bluuebunny/crossref_metadata_2025 huggingface dataset:
The Mucosal and Serological Immune Responses to the Novel Coronavirus (SARS-CoV-2) Vaccines
Authors: Chan Renee W. Y. , Liu Shaojun , Cheung Jonathan Y. , Tsun Joseph G. S. , Chan Kate C. , Chan Kathy Y. Y. , Fung Genevieve P. G. , Li Albert M. , Lam Hugh Simon
Published: October 2021

Background

Although the serological antibody responses induced by SARS-CoV-2 vaccines are well characterized, little is known about their ability to elicit mucosal immunity.

Objectives

This study aims to examine and compare the mucosal and systemic responses of recipients of two different vaccination platforms: mRNA (Comirnaty) and inactivated virus (CoronaVac).

Methods

Serial blood and nasal epithelial lining fluid (NELF) samples were collected from the recipients of either Comirnaty or CoronaVac. The plasma and NELF immunoglobulins A and G (IgA and IgG) specific to SARS-CoV-2 S1 protein (S1) and their neutralization effects were quantified.

Results

Comirnaty induced nasal S1-specific immunoglobulin responses, which were evident as early as 14 ± 2 days after the first dose. In 64% of the subjects, the neutralizing effects of NELF persisted for at least 50 days. Moreover, 85% of Comirnaty recipients exhibited S1-specific IgA and IgG responses in plasma by 14 ± 2 days after the first dose. By 7 ± 2 days after the booster, all plasma samples possessed S1-specific IgA and IgG responses and were neutralizing. The induction of S1-specific plasma antibodies by CoronaVac was IgG dominant, and 83% of the subjects possessed S1-specific IgG by 7 ± 2 days after the booster, with neutralizing effects.

Conclusion

Comirnaty induces S1-specific IgA and IgG responses with neutralizing activity in the nasal mucosa; a similar response is not seen with CoronaVac.

Clinical Implication

The presence of a nasal response with mRNA vaccine may provide additional protection compared with inactivated virus vaccine. However, whether such widespread immunological response may produce inadvertent adverse effects in other tissues warrants further investigation.
Oxidative and Non-Oxidative Antimicrobial Activities of the Granzymes
Authors: Lavergne Marilyne , Hernández-Castañeda Maria Andrea , Mantel Pierre-Yves , Martinvalet Denis , Walch Michael
Published: October 2021

Cell-mediated cytotoxicity is an essential immune defense mechanism to fight against viral, bacterial or parasitic infections. Upon recognition of an infected target cell, killer lymphocytes form an immunological synapse to release the content of their cytotoxic granules. Cytotoxic granules of humans contain two membrane-disrupting proteins, perforin and granulysin, as well as a homologous family of five death-inducing serine proteases, the granzymes. The granzymes, after delivery into infected host cells by the membrane disrupting proteins, may contribute to the clearance of microbial pathogens through different mechanisms. The granzymes can induce host cell apoptosis, which deprives intracellular pathogens of their protective niche, therefore limiting their replication. However, many obligate intracellular pathogens have evolved mechanisms to inhibit programed cells death. To overcome these limitations, the granzymes can exert non-cytolytic antimicrobial activities by directly degrading microbial substrates or hijacked host proteins crucial for the replication or survival of the pathogens. The granzymes may also attack factors that mediate microbial virulence, therefore directly affecting their pathogenicity. Many mechanisms applied by the granzymes to eliminate infected cells and microbial pathogens rely on the induction of reactive oxygen species. These reactive oxygen species may be directly cytotoxic or enhance death programs triggered by the granzymes. Here, in the light of the latest advances, we review the antimicrobial activities of the granzymes in regards to their cytolytic and non-cytolytic activities to inhibit pathogen replication and invasion. We also discuss how reactive oxygen species contribute to the various antimicrobial mechanisms exerted by the granzymes.
Mechanisms by Which Obesity Promotes Acute Graft-Versus-Host Disease in Mice
Authors: Khuat Lam T. , Vick Logan V. , Choi Eunju , Dunai Cordelia , Merleev Alexander A. , Maverakis Emanual , Blazar Bruce R. , Monjazeb Arta M. , Murphy William J.
Published: October 2021

The efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by the occurrence of acute and chronic graft-versus-host disease (GVHD). We have recently demonstrated that obesity results in exacerbated acute gastrointestinal GVHD in both mouse models and clinical outcomes due to increased pro-inflammatory cytokine responses and microbiota alterations. We therefore wanted to delineate the role of the various parameters in obesity, adiposity, effects of high-fat (HF) diet, and the role of microbiome on GVHD pathogenesis, by taking advantage of a mouse strain resistant to diet-induced obesity (DIO). Female BALB/c mice are resistant to DIO phenotype with approximately 50% becoming DIO under HF diets. The DIO-susceptible recipients rapidly succumb to acute gut GVHD, whereas the DIO-resistant recipient littermates, which do not become obese, are partially protected from GVHD, indicating that being on HF diet alone contributes to but is not the primary driver of GVHD. Microbiome assessment revealed restricted diversity in both cohorts of mice, but coprophagy normalizes the microbiota in mice housed together. We then individually housed DIO-resistant, DIO-susceptible, and lean control mice. Notably, each of the individually housed groups demonstrates marked restricted diversity that has been shown to occur from the stress of single housing. Despite the restricted microbiome diversity, the GVHD pathogenesis profile remains consistent in the group-housed mice, with the lean control single-housed mice exhibiting no acute GVHD and DIO-resistant recipients showing again partial protection. These results demonstrate that the deleterious effects of obesity on acute gut GVHD are critically dependent on adiposity with the HF diet also playing a lesser role, and the microbiome alterations with obesity instead appear to fuel ongoing acute GVHD processes.
Characterization of the Infant Immune System and the Influence and Immunogenicity of BCG Vaccination in Infant and Adult Rhesus Macaques
Authors: Sarfas Charlotte , White Andrew D. , Sibley Laura , Morrison Alexandra L. , Gullick Jennie , Lawrence Steve , Dennis Mike J. , Marsh Philip D. , Fletcher Helen A. , Sharpe Sally A.
Published: October 2021

