bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrated Analysis of Key Genes and Pathways Involved in Fetal Growth Restriction and Their Associations With the Dysregulation of the Maternal Immune System
Authors: Wang Xue , Zhu Hong , Lei Lei , Zhang Yang , Tang Chao , Wu Jia-xing , Zhou Jie-ru , Xiao Xi-rong
Published: January 2021

Fetal growth restriction (FGR) is a common pregnancy complication and a risk factor for infant death. Most patients with FGR have preeclampsia, gestational diabetes mellitus, or other etiologies, making it difficult to determine the specific molecular mechanisms underlying FGR. In this study, an integrated analysis was performed using gene expression profiles obtained from Gene Expression Omnibus. Differentially expressed genes (DEGs) between healthy and FGR groups were screened and evaluated by functional enrichment and network analyses. In total, 80 common DEGs (FDR < 0.05) and 17 significant DEGs (FDR < 0.005) were screened. These genes were enriched for functions in immune system dysregulation in the placenta based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Among hub genes identified as candidates for FGR and fetal reprogramming, LEP, GBP5, HLA–DQA1, and CTGF were checked by quantitative polymerase chain reaction, immunohistochemistry, and western blot assays in placental tissues. Immune imbalance could cause hypoxia environment in placenta tissues, thus regulating the fetal-reprogramming. A significant association between CTGF and HIF-1α levels was confirmed in placenta tissues and HTR8 cells under hypoxia. Our results suggest that an immune imbalance in the placenta causes FGR without other complications. We provide the first evidence for roles of CTGF in FGR and show that CTGF may function via HIF-1α-related pathways. Our findings elucidate the pathogenesis of FGR and provide new therapeutic targets.
Identification of Inhibitors of Integrin Cytoplasmic Domain Interactions With Syk
Authors: Bakthavatsalam Deenadayalan , Craft John W. , Kazansky Anna , Nguyen Nghi , Bae Goeun , Caivano Amy R. , Gundlach C. William , Aslam Asra , Ali Safa , Gupta Shashikant , Lin Sophie Y. , Parthiban Hema D. , Vanderslice Peter , Stephan Clifford C. , Woodside Darren G.
Published: January 2021

Leukocyte inflammatory responses require integrin cell-adhesion molecule signaling through spleen tyrosine kinase (Syk), a non-receptor kinase that binds directly to integrin β-chain cytoplasmic domains. Here, we developed a high-throughput screen to identify small molecule inhibitors of the Syk-integrin cytoplasmic domain interactions. Screening small molecule compound libraries identified the β-lactam antibiotics cefsulodin and ceftazidime, which inhibited integrin β-subunit cytoplasmic domain binding to the tandem SH2 domains of Syk (IC50 range, 1.02–4.9 µM). Modeling suggested antagonist binding to Syk outside the pITAM binding site. Ceftazidime inhibited integrin signaling via Syk, including inhibition of adhesion-dependent upregulation of interleukin-1β and monocyte chemoattractant protein-1, but did not inhibit ITAM-dependent phosphorylation of Syk mediated by FcγRI signaling. Our results demonstrate a novel means to target Syk independent of its kinase and pITAM binding sites such that integrin signaling via this kinase is abrogated but ITAM-dependent signaling remains intact. As integrin signaling through Syk is essential for leukocyte activation, this may represent a novel approach to target inflammation.
Photochemical Internalization Enhanced Vaccination Is Safe, and Gives Promising Cellular Immune Responses to an HPV Peptide-Based Vaccine in a Phase I Clinical Study in Healthy Volunteers
Authors: Otterhaug Tone , Janetzki Sylvia , Welters Marij J. P. , Håkerud Monika , Nedberg Anne Grete , Edwards Victoria Tudor , Boekestijn Sanne , Loof Nikki M. , Selbo Pål Kristian , Olivecrona Hans , van der Burg Sjoerd H. , Høgset Anders
Published: January 2021

Background and Aims

Photochemical internalization (PCI) is a technology for inducing release of endocytosed antigens into the cell cytosolviaa light-induced process. Preclinical experiments have shown that PCI improves MHC class I antigen presentation, resulting in strongly enhanced CD8+ T-cell responses to polypeptide antigens. In PCI vaccination a mixture of the photosensitizing compound fimaporfin, vaccine antigens, and an adjuvant is administered intradermally followed by illumination of the vaccination site. This work describes an open label, phase I study in healthy volunteers, to assess the safety, tolerability, and immune response to PCI vaccination in combination with the adjuvant poly-ICLC (Hiltonol) (ClinicalTrials.govIdentifier: NCT02947854).

Methods

The primary objective of the study was to assess the safety and local tolerance of PCI mediated vaccination, and to identify a safe fimaporfin dose for later clinical studies. A secondary objective was to analyze the immunological responses to the vaccination. Each subject received 3 doses of HPV16 E7 peptide antigens and two doses of Keyhole Limpet Hemocyanin (KLH) protein. A control group received Hiltonol and vaccine antigens only, whereas the PCI groups in addition received fimaporfin + light. Local and systemic adverse effects were assessed by standard criteria, and cellular and humoral immune responses were analyzed by ELISpot, flow cytometry, and ELISA assays.

Results

96 healthy volunteers were vaccinated with fimaporfin doses of 0.75–50 µg. Doses below 17.5 µg were safe and tolerable, higher doses exhibited local tolerability issues in some study subjects, mainly erythema, and pain during illumination. There were few, and only mild and expected systemic adverse events. The employment of PCI increased the number of subjects exhibiting a T-cell response to the HPV peptide vaccine about 10-fold over what was achieved with the antigen/Hiltonol combination without PCI. Moreover, the use of PCI seemed to result in a more consistent and multifunctional CD8+ T-cell response. An enhancement of the humoral immune response to KLH vaccination was also observed.

