Immortalized Bovine Mammary Cells
Authors: Ford Hunter R. , Busato Sebastiano , Bionaz Massimo
Published: June 2021

Nuclear factor erythroid 2-related factor 2 (NRF2) plays a key role in the response to oxidative stress. Diets containing known NRF2 modulators could be used to minimize oxidative stress in dairy cows. Currently, studies evaluating the activity of NRF2 in bovine have used the classical in vitro approach using synthetic media, which is very different than in vivo conditions. Furthermore, studies carried out in vivo cannot capture the short-term and dynamic response of NRF2. Thus, there is a need to develop new approaches to study NRF2 modulation. The aim of the present study was to establish an in vitro–in vivo hybrid system to investigate activation of NRF2 in bovine cells that can serve as an intermediate model with results closer to what is expected in vivo. To accomplish the aim, we used a combination of a gene reporter assay in immortalized bovine mammary cells, synthetic NRF2 modulators, and blood serum from periparturient cows. Synthetic agonist tert-butylhydroquinone and sulforaphane confirmed to be effective activators of bovine NRF2 with acute and large effect at 30 and 5 μM, respectively, with null response after the above doses due to cytotoxicity. When the agonists were added to blood serum the response was more linear with maximum activation of NRF2 at 100 and 30 μM, respectively, and the cytotoxicity was prevented. High concentration of albumin in blood serum plays an important role in such an effect. Brusatol (100 nM) was observed to be an effective NRF2 inhibitor while also displaying general protein synthesis inhibition and cytotoxicity when added to synthetic media. A consistent inhibition of NRF2 was observed when brusatol was added to the blood serum but the cytotoxicity was reduced. The synthetic inhibitor ML385 had no effect on modulation of bovine NRF2. Hydrogen peroxide activates NRF2 in bovine mammary cells starting from 100 μM; however, strong cytotoxicity was detected starting at 250 μM when cells were cultivated in the synthetic media, while blood serum prevented cytotoxicity. Overall, our data indicated that the use of synthetic media can be misleading in the study of NRF2 in bovine and the use of blood serum appears necessary.
Ulk4, a Newly Discovered Susceptibility Gene for Schizophrenia, Regulates Corticogenesis in Mice
Authors: Hu Ling , Chen Yi , Yang Cui-Ping , Huang Ying , Song Ning-Ning , Chen Jia-Yin , Sun Yu-Ling , Ding Yu-Qiang , Lang Bing
Published: June 2021

Schizophrenia (SCZ) is a chronic and severe mental disease that affects around 1% of the population. The precise etiology of SCZ still remains largely unknown, and no conclusive mechanisms are firmly established. Recent advances in epidemiological and clinical investigation support an overwhelmingly strong neurodevelopmental origin for SCZ. Here, we demonstrated that Unc-51-like kinase 4 (Ulk4), a novel risk factor for major mental disorders including schizophrenia, is involved in the corticogenesis. Deletion of Ulk4 in mice led to significantly thinner layers of II–III, and V in the cerebral cortex, which was confirmed in conditional Ulk4 deletion mice achieved by Cre-loxp strategy. This abnormality might be caused by decreased intermediate neural progenitors and increased apoptosis. Thus, our data suggest that Ulk4 manipulates the behaviors of neural progenitors during brain development and, when functionally defective, leads to the reduction of specific cortical layers. This anomaly may increase predisposition to a range of neurodevelopmental disorders, including SCZ.
Sox9 Determines Translational Capacity During Early Chondrogenic Differentiation of ATDC5 Cells by Regulating Expression of Ribosome Biogenesis Factors and Ribosomal Proteins
Authors: Caron Marjolein M. J. , Eveque Maxime , Cillero-Pastor Berta , Heeren Ron M. A. , Housmans Bas , Derks Kasper , Cremers Andy , Peffers Mandy J. , van Rhijn Lodewijk W. , van den Akker Guus , Welting Tim J. M.
Published: June 2021

Introduction

In addition to the well-known cartilage extracellular matrix-related expression of Sox9, we demonstrated that chondrogenic differentiation of progenitor cells is driven by a sharply defined bi-phasic expression of Sox9: an immediate early and a late (extracellular matrix associated) phase expression. In this study, we aimed to determine what biological processes are driven by Sox9 during this early phase of chondrogenic differentiation.

Materials

Sox9 expression in ATDC5 cells was knocked down by siRNA transfection at the day before chondrogenic differentiation or at day 6 of differentiation. Samples were harvested at 2 h and 7 days of differentiation. The transcriptomes (RNA-seq approach) and proteomes (Label-free proteomics approach) were compared using pathway and network analyses. Total protein translational capacity was evaluated with the SuNSET assay, active ribosomes were evaluated with polysome profiling, and ribosome modus was evaluated with bicistronic reporter assays.