In many countries where tuberculosis (TB) is endemic, the Bacillus Calmette–Guérin (BCG) vaccine is given as close to birth as possible to protect infants and children from severe forms of TB. However, BCG has variable efficacy and is not as effective against adult pulmonary TB. At present, most animal models used to study novel TB vaccine candidates rely on the use of adult animals. Human studies show that the infant immune system is different to that of an adult. Understanding how the phenotypic profile and functional ability of the immature host immune system compares to that of a mature adult, together with the subsequent BCG immune response, is critical to ensuring that new TB vaccines are tested in the most appropriate models. BCG-specific immune responses were detected in macaques vaccinated within a week of birth from six weeks after immunization indicating that neonatal macaques are able to generate a functional cellular response to the vaccine. However, the responses measured were significantly lower than those typically observed following BCG vaccination in adult rhesus macaques and infant profiles were skewed towards the activation and attraction of macrophages and monocytes and the synthesis in addition to release of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-α. The frequency of specific immune cell populations changed significantly through the first three years of life as the infants developed into young adult macaques. Notably, the CD4:CD8 ratio significantly declined as the macaques aged due to a significant decrease in the proportion of CD4+ T-cells relative to a significant increase in CD8+ T-cells. Also, the frequency of both CD4+ and CD8+ T-cells expressing the memory marker CD95, and memory subset populations including effector memory, central memory and stem cell memory, increased significantly as animals matured. Infant macaques, vaccinated with BCG within a week of birth, possessed a significantly higher frequency of CD14+ classical monocytes and granulocytes which remained different throughout the first three years of life compared to unvaccinated age matched animals. These findings, along with the increase in monokines following vaccination in infants, may provide an insight into the mechanism by which vaccination with BCG is able to provide non-specific immunity against non-mycobacterial organisms.
Biophysical Evaluation of Rhesus Macaque Fc Gamma Receptors Reveals Similar IgG Fc Glycoform Preferences to Human Receptors
Authors: Crowley Andrew R. , Osei-Owusu Nana Yaw , Dekkers Gillian , Gao Wenda , Wuhrer Manfred , Magnani Diogo M. , Reimann Keith A. , Pincus Seth H. , Vidarsson Gestur , Ackerman Margaret E.
Published: October 2021

Rhesus macaques are a common non-human primate model used in the evaluation of human monoclonal antibodies, molecules whose effector functions depend on a conserved N-linked glycan in the Fc region. This carbohydrate is a target of glycoengineering efforts aimed at altering antibody effector function by modulating the affinity of Fcγ receptors. For example, a reduction in the overall core fucose content is one such strategy that can increase antibody-mediated cellular cytotoxicity by increasing Fc-FcγRIIIa affinity. While the position of the Fc glycan is conserved in macaques, differences in the frequency of glycoforms and the use of an alternate monosaccharide in sialylated glycan species add a degree of uncertainty to the testing of glycoengineered human antibodies in rhesus macaques. Using a panel of 16 human IgG1 glycovariants, we measured the affinities of macaque FcγRs for differing glycoforms via surface plasmon resonance. Our results suggest that macaques are a tractable species in which to test the effects of antibody glycoengineering.
Recent Metabolic Advances for Preventing and Treating Acute and Chronic Graft Versus Host Disease
Authors: Mohamed Fathima A. , Thangavelu Govindarajan , Rhee Stephanie Y. , Sage Peter T. , O’Connor Roddy S. , Rathmell Jeffrey C. , Blazar Bruce R.
Published: October 2021

The therapeutic efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by the development of graft-versus-host disease (GVHD). In GVHD, rigorous pre-conditioning regimen resets the immune landscape and inflammatory milieu causing immune dysregulation, characterized by an expansion of alloreactive cells and a reduction in immune regulatory cells. In acute GVHD (aGVHD), the release of damage- and pathogen- associated molecular patterns from damaged tissue caused by the conditioning regimen sets the stage for T cell priming, activation and expansion further exacerbating tissue injury and organ damage, particularly in the gastrointestinal tract. Studies have shown that donor T cells utilize multiple energetic and biosynthetic pathways to mediate GVHD that can be distinct from the pathways used by regulatory T cells for their suppressive function. In chronic GVHD (cGVHD), donor T cells may differentiate into IL-21 producing T follicular helper cells or tissue resident T helper cells that cooperate with germinal center B cells or memory B cells, respectively, to produce allo- and auto-reactive antibodies with subsequent tissue fibrosis. Alternatively, donor T cells can become IFN- γ/IL-17 cytokine expressing T cells that mediate sclerodermatous skin injury. Patients refractory to the first line standard regimens for GVHD treatment have a poor prognosis indicating an urgent need for new therapies to restore the balance between effector and regulatory immune cells while preserving the beneficial graft-versus-tumor effect. Emerging data points toward a role for metabolism in regulating these allo- and auto-immune responses. Here, we will discuss the preclinical and clinical data available on the distinct metabolic demands of acute and chronic GVHD and recent efforts in identifying therapeutic targets using metabolomics. Another dimension of this review will examine the changing microbiome after allo-HSCT and the role of microbial metabolites such as short chain fatty acids and long chain fatty acids on regulating immune responses. Lastly, we will examine the metabolic implications of coinhibitory pathway blockade and cellular therapies in allo-HSCT. In conclusion, greater understanding of metabolic pathways involved in immune cell dysregulation during allo-HSCT may pave the way to provide novel therapies to prevent and treat GVHD.
Development of a Scrub Typhus Diagnostic Platform Incorporating Cell-Surface Display Technology
Authors: Liao Chih-Chi , Tsai Chih-Hsuan , Lo Huei-Ru , Lin Pey-Ru , Lin Chang-Chi , Chao Yu-Chan
Published: October 2021

