bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Mechanisms of Leukocyte Migration and Its Potential Targeting—Lessons Learned From MKL1/SRF-Related Primary Immunodeficiency Diseases
Authors: Sprenkeler Evelien G. G. , Guenther Carla , Faisal Imrul , Kuijpers Taco W. , Fagerholm Susanna C.
Published: February 2021

Megakaryoblastic leukemia 1 (MKL1) deficiency is one of the most recently discovered primary immunodeficiencies (PIDs) caused by cytoskeletal abnormalities. These immunological “actinopathies” primarily affect hematopoietic cells, resulting in defects in both the innate immune system (phagocyte defects) and adaptive immune system (T-cell and B-cell defects). MKL1 is a transcriptional coactivator that operates together with serum response factor (SRF) to regulate gene transcription. The MKL/SRF pathway has been originally described to have important functions in actin regulation in cells. Recent results indicate that MKL1 also has very important roles in immune cells, and that MKL1 deficiency results in an immunodeficiency affecting the migration and function of primarily myeloid cells such as neutrophils. Interestingly, several actinopathies are caused by mutations in genes which are recognized MKL(1/2)-dependent SRF-target genes, namely ACTB, WIPF1, WDR1, and MSN. Here we summarize these and related (ARPC1B) actinopathies and their effects on immune cell function, especially focusing on their effects on leukocyte adhesion and migration. Furthermore, we summarize recent therapeutic efforts targeting the MKL/SRF pathway in disease.
Interleukin-22 Influences the Th1/Th17 Axis
Authors: Lindahl Hannes , Olsson Tomas
Published: February 2021

Interleukin-22 (IL-22) is secreted by a wide range of immune cells and its downstream effects are mediated by the IL-22 receptor, which is present on non-immune cells in many organs throughout the body. IL-22 is an inflammatory mediator that conditions the tissue compartment by upregulating innate immune responses and is also a homeostatic factor that promotes tissue integrity and regeneration. Interestingly, the IL-22 system has also been linked to many T cell driven inflammatory diseases. Despite this, the downstream effects of IL-22 on the adaptive immune system has received little attention. We have reviewed the literature for experimental data that suggest IL-22 mediated effects on T cells, either transduced directly or via mediators expressed by innate immune cells or non-immune cells in response to IL-22. Collectively, the reviewed data indicate that IL-22 has a hitherto unappreciated influence on T helper cell polarization, or the secretion of signature cytokines, that is context dependent but in many cases results in a reduction of the Th1 type response and to some extent promotion of regulatory T cells. Further studies are needed that specifically address these aspects of IL-22 signaling, which can benefit the understanding and treatment of a wide range of diseases.
WSB1 and IL21R Genetic Variants Are Involved in Th2 Immune Responses to Ascaris lumbricoides
Authors: Carneiro Valdirene Leão , da Silva Hugo Bernardino Ferreira , Queiroz Gerson de Almeida , Veiga Rafael Valente , Oliveira Pablo Rafael Silveira , Carneiro Norma Vilany Queiroz , Pires Anaque de Oliveira , da Silva Raimon Rios , Sena Flavia , Belitardo Emilia , Nascimento Regina , Silva Milca , Marques Cintia Rodrigues , Costa Ryan dos Santos , Alcantra-Neves Neuza Maria , Barreto Mauricio L. , Cooper Philip J. , Figueiredo Camila Alexandrina
Published: February 2021

Genetic and epigenetic factors are considered to be critical for host-parasite interactions. There are limited data on the role of such factors during human infections with Ascaris lumbricoides. Here, we describe the potential role of genetic factors as determinants of the Th2 immune response to A. lumbricoides in Brazilian children. Stool samples were collected from the children to detect A. lumbricoides by microscopy and peripheral blood leukocytes (PBLs) were cultured in whole blood cultures for detection of cytokines (IL-5, IL-10, and IL-13) in vitro. Levels of anti-A. lumbricoides IgE and IgG4 were measured in plasma. DNA was extracted from PBLs and genotyped using Illumina 2.5 Human Omni Beadchip. Candidate genes associated with A. lumbricoides responses were identified and SNVs in these selected genes associated with the Th2 immune response to A. lumbricoides. Haplotype, gene expression, and epigenetic analyses were done to identify potential associations with Th2 immune responses. GWAS on samples from 1,189 children identified WSB1 as a candidate gene, and IL-21R was selected as a biologically relevant linked gene for further analysis. Variants in WSB1 and IL21R were associated with markers of Th2 immune responses: increased A. lumbricoides-specific IgE and IL-5/IL-13 by PBLs from infected compared to uninfected individuals. In infected children, WSB1 but not IL21R gene expression was suppressed and increased methylation was observed in the WSB1 promoter region. This is the first study to show an association between genetic variants in WSB1 and IL21R and Th2 immune responses during A. lumbricoides infections in children. WSB1/IL21R pathways could provide a potential target for the treatment of Th2-mediated diseases.
Differential miRNA Profiles Correlate With Disparate Immunity Outcomes Associated With Vaccine Immunization and Chlamydial Infection
Authors: Howard Simone , Richardson Shakyra , Benyeogor Ifeyinwa , Omosun Yusuf , Dye Kamran , Medhavi Fnu , Lundy Stephanie , Adebayo Olayinka , Igietseme Joseph U. , Eko Francis O.
Published: February 2021