Results

Early Sox9 knockdown severely inhibited chondrogenic differentiation weeks later. Sox9 expression during the immediate early phase of ATDC5 chondrogenic differentiation regulated the expression of ribosome biogenesis factors and ribosomal protein subunits. This was accompanied by decreased translational capacity following Sox9 knockdown, and this correlated to lower amounts of active mono- and polysomes. Moreover, cap- versus IRES-mediated translation was altered by Sox9 knockdown. Sox9 overexpression was able to induce reciprocal effects to the Sox9 knockdown.

Conclusion

Here, we identified an essential new function for Sox9 during early chondrogenic differentiation. A role for Sox9 in regulation of ribosome amount, activity, and/or composition may be crucial in preparation for the demanding proliferative phase and subsequent cartilage extracellular matrix production of chondroprogenitors in the growth platein vivo.
Evolution of Developmental Programs for the Midline Structures in Chordates: Insights From Gene Regulation in the Floor Plate and Hypochord Homologues of Ciona Embryos
Authors: Oonuma Kouhei , Yamamoto Maho , Moritsugu Naho , Okawa Nanako , Mukai Megumi , Sotani Miku , Tsunemi Shuto , Sugimoto Haruka , Nakagome Eri , Hasegawa Yuichi , Shimai Kotaro , Horie Takeo , Kusakabe Takehiro G.
Published: June 2021

In vertebrate embryos, dorsal midline tissues, including the notochord, the prechordal plate, and the floor plate, play important roles in patterning of the central nervous system, somites, and endodermal tissues by producing extracellular signaling molecules, such as Sonic hedgehog (Shh). In Ciona, hedgehog.b, one of the two hedgehog genes, is expressed in the floor plate of the embryonic neural tube, while none of the hedgehog genes are expressed in the notochord. We have identified a cis-regulatory region of hedgehog.b that was sufficient to drive a reporter gene expression in the floor plate. The hedgehog.b cis-regulatory region also drove ectopic expression of the reporter gene in the endodermal strand, suggesting that the floor plate and the endodermal strand share a part of their gene regulatory programs. The endodermal strand occupies the same topographic position of the embryo as does the vertebrate hypochord, which consists of a row of single cells lined up immediately ventral to the notochord. The hypochord shares expression of several genes with the floor plate, including Shh and FoxA, and play a role in dorsal aorta development. Whole-embryo single-cell transcriptome analysis identified a number of genes specifically expressed in both the floor plate and the endodermal strand in Ciona tailbud embryos. A Ciona FoxA ortholog FoxA.a is shown to be a candidate transcriptional activator for the midline gene battery. The present findings suggest an ancient evolutionary origin of a common developmental program for the midline structures in Olfactores.
Rapid Trio Exome Sequencing for Autosomal Recessive Renal Tubular Dysgenesis in Recurrent Oligohydramnios
Authors: Lin Shin-Yu , Chuang Gwo-Tsann , Hung Chien-Hui , Lin Wei-Chou , Jeng Yung-Ming , Yen Ting-An , Chang Karine , Chien Yin-Hsiu , Hwu Wuh-Liang , Lee Chien-Nan , Tsai I-Jung , Lee Ni-Chung
Published: June 2021

Oligohydramnios is not a rare prenatal finding. However, recurrent oligohydramnios is uncommon, and genetic etiology should be taken into consideration. We present two families with recurrent fetal oligohydramnios that did not respond to amnioinfusion. Rapid trio-whole-exome sequencing (WES) revealed mutations in the AGT gene in both families within 1 week. The first family had a compound heterozygous mutation with c.856 + 1G > T and c.857-619_1269 + 243delinsTTGCCTTGC changes. The second family had homozygous c.857-619_1269 + 243delinsTTGCCTTGC mutations. AGT gene mutation may lead to autosomal recessive renal tubular dysgenesis, a rare and lethal disorder that can result in early neonatal death. Both the alleles identified are known alleles associated with pathogenicity. Our findings suggest that trio-WES analysis may help rapidly identify causative etiologies that can inform prompt counseling and decision-making prenatally.
CircCA12 Promotes Malignant Process via Sponging miR-1184 and Upregulating RAS Family in Bladder Cancer
Authors: Jiang Lijuan , Wang Yanjun , Tang Huancheng , Li Xiangdong , Huang Chaowen , Liu Zhuowei , Zhou Fangjian , Wang Xiaolan , Li Yonghong
Published: June 2021