Scrub typhus (ST), also known as tsutsugamushi disease and caused by rickettsia Orientia tsutsugamushi, is an underestimated fatal epidemic in the Asia-Pacific region, resulting in a million human infections each year. ST is easily misdiagnosed as clinical diagnosis is based on non-specific skin eschar and flu-like symptoms. Thus, the lack of accurate, convenient, and low-cost detection methods for ST poses a global health threat. To address this problem, we adopted baculovirus surface-display technology to express three variants of TSA56, the major membrane antigen of O. tsutsugamushi, as well as the passenger domain of ScaC (ScaC-PD), on insect Sf21 cell surfaces rather than biosafety level 3 bacteria in an enzyme-linked immunosorbent assay (ELISA). Recombinant TSA56 and ScaC-PD were all properly expressed and displayed on Sf21 cells. Our cell-based ELISA comprising the four antigen-displaying cell types interacted with monoclonal antibodies as well as serum samples from ST-positive field-caught rats. This cell-based ELISA presented high accuracy (96.3%), sensitivity (98.6%), and specificity (84.6%) when tested against the ST-positive rat sera. Results of a pilot study using human sera were also highly consistent with the results of immunofluorescence analyses. By adopting this approach, we circumvented complex purification and refolding processes required to generate recombinant O. tsutsugamushi antigens and reduced the need for expensive equipment and extensively trained operators. Thus, our system has the potential to become a widely used serological platform for diagnosing ST.
Intra-Group Orca Call Rate Modulation Estimation Using Compact Four Hydrophones Array
Authors: Poupard Marion , Symonds Helena , Spong Paul , Glotin Hervé
Published: October 2021

Acoustic emissions are vital for orca (Orcinus orca) socializing, hunting, and maintaing spatial awareness. Studying the acoustic emissions of orcas on an individual basis often results in interference with their natural behaviors through mounting tags or following by boat. In order to analyze their inter- and intra-group communication, we propose a study allowing us to associate vocalizations with their emitter (matriline and when possible individual). Such a non-interfering device for allocating calls to individual orcas could substantially boost our understanding of their complex acoustic world. Our experimental protocol was based on a compact array of four hydrophones fixed near the shore, operable up to 1 km away from the path of orcas. It was used during summer 2019 at the research station OrcaLab, northern Vancouver Island, Canada. A total of 722 calls were extracted, jointly with visual identification and azimuth of surfacing orcas, allowing validation of the acoustic diarization and azimuth estimations of the orca calls. We then calculated the Call Rate (CR) for each matriline or when possible individual in order to describe their acoustic activity. Preliminary results show that CR could be modulated according to the distance of the signaler from a group, the presence of another group, or anthropic pressure.
Intra- and Inter-Specific Variation in Edible Jellyfish Biomarkers and Implications for Origin Traceability and Authentication
Authors: Wang Yaxin , Gong Yi , Zhang Jian , Tang Yi , Shi Xiaofei , Shi Jiangao
Published: October 2021

With the continuous development of jellyfish fisheries and food products around the world, an effective traceability system has become increasingly prominent. This study provides insight into the origin traceability and authentication of two commercially important jellyfish species, flame jellyfish Rhopilema esculentum and Nomura’s jellyfish Nemopilema nomurai, while investigating the intra- and inter-specific variation in fatty acid (FA) profiles and carbon and nitrogen stable isotope ratios (δ13C and δ15N). Results showed significant differences in FA profiles and isotopic values in fresh bell tissues between wild and farmed R. esculentum and among geographic origins, possibly due to different food sources, nutritional status, and energy costs that each group experiences at a given location. The linear discriminant analysis indicated that δ13C, δ15N, C16:0, C17:0, C18:0, C16:1n7, and C20:5n3 were suitable discriminatory variables with a high rate of correct classification for distinguishing origins of R. esculentum. In addition, inter-specific FA profiles/biomarkers, combined with isotopic values, suggests the variety of dietary sources and trophic positions of sympatric similar-sized R. esculentum and N. nomurai and the potential use of biomarkers, especially stable isotope analysis, for distinguishing sympatric jellyfish species. These results highlighted the complementarity of FA and stable isotope analyses and provide an alternative approach for improving the origin traceability and authenticity evaluation of untreated edible jellyfish. Furthermore, this study adds new information regarding the biochemical compositions of jellyfish species.
Managing Biofouling on Submerged Static Artificial Structures in the Marine Environment – Assessment of Current and Emerging Approaches
Authors: Hopkins Grant , Davidson Ian , Georgiades Eugene , Floerl Oliver , Morrisey Donald , Cahill Patrick
Published: October 2021