Conclusions

Using PCI in combination with Hiltonol for intradermal vaccination is safe at fimaporfin doses below 17.5 µg, and gives encouraging immune responses to peptide and protein based vaccination.
Characterization of Treponema pallidum Dissemination in C57BL/6 Mice
Authors: Lu Simin , Zheng Kang , Wang Jianye , Xu Man , Xie Yafeng , Yuan Shuai , Wang Chuan , Wu Yimou
Published: January 2021

The spirochetal pathogenTreponema pallidumcauses 5 million new cases of venereal syphilis worldwide each year. One major obstacle to syphilis prevention and treatment is the lack of suitable experimental animal models to study its pathogenesis. Accordingly, in this study, we further evaluated the responses of mice toTreponema pallidum. Quantitative polymerase chain reaction showed thatTreponema pallidumcould colonize the heart, liver, spleen, kidneys, and testicles of C57BL/6 mice, and the organism may be able to rapidly penetrate the blood-brain barrier in mice by 24 h after infection. In subsequent rabbit infectivity tests, we observed evident signs of the microorganism in the mouse lymph node suspension. After infection, bacterial loads were higher in the tissues than in the blood of C57BL/6 mice. Moreover, a significant Th1 immune response was recorded by cytokine assays. Flow cytometric analysis suggested an obvious increase in the proportion of CD3+T and CD4+T cells in the spleen cells in the infected mice. Thus, improving our understanding of the response of C57BL/6 mice forTreponema pallidumwill help to comprehensive elucidate the pathogenic mechanisms of this bacterium and lay the foundation for the development of a new research model ofTreponema pallidum.
Proteus mirabilis Targets Atherosclerosis Plaques in Human Coronary Arteries via DC-SIGN (CD209)
Authors: Xue Ying , Li Qiao , Park Chae Gyu , Klena John D. , Anisimov Andrey P. , Sun Ziyong , Wei Xiang , Chen Tie
Published: January 2021

Bacterial DNAs are constantly detected in atherosclerotic plaques (APs), suggesting that a combination of chronic infection and inflammation may have roles in AP formation. A series of studies suggested that certain Gram-negative bacteria were able to interact with dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin [DC-SIGN; cluster of differentiation (CD) 209] or langerin (CD207), thereby resulting in deposition of CD209s at infection sites. We wondered if Proteus mirabilis (a member of Proteobacteria family) could interact with APs through CD209/CD207. In this study, we first demonstrated that CD209/CD207 were also receptors for P. mirabilis that mediated adherence and phagocytosis by macrophages. P. mirabilis interacted with fresh and CD209s/CD207-expressing APs cut from human coronary arteries, rather than in healthy and smooth arteries. These interactions were inhibited by addition of a ligand-mimic oligosaccharide and the coverage of the ligand, as well as by anti-CD209 antibody. Finally, the hearts from an atherosclerotic mouse model contained higher numbers of P. mirabilis than that of control mice during infection-challenging. We therefore concluded that the P. mirabilis interacts with APs in human coronary arteries via CD209s/CD207. It may be possible to slow down the progress of atherosclerosis by blocking the interactions between CD209s/CD207 and certain atherosclerosis-involved bacteria with ligand-mimic oligosaccharides.
Engineering of Humanized Antibodies Against Human Interleukin 5 Receptor Alpha Subunit That Cause Potent Antibody-Dependent Cell-Mediated Cytotoxicity
Authors: Kim Jung-Eun , Lee Dong-Hyun , Jung Keunok , Kim Eun-Ji , Choi Youngwoo , Park Hae-Sim , Kim Yong-Sung
Published: January 2021

Patients with severe eosinophilic asthma (SEA; characterized by persistent eosinophilia in blood and airway tissues) experience frequent asthma exacerbations with poor clinical outcomes. Interleukin 5 (IL-5) and IL-5 receptor alpha subunit (IL-5α) play key roles in eosinophilia maintenance, and relevant therapeutic strategies include the development of antibodies (Abs) against IL-5 or IL-5α to control eosinophilia. Benralizumab, an anti–IL-5α Ab that depletes eosinophils mainly via Ab-dependent cell-mediated cytotoxicity and through blockage of IL-5 function on eosinophils, has been clinically approved for patients with SEA. Here, we report engineering of a new humanized anti–IL-5Rα Ab with potent biological activity. We first raised murine Abs against human IL-5Rα, humanized a leading murine Ab, and then further engineered the humanized Abs to enhance their affinity for IL-5Rα using the yeast surface display technology. The finally engineered version of the Ab, 5R65.7, with affinity (KD ≈ 4.64 nM) stronger than that of a clinically relevant benralizumab analogue (KD ≈ 26.8 nM) showed improved neutralizing activity toward IL-5–dependent cell proliferation in a reporter cell system. Domain level Ab epitope mapping revealed that 5R65.7 recognizes membrane-proximal domain 3 of IL-5Rα, distinct from domain I epitope of the benralizumab analogue. In ex vivo assays with peripheral eosinophils from patients with SEA and healthy donors, 5R65.7 manifested more potent biological activities than the benralizumab analogue did, including inhibition of IL-5–dependent proliferation of eosinophils and induction of eosinophil apoptosis through autologous natural-killer-cell–mediated Ab-dependent cell-mediated cytotoxicity. Our study provides a potent anti–IL-5Rα Ab, 5R65.7, which is worthy of further testing in preclinical and clinical trials against SEA as a potential alternative to the current therapeutic arsenal.
Sex Differences in Immunity: Implications for the Development of Novel Vaccines Against Emerging Pathogens
Authors: Fathi Anahita , Addo Marylyn M. , Dahlke Christine
Published: January 2021