Vaccine-induced immune responses following immunization with promising Chlamydia vaccines protected experimental animals from Chlamydia-induced upper genital tract pathologies and infertility. In contrast, primary genital infection with live Chlamydia does not protect against these pathologies. We hypothesized that differential miRNA profiles induced in the upper genital tracts (UGT) of mice correlate with the disparate immunity vs. pathologic outcomes associated with vaccine immunization and chlamydial infection. Thus, miRNA expression profiles in the UGT of mice after Chlamydia infection (Live EB) and immunization with dendritic cell (DC)-based vaccine (DC vaccine) or VCG-based vaccine (VCG vaccine) were compared using the NanoString nCounter Mouse miRNA assay. Of the 602 miRNAs differentially expressed (DE) in the UGT of immunized and infected mice, we selected 58 with counts >100 and p-values < 0.05 for further analysis. Interestingly, vaccine immunization and Chlamydia infection induced the expression of distinct miRNA profiles with a higher proportion in vaccine-immunized compared to Chlamydia infected mice; DC vaccine (41), VCG vaccine (23), and Live EB (15). Hierarchical clustering analysis showed notable differences in the uniquely DE miRNAs for each experimental group, with DC vaccine showing the highest number (21 up-regulated, five down-regulated), VCG vaccine (two up-regulated, five down-regulated), and live EB (two up-regulated, four down-regulated). The DC vaccine-immunized group showed the highest number (21 up-regulated and five down-regulated compared to two up-regulated and four down-regulated in the live Chlamydia infected group). Pathway analysis showed that the DE miRNAs target genes that regulate several biological processes and functions associated with immune response and inflammation. These results suggest that the induction of differential miRNA expression plays a significant role in the disparate immunity outcomes associated with Chlamydia infection and vaccination.
Case Report: A Case of Acute Cellular Rejection Due to Atopic Dermatitis Exacerbation 3 Years After Heart Transplantation
Authors: Kakuda Nobutaka , Amiya Eisuke , Hatano Masaru , Maki Hisataka , Bujo Chie , Tsuji Masaki , Narita Koichi , Fujita Kanna , Ishida Junichi , Ono Minoru , Komuro Issei
Published: February 2021

Background

Little evidence has been presented about the association between previous atopic/allergic disease and graft rejection after solid organ transplantation. Thus, we present a case wherein acute cellular rejection (ACR) after heart transplantation (HTx) was noted along with exacerbation of atopic disease.

Case Summary

A 32-year-old man was admitted at our hospital for regular monitoring of graft rejection. He had undergone heart transplant 3 years prior due to dilated cardiomyopathy. Echocardiogram revealed good biventricular function, and no abnormal findings were found in blood sampling tests. However, biopsy showed moderate ACR [Grade 2R(ISHLT 2004)/3A(ISHLT 1990)], which required twice-repeated steroid pulses with intensified immunosuppression. Meanwhile, his atopic dermatitis, which was diagnosed before having heart failure, was getting worse for the past 6 months. The exacerbation of atopic dermatitis was presumed to be related to the development of the intractable cellular rejection.

Discussion

This case suggested the association of atopic disease and graft rejection after HTx. We examined 76 patients from a cohort of previous studies who underwent HTx at our hospital, which suggested that patients with atopic/allergic disorders such as atopic dermatitis and asthma tended to have a significantly higher frequency of moderate rejection than non-allergic patients. (p = 0.012; Fisher’s exact test). Our case also suggests that exacerbation of atopic dermatitis might cause graft rejection of the transplanted organ, so that it is important to carefully evaluate the risk of graft rejection if there is a previous history of atopic/allergic disease.
Role of Peripheral Immune Cells for Development and Recovery of Chronic Pain
Authors: Bethea John R. , Fischer Roman
Published: February 2021

Chronic neuropathic pain (CNP) is caused by a lesion or disease of the somatosensory nervous system. It affects ~8% of the general population and negatively impacts a person's level of functioning and quality of life. Its resistance to available pain therapies makes CNP a major unmet medical need. Immune cells have been shown to play a role for development, maintenance and recovery of CNP and therefore are attractive targets for novel pain therapies. In particular, in neuropathic mice and humans, microglia are activated in the dorsal horn and peripheral immune cells infiltrate the nervous system to promote chronic neuroinflammation and contribute to the initiation and progression of CNP. Importantly, immunity not only controls pain development and maintenance, but is also essential for pain resolution. In particular, regulatory T cells, a subpopulation of T lymphocytes with immune regulatory function, and macrophages were shown to be important contributors to pain recovery. In this review we summarize the interactions of the peripheral immune system with the nervous system and outline their contribution to the development and recovery of pain.
Development and Characterization of Nanobodies Targeting the Kupffer Cell
Authors: Zheng Fang , Zhou Jinhong , Ouyang Zhenlin , Zhang Jiaxin , Wang Xinyi , Muyldermans Serge , Van Ginderachter Jo , Devoogdt Nick , Wen Yurong , Schoonooghe Steve , Raes Geert
Published: February 2021