The number, extent, diversity, and global reach of submerged static artificial structures (SSAS) in the marine environment is increasing. These structures are prone to the accumulation of biofouling that can result in unwanted impacts, both immediate and long-term. Therefore, management of biofouling on SSAS has a range of potential benefits that can improve structure functions, cost-efficiency, sustainability, productivity, and biosecurity. This review and synthesis collates the range of methods and tools that exist or are emerging for managing SSAS biofouling for a variety of sectors, highlighting key criteria and knowledge gaps that affect development, and uptake to improve operational and environmental outcomes. The most common methods to manage biofouling on SSAS are mechanical and are applied reactively to manage biofouling assemblages after they have developed to substantial levels. Effective application of reactive methods is logistically challenging, occurs after impacts have accumulated, can pose health and safety risks, and is costly at large scales. Emerging technologies aim to shift this paradigm to a more proactive and preventive management approach, but uncertainty remains regarding their long-term efficacy, feasibility, and environmental effects at operational scales. Key priorities to promote more widespread biofouling management of SSAS include rigorous and transparent independent testing of emerging treatment systems, with more holistic cost-benefit analyses where efficacy is demonstrated.
A Dual-Factor Releasing Hydrogel for Rotator Cuff Injury Repair
Authors: Teng Chong , Fang Yifei , Zhu Huangrong , Huang Leyi , Jin Yanglei , Ye Zhaoming
Published: October 2021

Rotator cuff injury causes pain in the shoulder and is a challenge to be repaired even after surgical reconstruction. Here, we developed a dual-factor releasing hydrogel based on sulfhydrylated chitosan to deliver KGN and FGF-2 to the injured area to enable fast healing of the tendon–bone interface, which is essential for the repair of rotator cuff injury. We found that the two factors could be easily loaded into the hydrogel, which could in turn continuously release the factors in physiological conditions. The hydrogel was found to be a porous structure through a scanning electron microscope (SEM). The micropores in the hydrogel structure enable the loading and releasing of these molecules. This study showed that KGN and FGF-2 could play a synergistic effect by recruiting and promoting stem cell proliferation and chondrogenesis, thus accelerating the healing of the tendon–bone interface. An in vivo study based on a rabbit rotator cuff injury model demonstrated that the dual-factor releasing hydrogel possesses superior repair capacity than a single-factor releasing hydrogel and the untreated groups. In conclusion, the KGN and FGF-2 dual-factor releasing hydrogel could be a promising biomaterial for the regeneration of the tendon–bone interface and rotator cuff injury repair.
Safety and Efficacy of a Novel Centrifugal Pump and Driving Devices of the OASSIST ECMO System: A Preclinical Evaluation in the Ovine Model
Authors: Gao Sizhe , Wang Weining , Qi Jiachen , Liu Gang , Wang Jian , Yan Shujie , Teng Yuan , Zhou Chun , Wang Qian , Yan Weidong , Zhang Qiaoni , Liu Youjun , Gao Bin , Ji Bingyang
Published: October 2021

Background: Extracorporeal membrane oxygenation (ECMO) provides cardiopulmonary support for critically ill patients. Portable ECMO devices can be applied in both in-hospital and out-of-hospital emergency conditions. We evaluated the safety and biocompatibility of a novel centrifugal pump and ECMO device of the OASSIST ECMO System (Jiangsu STMed Technologies Co., Suzhou, China) in a 168-h ovine ECMO model.

Methods: The portable OASSIST ECMO system consists of the control console, the pump drive, and the disposable centrifugal pump. Ten healthy sheep were used to evaluate the OASSIST ECMO system. Five were supported on veno-venous ECMO and five on veno-arterial ECMO, each for 168 h. The systemic anticoagulation was achieved by continuous heparin infusion to maintain the activated clotting time (ACT) between 220 and 250 s. The rotary speed was set at 3,200–3,500 rpm. The ECMO configurations and ACT were recorded every 6 hours (h). The free hemoglobin (fHb), complete blood count, and coagulation action test were monitored, at the 6th h and every 24 h after the initiation of the ECMO. The dissection of the pump head and oxygenator were conducted to explore thrombosis.

Results: Ten sheep successfully completed the study duration without device-related accidents. The pumps ran stably, and the ECMO flow ranged from 1.6 ± 0.1 to 2.0 ± 0.11 L/min in the V-V group, and from 1.8 ± 0.1 to 2.4 ± 0.14 L/min in the V-A group. The anticoagulation was well-performed. The ACT was maintained at 239.78 ± 36.31 s, no major bleeding or thrombosis was observed during the ECMO run or in the autopsy. 3/5 in the V-A group and 4/5 in the V-V group developed small thrombus in the bearing pedestal. No obvious thrombus formed in the oxygenator was observed. The hemolytic blood damage was not significant. The average fHb was 0.17 ± 0.12 g/L. Considering hemodilution, the hemoglobin, white blood cell, and platelets didn't reduce during the ECMO runs.