Circular RNAs (circRNAs) are a panel of non-coding RNAs that mediate the regulation of gene expression, as well as pathological responses. Nonetheless, the function and expression pattern of circRNAs in urinary bladder cancer (UBC) remain unclear. Herein, we examined the function of circCA12 in UBC development. qRT-PCR results demonstrated remarkable circCA12 upregulation in UBC cell lines, as well as tissues. CCK-8, colony formation, and xenograft assays were employed to determine the effect of circCA12 on UBC. Our data illustrated silencing circCA12 repressed the proliferation along with the colony-formation capability of UBC cells. The migration and metastasis potential of UBC cells were remarkably abated in vivo, as well as in vitro after transfection with si-cirCA12 or sh-circCA12. Moreover, luciferase reporter and RIP assays indicated that circCA12 binds to miRNA-1184 through sponging miRNA, thereby up-regulating the expression of RAS family genes (NRAS, KRAS, and HRAS). In conclusion, the circCA12/miRNA-1184/RAS family was identified as a regulatory axis in UBC progression.
The Inhibitory Receptor CLEC12A Regulates PI3K-Akt Signaling to Inhibit Neutrophil Activation and Cytokine Release
Authors: Paré Guillaume , Vitry Julien , Merchant Michael L. , Vaillancourt Myriam , Murru Andréa , Shen Yunyun , Elowe Sabine , Lahoud Mireille H. , Naccache Paul H. , McLeish Kenneth R. , Fernandes Maria J.
Published: June 2021

The myeloid inhibitory C-type lectin receptor CLEC12A limits neutrophil activation, pro-inflammatory pathways and disease in mouse models of inflammatory arthritis by a molecular mechanism that remains poorly understood. We addressed how CLEC12A-mediated inhibitory signaling counteracts activating signaling by cross-linking CLEC12A in human neutrophils. CLEC12A cross-linking induced its translocation to flotillin-rich membrane domains where its ITIM was phosphorylated in a Src-dependent manner. Phosphoproteomic analysis identified candidate signaling molecules regulated by CLEC12A that include MAPKs, phosphoinositol kinases and members of the JAK-STAT pathway. Stimulating neutrophils with uric acid crystals, the etiological agent of gout, drove the hyperphosphorylation of p38 and Akt. Ultimately, one of the pathways through which CLEC12A regulates uric acid crystal-stimulated release of IL-8 by neutrophils is through a p38/PI3K-Akt signaling pathway. In summary this work defines early molecular events that underpin CLEC12A signaling in human neutrophils to modulate cytokine synthesis. Targeting this pathway could be useful therapeutically to dampen inflammation.
The OX40/OX40L Axis Regulates T Follicular Helper Cell Differentiation: Implications for Autoimmune Diseases
Authors: Fu NanNan , Xie Fang , Sun ZhongWen , Wang Qin
Published: June 2021

T Follicular helper (Tfh) cells, a unique subset of CD4+T cells, play an essential role in B cell development and the formation of germinal centers (GCs). Tfh differentiation depends on various factors including cytokines, transcription factors and multiple costimulatory molecules. Given that OX40 signaling is critical for costimulating T cell activation and function, its roles in regulating Tfh cells have attracted widespread attention. Recent data have shown that OX40/OX40L signaling can not only promote Tfh cell differentiation and maintain cell survival, but also enhance the helper function of Tfh for B cells. Moreover, upregulated OX40 signaling is related to abnormal Tfh activity that causes autoimmune diseases. This review describes the roles of OX40/OX40L in Tfh biology, including the mechanisms by which OX40 signaling regulates Tfh cell differentiation and functions, and their close relationship with autoimmune diseases.
Coastal Flooding in the Maldives Induced by Mean Sea-Level Rise and Wind-Waves: From Global to Local Coastal Modelling
Authors: Amores Angel , Marcos Marta , Pedreros Rodrigo , Le Cozannet Gonéri , Lecacheux Sophie , Rohmer Jérémy , Hinkel Jochen , Gussmann Geronimo , van der Pol Thomas , Shareef Ali , Khaleel Zammath
Published: June 2021

The Maldives, with one of the lowest average land elevations above present-day mean sea level, is among the world regions that will be the most impacted by mean sea-level rise and marine extreme events induced by climate change. Yet, the lack of regional and local information on marine drivers is a major drawback that coastal decision-makers face to anticipate the impacts of climate change along the Maldivian coastlines. In this study we focus on wind-waves, the main driver of extremes causing coastal flooding in the region. We dynamically downscale large-scale fields from global wave models, providing a valuable source of climate information along the coastlines with spatial resolution down to 500 m. This dataset serves to characterise the wave climate around the Maldives, with applications in regional development and land reclamation, and is also an essential input for local flood hazard modelling. We illustrate this with a case study of HA Hoarafushi, an atoll island where local topo-bathymetry is available. This island is exposed to the highest incoming waves in the archipelago and recently saw development of an airport island on its reef via land reclamation. Regional waves are propagated toward the shoreline using a phase-resolving model and coastal inundation is simulated under different mean sea-level rise conditions of up to 1 m above present-day mean sea level. The results are represented as risk maps with different hazard levels gathering inundation depth and speed, providing a clear evidence of the impacts of the sea level rise combined with extreme wave events.
The Relationship Between Food Consumption and Bowel Symptoms Among Patients With Rectal Cancer After Sphincter-Saving Surgery
Authors: Liu Wen , Xu Jian Min , Zhang Yu Xia , Lu Hui Juan , Xia Hai Ou
Published: June 2021