Vaccines are one of the greatest public health achievements and have saved millions of lives. They represent a key countermeasure to limit epidemics caused by emerging infectious diseases. The Ebola virus disease crisis in West Africa dramatically revealed the need for a rapid and strategic development of vaccines to effectively control outbreaks. Seven years later, in light of the SARS-CoV-2 pandemic, this need has never been as urgent as it is today. Vaccine development and implementation of clinical trials have been greatly accelerated, but still lack strategic design and evaluation. Responses to vaccination can vary widely across individuals based on factors like age, microbiome, co-morbidities and sex. The latter aspect has received more and more attention in recent years and a growing body of data provide evidence that sex-specific effects may lead to different outcomes of vaccine safety and efficacy. As these differences might have a significant impact on the resulting optimal vaccine regimen, sex-based differences should already be considered and investigated in pre-clinical and clinical trials. In this Review, we will highlight the clinical observations of sex-specific differences in response to vaccination, delineate sex differences in immune mechanisms, and will discuss the possible resulting implications for development of vaccine candidates against emerging infections. As multiple vaccine candidates against COVID-19 that target the same antigen are tested, vaccine development may undergo a decisive change, since we now have the opportunity to better understand mechanisms that influence vaccine-induced reactogenicity and effectiveness of different vaccines.
The Trajectory of Alterations in Immune-Cell Counts in Severe-Trauma Patients Is Related to the Later Occurrence of Sepsis and Mortality: Retrospective Study of 917 Cases
Authors: Dong Xijie , Wang Chuntao , Liu Xinghua , Bai Xiangjun , Li Zhanfei
Published: January 2021

Background

Severe trauma is believed to disrupt the homeostasis of the immune system, and lead to dramatic changes in the circulating immune-cell count (ICC). The latter fluctuates widely over time. Knowledge about the relationship between these dramatic changes and dynamic fluctuations and the late prognosis of trauma patients is sparse. We investigated the relationship between the trajectory of alterations in the circulating ICC within 7 days in severe-trauma patients and subsequent sepsis and mortality.

Methods

A retrospective analysis of 917 patients with an Injury Severity Score ≥16 was undertaken. The absolute neutrophil, lymphocyte, and monocyte counts (ANC, ALC, and AMC, respectively) on days 1, 3, and 7 (D1, D3, and D7, respectively) after trauma, and whether sepsis or death occurred within 60 days, were recorded. As the disordered circulating ICCs fluctuated widely, their time-varying slopes (D3/D1 and D7/D3) were calculated. Patients were divided into “sepsis” and “non-sepsis” groups, as well as “alive” and “death” groups. Comparative studies were conducted between every two groups. Univariate and multivariate logistic regression analyses were used to identify variables related to the risk of sepsis and mortality. Receiver operating characteristic curves were plotted to assess the predictive value of various risk factors.

Results

More severe trauma caused more pronounced increases in the ANC and slower recovery of the ALC within 7 days. The ALC (D3), ANC (D7), ALC (D3/D1), and ANC (D7/D3) were independent risk factors for sepsis. The ALC (D3), ALC (D7), AMC (D7), and ALC (D3/D1) were independent risk factors for mortality. A combination of the ALC (D3) and ALC (D3/D1) exerted a good predictive value for sepsis and death.

Conclusions

The trajectory of alterations in the circulating ICC in the early stage after trauma is related to subsequent sepsis and mortality.
Zdhhc2 Is Essential for Plasmacytoid Dendritic Cells Mediated Inflammatory Response in Psoriasis
Authors: Zhou Binhui , Yang Wenyi , Li Wushan , He Le , Lu Liaoxun , Zhang Lichen , Liu Zhuangzhuang , Wang Ying , Chao Tianzhu , Huang Rong , Gu Yanrong , Jia Tingting , Liu Qiaoli , Tian Shuanghua , Pierre Philippe , Maeda Takahiro , Liang Yinming , Kong Eryan
Published: January 2021

Zdhhc family genes are composed of 24 members that regulate palmitoylation, a post-translational modification process for proteins. Mutations in genes that alter palmitoylation or de-palmitoylation could result in neurodegenerative diseases and inflammatory disorders. In this study, we found that Zdhhc2 was robustly induced in psoriatic skin and loss of Zdhhc2 in mice by CRISPR/Cas9 dramatically inhibited pathology of the ear skin following imiquimod treatment. As psoriasis is an inflammatory disorder, we analyzed tissue infiltrating immune cells and cytokine production. Strikingly we found that a master psoriatic cytokine interferon-α (IFN-α) in the lesioned skin of wildtype (WT) mice was 23-fold higher than that in Zdhhc2 deficient counterparts. In addition, we found that CD45+ white blood cells (WBC) infiltrating in the skin of Zdhhc2 deficient mice were also significantly reduced. Amelioration in psoriasis and dramatically reduced inflammation of Zdhhc2 deficient mice led us to analyze the cellular components that were affected by loss of Zdhhc2. We found that imiquimod induced plasmacytoid dendritic cell (pDC) accumulation in psoriatic skin, spleen, and draining lymph nodes (DLN) were drastically decreased in Zdhhc2 deficient mice, and the expression of pDC activation marker CD80 also exhibited significantly inhibited in psoriatic skin. In further experiments, we confirmed the cell intrinsic effect of Zdhhc2 on pDCs as we found that loss of zDHHC2 in human CAL-1 pDC dampened both interferon regulatory factor 7 (IRF7) phosphorylation and IFN-α production. Therefore, we identified novel function of Zdhhc2 in controlling inflammatory response in psoriasis in mice and we also confirmed that crucial role of Zdhhc2 in pDCs by regulating IRF7 activity and production of the critical cytokine. Our results finding the dependence of IFN-α production on Zdhhc2 in inflamed murine skin and in human pDCs provide rationale for targeting this new molecule in treatment of inflammation.
MicroRNAs as Potential Regulators of Immune Response Networks in Asthma and Chronic Obstructive Pulmonary Disease
Authors: Cañas José A. , Rodrigo-Muñoz José M. , Sastre Beatriz , Gil-Martinez Marta , Redondo Natalia , del Pozo Victoria
Published: January 2021