Conclusions: The OASSIST ECMO system shows satisfactory safety and biocompatibility for the 168-h preclinical evaluation in the ovine model. The OASSIST ECMO system is promising to be applied in clinical conditions in the future.
iPSC-Derived Organoids as Therapeutic Models in Regenerative Medicine and Oncology
Authors: Turhan Ali G. , Hwang Jinwook W. , Chaker Diana , Tasteyre Albert , Latsis Theodoros , Griscelli Frank , Desterke Christophe , Bennaceur-Griscelli Annelise
Published: October 2021

Progress made during the last decade in stem cell biology allows currently an unprecedented potential to translate these advances into the clinical applications and to shape the future of regenerative medicine. Organoid technology is amongst these major developments, derived from primary tissues or more recently, from induced pluripotent stem cells (iPSC). The use of iPSC technology offers the possibility of cancer modeling especially in hereditary cancers with germline oncogenic mutations. Similarly, it has the advantage to be amenable to genome editing with introduction of specific oncogenic alterations using CRISPR-mediated gene editing. In the field of regenerative medicine, iPSC-derived organoids hold promise for the generation of future advanced therapeutic medicinal products (ATMP) for organ repair. Finally, it appears that they can be of highly useful experimental tools to determine cell targets of SARS-Cov-2 infections allowing to test anti-Covid drugs. Thus, with the possibilities of genomic editing and the development of new protocols for differentiation toward functional tissues, it is expected that iPSC-derived organoid technology will represent also a therapeutic tool in all areas of medicine.
No Sex Differences in Psychological Burden and Health Behaviors of Healthcare Workers During the COVID-19 Stay-at-Home Orders
Authors: Gu Wenli , Liu Xiao , Sun Runlu , Jiang Yuan , Cao Zhengyu , Wu Maoxiong , Ma Jianyong , Chen Zhiteng , Chen Yangxin , Zhang Yuling , Wang Jingfeng
Published: October 2021

Background: Females with novel coronavirus disease 2019 (COVID-19) state-ordered home isolation were associated with higher anxiety and reduced sleep quality than males. Sex differences in psychobehavioral changes during the COVID-19 stay-at home orders among healthcare workers remained unclear. The purpose of this study was to explore the sex differences in psychological burden and health behaviors among these persons.

Methods: This was a cross-sectional study using online data available in the open Interuniversity Consortium for Political and Social Research (OPENICPSR). Healthcare workers including females and males who transitioned to working from home during the COVID-19 stay-at-home orders were included. Sex differences were compared using the chi-square test and Student's t-test. We performed logistic and linear regression analyses to determine the association of females with psychological burden and health behaviors.

Results: A total of 537 respondents (425 females and 112 males) were enrolled in our study. Sex differences in age (42.1 ± 12.3 years vs. 46.6 ± 15.7 years, t = −2.821, p = 0.005), occupation (χ2 = 41.037, p < 0.001), mood change (n = 297, 69.9% vs. n = 61, 54.5%, χ2 = 9.482, p = 0.002), bedtime schedule (χ2 = 6.254, p = 0.044) and news consumption (n = 344, 80.9% vs. n = 76, 67.9%, χ2 = 8.905, p = 0.003) were statistically significant. Logistic regression showed that females was negatively associated with better mood status (OR = 0.586, 95% CI 0.153–2.247, p = 0.436). In addition, linear regression showed that females were not correlated with total sleep time after adjusting for sio-demographics, mental health outcomes and health behaviors (B = 0.038, 95% CI −0.313–0.388, p = 0.833).

Conclusion: No sex differences in psychological burden and health behaviors of healthcare workers were found during the COVID-19 stay-at-home orders. The COVID-19 state-ordered home isolation may be a potential way to reduce disproportionate effects of COVID-19 pandemic on females and help to minimize sex differences in psychological burden and health behaviors among healthcare workers.
Liver Histopathological Analysis of 24 Postmortem Findings of Patients With COVID-19 in China
Authors: Chu Huikuan , Peng Li , Hu Lilin , Zhu Yixin , Zhao Jinfang , Su Hua , Yao Lin , Zhu Qingjing , Nie Xiu , Yang Ling , Hou Xiaohua
Published: October 2021

Although the pathologic investigation of liver injury was observed in a couple of cases in China, the detailed description of liver histopathologic and ultrastructural changes in a relatively larger series of liver tissues from COVID-19 patients is lacking. Samples from the liver were obtained from 24 COVID-19 cases from February 1 to April 1, 2020. Light microscopy showed that all liver sections had different degrees of liver injury manifested as swelling of the hepatocytes, hepatocellular necrosis, steatosis, lobular inflammation, portal inflammation, dilatation of sinusoids, and so on. SARS-CoV-2 induced liver injury might be independent of pre-existing Schistosoma infection or obstructive cholestasis. Patients combined with respiratory failure had more severe hepatocellular necrosis and male patients were more susceptible to liver injury. Although coronavirus particles or viral inclusions were not detected in the liver tissues for all cases, vacuolar degenerations in hepatocytes, edematous of mitochondria with the disruption of cristae, and expansions of the endoplasmic reticulum were observed. In conclusion, pathologic changes of liver tissues provide us a further understanding of liver injury in COVID-19 patients. Changes in the liver seem to be related to the underlying diseases/conditions.
Gastrointestinal Bleeding, but Not Other Gastrointestinal Symptoms, Is Associated With Worse Outcomes in COVID-19 Patients
Authors: Chen Hongxin , Tong Zhenhua , Ma Zhuang , Luo Li , Tang Yufu , Teng Yue , Yu Hao , Meng Hao , Peng Chengfei , Zhang Quanyu , Zhu Tianyi , Zhao Haitao , Chu Guiyang , Li Hongyu , Lu Hui , Qi Xingshun
Published: October 2021

Background: Patients with coronavirus disease 2019 (COVID-19) can present with gastrointestinal (GI) symptoms. However, the prevalence of GI symptoms and their association with outcomes remain controversial in COVID-19 patients.