Dietary self-management is an important strategy for controlling bowel symptoms after sphincter-saving surgery; however, the dietary factors influencing bowel symptoms are not completely clear. This study aimed to explore the relationship between the specific consumption of food components and bowel symptoms. This study applied a cross-sectional study design. Using convenience sampling, a total of 169 patients with rectal cancer after sphincter-saving surgery were selected from a tertiary hospital. Data were collected through three questionnaires, including general and treatment-related questionnaires, the Memorial Sloan Kettering Cancer Center (MSKCC) bowel function scale—Chinese version, and the Food Frequency Questionnaire. Multiple linear regression analysis was used to analyze the collected data. It was found that the consumption of fruit, cholesterol, and protein and the interaction of cereals and milk products were the main dietary factors affecting bowel symptoms in patients after sphincter-saving surgery. The consumption of protein and fruit was negatively correlated with the symptoms of frequent and urgent defecation, and the consumption of fruit and protein was negatively correlated with general bowel function. The consumption of fruit was negatively correlated with the abnormal feeling of defecation, and the interaction between cereals and milk products was positively correlated with the abnormal feeling of defecation. The results of this study provide evidence for medical staff to further develop scientific dietary education programs to relieve bowel symptoms and promote the quality of life of patients in the future. More research is also needed to explore the mechanisms of the effects of different food components on bowel symptoms in patients after sphincter-saving surgery in the future.
Effects of Sacubitril-Valsartan in Heart Failure With Preserved Ejection Fraction in Patients Undergoing Peritoneal Dialysis
Authors: Fu Sha , Xu Zhenjian , Lin Baojuan , Chen Junzhe , Huang Qiuyan , Xu Yanchun , Xu Anping , Chen Yangxin , Tang Ying
Published: June 2021

Aims: The effect of the angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril-valsartan in patients with heart failure with preserved ejection fraction (HFpEF) remains unclear, and data on ARNI treatment in peritoneal dialysis (PD) patients are lacking. The present study was designed to assess the efficacy and safety of sacubitril-valsartan in patients with HFpEF undergoing peritoneal dialysis.

Methods and Results: End-stage kidney disease (ESKD) patients undergoing PD for 3 months with New York Heart Association (NYHA) class II–IV heart failure, ejection fraction of 50% or higher, and elevated levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP) were assigned to receive sacubitril-valsartan. Patients were followed up regularly after medication treatment. The alterations in clinical and biochemical parameters before and after taking sacubitril-valsartan (generally 50–100 mg b.i.d) were investigated, and safety was also assessed. Twenty-one patients were recruited in this study. Compared with baseline levels, NT-proBNP levels [9769.0 (3093.5–21941.0) vs. 3034.0 (1493.2–6503.0), P = 0.002], and heart rate [80.0 (74.5–90.5) vs. 75.0 (70.3–87.0), P = 0.031] were markedly decreased after treatment with sacubitril-valsartan. Signs and symptoms of heart failure (21/21 vs. 15/21, P = 0.021) were obviously alleviated, NYHA classification and E/e' ratio showed a notable trend of improvement after 3–12 months of follow-up. None of the patients showed adverse drug reactions.

Conclusions: The present data suggested that sacubitril-valsartan treatment in patients with HFpEF undergoing PD was effective and safe.
Multigene Phylogeny and Morphology Reveal Three Novel Species and a Novel Record of Agaricus From Northern Thailand
Authors: Jaichaliaw Chanyawat , Kumla Jaturong , Vadthanarat Santhiti , Suwannarach Nakarin , Lumyong Saisamorn
Published: June 2021

Agaricus is a saprophytic mushroom genus widely distributed throughout the world. In this study, a survey of the Agaricus species carried out around Chiang Mai University in northern Thailand from 2018 to 2019 yielded 12 collections. Morphological characteristics and phylogenic analyses based on the internal transcribed spacers (ITS) and a fragment of the large subunit (LSU) of the nuclear ribosomal DNA (rDNA), and a fragment of the translation elongation factor 1-alpha (tef1) genes were investigated. The results revealed that these collections belong to six species including Agaricus erectosquamosus, Agaricus pallidobrunneus, Agaricus subrufescens, and three new species. Agaricus thailandensis sp. nov. was found to belong to Agaricus sect. Minores, which is placed in Agaricus subg. Minores. Aagricus pseudoerectosquamosus sp. nov. was placed in Agaricus sect. Brunneopicti within Agaricus subg. Pseudochitonia. Furthermore, Agaricus lannaensis remains an incertae sedis in Agaricus subg. Pseudochitonia. Additionally, this study was proposed that A. pallidobrunneus was discovered in Thailand for the first time. Full descriptions, color photographs, illustrations, and phylogenetic trees are provided.
Isolation and Characterization of a Novel Salmonella Phage vB_SalP_TR2
Authors: Shang Yuting , Sun Qifan , Chen Hanfang , Wu Qingping , Chen Moutong , Yang Shuanghong , Du Mingzhu , Zha Fei , Ye Qinghua , Zhang Jumei
Published: June 2021

