bluuebunny/crossref_metadata_2025 huggingface dataset:
Intranasal Delivery of Recombinant S100A8 Protein Delays Lung Cancer Growth by Remodeling the Lung Immune Microenvironment
Authors: Wong Sze Wing , McCarroll Joshua , Hsu Kenneth , Geczy Carolyn L. , Tedla Nicodemus
Published: May 2022

Lung cancer is the leading cause of cancer-related death worldwide. Increasing evidence indicates a critical role for chronic inflammation in lung carcinogenesis. S100A8 is a protein with reported pro- and anti-inflammatory functions. It is highly expressed in myeloid-derived suppressor cells (MDSC) that accumulate in the tumor microenvironment and abrogate effective anti-cancer immune responses. Mechanisms of MDSC-mediated immunosuppression include production of reactive oxygen species and nitric oxide, and depletion of L-arginine required for T cell function. Although S100A8 is expressed in MDSC, its role in the lung tumor microenvironment is largely unknown. To address this, mouse recombinant S100A8 was repeatedly administered intranasally to mice bearing orthotopic lung cancers. S100A8 treatment prolonged survival from 19 days to 28 days (p < 0.001). At midpoint of survival, whole lungs and bronchoalveolar lavage fluid (BALF) were collected and relevant genes/proteins measured. We found that S100A8 significantly lowered expression of cytokine genes and proteins that promote expansion and activation of MDSC in lungs and BALF from cancer-bearing mice. Moreover, S100A8 enhanced activities of antioxidant enzymes and suppressed production of nitrite to create a lung microenvironment conducive to cytotoxic lymphocyte expansion and function. In support of this, we found decreased MDSC numbers, and increased numbers of CD4+T cells and natural killer T (NK-T) cells in lungs from cancer-bearing mice treated with S100A8.Ex-vivotreatment of splenocytes with S100A8 protein activated NK cells. Our results indicate that treatment with S100A8 may favourably modify the lung microenvironment to promote an effective immune response in lungs, thereby representing a new strategy that could complement current immunotherapies in lung cancer.
Therapy Targets SARS-CoV-2 Infection-Induced Cell Death
Authors: Zhu Zhoujie , Shi Jiayi , Li Long , Wang Jinling , Zhao Yufen , Ma Huabin
Published: May 2022

Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV-2 has become a global health issue. The clinical presentation of COVID-19 is highly variable, ranging from asymptomatic and mild disease to severe. However, the mechanisms for the high mortality induced by SARS-CoV-2 infection are still not well understood. Recent studies have indicated that the cytokine storm might play an essential role in the disease progression in patients with COVID-19, which is characterized by the uncontrolled release of cytokines and chemokines leading to acute respiratory distress syndrome (ARDS), multi-organ failure, and even death. Cell death, especially, inflammatory cell death, might be the initiation of a cytokine storm caused by SARS-CoV-2 infection. This review summarizes the forms of cell death caused by SARS-CoV-2 in vivo or in vitro and elaborates on the dedication of apoptosis, necroptosis, NETosis, pyroptosis of syncytia, and even SARS-CoV-2 E proteins forming channel induced cell death, providing insights into targets on the cell death pathway for the treatment of COVID-19.
At Least Three Doses of Leading Vaccines Essential for Neutralisation of SARS-CoV-2 Omicron Variant
Authors: Singanallur Nagendrakumar B. , van Vuren Petrus Jansen , McAuley Alexander J. , Bruce Matthew P. , Kuiper Michael J. , Gwini Stella M. , Riddell Shane , Goldie Sarah , Drew Trevor W. , Blasdell Kim R. , Tachedjian Mary , Mangalaganesh Shruthi , Chahal Simran , Caly Leon , Druce Julian D. , Juno Jennifer A. , Kent Stephen J. , Wheatley Adam K. , Vasan Seshadri S.
Published: May 2022

Plasma samples taken at different time points from donors who received either AstraZeneca (Vaxzevria) or Pfizer (Comirnaty) or Moderna (Spikevax) coronavirus disease-19 (COVID-19) vaccine were assessed in virus neutralization assays against Delta and Omicron variants of concern and a reference isolate (VIC31). With the Pfizer vaccine there was 6-8-fold reduction in 50% neutralizing antibody titres (NT50) against Delta and VIC31 at 6 months compared to 2 weeks after the second dose; followed by 25-fold increase at 2 weeks after the third dose. Neutralisation of Omicron was only consistently observed 2 weeks after the third dose, with most samples having titres below the limit of detection at earlier timepoints. Moderna results were similar to Pfizer at 2 weeks after the second dose, while the titres for AstraZeneca samples derived from older donors were 7-fold lower against VIC31 and below the limit of detection against Delta and Omicron. Age and gender were not found to significantly impact our results. These findings indicate that vaccine matching may be needed, and that at least a third dose of these vaccines is necessary to generate sufficient neutralising antibodies against emerging variants of concern, especially Omicron, amidst the challenges of ensuring vaccine equity worldwide.
The Potential Role of Basophils in Urticaria
Authors: Takimoto-Ito Riko , Ma Ni , Kishimoto Izumi , Kabashima Kenji , Kambe Naotomo
Published: May 2022