Methods: All COVID-19 patients consecutively admitted to the Wuhan Huoshenshan hospital from February 2020 to April 2020 were collected. Disease severity and outcomes were compared between COVID-19 patients with and without GI symptoms. Logistic regression analyses were performed to evaluate the association of GI symptoms with the composite endpoint and death in COVID-19 patients. A composite endpoint was defined as transfer to intensive care unit, requirement of mechanical ventilation, and death. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated.

Results: Overall, 2,552 COVID-19 patients were included. The prevalence of GI symptoms was 21.0% (537/2,552). Diarrhea (8.9%, 226/2,552) was the most common GI symptom. Patients with GI symptoms had significantly higher proportions of severe COVID-19 and worse outcomes than those without. Univariate logistic regression analyses demonstrated that GI symptoms were significantly associated with the composite endpoint (OR = 2.426, 95% CI = 1.608–3.661; P < 0.001) and death (OR = 2.137, 95% CI = 1.209–3.778; P = 0.009). After adjusting for age, sex, and severe/critical COVID-19, GI symptoms were still independently associated with the composite endpoint (OR = 2.029, 95% CI = 1.294–3.182; P = 0.002), but not death (OR = 1.726, 95% CI = 0.946–3.150; P = 0.075). According to the type of GI symptoms, GI bleeding was an independent predictor of the composite endpoint (OR = 8.416, 95% CI = 3.465–20.438, P < 0.001) and death (OR = 6.640, 95% CI = 2.567–17.179, P < 0.001), but not other GI symptoms (i.e., diarrhea, abdominal discomfort, nausea and/or vomiting, constipation, acid reflux and/or heartburn, or abdominal pain).

Conclusion: GI symptoms are common in COVID-19 patients and may be associated with their worse outcomes. Notably, such a negative impact of GI symptoms on the outcomes should be attributed to GI bleeding.
Evaluating the Cost of Pharmaceutical Purification for a Long-Duration Space Exploration Medical Foundry
Authors: McNulty Matthew J. , Berliner Aaron J. , Negulescu Patrick G. , McKee Liber , Hart Olivia , Yates Kevin , Arkin Adam P. , Nandi Somen , McDonald Karen A.
Published: October 2021

There are medical treatment vulnerabilities in longer-duration space missions present in the current International Space Station crew health care system with risks, arising from spaceflight-accelerated pharmaceutical degradation and resupply lag times. Bioregenerative life support systems may be a way to close this risk gap by leveraging in situ resource utilization (ISRU) to perform pharmaceutical synthesis and purification. Recent literature has begun to consider biological ISRU using microbes and plants as the basis for pharmaceutical life support technologies. However, there has not yet been a rigorous analysis of the processing and quality systems required to implement biologically produced pharmaceuticals for human medical treatment. In this work, we use the equivalent system mass (ESM) metric to evaluate pharmaceutical purification processing strategies for longer-duration space exploration missions. Monoclonal antibodies, representing a diverse therapeutic platform capable of treating multiple space-relevant disease states, were selected as the target products for this analysis. We investigate the ESM resource costs (mass, volume, power, cooling, and crew time) of an affinity-based capture step for monoclonal antibody purification as a test case within a manned Mars mission architecture. We compare six technologies (three biotic capture methods and three abiotic capture methods), optimize scheduling to minimize ESM for each technology, and perform scenario analysis to consider a range of input stream compositions and pharmaceutical demand. We also compare the base case ESM to scenarios of alternative mission configuration, equipment models, and technology reusability. Throughout the analyses, we identify key areas for development of pharmaceutical life support technology and improvement of the ESM framework for assessment of bioregenerative life support technologies.
Compositional Data Analysis of Microbiome and Any-Omics Datasets: A Validation of the Additive Logratio Transformation
Authors: Greenacre Michael , Martínez-Álvaro Marina , Blasco Agustín
Published: October 2021

Microbiome and omics datasets are, by their intrinsic biological nature, of high dimensionality, characterized by counts of large numbers of components (microbial genes, operational taxonomic units, RNA transcripts, etc.). These data are generally regarded as compositional since the total number of counts identified within a sample is irrelevant. The central concept in compositional data analysis is the logratio transformation, the simplest being the additive logratios with respect to a fixed reference component. A full set of additive logratios is not isometric, that is they do not reproduce the geometry of all pairwise logratios exactly, but their lack of isometry can be measured by the Procrustes correlation. The reference component can be chosen to maximize the Procrustes correlation between the additive logratio geometry and the exact logratio geometry, and for high-dimensional data there are many potential references. As a secondary criterion, minimizing the variance of the reference component's log-transformed relative abundance values makes the subsequent interpretation of the logratios even easier. On each of three high-dimensional omics datasets the additive logratio transformation was performed, using references that were identified according to the abovementioned criteria. For each dataset the compositional data structure was successfully reproduced, that is the additive logratios were very close to being isometric. The Procrustes correlations achieved for these datasets were 0.9991, 0.9974, and 0.9902, respectively. We thus demonstrate, for high-dimensional compositional data, that additive logratios can provide a valid choice as transformed variables, which (a) are subcompositionally coherent, (b) explain 100% of the total logratio variance and (c) come measurably very close to being isometric. The interpretation of additive logratios is much simpler than the complex isometric alternatives and, when the variance of the log-transformed reference is very low, it is even simpler since each additive logratio can be identified with a corresponding compositional component.
Disentangling the Progression of Non-alcoholic Fatty Liver Disease in the Human Gut Microbiota
Authors: Wang Tianjiao , Guo Xue-Kun , Xu Huji
Published: October 2021