Chronic respiratory diseases (CRDs) are an important factor of morbidity and mortality, accounting for approximately 6% of total deaths worldwide. The main CRDs are asthma and chronic obstructive pulmonary disease (COPD). These complex diseases have different triggers including allergens, pollutants, tobacco smoke, and other risk factors. It is important to highlight that although CRDs are incurable, various forms of treatment improve shortness of breath and quality of life. The search for tools that can ensure accurate diagnosis and treatment is crucial. MicroRNAs (miRNAs) are small non-coding RNAs and have been described as promising diagnostic and therapeutic biomarkers for CRDs. They are implicated in multiple processes of asthma and COPD, regulating pathways associated with inflammation, thereby showing that miRNAs are critical regulators of the immune response. Indeed, miRNAs have been found to be deregulated in several biofluids (sputum, bronchoalveolar lavage, and serum) and in both structural lung and immune cells of patients in comparison to healthy subjects, showing their potential role as biomarkers. Also, miRNAs play a part in the development or termination of histopathological changes and comorbidities, revealing the complexity of miRNA regulation and opening up new treatment possibilities. Finally, miRNAs have been proposed as prognostic tools in response to both conventional and biologic treatments for asthma or COPD, and miRNA-based treatment has emerged as a potential approach for clinical intervention in these respiratory diseases; however, this field is still in development. The present review applies a systems biology approach to the understanding of miRNA regulatory networks in asthma and COPD, summarizing their roles in pathophysiology, diagnosis, and treatment.
Development and Validation of a Contrast-Enhanced CT-Based Radiomics Nomogram for Prediction of Therapeutic Efficacy of Anti-PD-1 Antibodies in Advanced HCC Patients
Authors: Yuan Guosheng , Song Yangda , Li Qi , Hu Xiaoyun , Zang Mengya , Dai Wencong , Cheng Xiao , Huang Wei , Yu Wenxuan , Chen Mian , Guo Yabing , Zhang Qifan , Chen Jinzhang
Published: January 2021

Background

There is no study accessible now assessing the prognostic aspect of radiomics for anti-PD-1 therapy for patients with HCC.

Aim

The aim of this study was to develop and validate a radiomics nomogram by incorporating the pretreatment contrast-enhanced Computed tomography (CT) images and clinical risk factors to estimate the anti-PD-1 treatment efficacy in Hepatocellular Carcinoma (HCC) patients.

Methods

A total of 58 patients with advanced HCC who were refractory to the standard first-line of therapy, and received PD-1 inhibitor treatment with Toripalimab, Camrelizumab, or Sintilimab from 1st January 2019 to 31 July 2020 were enrolled and divided into two sets randomly: training set (n = 40) and validation set (n = 18). Radiomics features were extracted from non-enhanced and contrast-enhanced CT scans and selected by using the least absolute shrinkage and selection operator (LASSO) method. Finally, a radiomics nomogram was developed based on by univariate and multivariate logistic regression analysis. The performance of the nomogram was evaluated by discrimination, calibration, and clinical utility.

Results

Eight radiomics features from the whole tumor and peritumoral regions were selected and comprised of the Fusion Radiomics score. Together with two clinical factors (tumor embolus and ALBI grade), a radiomics nomogram was developed with an area under the curve (AUC) of 0.894 (95% CI, 0.797–0.991) and 0.883 (95% CI, 0.716–0.998) in the training and validation cohort, respectively. The calibration curve and decision curve analysis (DCA) confirmed that nomogram had good consistency and clinical usefulness.

Conclusions

This study has developed and validated a radiomics nomogram by incorporating the pretreatment CECT images and clinical factors to predict the anti-PD-1 treatment efficacy in patients with advanced HCC.
SARS-CoV-2 Viral RNA Shedding for More Than 87 Days in an Individual With an Impaired CD8+ T Cell Response
Authors: Turner Jackson S. , Day Aaron , Alsoussi Wafaa B. , Liu Zhuoming , O’Halloran Jane A. , Presti Rachel M. , Patterson Bruce K. , Whelan Sean P. J. , Ellebedy Ali H. , Mudd Philip A.
Published: January 2021

Prolonged shedding of viral RNA occurs in some individuals following SARS-CoV-2 infection. We perform comprehensive immunologic evaluation of one individual with prolonged shedding. The case subject recovered from severe COVID-19 and tested positive for SARS-CoV-2 viral RNA repeatedly as many as 87 days after the first positive test, 97 days after symptom onset. The subject did not have any associated rise in anti-Spike protein antibody titers or plasma neutralization activity, arguing against re-infection. This index subject exhibited a profoundly diminished circulating CD8+ T cell population and correspondingly low SARS-CoV-2-specific CD8+ T cell responses when compared with a cohort of other recovering COVID-19 subjects. CD4+ T cell responses and neutralizing antibody responses developed as expected in this individual. Our results demonstrate that detectable viral RNA shedding in the upper airway can occur more than 3 months following infection in some individuals with COVID-19 and suggest that impaired CD8+ T cells may play a role in prolonged viral RNA shedding.
Annelid Fauna of the Prince Gustav Channel, a Previously Ice-Covered Seaway on the Northeastern Antarctic Peninsula
Authors: Drennan Regan , Dahlgren Thomas G. , Linse Katrin , Glover Adrian G.
Published: January 2021