Nanobodies that are derived from single-chain antibodies of camelids have served as powerful tools in diagnostics, therapeutics and investigation of membrane receptors' structure and function. In this study, we developed a series of nanobodies by a phage display screening building from lymphocytes isolated from an alpaca immunized with recombinant mouse Kupffer cell receptor Clec4F, which is involved in pathogen recognition by binding to galactose and N-acetylgalactosamine. Bio-panning selections retrieved 14 different nanobodies against Clec4F with an affinity ranging from 0.2 to 2 nM as determined by SPR. Those nanobodies mainly recognize 4 different epitopes as analyzed via competitive epitope binning. By analysis of the radioactivity in each organ after injection of 99mTc labeled Clec4F nanobodies in naïve mice, we found that these nanobodies are targeting the liver. Furthermore, we performed a structural characterization at atomic resolution of two of the Clec4F nanobodies from different epitope groups, which revealed distinct features within the CDR2 and CDR3 regions. Taken together, we developed a series of nanobodies targeting multiple distinct recognition epitopes of the Kupffer cell-specific receptor Clec4F which may be useful for its structural and functional investigation as well as for use as molecular imaging and therapeutic agents.
Conceptual Design of a Modular Floating Multi-Purpose Island
Authors: Drummen Ingo , Olbert Gerrit
Published: February 2021

The design of a modular floating multi-purpose island inherently involves interaction within a group with a large range of backgrounds such as engineering, architecture, sociology, climate modeling, and more. A heuristic design approach was adopted for future island developers to make a first conceptual design. Four major design considerations were distinguished to discretize the design space: module size, module shape, module principle, and module connection and mooring. For each consideration a set of evaluation criteria were defined. This article describes the heuristic conceptual design procedure that was applied to the design of a modular floating island for offshore energy, offshore accommodation, aquafarming, and offshore transport and logistics. Two reference installation scenarios with a different respective focus of functionality, located in the North Sea and in the Mediterranean Sea, were created as a basis for the design. The first step of the design procedure consisted of a participatory process involving stakeholders and experts to rate design options for each category of design considerations based on the evaluation criteria and with regard to the installation scenario. As a result, all design configurations could be associated with an overall rating. In a second step, the most favorable designs identified during the participatory design procedure were investigated numerically to assess force distribution throughout the island when exposed to wave and current loads. The numerical results indicate that contrary to initial estimates during Phase 1, wave forces on an island consisting of quadrangular modules do not significantly exceed those experienced by triangular base shapes. As quadrangular modules can be shown to provide a higher Ground-Space-Index, this gives them a distinct advantage. As a result of the design process for this application, a barge-like, square structure with a base size of 45 m was chosen as the base module.
Abundance of Environmental Data vs. Low Public Interest in Climate and Ocean Issues. Where Is the Missing Link?
Authors: Zielinski Tymon , Bolzacchini Ezio , Evans Karen , Ferrero Luca , Gregorczyk Klaudia , Kijewski Tomasz , Kotynska-Zielinska Izabela , Mrowiec Patrycja , Oleszczuk Barbara , Pakszys Paulina , Piechowska Ewa , Piwowarczyk Joanna , Sobieszczanski Jan , Wichorowski Marcin
Published: February 2021

Climate change and associated modification of the ocean is a fact, however, it seems to be the most undervalued and little understood “pandemic” challenge of this century. We live in a world where environmental data is increasingly being amassed and models are generating finer scale and increasingly dense numbers of outputs, resulting in the production of high level scientific information on climate and ocean. However, the knowledge generated is often inaccessible, incomprehensible and misunderstood by society. Given that society has access to many levels of information through various forms of media, how do we better share this knowledge, and improve understanding of how society is impacting their immediate and remote surroundings and what behavioral changes are needed for reducing those impacts? In this paper, we assess the level of environmental and ocean awareness among young learners. We argue that, despite the wide range of environmental data available and a common use of a broad range of media, this group is not aware of or interested in climate related issues. This paper highlights the challenges in bringing researchers, data managers and educators together to provide consistent, up-to-date messages that can appeal to and can be understood by modern societies. It also highlights insufficiencies in environmental school education, including those concerning the “uncertainty” concept, which is a fundamental part of any scientific process. In identifying these challenges, we propose a pathway for improving societal knowledge on climate and ocean changes that takes advantage of the technological abilities for environmental data collection, storage and processing, global and regional research, as well as good practices in ocean literacy and climate and ocean education.
Hysterectomy and Adnexal Procedures by Vaginal Natural Orifice Transluminal Endoscopic Surgery (VNH): Initial Findings From a Korean Surgeon
Authors: Kim Myeong-Seon , Noh Joseph J. , Kim Tae-Joong
Published: February 2021

Objective: To evaluate feasibility and safety of hysterectomy and adnexal procedures by vaginal natural orifice transluminal endoscopic surgery (vNOTES).

Study Design: This is a prospective observational study at a tertiary center and teaching University hospital. We enrolled prospectively 34 patients with benign diseases sequentially.