Salmonella is a widely distributed foodborne pathogen. The use of Salmonella phages as biocontrol agents has recently gained significant interest. Because the Salmonella genus has high diversity, efforts are necessary to identify lytic Salmonella phages focusing on different serovars. Here, five Salmonella phages were isolated from soil samples, and vB_SalP_TR2 was selected as a novel phage with high lytic potential against the host Salmonella serovar Albany, as well as other tested serovars, including Corvallis, Newport, Kottbus, and Istanbul. Morphological analyses demonstrated that phage vB_SalP_TR2 belongs to the Podoviridae family, with an icosahedral head (62 ± 0.5 nm in diameter and 60 ± 1 nm in length) and a short tail (35 ± 1 nm in length). The latent period and burst size of phage vB_SalP_TR2 was 15 min and 211 PFU/cell, respectively. It contained a linear dsDNA of 71,453 bp, and G + C content was 40.64%. Among 96 putative open reading frames detected, only 35 gene products were found in database searches, with no virulence or antibiotic resistance genes being identified. As a biological control agent, phage vB_SalP_TR2 exhibited a high temperature and pH tolerance. In vitro, it lysed most S. Albany after 24 h at 37°C with multiplicities of infection of 0.0001, 0.001, 0.01, 0.1, 1, 10, and 100. In food matrices (milk and chicken meat), treatment with phage vB_SalP_TR2 also reduced the number of S. Albany compared with that in controls. These findings highlighted phage vB_SalP_TR2 as a potential antibacterial agent for the control of Salmonella in food samples.
A Novel SARS-CoV-2 Viral Sequence Bioinformatic Pipeline Has Found Genetic Evidence That the Viral 3′ Untranslated Region (UTR) Is Evolving and Generating Increased Viral Diversity
Authors: Farkas Carlos , Mella Andy , Turgeon Maxime , Haigh Jody J.
Published: June 2021

An unprecedented amount of SARS-CoV-2 sequencing has been performed, however, novel bioinformatic tools to cope with and process these large datasets is needed. Here, we have devised a bioinformatic pipeline that inputs SARS-CoV-2 genome sequencing in FASTA/FASTQ format and outputs a single Variant Calling Format file that can be processed to obtain variant annotations and perform downstream population genetic testing. As proof of concept, we have analyzed over 229,000 SARS-CoV-2 viral sequences up until November 30, 2020. We have identified over 39,000 variants worldwide with increased polymorphisms, spanning the ORF3a gene as well as the 3′ untranslated (UTR) regions, specifically in the conserved stem loop region of SARS-CoV-2 which is accumulating greater observed viral diversity relative to chance variation. Our analysis pipeline has also discovered the existence of SARS-CoV-2 hypermutation with low frequency (less than in 2% of genomes) likely arising through host immune responses and not due to sequencing errors. Among annotated non-sense variants with a population frequency over 1%, recurrent inactivation of the ORF8 gene was found. This was found to be present in the newly identified B.1.1.7 SARS-CoV-2 lineage that originated in the United Kingdom. Almost all VOC-containing genomes possess one stop codon in ORF8 gene (Q27∗), however, 13% of these genomes also contains another stop codon (K68∗), suggesting that ORF8 loss does not interfere with SARS-CoV-2 spread and may play a role in its increased virulence. We have developed this computational pipeline to assist researchers in the rapid analysis and characterization of SARS-CoV-2 variation.
Horizontally Acquired Polysaccharide-Synthetic Gene Cluster From Weissella cibaria Boosts the Probiotic Property of Lactiplantibacillus plantarum
Authors: Gao Yuqi , Niu Mingze , Yu Xiaohui , Bao Tingting , Wu Zhaowei , Zhao Xin
Published: June 2021