The Prince Gustav Channel is a narrow seaway located in the western Weddell Sea on the northeastern-most tip of the Antarctic Peninsula. The channel is notable for both its deep (>1200 m) basins, and a dynamic glacial history that most recently includes the break-up of the Prince Gustav Ice Shelf, which covered the southern portion of the channel until its collapse in 1995. However, the channel remains mostly unsampled, with very little known about its benthic biology. We present a preliminary account of the benthic annelid fauna of the Prince Gustav Channel in addition to samples from Duse Bay, a sheltered, glacier-influenced embayment in the northwestern portion of the channel. Samples were collected using an Agassiz Trawl, targeting megafaunal and large macrofaunal sized animals at depths ranging between 200–1200 m; the seafloor and associated fauna were also documented in situ using a Shallow Underwater Camera System (SUCS). Sample sites varied in terms of depth, substrate type, and current regime, and communities were locally variable across sites in terms of richness, abundance, and both taxonomic and functional composition. The most diverse family included the motile predator/scavenger Polynoidae, with 105 individuals in at least 12 morphospecies, primarily from a single site. This study provides first insights into diverse and spatially heterogeneous benthic communities in a dynamic habitat with continuing glacial influence, filling sampling gaps in a poorly studied region of the Southern Ocean at direct risk from climate change. These specimens will also be utilized in future molecular investigations, both in terms of describing the genetic biodiversity of this site and as part of wider phylogeographic and population genetic analyses assessing the connectivity, evolutionary origins, and demographic history of annelid fauna in the region.
Seasonal Variability in Near-bed Environmental Conditions in the Vazella pourtalesii Glass Sponge Grounds of the Scotian Shelf
Authors: Hanz Ulrike , Beazley Lindsay , Kenchington Ellen , Duineveld Gerard , Rapp Hans Tore , Mienis Furu
Published: January 2021

The Scotian Shelf harbors unique aggregations of the glass sponge Vazella pourtalesii that provides an important habitat for benthic and pelagic fauna. Recent studies have shown that these sponge grounds have persisted in the face of strong inter-annual and multi-decadal variability in temperature and salinity. However, little is known of these environmental characteristics on hourly-seasonal time scales. This study presents the first hydrodynamic observations and associated (food) particle supply mechanisms for the Vazella sponge grounds, highlighting the influence of natural variability in environmental conditions on sponge growth and resilience. Near-bottom environmental conditions were characterized by high temporal resolution data collected with a benthic lander, deployed during a period of 10 months in the Sambro Bank Sponge Conservation Area. The lander was equipped with temperature and oxygen sensors, a current meter, a sediment trap and a video camera. In addition, water column profiles of temperature and salinity were collected in an array across the sponge grounds from high to lower sponge presence probability. Over the course of the lander deployment, temperature fluctuated between 8.8–12°C with an average of 10.6 ± 0.4°C. Dissolved oxygen concentration was on average 6.3 mg l–1, and near-bottom current speed was on average 0.12 m s–1, with peaks up to 0.47 m s–1. Semi-diurnal tidal currents promoted constant resuspension of particulate matter in the benthic boundary layer. Surface storm events episodically caused extremely turbid conditions on the seafloor that persisted for several days, with particles being resuspended to more than 13 m above the seabed. The carbon flux in the near-bottom sediment trap peaked during storm events and also after a spring bloom in April, when fresh phytodetritus was observed in the bottom boundary layer. While resuspension events can represent a major stressor for sponges, limiting their filtration capability and remobilizing them, episodes of strong currents and lateral particle transport likely play an important role in food supply and the replenishment of nutrients and oxygen. Our results contextualize human-induced threats such as bottom fishing and climate change by providing more knowledge of the natural environmental conditions under which sponge grounds persist.
Coastal Upwelling Limitation by Onshore Geostrophic Flow in the Gulf of Guinea Around the Niger River Plume
Authors: Alory Gaël , Da-Allada Casimir Yélognissè , Djakouré Sandrine , Dadou Isabelle , Jouanno Julien , Loemba Dorelle Prudence
Published: January 2021

Wind-driven coastal upwelling can be compensated by onshore geostrophic flow, and river plumes are associated with such flow. We investigate possible limitation of the northeast Gulf of Guinea upwelling by the Niger River plume, using regional ocean model simulations with or without river and dynamical upwelling indices. Here, the upwelling is weakened by 50% due to an onshore geostrophic flow equally controlled by alongshore thermosteric and halosteric sea-level changes. The river contributes to only 20% of this flow, as its plume is shallow while upwelling affects coastal temperature and salinity over a larger depth. Moreover, the river-induced mixed-layer thinning compensates the current increase, with no net effect on upwelling. The geostrophic compensation is due to an abrupt change in coastline orientation that creates the upwelling cross-shore front. The river nonetheless warms the upwelling tongue by 1°C, probably due to induced changes in horizontal advection and/or stratification.
Combining Ecosystem and Single-Species Modeling to Provide Ecosystem-Based Fisheries Management Advice Within Current Management Systems
Authors: Howell Daniel , Schueller Amy M. , Bentley Jacob W. , Buchheister Andre , Chagaris David , Cieri Matthew , Drew Katie , Lundy Mathieu G. , Pedreschi Debbi , Reid David G. , Townsend Howard
Published: January 2021