Results: We measured baseline characteristics, surgical data, and pain score (VAS) after surgery. We surveyed before/after surgery. The time of port installation and each stage of surgery was measured. The learning curve was assessed through the graph according to the number of operations using linear and logarithmic regression curve estimation. The complications of surgery were investigated. The median age of the patients was 47.5 years (38–73). Median BMI was 22.4 (18.2–30.0). 20 cases of leiomyoma, four cases of adenomyosis, three cases of uterine prolapse, four cases of endometrial hyperplasia, and three cases of CIN were diagnosed. The median uterine weight was 180.0 g. The median port-installation time was 15.0 min (range, 4–35 min) and median total operation time was 85.5 min (range 43.0–132.0). Complications occurred in three patients. Two cases of bladder injury happened during vesicovaginal space dissection before the installation of the Wound Retractor (WR). One patient underwent transumbilical single-port surgery because of late-onset postoperative bleeding on the 13th postoperative day. The mean postoperative VAS scores were 3.36 immediately after surgery and 3.06, 2.79, and 2.45 at 6, 12, and 24 h after surgery, respectively. In continuous variable analysis, we detected a correlation between port-installation time and postoperative VAS ≥4 (pain score as need for medication). Based on a learning curve, port-installation time and total operation time appeared to reach the proficiency level by the 10th case.

Conclusions: Although there were three complications, vNOTES offers advantages to patients and surgeons. More surgical techniques will be developed in vNOTES.
CircHIPK3: Key Player in Pathophysiology and Potential Diagnostic and Therapeutic Tool
Authors: Zhou Jiang , Wang Baisheng , Bin Xin , Xie Changqing , Li Bo , Liu Ousheng , Tang Zhangui
Published: February 2021

A large number of studies in China and other countries have confirmed that circularHIPK3 (circHIPK3) plays an important role in the pathophysiological processes of various diseases. Through the action of sponge miRNA (miR), circHIPK3 regulates cell proliferation, differentiation, and migration, and plays a key role in disease processes. By referring to a large number of research reports, this article explores the specific functional role of circHIPK3 in fibrotic diseases, cancer, and other diseases. This review aims to clarify the role of circHIPK3 in disease processes in order to aid further studies into the specific pathogenesis and clinical diagnosis of various diseases and provide new ideas for treatments.
Machine Learning for the Prediction of Red Blood Cell Transfusion in Patients During or After Liver Transplantation Surgery
Authors: Liu Le-Ping , Zhao Qin-Yu , Wu Jiang , Luo Yan-Wei , Dong Hang , Chen Zi-Wei , Gui Rong , Wang Yong-Jun
Published: February 2021

Aim: This study aimed to use machine learning algorithms to identify critical preoperative variables and predict the red blood cell (RBC) transfusion during or after liver transplantation surgery.

Study Design and Methods: A total of 1,193 patients undergoing liver transplantation in three large tertiary hospitals in China were examined. Twenty-four preoperative variables were collected, including essential population characteristics, diagnosis, symptoms, and laboratory parameters. The cohort was randomly split into a train set (70%) and a validation set (30%). The Recursive Feature Elimination and eXtreme Gradient Boosting algorithms (XGBOOST) were used to select variables and build machine learning prediction models, respectively. Besides, seven other machine learning models and logistic regression were developed. The area under the receiver operating characteristic (AUROC) was used to compare the prediction performance of different models. The SHapley Additive exPlanations package was applied to interpret the XGBOOST model. Data from 31 patients at one of the hospitals were prospectively collected for model validation.

Results: In this study, 72.1% of patients in the training set and 73.2% in the validation set underwent RBC transfusion during or after the surgery. Nine vital preoperative variables were finally selected, including the presence of portal hypertension, age, hemoglobin, diagnosis, direct bilirubin, activated partial thromboplastin time, globulin, aspartate aminotransferase, and alanine aminotransferase. The XGBOOST model presented significantly better predictive performance (AUROC: 0.813) than other models and also performed well in the prospective dataset (accuracy: 76.9%).

Discussion: A model for predicting RBC transfusion during or after liver transplantation was successfully developed using a machine learning algorithm based on nine preoperative variables, which could guide high-risk patients to take appropriate preventive measures.
Clinical Aspects of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis With Severe Ocular Complications in South Korea
Authors: Kim Mee Kum , Yoon Kyung Chul , Yoon Sook Hyun , Seo Kyoung Yul
Published: February 2021

This review describes the current knowledge regarding genetic susceptibilities and treatment strategies for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), with ocular complications, in Korea. In a case-control study, the gene frequencies of both HLA-A*0206 (20.0%) and HLA-Cw*0304 (15.0%) increased but the gene frequency of HLA-Cw*0303 (1.3%) decreased with cold medicine (CM)-SJS/TEN with severe ocular complications (SOCs). In a case-series, positive genotyping of HLA-B*5801 was 80.0% in allopurinol-induced SJS/TEN without SOCs. In a genome-wide association study, HLA-A*0206 was substantially related to CM-SJS/TEN with SOCs. Both HLA-A*0206 and prostaglandin-E receptor 3 (PTGER3) single nucleotide polymorphism (SNP) rs1327464 exert a synergistic effect on SOCs in CM-SJS/TEN. In the acute stage, conventional procedures, amniotic membrane transplantation or suture-less amniotic contact lenses are applied. Applications of intravenous Immunoglobulin (IVIG) or mega-dose steroids are attempted in patients with high acute ocular and systemic involvement scores. In the chronic stage, keratolimbal transplantation and penetrating keratoplasty are the standard procedures. Either autologous nasal or oral mucosal grafts, or biomaterial-free cultured oral mucosal epithelial cell sheets are transplanted as alternative therapies. Deep anterior lamellar keratoplasty is attempted. Combined photodynamic therapy with intrastromal bevacizumab injection or intense pulse laser are used to resolve chronic ocular complication. Corneoscleral contact lenses are available for a visual rehabilitation. As a last resort, Seoul-type keratoprosthesis had been transplanted. There are unmet needs to standardize nationwide ocular grading system and to correct tarsal scarring using mucosal grafting. This review provides a perspective on the current practices to treat ocular complications in SJS/TEN.
Evaluation of the Clinical Systems for Polymyxin Susceptibility Testing of Clinical Gram-Negative Bacteria in China
Authors: Zhu Ying , Jia Peiyao , Zhou Menglan , Zhang Jingjia , Zhang Ge , Kang Wei , Duan Simeng , Wang Tong , Xu Yingchun , Yang Qiwen
Published: February 2021