Lactiplantibacillus plantarum are probiotic bacteria, maintaining the integrity of the gastrointestinal epithelial barrier, and preventing the infection of pathogenic bacteria. Exopolysaccharides (EPSs) are often involved in the probiotic property of L. plantarum. Here, we identified a new EPS-synthetic gene cluster, cpsWc, carrying 13 genes, laid on a large plasmid in a well-characterized probiotic L. plantarum strain LTC-113. The cpsWc gene cluster was horizontally acquired from Weissella cibaria, enhancing the biofilm formation ability of the host strain and its tolerance to harsh environmental stresses, including heat, acid, and bile. Transfer of cpsWc also conferred the probiotic properties to other L. plantarum strains. Moreover, cpsWc strengthened the adhesion of LTC-113 to intestinal epithelial cells. Both the cpsWc-carrying LTC-113 and its EPSs per se effectively attenuated the LPS-induced pro-inflammatory effect of intestinal epithelial cells, and inhibited the adhesion of pathogenic bacteria, such as S. typhimurium and E. coli by exclusion and competition. The newly identified cpsWc gene cluster emphasized the contribution of mobile EPS-synthetic element on the probiotic activity of L. plantarum, and shed a light on the engineering of probiotic bacteria.
GSK-3 Inhibition Modulates Metalloproteases in a Model of Lung Inflammation and Fibrosis
Authors: Cinetto Francesco , Ceccato Jessica , Caputo Ilaria , Cangiano Daniela , Montini Barbara , Lunardi Francesca , Piazza Maria , Agostini Carlo , Calabrese Fiorella , Semenzato Gianpietro , Rattazzi Marcello , Gurrieri Carmela , Scarpa Riccardo , Felice Carla , Vianello Fabrizio
Published: June 2021

Idiopathic pulmonary fibrosis (IPF) is mainly characterized by aberrant extracellular matrix deposition, consequent to epithelial lung injury and myofibroblast activation, and inflammatory response. Glycogen synthase kinase 3 (GSK-3) is a serine–threonine kinase involved in several pathways, and its inhibition has been already suggested as a therapeutic strategy for IPF patients. There is evidence that GSK-3 is able to induce matrix metalloproteinase (MMP) expression and that its inhibition modulates MMP expression in the tissues. The aim of our study was to investigate the role of GSK-3 and its inhibition in the modulation of MMP-9 and -2 in anin vivomouse model of lung fibrosis andin vitrousing different cell lines exposed to pro-inflammatory or pro-fibrotic stimuli. We found that GSK-3 inhibition down-modulates gene expression and protein levels of MMP-9, MMP-2, and their inhibitors TIMP-1 and TIMP-2 in inflammatory cells harvested from bronchoalveolar lavage fluid (BALF) of mice treated with bleomycin as well as in interstitial alveolar macrophages and cuboidalized epithelial alveolar cells. To the same extent, GSK-3 inhibition blunted the increased MMP-9 and MMP-2 activity induced by pro-fibrotic stimuli in a human lung fibroblast cell line. Moreover, the αSMA protein level, a marker of fibroblast-to-myofibroblast transition involved in fibrosis, was decreased in primary fibroblasts treated with TGFβ following GSK-3 inhibition. Our results confirm the implication of GSK-3 in lung inflammation and fibrosis, suggesting that it might play its role by modulating MMP expression and activity but also pushing fibroblasts toward a myofibroblast phenotype and therefore enhancing extracellular matrix deposition. Thus, its inhibition could represent a possible therapeutic strategy.
Functional Contribution of the Medial Prefrontal Circuitry in Major Depressive Disorder and Stress-Induced Depressive-Like Behaviors
Authors: Bittar Thibault P. , Labonté Benoit
Published: June 2021

Despite decades of research on the neurobiology of major depressive disorder (MDD), the mechanisms underlying its expression remain unknown. The medial prefrontal cortex (mPFC), a hub region involved in emotional processing and stress response elaboration, is highly impacted in MDD patients and animal models of chronic stress. Recent advances showed alterations in the morphology and activity of mPFC neurons along with profound changes in their transcriptional programs. Studies at the circuitry level highlighted the relevance of deciphering the contributions of the distinct prefrontal circuits in the elaboration of adapted and maladapted behavioral responses in the context of chronic stress. Interestingly, MDD presents a sexual dimorphism, a feature recognized in the molecular field but understudied on the circuit level. This review examines the recent literature and summarizes the contribution of the mPFC circuitry in the expression of MDD in males and females along with the morphological and functional alterations that change the activity of these neuronal circuits in human MDD and animal models of depressive-like behaviors.
Engagement of Neurotropic Viruses in Fast Axonal Transport: Mechanisms, Potential Role of Host Kinases and Implications for Neuronal Dysfunction
Authors: Richards Alexsia , Berth Sarah H. , Brady Scott , Morfini Gerardo
Published: June 2021