Gut microbiome dysbiosis has been known to be associated with all stages of non-alcoholic fatty liver disease (NAFLD), but questions remain about microbial profiles in progression and homogeneity across NAFLD stages. We performed a meta-analysis of three publicly shotgun datasets and built predictive models to determine diagnostic capacity. Here, we found consistently microbiome shifts across NAFLD stages, of which co-occurrence patterns and core sets of new biomarkers significantly correlated with NAFLD progression were identified. Machine learning models that are able to distinguish patients with any NAFLD stage from healthy controls remained predictive when applied to patients with other NAFLD stages, suggesting the homogeneity across stages once again. Focusing on species and metabolic pathways specifically associated with progressive stages, we found that increased toxic metabolites and decreased protection of butyrate and choline contributed to advanced NAFLD. We further built models discriminating one stage from the others with an average of 0.86 of area under the curve. In conclusion, this meta-analysis firmly establishes generalizable microbiome dysbiosis and predictive taxonomic and functional signatures as a basis for future diagnostics across NAFLD stages.
Uncovering the Oral Dysbiotic Microbiota as Masters of Neutrophil Responses in the Pathobiology of Periodontitis
Authors: Prucsi Zsombor , Płonczyńska Alicja , Potempa Jan , Sochalska Maja
Published: October 2021

Numerous bacterial species participate in the shift of the oral microbiome from beneficial to dysbiotic. The biggest challenge lying ahead of microbiologists, immunologists and dentists is the fact that the bacterial species act differently, although usually synergistically, on the host immune cells, including neutrophils, and on the surrounding tissues, making the investigation of single factors challenging. As biofilm is a complex community, the members interact with each other, which can be a key issue in future studies designed to develop effective treatments. To understand how a patient gets to the stage of the late-onset (previously termed chronic) periodontitis or develops other, in some cases life-threatening, diseases, it is crucial to identify the microbial composition of the biofilm and the mechanisms behind its pathogenicity. The members of the red complex (Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia) have long been associated as the cause of periodontitis and stayed in the focus of research. However, novel techniques, such as 16S clonal analysis, demonstrated that the oral microbiome diversity is greater than ever expected and it opened a new era in periodontal research. This review aims to summarize the current knowledge concerning bacterial participation beyond P. gingivalis and the red complex in periodontal inflammation mediated by neutrophils and to spread awareness about the associated diseases and pathological conditions.
Molecular Epidemiology and Characteristics of CTX-M-55 Extended-Spectrum β-Lactamase-Producing Escherichia coli From Guangzhou, China
Authors: Zeng Shihan , Luo Jiajun , Chen Xiankai , Huang LiShao , Wu Aiwu , Zhuo Chao , Li Xiaoyan
Published: October 2021

In recent years, the CTX-M-55 extended-spectrum β-lactamase (ESBL)-positive rate has gradually increased in the clinic. To identify the molecular epidemiology and characteristics of blaCTX–M–55-positive isolates, a total of 374 non-repetitive ESBL-producing Escherichia coli strains were collected from patients in two hospitals in Guangzhou, and 89 blaCTX–M–55-positive isolates were selected by CTX-M-1-group PCR amplification and confirmed by DNA sequencing. Whole-genome sequencing was used to analyze the resistance phenotype, plasmid types, phylogenetic relationships and genetic environment of the blaCTX–M–55 gene. Conjugation experiments and PCR were performed to confirm whether the plasmid harboring blaCTX–M–55 gene could be transferred. The results showed that all blaCTX–M–55-positive isolates were resistant to ceftriaxone, and 88.76 and 76.40% were resistant to ceftazidime and cefepime, respectively. The resistance rates to levofloxacin and sulfamethoxazole were 66.29 and 59.55%, respectively. However, the sensitivity rate of piperacillin/tazobactam, amoxicillin/clavulanate, and amikacin exceeded 90%. All blaCTX–M–55-positive isolates were sensitive to carbapenems. Thirty-two STs were detected in the blaCTX–M–55-positive isolates, among which the detection rate of ST1193 was relatively high (19.10%, 17/89), and other ST types were scattered. It remains to be seen whether ST1193 carrying the blaCTX–M–55 gene can become a popular clone strain in this region in the future. The plasmid types carrying the blaCTX–M–55 gene included IncI1, IncFII, IncFIC, IncFIB, IncHI2, IncI2, and IncX/Y, among which the IncI1 and IncFII plasmids were the main plasmids, accounting for 37.80 and 28.09%, respectively. Among them, 11 strains of the IncI1 plasmid existed in ST1193 strains. The blaCTX–M–55 gene was found on chromosomes of 13 isolates, and seemed to be increasing annually. Up to five distinct types of genetic environments surrounding the blaCTX–M–55 gene were analyzed. The most common structure was type II “ISEcp1-blaCTX–M–55-ORF477.” In conclusion, whether ST1193, which carries blaCTX–M–55 gene, will be an epidemic clone of this region in the future remains to be concerned. The plasmids IncI1 and IncFII, and mobile elements such as ISEcp1 and IS26 may be the main factors leading to the spread and prevalence of CTX-M-55 genotypes.
Potential Probiotic Pediococcus pentosaceus M41 Modulates Its Proteome Differentially for Tolerances Against Heat, Cold, Acid, and Bile Stresses
Authors: Baig Mohd Affan , Turner Mark S. , Liu Shao-Quan , Al-Nabulsi Anas A. , Shah Nagendra P. , Ayyash Mutamed M.
Published: October 2021