Objectives

The performance of mainstream commercial antimicrobial susceptibility testing systems on polymyxins has not been well evaluated in China. In this study, three antimicrobial susceptibility testing systems were evaluated for polymyxin B and colistin.

Methods

The MICs of 257 Gram-negative strains collected from clinical cases and livestock were determined and analyzed. Using Broth Microdilution as the gold standard, the performance of VITEK 2® COMPACT, PhoenixTM M50, and Bio-kont AST System were evaluated. Essential agreement (EA), category agreement (CA), very major error (VME), and major error (ME) were calculated for comparison. The results of mcr-1 positive strains were separately discussed.

Results

The EA, CA, VME, and ME to polymyxin B for Bio-kont were 83.5, 95.6, 13.1, and 0.6%, respectively. The EAs, CAs, VMEs, and MEs to colistin were as follows: Bio-kont, 86.7%/96.5%/7.2%/1.7%; Vitek 2, 64.2%/86.8%/41.0%/0%, and Phoenix M50, 92.9%/92.9%/21.7%/0%. The performance of Bio-kont to polymyxin B and colistin for Pseudomonas spp. (EA, CA < 90%, VME > 1.5%, ME = 5.6%/10%) and Enterobacter spp. (EA, CA < 90%, VME > 1.5% and ME = 0%), Vitek to colistin for most genera, and Phoenix to colistin for Enterobacter spp. (EA, CA < 90%, VME > 1.5%, ME = 0%) were unsatisfactory compared with other genera. The performance of Bio-kont to polymyxins for Escherichia spp. and Phoenix to colistin for Citrobacter spp., Escherichia spp., and Klebsiella spp., which all met the CLSI standard, were satisfactory. When the susceptibility of mcr-1 positive E. coli was tested, Bio-kont and Phoenix M50 presented excellent performance with no category errors, while Vitek 2 performed a high VME (25.5%).

Conclusion

With relatively more accurate results for polymyxin B and colistin and lower VME, Bio-kont has an advantage in polymyxin antimicrobial susceptibility testing, especially for Escherichia spp., Klebsiella spp., Citrobacter spp. and Acinetobacter spp.
Impact of Phosphate Availability on Membrane Lipid Content of the Model Strains, Streptomyces lividans and Streptomyces coelicolor
Authors: Lejeune Clara , Abreu Sonia , Chaminade Pierre , Dulermo Thierry , David Michelle , Werten Sebastiaan , Virolle Marie-Joelle
Published: February 2021

In this issue we demonstrated that the phospholipid content of Streptomyces lividans varies greatly with Pi availability being was much lower in Pi limitation than in Pi proficiency whereas that of Streptomyces coelicolor varied little with Pi availability. In contrast the content in phosphate free ornithine lipids was enhanced in both strains in condition of phosphate limitation. Ornithine lipids biosynthesis starts with the N-acylation of ornithine to form lyso-ornithine that is then O-acylated to yield ornithine lipid. The operon sco1222-23 was proposed to be involved in the conversion of specific amino acids into ornithine in condition of phosphate limitation whereas the sco0921-20 operon encoding N- and O-acyltransferase, respectively, was shown to be involved in the biosynthesis of these lipids. The expression of these two operons was shown to be under the positive control of the two components system PhoR/PhoP and thus induced in phosphate limitation. The expression of phoR/phoP being weak in S. coelicolor, the poor expression of these operons resulted into a fivefold lower ornithine lipids content in this strain compared to S. lividans. In the deletion mutant of the sco0921-20 operon of S. lividans, lyso-ornithine and ornithine lipids were barely detectable and TAG content was enhanced. The complementation of this mutant by the sco0921-20 operon or by sco0920 alone restored ornithine lipids and TAG content to wild type level and was correlated with a twofold increase in the cardiolipin content. This suggested that SCO0920 bears, besides its broad O-acyltransferase activity, an N-acyltransferase activity and this was confirmed by the detection of lyso-ornithine in this strain. In contrast, the complementation of the mutant by sco0921 alone had no impact on ornithine lipids, TAG nor cardiolipin content but was correlated with a high lyso-ornithine content. This confirmed that SCO0921 is a strict N-acyltransferase. However, interestingly, the over-expression of the sco0921-20 operon or of sco0921 alone in S. coelicolor, led to an almost total disappearance of phosphatidylinositol that was correlated with an enhanced DAG and TAG content. This suggested that SCO0921 also acts as a phospholipase C, degrading phosphatidylinositol to indirectly supply of phosphate in condition of phosphate limitation.
Taxonomic Description and Genome Sequence of Christensenella intestinihominis sp. nov., a Novel Cholesterol-Lowering Bacterium Isolated From Human Gut
Authors: Zou Yuanqiang , Xue Wenbin , Lin Xiaoqian , Hu Tongyuan , Liu Shao-Wei , Sun Cheng-Hang , Luo Guangwen , Lv Mei , Dai Ying , Kristiansen Karsten , Xiao Liang
Published: February 2021