Although many countries have formally committed to Ecosystem-Based Fisheries Management (EBFM), actual progress toward these goals has been slow. This paper presents two independent case studies that have combined strategic advice from ecosystem modeling with the tactical advice of single-species assessment models to provide practical ecosystem-based management advice. With this approach, stock status, reference points, and initial target F are computed from a single-species model, then an ecosystem model rescales the target F according to ecosystem indicators without crossing pre-calculated single-species precautionary limits. Finally, the single-species model computes the quota advice from the rescaled target F, termed here Feco. Such a methodology incorporates both the detailed population reconstructions of the single-species model and the broader ecosystem perspective from ecosystem-based modeling, and fits into existing management schemes. The advocated method has arisen from independent work on EBFM in two international fisheries management systems: (1) Atlantic menhaden in the United States and (2) the multi species fisheries of the Irish Sea, in the Celtic Seas ecoregion. In the Atlantic menhaden example, the objective was to develop ecological reference points (ERPs) that account for the effect of menhaden harvest on predator populations and the tradeoffs associated with forage fish management. In the Irish Sea, the objective was to account for ecosystem variability when setting quotas for the individual target species. These two exercises were aimed at different management needs, but both arrived at a process of adjusting the target F used within the current single-species management. Although the approach has limitations, it represents a practical step toward EBFM, which can be adapted to a range of ecosystem objectives and applied within current management systems.
The Clinical Characteristics of Other HLA-B Types in Chinese Ankylosing Spondylitis Patients
Authors: Wu Xinyu , Wu Jialing , Li Xiaomin , Wei Qiujing , Lv Qing , Zhang Pingping , Zheng Xuqi , Chen Zena , Cao Shuangyan , Tu Liudan , Gu Jieruo
Published: January 2021

HLA-B27 has an established relationship with the development of ankylosing spondylitis (AS). After reviewing the HLA-B genotype from 407 Chinese subjects (318 patients and 89 sex-matched controls), we found that 252 patients and 32 controls were HLA-B27(+) and that HLA-B*27:04 was the dominant HLA-B27 subtype (N = 224). In all participants, HLA*27:04 homozygous were only detected in two patients. In the HLA-B27(+) group, HLA-B40 was observed in 51 cases and one control (p < 0.05, OR = 7.87, 95% CI 1.05–59.0); of these, the most genotype was HLA-B*27:04/B*40:01(N = 38). Two hundred thirty-nine patients' clinical information was recorded. Cases with HLA-B27/B46 had more peripheral joint involvement (OR = 3.95, 95% CI 1.77–8.79) in HLA-B27(+) AS. HLA-B*15:02 may be a significant risk element to peripheral joint involvement (p < 0.05) in HLA-B27(−) patients. Therefore, we believe HLA-B*40:01, HLA-B*46:01, and HLA-B*15:02 can be the test indicators for AS diagnostic value.
Aspirin Use and the Incidence of Hepatocellular Carcinoma in Patients With Hepatitis B Virus or Hepatitis C Virus Infection: A Meta-Analysis of Cohort Studies
Authors: Li Xiaofei , Wu Shuang , Yu Yuexiao
Published: January 2021

Background: The association between aspirin use and the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV) or hepatitis C (HCV) virus infection remains not fully determined. A meta-analysis was performed to summarize the findings of cohort studies.

Methods: Relevant cohort studies were retrieved via a search of PubMed Cochrane's Library and Embase databases. A random-effect model was used to pool the results. Subgroup analyses were performed to evaluate the influence of study characteristics on the association.

Results: Seven cohort studies with 120,945 adult patients with HBV or HCV infection were included. Pooled results showed that aspirin use was independently associated with a reduced risk of HCC in these patients (risk ratio: 0.73, 95% confidence interval: 0.64 to 0.83, p < 0.001; I2 = 86%). Subgroup analyses showed that aspirin use was associated with a reduced HCC risk regardless of the viral type, age, sex, the diabetic, and cirrhotic status of the patients, and the follow-up durations. Moreover, consistent results were obtained in studies with and without adjustment of antiviral treatment and statin use. Pooled results of four studies showed that aspirin use was associated with an increased risk of gastrointestinal bleeding in these patients (risk ratio: 1.15, 95% confidence interval: 1.02 to 1.28, p = 0.02; I2 = 0%).

Conclusions: Aspirin use was independently associated with a reduced risk of HCC in patients with HBV or HCV infection, whereas the risk of gastrointestinal bleeding may be increased. These results should be validated in clinical trials.
Macrophage Activation Markers, Soluble CD163 and Mannose Receptor, in Liver Fibrosis
Authors: Gantzel Rasmus Hvidbjerg , Kjær Mikkel Breinholt , Laursen Tea Lund , Kazankov Konstantin , George Jacob , Møller Holger Jon , Grønbæk Henning
Published: January 2021

Macrophages are essential components of the human host immune system, which upon activation facilitates a broad pallet of immunomodulatory events including release of pro- or anti-inflammatory cytokines and chemokines, restoration of immune homeostasis and/or wound healing. Moreover, some macrophage phenotypes are crucially involved in fibrogenesis through stimulation of myofibroblasts, while others promote fibrolysis. During the last decades, the role of resident liver macrophages viz. Kupffer cells and recruited monocytes/macrophages in acute and chronic liver diseases has gained interest and been extensively investigated. Specifically, the scavenger receptors CD163 and mannose receptor (CD206), expressed by macrophages, are of utmost interest since activation by various stimuli induce their shedding to the circulation. Thus, quantifying concentrations of these soluble biomarkers may be of promising clinical relevance in estimating the severity of inflammation and fibrosis and to predict outcomes such as survival. Here, we review the existing literature on soluble CD163 and soluble mannose receptor in liver diseases with a particular focus on their relationship to hepatic fibrosis in metabolic associated fatty liver disease, as well as in chronic hepatitis B and C.
Genomic Distinctions of LA-MRSA ST398 on Dairy Farms From Different German Federal States With a Low Risk of Severe Human Infections
Authors: Lienen Tobias , Schnitt Arne , Hammerl Jens Andre , Maurischat Sven , Tenhagen Bernd-Alois
Published: January 2021