Much remains unknown about mechanisms sustaining the various stages in the life cycle of neurotropic viruses. An understanding of those mechanisms operating before their replication and propagation could advance the development of effective anti-viral strategies. Here, we review our current knowledge of strategies used by neurotropic viruses to undergo bidirectional movement along axons. We discuss how the invasion strategies used by specific viruses might influence their mode of interaction with selected components of the host’s fast axonal transport (FAT) machinery, including specialized membrane-bounded organelles and microtubule-based motor proteins. As part of this discussion, we provide a critical evaluation of various reported interactions among viral and motor proteins and highlight limitations of some in vitro approaches that led to their identification. Based on a large body of evidence documenting activation of host kinases by neurotropic viruses, and on recent work revealing regulation of FAT through phosphorylation-based mechanisms, we posit a potential role of host kinases on the engagement of viruses in retrograde FAT. Finally, we briefly describe recent evidence linking aberrant activation of kinase pathways to deficits in FAT and neuronal degeneration in the context of human neurodegenerative diseases. Based on these findings, we speculate that neurotoxicity elicited by viral infection may involve deregulation of host kinases involved in the regulation of FAT and other cellular processes sustaining neuronal function and survival.
High-Resolution Magnetic Resonance Black Blood Thrombus Imaging and Serum D-Dimer in the Confirmation of Acute Cortical Vein Thrombosis
Authors: Song Si-ying , Dornbos David , Lan Duo , Jiao Bao-lian , Wan Shu-ling , Guo Yi-bing , Ding Yu-chuan , Yang Qi , Ji Xun-ming , Meng Ran
Published: June 2021

Cerebral cortical vein thrombosis (CCVT) is often misdiagnosed because of its non-specific diagnostic symptoms. Here, we analyzed a cohort of patients with CCVT in hopes of improving understandings and treatments of the disease. A total of 23 patients with CCVT (confirmed with high-resolution imaging), who had been diagnosed between 2017 and 2019, were enrolled in this cohort study. Baseline demographics, clinical manifestations, laboratory data, radiological findings, treatment, and outcomes were collected and analyzed. Fourteen females and nine males were enrolled (mean age: 32.7 ± 11.9 years), presenting in the acute (within 7 days, n = 9), subacute (8–30 days, n = 7), and chronic (over 1 month, n = 7) stages. Headaches (65.2%) and seizures (39.1%) were the most common symptoms. Abnormally elevated plasma D-dimers were observed in the majority of acute stage patients (87.5%). The diagnostic accuracy of contrast-enhanced magnetic resonance venography (CE-MRV) and high-resolution magnetic resonance black-blood thrombus imaging (HR-MRBTI) in detecting CCVT were 57.1 and 100.0%, respectively. All patients had good functional outcomes after 6-month of standard anticoagulation (mRS 0–1) treatment. However, four CCVT patients that had cases involving multiple veins showed symptom relief after batroxobin therapy (p = 0.030). HR-MRBTI may be a fast and accurate tool for non-invasive CCVT diagnosis. HR-MRBTI combined with D-dimer can also precisely identify the pathological stage of CCVT. Batroxobin may safely accelerate cortical venous recanalization in combination with anticoagulation. Follow-up studies with larger sample sizes are suggested to evaluate the safety and efficacy of batroxobin for treating CCVT.
Neurofilament Light Chain as Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
Authors: Verde Federico , Otto Markus , Silani Vincenzo
Published: June 2021

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related currently incurable neurodegenerative diseases. ALS is characterized by degeneration of upper and lower motor neurons causing relentless paralysis of voluntary muscles, whereas in FTD, progressive atrophy of the frontal and temporal lobes of the brain results in deterioration of cognitive functions, language, personality, and behavior. In contrast to Alzheimer’s disease (AD), ALS and FTD still lack a specific neurochemical biomarker reflecting neuropathology ex vivo. However, in the past 10 years, considerable progress has been made in the characterization of neurofilament light chain (NFL) as cerebrospinal fluid (CSF) and blood biomarker for both diseases. NFL is a structural component of the axonal cytoskeleton and is released into the CSF as a consequence of axonal damage or degeneration, thus behaving in general as a relatively non-specific marker of neuroaxonal pathology. However, in ALS, the elevation of its CSF levels exceeds that observed in most other neurological diseases, making it useful for the discrimination from mimic conditions and potentially worthy of consideration for introduction into diagnostic criteria. Moreover, NFL correlates with disease progression rate and is negatively associated with survival, thus providing prognostic information. In FTD patients, CSF NFL is elevated compared with healthy individuals and, to a lesser extent, patients with other forms of dementia, but the latter difference is not sufficient to enable a satisfying diagnostic performance at individual patient level. However, also in FTD, CSF NFL correlates with several measures of disease severity. Due to technological progress, NFL can now be quantified also in peripheral blood, where it is present at much lower concentrations compared with CSF, thus allowing less invasive sampling, scalability, and longitudinal measurements. The latter has promoted innovative studies demonstrating longitudinal kinetics of NFL in presymptomatic individuals harboring gene mutations causing ALS and FTD. Especially in ALS, NFL levels are generally stable over time, which, together with their correlation with progression rate, makes NFL an ideal pharmacodynamic biomarker for therapeutic trials. In this review, we illustrate the significance of NFL as biomarker for ALS and FTD and discuss unsolved issues and potential for future developments.
The Preparation, Antioxidant Activity Evaluation, and Iron-Deficient Anemic Improvement of Oat (Avena sativa L.) Peptides–Ferrous Chelate
Authors: Yuanqing He , Pengyao Yang , Yangyang Ding , Min Chen , Rui Guo , Yuqing Duan , Haihui Zhang , Haile Ma
Published: June 2021