A Gram-staining-negative, non-spore-forming, short, straight rod, non-motile, and obligate anaerobic bacterial strain, AF73-05CM02T, was isolated from a fecal sample of a 30 years old healthy male living in Shenzhen, China. Colonies were approximately 0.2 mm in diameter, beige, and circular after 4 days of incubation on PYG agar under anaerobic conditions at 37°C. Strain AF73-05CM02T grew in a temperature range between 30 and 42°C and a pH range from 6.0 to 8.5, with optimum growth at 37–42°C and pH 7.0. 16S rRNA gene sequence analysis demonstrated that strain AF73-05CM02T belongs to the genus Christensenella and showed the highest level of sequence similarity (98.68%) with Christensenella minuta DSM 22607T. The predominant fatty acids of strain AF73-05CM02T were C10:0 (7.5%), iso-C11:0 (5.6%), C12:0 (7.2%), C14:0 (46.6%), iso-C15:0 (7.4%), C16:0 (9.7%), and C18:1 ω9c (6.9%). Acetic acid, formic acid, butyric acid, and lactic acid were the end products of glucose fermentation. The strain was negative for catalase, indole production, and hydrolysis of gelatin. Genomic relatedness analyses based on average nucleotide identity (ANI) indicated that strain AF73-05CM02T significantly differed from other species of the genus Christensenella, showing ANI values less than 82.89% with the phylogenetically closest species. The G + C content of the genomic DNA was 52.07 mol% from the genome sequence, which differs from that of Christensenella minuta. Several physiological, biochemical, and genotypic properties differentiated the novel bacterial strain from the related species, indicating that the strain represents a new species of the genus Christensenella for which the name Christensenella intestinihominis sp. nov. is proposed, with strain AF73-05CM02T ( = CGMCC 1.5207T = DSM 103477T ) being the type strain. The following study explored the cholesterol-lowering function of strains AF73-05CM02T and Christensenella minuta DSM 22067T and revealed that the two strains exhibit the capacity for removing cholesterol with efficiency rates of 36.6 and 54.3% and produce exopolysaccharide of 234 and 271 mg/L, respectively.
Discovery of Cymopolyphenols A–F From a Marine Mesophotic Zone Aaptos Sponge-Associated Fungus Cymostachys sp. NBUF082
Authors: Wang Tingting , Zhou Jing , Zou Jiabin , Shi Yutong , Zhou Wenli , Shao Peng , Yu Tianze , Cui Wei , Li Xiaohui , Wu Xingxin , Ye Jing , Yan Xiaojun , Naman C. Benjamin , Lazaro J. Enrico H. , He Shan
Published: February 2021

Mesophotic coral ecosystems (MCEs) have complex but understudied biodiversity, especially for natural products discovery. Untargeted metabolomics research on 80 extracts prepared from marine sponge-associated fungi, half from shallow reefs (<30 m) and half from MCEs (30–150 m), facilitated prioritization for further study a Cymostachys fungus from a 103 m deep Aaptos sponge. LC-MS target-directed isolation yielded a series of new compounds, cymopolyphenols A−F (1–6), and two known phenylspirodrimanes, F1839-I (7) and stachybotrylactone (8). This is the first report of natural products from the recently described genus, Cymostachys. Compounds 1–6 and 8 contain a dihydroisobenzofuran moiety, and 4–6 are low-order polymers of 1 with novel scaffolds. The structures of the compounds were established by spectroscopic and spectrometric data interpretation, with further support from X-ray crystallography studies of 3 and 4. Compound 3 undergoes facile racemization in solution and was found to crystalize as a racemic mixture. Compound 5 was also obtained in racemic form, and after chiral chromatography, both separated enantiomers racemized in solution by a presumed keto-enol tautomerization. Compounds 1 and 3–6 were found to be weakly antimicrobial (MIC 16–64 μg/ml) in vitro against several Gram-positive and Gram-negative human or aquatic pathogens, compound 5 was shown to chelate iron in vitro at 10 μM, and 8 activated plant disease resistance in vivo in a transgenic model organism.
Dissimilatory Fe(III) Reduction Controls on Arsenic Mobilization: A Combined Biogeochemical and NanoSIMS Imaging Approach
Authors: Lopez-Adams Rebeca , Newsome Laura , Moore Katie L. , Lyon Ian C. , Lloyd Jonathan R.
Published: February 2021