Methicillin-resistant Staphylococcus aureus (MRSA) have been found on German dairy farms and may be the cause of difficult-to-treat bovine mastitis. Considering the one health approach, MRSA might be transmitted from animals to humans raising the risk for severe infections. On 17 German dairy farms with a history of MRSA detection, MRSA strains were isolated from quarter milk, bulk tank milk, and swab samples of calves, heifers, pigs, and the environment. A selection of 33 isolates was analyzed using whole-genome sequencing and antimicrobial resistance testing. All detected MRSA strains were attributed to the livestock-associated sequence type 398. Methicillin-resistance was associated with the mecA gene in the staphylococcal cassette chromosome (SCC)mec types IVa (7/33) or V (26/33). The MRSA strains across the German federal states showed large allelic differences indicating independent development and distribution. On one farm, a clonal MRSA isolate was widely spread among different animals and the milking equipment. Moreover, MRSA transmission between two dairy farms in one federal state seems to be likely. In depth studies indicated that the resistance gene prediction and phenotypic resistance are in good agreement. Twenty eight strains were determined to exhibit a non-wildtype phenotype (resistant) against up to seven antimicrobial substances with an overall resistance to β-lactams and tetracycline. Ten different phenotypic antimicrobial resistance patterns were found among the MRSA strains. The strains harbored a wide virulence gene repertoire, of which some of them are related to bovine mastitis. However, the isolates lacked typical human infection associated factors such as the immune evasion cluster genes, staphylococcal enterotoxin genes, or Panton-Valentine leukocidin genes leading to the assumption for a low risk for severe human infections and foodborne diseases.
Mechanisms for Development of Ciprofloxacin Resistance in a Clinical Isolate of Pseudomonas aeruginosa
Authors: Xu Congjuan , Liu Huimin , Pan Xiaolei , Ma Zhenzhen , Wang Dan , Zhang Xinxin , Zhu Guangbo , Bai Fang , Cheng Zhihui , Wu Weihui , Jin Yongxin
Published: January 2021

Treatment of infections by Pseudomonas aeruginosa is difficult due to its high intrinsic and acquired antibiotic resistance. Upon colonization in the human hosts, P. aeruginosa accumulates genetic mutations that confer the bacterium antibiotic resistance and ability to better live in the host environment. Characterizing the evolutionary traits would provide important insights into the development of effective combinatory antibiotic therapies to cure P. aeruginosa infections. In this work, we performed a detailed analysis of the molecular mechanisms by which a clinical isolate (CSP18) yields a ciprofloxacin-resistant derivative (CRP42). Genomic DNA re-sequencing and RNAseq were carried out to compare the genomic mutational signature and transcriptional profiles between the two isolates. The results indicated that D87G mutation in GyrA, together with MexEF-OprN hyper-expression caused by F7S mutation in MexS, was responsible for the increased resistance to ciprofloxacin in the isolate CRP42. Further simulation of CRP42 by gene editing in CSP18 demonstrated that D87G mutation in GyrA rendered CSP18 a fourfold increase in minimum inhibitory concentration against ciprofloxacin, while F7S mutation in MexS conferred an additional eightfold increase. Our experimental results demonstrate for the first time that the clinically relevant F7S point mutation in MexS results in hyper-expression of the mexEF-oprN and thus confers P. aeruginosa resistance to ciprofloxacin.
Dynamics and Complexity of Dark Fermentation Microbial Communities Producing Hydrogen From Sugar Beet Molasses in Continuously Operating Packed Bed Reactors
Authors: Detman Anna , Laubitz Daniel , Chojnacka Aleksandra , Wiktorowska-Sowa Ewa , Piotrowski Jan , Salamon Agnieszka , Kaźmierczak Wiktor , Błaszczyk Mieczysław K. , Barberan Albert , Chen Yongjian , Łupikasza Ewa , Yang Fei , Sikora Anna
Published: January 2021