Iron-chelating peptides have been widely considered as one of the best iron supplements to alleviate the iron deficiency. In this study, a novel oat peptides–ferrous (OP-Fe2+) chelate was prepared from antioxidant oat peptides obtained in the laboratory of the authors. The optimal preparation condition was obtained through the single-factor and response surface methodology, and the chelating rate could reach up to 62.6%. After chelation, the OP-Fe2+ chelate exhibited a significantly higher 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity than oat peptides. It was discovered that the hemoglobin concentration and the number of red blood cell levels in OP-Fe2+-treated iron-deficient anemic (IDA) rats were significantly higher than untreated IDA rats. The OP-Fe2+ chelate could also improve the hypertrophy of the spleen, serum iron (SI), total iron and binding capacity, and serum ferritin levels in the IDA rats. In addition, the OP-Fe2+ treatment significantly increased the antioxidant activities of super oxidase and glutathione in the liver homogenate of the IDA rats. Therefore, the OP-Fe2+ chelate is an effective type of iron supplement for IDA rats, which could be a promising source with anti-anemia and antioxidant activity.
PDE2 Inhibits PKA-Mediated Phosphorylation of TFAM to Promote Mitochondrial Ca2+-Induced Colorectal Cancer Growth
Authors: Zhao Yilin , Wang Yaya , Zhao Jing , Zhang Zhaohui , Jin Mingpeng , Zhou Feng , Jin Chao , Zhang Jing , Xing Jinliang , Wang Nan , He Xianli , Ren Tingting
Published: June 2021

Growing evidence indicates that the dysregulation of mitochondrial calcium (Ca2+) plays a critical role in the growth of tumor cells, including colorectal cancer (CRC). However, the underling mechanism is not fully elucidated. In this study, the regulatory effects of mitochondrial Ca2+ on phosphodiesterase 2 (PDE2)/cAMP/PKA axis and the phosphorylation of mitochondrial transcription factor A (TFAM) as well as the growth of CRC cells were systematically investigated both in vitro and in vivo. Our findings demonstrated that MCU-induced mitochondrial Ca2+ uptake activated mitochondrial PDE2 in CRC cells. Moreover, overexpression MCU in CRC led to a 1.9-fold increase in Ca2+ uptake compared to control cells. However, knockdown of MCU resulted in 1.5-fould decrease in Ca2+ uptake in mitochondria compared to the controls. Activation of mitochondrial PDE2 significantly inhibited the activity of mitochondrial protein kinase A (PKA), which subsequently leads to decreased phosphorylation of TFAM. Our data further revealed that PKA regulates the phosphorylation of TFAM and promotes the degradation of phosphorylated TFAM. Thus, TFAM protein levels accumulated in mitochondria when the activity of PKA was inhibited. Overall, this study showed that the overexpression of MCU enhanced CRC growth through promoting the accumulation of TFAM proteins in mitochondria. Conversely, knockdown of MCU in CRC cells resulted in decreased CRC growth. Collectively, these data suggest that the mitochondrial Ca2+-activated PDE2/cAMP/PKA axis plays a key role in regulating TFAM stability and the growth of CRC cells.
Longitudinal Follow-Up of Children Born Preterm: Neurodevelopment From 2 to 10 Years of Age
Authors: Jansen Lisette , Peeters-Scholte Cacha M. P. C. D. , Berg-Huysmans Annette A. van den , Klink Jeanine M. M. van , Rijken Monique , Egmond-van Dam Janneke C. van , Vermeiren Robert R. J. M. , Steggerda Sylke J.
Published: June 2021

Objective: To investigate the rate and stability of impairments in children born preterm by assessing (1) early and school-age outcome in four developmental domains and (2) individual changes in outcome at both timepoints.

Design: Prospective, longitudinal cohort study in children born in 2006–2007, <32 weeks' gestation. Follow-up at 2 and 10 years of age included standardized neurological, motor, cognitive and behavioral assessments. Children were categorized as having no, mild or moderate-severe impairment in these four domains. A composite impairment score was composed and the number of domains with impairments counted. For each child, individual outcomes at both timepoints were compared.

Results: Follow-up at both time-points was available in 71/113(63%) children. At group level, there were no significant changes in the severity of impairments per domain. However, at individual level, there were less children with a mild abnormal composite score at 10 years of age (44 vs. 20%; p = 0.006), and more with a moderate-severe abnormal composite score (12 vs. 35%; p = 0.001). Especially children with normal/mild outcome at 2 years were likely to shift to other outcome categories over time.

Conclusions: Children with early severe impairment are likely experiencing impairments later on, but early normal/mild abnormal outcomes should be interpreted with care, considering the large individual shifts over time. Long-term follow-up in all children born very preterm should therefore be continued to at least school-age.