Microbial metabolism plays a key role in controlling the fate of toxic groundwater contaminants, such as arsenic. Dissimilatory metal reduction catalyzed by subsurface bacteria can facilitate the mobilization of arsenic via the reductive dissolution of As(V)-bearing Fe(III) mineral assemblages. The mobility of liberated As(V) can then be amplified via reduction to the more soluble As(III) by As(V)-respiring bacteria. This investigation focused on the reductive dissolution of As(V) sorbed onto Fe(III)-(oxyhydr)oxide by model Fe(III)- and As(V)-reducing bacteria, to elucidate the mechanisms underpinning these processes at the single-cell scale. Axenic cultures of Shewanella sp. ANA-3 wild-type (WT) cells [able to respire both Fe(III) and As(V)] were grown using 13C-labeled lactate on an arsenical Fe(III)-(oxyhydr)oxide thin film, and after colonization, the distribution of Fe and As in the solid phase was assessed using nanoscale secondary ion mass spectrometry (NanoSIMS), complemented with aqueous geochemistry analyses. Parallel experiments were conducted using an arrA mutant, able to respire Fe(III) but not As(V). NanoSIMS imaging showed that most metabolically active cells were not in direct contact with the Fe(III) mineral. Flavins were released by both strains, suggesting that these cell-secreted electron shuttles mediated extracellular Fe(III)-(oxyhydr)oxide reduction, but did not facilitate extracellular As(V) reduction, demonstrated by the presence of flavins yet lack of As(III) in the supernatants of the arrA deletion mutant strain. 3D reconstructions of NanoSIMS depth-profiled single cells revealed that As and Fe were associated with the cell surface in the WT cells, whereas for the arrA mutant, only Fe was associated with the biomass. These data were consistent with Shewanella sp. ANA-3 respiring As(V) in a multistep process; first, the reductive dissolution of the Fe(III) mineral released As(V), and once in solution, As(V) was respired by the cells to As(III). As well as highlighting Fe(III) reduction as the primary release mechanism for arsenic, our data also identified unexpected cellular As(III) retention mechanisms that require further investigation.
Optimizing Gō-MARTINI Coarse-Grained Model for F-BAR Protein on Lipid Membrane
Authors: Mahmood Md. Iqbal , Poma Adolfo B. , Okazaki Kei-ichi
Published: February 2021

Coarse-grained (CG) molecular dynamics (MD) simulations allow us to access much larger length and time scales than atomistic MD simulations, providing an attractive alternative to the conventional simulations. Based on the well-known MARTINI CG force field, the recently developed Gō-MARTINI model for proteins describes large-amplitude structural dynamics, which has not been possible with the commonly used elastic network model. Using the Gō-MARTINI model, we conduct MD simulations of the F-BAR Pacsin1 protein on lipid membrane. We observe that structural changes of the non-globular protein are largely dependent on the definition of the native contacts in the Gō model. To address this issue, we introduced a simple cutoff scheme and tuned the cutoff distance of the native contacts and the interaction strength of the Lennard-Jones potentials in the Gō-MARTINI model. With the optimized Gō-MARTINI model, we show that it reproduces structural fluctuations of the Pacsin1 dimer from atomistic simulations. We also show that two Pacsin1 dimers properly assemble through lateral interaction on the lipid membrane. Our work presents a first step towards describing membrane remodeling processes in the Gō-MARTINI CG framework by simulating a crucial step of protein assembly on the membrane.
Circulating Exosomes Are Strongly Involved in SARS-CoV-2 Infection
Authors: Barberis Elettra , Vanella Virginia V. , Falasca Marco , Caneapero Valeria , Cappellano Giuseppe , Raineri Davide , Ghirimoldi Marco , De Giorgis Veronica , Puricelli Chiara , Vaschetto Rosanna , Sainaghi Pier Paolo , Bruno Stefania , Sica Antonio , Dianzani Umberto , Rolla Roberta , Chiocchetti Annalisa , Cantaluppi Vincenzo , Baldanzi Gianluca , Marengo Emilio , Manfredi Marcello
Published: February 2021

Knowledge of the host response to the novel coronavirus SARS-CoV-2 remains limited, hindering the understanding of COVID-19 pathogenesis and the development of therapeutic strategies. During the course of a viral infection, host cells release exosomes and other extracellular vesicles carrying viral and host components that can modulate the immune response. The present study used a shotgun proteomic approach to map the host circulating exosomes’ response to SARS-CoV-2 infection. We investigated how SARS-CoV-2 infection modulates exosome content, exosomes’ involvement in disease progression, and the potential use of plasma exosomes as biomarkers of disease severity. A proteomic analysis of patient-derived exosomes identified several molecules involved in the immune response, inflammation, and activation of the coagulation and complement pathways, which are the main mechanisms of COVID-19–associated tissue damage and multiple organ dysfunctions. In addition, several potential biomarkers—such as fibrinogen, fibronectin, complement C1r subcomponent and serum amyloid P-component—were shown to have a diagnostic feature presenting an area under the curve (AUC) of almost 1. Proteins correlating with disease severity were also detected. Moreover, for the first time, we identified the presence of SARS-CoV-2 RNA in the exosomal cargo, which suggests that the virus might use the endocytosis route to spread infection. Our findings indicate circulating exosomes’ significant contribution to several processes—such as inflammation, coagulation, and immunomodulation—during SARS-CoV-2 infection. The study’s data are available via ProteomeXchange with the identifier PXD021144.
The Neurocognitive Effects of Bacopa monnieri and Cognitive Training on Markers of Brain Microstructure in Healthy Older Adults
Authors: McPhee Grace M. , Downey Luke A. , Wesnes Keith A. , Stough Con
Published: February 2021