This study describes the dynamics and complexity of microbial communities producing hydrogen-rich fermentation gas from sugar-beet molasses in five packed-bed reactors (PBRs). The bioreactors constitute a part of a system producing hydrogen from the by-products of the sugar-beet industry that has been operating continuously in one of the Polish sugar factories. PBRs with different working volumes, packing materials, construction and inocula were tested. This study focused on analysis (based on 16S rRNA profiling and shotgun metagenomics sequencing) of the microbial communities selected in the PBRs under the conditions of high (>100 cm3/g COD of molasses) and low (<50 cm3/g COD of molasses) efficiencies of hydrogen production. The stability and efficiency of the hydrogen production are determined by the composition of dark fermentation microbial communities. The most striking difference between the tested samples is the ratio of hydrogen producers to lactic acid bacteria. The highest efficiency of hydrogen production (130–160 cm3/g COD of molasses) was achieved at the ratios of HPB to LAB ≈ 4:2.5 or 2.5:1 as determined by 16S rRNA sequencing or shotgun metagenomics sequencing, respectively. The most abundant Clostridium species were C. pasteurianum and C. tyrobutyricum. A multiple predominance of LAB over HPB (3:1–4:1) or clostridia over LAB (5:1–60:1) results in decreased hydrogen production. Inhibition of hydrogen production was illustrated by overproduction of short chain fatty acids and ethanol. Furthermore, concentration of ethanol might be a relevant marker or factor promoting a metabolic shift in the DF bioreactors processing carbohydrates from hydrogen-yielding toward lactic acid fermentation or solventogenic pathways. The novelty of this study is identifying a community balance between hydrogen producers and lactic acid bacteria for stable hydrogen producing systems. The balance stems from long-term selection of hydrogen-producing microbial community, operating conditions such as bioreactor construction, packing material, hydraulic retention time and substrate concentration. This finding is confirmed by additional analysis of the proportions between HPB and LAB in dark fermentation bioreactors from other studies. The results contribute to the advance of knowledge in the area of relationships and nutritional interactions especially the cross-feeding of lactate between bacteria in dark fermentation microbial communities.
Candida albicans Colonizes and Disseminates to the Gastrointestinal Tract in the Presence of the Microbiota in a Severe Combined Immunodeficient Mouse Model
Authors: Pan Chien-Hsiung , Lo Hsiu-Jung , Yan Jia-Ying , Hsiao Yu-Ju , Hsueh Jun-Wei , Lin Di-Wei , Lin Tsung-Han , Wu Sze-Hsien , Chen Yee-Chun
Published: January 2021

Candida albicans is the leading cause of candidemia or other invasive candidiasis. Gastrointestinal colonization has been considered as the primary source of candidemia. However, few established mouse models that mimic this infection route are available. In the present study, we established a mouse model of disseminated candidiasis developed through the translocation ofCandidafrom the gut. In this study, we developed a novelC. albicansGI colonization and dissemination animal model by using severe combined immunodeficient Rag2–/–IL2γc–/–(Rag2γc) mice, which lack functional T, B, NK cells, and IL2γc-dependent signaling. Rag2γc mice were highly susceptible toC. albicansgastrointestinal infection even in the presence of the gut microbiota. Within 4 weeks post infection, Rag2γc mice showed dose-dependent weight loss and disseminated candidiasis in more than 58% (7/12) of moribund mice. Histological analysis demonstrated abundant hyphae penetrating the mucosa, with significant neutrophilic infiltration in mice infected with wild-typeC. albicansbut not a filamentation-defective mutant. In moribund Rag2γc mice, the necrotic lesions and disrupted epithelial cells were associated withC. albicanshyphae. Notably, removal of the gut microbiota by antibiotics exacerbated the severity of fungal infection in Rag2γc mice, as demonstrated by elevated fungal burdens and accelerated weight loss and death. Furthermore, higher fungal burden and IL-1β expression were prominently noted in the stomach of Rag2γc mice. In fact, a significant increase in circulating proinflammatory cytokines, including IL-6, TNF-α, and IL-10, indicative of a septic response, was evident in infected Rag2γc mice. Additionally, Rag2γc mice exhibited significantly lower levels of IL-22 but not IFN-γ or IL-17A than wild-type B6 mice, suggesting that IL-22 plays a role inC. albicansgastrointestinal infection. Collectively, our analysis of the Rag2γc mouse model revealed features ofC. albicansgastrointestinal colonization and dissemination without the interference from antibiotics or chemotherapeutic agents, thus offering a new investigative tool for delineating the pathogenesis ofC. albicansand its cross-talk with the gut microbiota.
Next-Generation Sequencing Reveals a Novel Emaravirus in Diseased Maple Trees From a German Urban Forest
Authors: Rumbou Artemis , Candresse Thierry , von Bargen Susanne , Büttner Carmen
Published: January 2021

While the focus of plant virology has been mainly on horticultural and field crops as well as fruit trees, little information is available on viruses that infect forest trees. Utilization of next-generation sequencing (NGS) methodologies has revealed a significant number of viruses in forest trees and urban parks. In the present study, the full-length genome of a novel Emaravirus has been identified and characterized from sycamore maple (Acer pseudoplatanus) – a tree species of significant importance in urban and forest areas – showing leaf mottle symptoms. RNA-Seq was performed on the Illumina HiSeq2500 system using RNA preparations from a symptomatic and a symptomless maple tree. The sequence assembly and analysis revealed the presence of six genomic RNA segments in the symptomatic sample (RNA1: 7,074 nt-long encoding the viral replicase; RNA2: 2,289 nt-long encoding the glycoprotein precursor; RNA3: 1,525 nt-long encoding the nucleocapsid protein; RNA4: 1,533 nt-long encoding the putative movement protein; RNA5: 1,825 nt-long encoding a hypothetical protein P5; RNA6: 1,179 nt-long encoding a hypothetical protein P6). Two independent NGS sequencing runs from the same symptomatic maple tree detected the same genome segments. For one of these sequencing runs the cDNA library was prepared using a primer targeting the conserved genome terminal region, known to be shared between emaraviruses genome segments. We suggest, therefore, that the six identified genome segments represent the complete genome of a novel emaravirus from maple, which we tentatively name maple mottle-associated virus (MaMaV). Phylogenetic and sequence homology analyses place this virus on the distinct “subgroup a” clade within the Emaravirus genus along with – among others – rose rosette virus, Actinidia emaravirus 2, and fig mosaic virus. Validation RT-PCR assays performed on symptomatic and non-symptomatic trees suggest that MaMaV may be the symptom-inducing virus in the diseased trees. To our knowledge, this is the first time an Emaravirus is described from maple and is fully genetically characterized. With the discovery of MaMaV, the genus Emaravirus comprising negative-sense single-stranded viruses with very divergent genomes – that were until recently overlooked – has substantially increased counting 22 established and putative members.