Probiotics containing functional food confer health benefits in addition to their nutritional properties. In this study, we have evaluated the differential proteomic responses of a potential novel probiotic Pediococcus pentosaceus M41 under heat, cold, acid, and bile stress conditions. We identified stress response proteins that could provide tolerances against these stresses and could be used as probiotic markers for evaluating stress tolerance. Pediococcus pentosaceus M41 was exposed for 2 h to each condition: 50°C (heat stress), 4°C (cold stress), pH 3.0 (acid stress) and 0.05% bile (bile stress). Proteomic analysis was carried out using 2D-IEF SDS PAGE and LC-MS/MS. Out of 60 identified proteins, 14 upregulated and 6 downregulated proteins were common among all the stress conditions. These proteins were involved in different biological functions such as translation-related proteins, carbohydrate metabolism (phosphoenolpyruvate phosphotransferase), histidine biosynthesis (imidazole glycerol phosphate synthase) and cell wall synthesis (tyrosine-protein kinase CapB). Proteins such as polysaccharide deacetylase, lactate oxidase, transcription repressor NrdR, dihydroxyacetone kinase were upregulated under three out of the four stress conditions. The differential expression of these proteins might be responsible for tolerance and protection of P. pentosaceus M41 against different stress conditions.
Nutrient Scarcity in a New Defined Medium Reveals Metabolic Resistance to Antibiotics in the Fish Pathogen Piscirickettsia salmonis
Authors: Ortiz-Severín Javiera , Stuardo Camila J. , Jiménez Natalia E. , Palma Ricardo , Cortés María P. , Maldonado Jonathan , Maass Alejandro , Cambiazo Verónica
Published: October 2021

Extensive use of antibiotics has been the primary treatment for the Salmonid Rickettsial Septicemia, a salmonid disease caused by the bacterium Piscirickettsia salmonis. Occurrence of antibiotic resistance has been explored in various P. salmonis isolates using different assays; however, P. salmonis is a nutritionally demanding intracellular facultative pathogen; thus, assessing its antibiotic susceptibility with standardized and validated protocols is essential. In this work, we studied the pathogen response to antibiotics using a genomic, a transcriptomic, and a phenotypic approach. A new defined medium (CMMAB) was developed based on a metabolic model of P. salmonis. CMMAB was formulated to increase bacterial growth in nutrient-limited conditions and to be suitable for performing antibiotic susceptibility tests. Antibiotic resistance was evaluated based on a comprehensive search of antibiotic resistance genes (ARGs) from P. salmonis genomes. Minimum inhibitory concentration assays were conducted to test the pathogen susceptibility to antibiotics from drug categories with predicted ARGs. In all tested P. salmonis strains, resistance to erythromycin, ampicillin, penicillin G, streptomycin, spectinomycin, polymyxin B, ceftazidime, and trimethoprim was medium-dependent, showing resistance to higher antibiotic concentrations in the CMMAB medium. The mechanism for antibiotic resistance to ampicillin in the defined medium was further explored and was proven to be associated to a decrease in the bacterial central metabolism, including the TCA cycle, the pentose-phosphate pathway, energy production, and nucleotide metabolism, and it was not associated with decreased growth rate of the bacterium or with the expression of any predicted ARG. Our results suggest that nutrient scarcity plays a role in the bacterial antibiotic resistance, protecting against the detrimental effects of antibiotics, and thus, we propose that P. salmonis exhibits a metabolic resistance to ampicillin when growing in a nutrient-limited medium.
Shedding Light on Microbial “Dark Matter”: Insights Into Novel Cloacimonadota and Omnitrophota From an Antarctic Lake
Authors: Williams Timothy J. , Allen Michelle A. , Berengut Jonathan F. , Cavicchioli Ricardo
Published: October 2021

The potential metabolism and ecological roles of many microbial taxa remain unknown because insufficient genomic data are available to assess their functional potential. Two such microbial “dark matter” taxa are the Candidatus bacterial phyla Cloacimonadota and Omnitrophota, both of which have been identified in global anoxic environments, including (but not limited to) organic-carbon-rich lakes. Using 24 metagenome-assembled genomes (MAGs) obtained from an Antarctic lake (Ace Lake, Vestfold Hills), novel lineages and novel metabolic traits were identified for both phyla. The Cloacimonadota MAGs exhibited a capacity for carbon fixation using the reverse tricarboxylic acid cycle driven by oxidation of hydrogen and sulfur. Certain Cloacimonadota MAGs encoded proteins that possess dockerin and cohesin domains, which is consistent with the assembly of extracellular cellulosome-like structures that are used for degradation of polypeptides and polysaccharides. The Omnitrophota MAGs represented phylogenetically diverse taxa that were predicted to possess a strong biosynthetic capacity for amino acids, nucleosides, fatty acids, and essential cofactors. All of the Omnitrophota were inferred to be obligate fermentative heterotrophs that utilize a relatively narrow range of organic compounds, have an incomplete tricarboxylic acid cycle, and possess a single hydrogenase gene important for achieving redox balance in the cell. We reason that both Cloacimonadota and Omnitrophota form metabolic interactions with hydrogen-consuming partners (methanogens and Desulfobacterota, respectively) and, therefore, occupy specific niches in Ace Lake.