Bacopa monnieri(BM) is a herbal supplement that increases signaling molecules implicated in synaptogenesis. Combined with cognitive stimulation, it may be a viable supplement to enhance long-term potentiation (LTP) and improve cognitive health in older adults. This randomized, double-blind, placebo-controlled trial asked 28 healthy adults aged over 55 years to complete cognitive training (CT) 3 hours weekly for 12 weeks. Fifteen consumed a standardized extract of BM and 13 consumed a placebo daily. Cognitive tasks, life-satisfaction, memory complaints and mood were assessed, and bloods analyzed for serum brain-derived neurotrophic factor (BDNF) before and after 12-weeks of the intervention. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) in gray (GM) and white matter (WM) were also analyzed. Results demonstrated slower reaction time in an image discrimination task in the BM group and faster reaction time in a spatial working memory task (SWM-O RT) in the placebo group. Mean accuracy was higher in the BM group for these tasks, suggesting a change in the speed accuracy trade-off. Exploratory neuroimaging analysis showed increased WM mean diffusivity (MD) and GM dispersion of neurites (orientation dispersion index, ODI) and decreased WM fractional anisotropy (FA) and GM neurite density (ND) in the BM group. No other outcomes reached statistical significance. An increase in ODI with a decrease in MD and ND in the BM group may indicate an increase in network complexity (through higher dendritic branching) accompanied by dendritic pruning to enhance network efficiency. These neuroimaging outcomes conflict with the behavioral results, which showed poorer reaction time in the BM group. Given the exploratory outcomes and inconsistent findings between the behavioral and neuroimaging data, a larger study is needed to confirm the synaptogenic mechanisms of BM.
Outcome Prediction in Unresponsive Wakefulness Syndrome and Minimally Conscious State by Non-linear Dynamic Analysis of the EEG
Authors: Liu Baohu , Zhang Xu , Wang Lijia , Li Yuanyuan , Hou Jun , Duan Guoping , Guo Tongtong , Wu Dongyu
Published: February 2021

Objectives: This study aimed to investigate the role of non-linear dynamic analysis (NDA) of the electroencephalogram (EEG) in predicting patient outcome in unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS).

Methods: This was a prospective longitudinal cohort study. A total of 98 and 64 UWS and MCS cases, respectively, were assessed. During admission, EEGs were acquired under eyes-closed and pain stimulation conditions. EEG nonlinear indices, including approximate entropy (ApEn) and cross-ApEn, were calculated. The modified Glasgow Outcome Scale (mGOS) was employed to assess functional prognosis 1 year following brain injury.

Results: The mGOS scores were improved in 25 (26%) patients with UWS and 42 (66%) with MCS. Under the painful stimulation condition, both non-linear indices were lower in patients with UWS than in those with MCS. The frontal region, periphery of the primary sensory area (S1), and forebrain structure might be the key points modulating disorders of consciousness. The affected local cortical networks connected to S1 and unaffected distant cortical networks connecting S1 to the prefrontal area played important roles in mGOS score improvement.

Conclusions: NDA provides an objective assessment of cortical excitability and interconnections of residual cortical functional islands. The impaired interconnection of the residual cortical functional island meant a poorer prognosis. The activation in the affected periphery of the S1 and the increase in the interconnection of affected local cortical areas around the S1 and unaffected S1 to the prefrontal and temporal areas meant a relatively favorable prognosis.
Investigation of Cerebral White Matter Changes After Spinal Cord Injury With a Measure of Fiber Density
Authors: Huynh Vincent , Staempfli Philipp , Luetolf Robin , Luechinger Roger , Curt Armin , Kollias Spyros , Hubli Michèle , Michels Lars
Published: February 2021

Remote neurodegenerative changes in supraspinal white matter (WM) can manifest after central lesions such as spinal cord injury (SCI). The majority of diffusion tensor imaging (DTI) studies use traditional metrics such as fractional anisotropy (FA) and mean diffusivity (MD) to investigate microstructural changes in cerebral WM after SCI. However, interpretation of FA readouts is often challenged by inherent limitations of the tensor model. Recent developments in novel diffusion markers, such as fiber density (FD), allows more accurate depictions of WM pathways and has shown more reliable quantification of WM alterations compared to FA in recent studies of neurological diseases. This study investigated if FD provides useful characterization of supraspinal WM integrity after SCI in addition to the traditional DTI readouts. FA, MD, and FD maps were derived from diffusion datasets of 20 patients with chronic SCI and compared with 19 healthy controls (HC). Group differences were investigated across whole brain WM using tract-based spatial statistics and averaged diffusion values of the corticospinal tract (CST) and thalamic radiation (TR) were extracted for comparisons between HC and SCI subgroups. We also related diffusion readouts of the CST and TR with clinical scores of sensorimotor function. To investigate which diffusion markers of the CST and TR delineate HC and patients with SCI a receiver operating characteristic (ROC) analysis was performed. Overall, patients with an SCI showed decreased FA of the TR and CST. ROC analysis differentiated HC and SCI based on diffusion markers of large WM tracts including FD of the TR. Furthermore, patients' motor function was positively correlated with greater microstructural integrity of the CST. While FD showed the strongest correlation, motor function was also associated with FA and MD of the CST. In summary, microstructural changes of supraspinal WM in patients with SCI can be detected using FD as a complementary marker to traditional DTI readouts and correlates with their clinical characteristics. Future DTI studies may benefit from utilizing this novel marker to investigate complex large WM tracts in patient cohorts with varying presentations of SCI or neurodegenerative diseases.