Urticaria is a symptom of acute skin allergies that is not clearly understood, but mast cell histamine is hypothesized to cause swelling and itching. Omalizumab, an anti-human IgE antibody that traps IgE and prevents its binding to high-affinity IgE receptors, is effective in treating urticaria. We recently experienced a case of urticaria refractory to antihistamine therapy in which the peripheral-blood basophil count responded to omalizumab therapy and its withdrawal. Furthermore, the peripheral-blood basophils showed an unexpected increase in the expression of a cell surface activation marker. This phenomenon has been reported by other analyses of basophil and mast cell dynamics during omalizumab treatment. Here, we analyze these observations and formulate a hypothesis for the role of basophils in urticaria. Specifically, that activated basophils migrate to the local skin area, lowering peripheral-blood counts, omalizumab therapy alters basophilic activity and causes their stay in the peripheral blood. We hope that our analysis will focus urticaria research on basophils and reveal new aspects of its pathogenesis.
Dysregulated Interferon Response and Immune Hyperactivation in Severe COVID-19: Targeting STATs as a Novel Therapeutic Strategy
Authors: Eskandarian Boroujeni Mahdi , Sekrecka Agata , Antonczyk Aleksandra , Hassani Sanaz , Sekrecki Michal , Nowicka Hanna , Lopacinska Natalia , Olya Arta , Kluzek Katarzyna , Wesoly Joanna , Bluyssen Hans A. R.
Published: May 2022

A disease outbreak in December 2019, caused by a novel coronavirus SARS-CoV-2, was named COVID-19. SARS-CoV-2 infects cells from the upper and lower respiratory tract system and is transmitted by inhalation or contact with infected droplets. Common clinical symptoms include fatigue, fever, and cough, but also shortness of breath and lung abnormalities. Still, some 5% of SARS-CoV-2 infections progress to severe pneumonia and acute respiratory distress syndrome (ARDS), with pulmonary edema, acute kidney injury, and/or multiple organ failure as important consequences, which can lead to death. The innate immune system recognizes viral RNAs and triggers the expression of interferons (IFN). IFNs activate anti-viral effectors and components of the adaptive immune system by activating members of the STAT and IRF families that induce the expression of IFN-stimulated genes (ISG)s. Among other coronaviruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV, common strategies have been identified to antagonize IFN signaling. This typically coincides with hyperactive inflammatory host responses known as the “cytokine storm” that mediate severe lung damage. Likewise, SARS-CoV-2 infection combines a dysregulated IFN response with excessive production of inflammatory cytokines in the lungs. This excessive inflammatory response in the lungs is associated with the local recruitment of immune cells that create a pathogenic inflammatory loop. Together, it causes severe lung pathology, including ARDS, as well as damage to other vulnerable organs, like the heart, spleen, lymph nodes, and kidney, as well as the brain. This can rapidly progress to multiple organ exhaustion and correlates with a poor prognosis in COVID-19 patients. In this review, we focus on the crucial role of different types of IFN that underlies the progression of SARS-CoV-2 infection and leads to immune cell hyper-activation in the lungs, exuberant systemic inflammation, and multiple organ damage. Consequently, to protect from systemic inflammation, it will be critical to interfere with signaling cascades activated by IFNs and other inflammatory cytokines. Targeting members of the STAT family could therefore be proposed as a novel therapeutic strategy in patients with severe COVID-19.
Efficient and Sustainable Platform for Preparation of a High-Quality Immunoglobulin G as an Urgent Treatment Option During Emerging Virus Outbreaks
Authors: Kurtović Tihana , Ravlić Sanda , Štimac Adela , Mateljak Lukačević Sanja , Hećimović Ana , Kazazić Saša , Halassy Beata
Published: May 2022

During the pre-vaccine era of the COVID-19 pandemic convalescent plasma has once again emerged as a major potential therapeutic form of passive immunization that in specific cases still represents irreplaceable treatment option. There is a growing concern that variable concentration of neutralizing antibodies, present in convalescent plasma which originates from different donors, apparently affects its effectiveness. The drawback can be overcome through the downstream process of immunoglobulin fraction purification into a standardized product of improved safety and efficacy. All modern procedures are quite lengthy processes. They are also based on fractionation of large plasma quantities whose collection is not attainable during an epidemic. When outbreaks of infectious diseases are occurring more frequently, there is a great need for a more sustainable production approach that would be goal-oriented towards assuring easily and readily available immunoglobulin of therapeutic relevance. We propose a refinement strategy for the IgG preparation achieved through simplification and reduction of the processing steps. It was designed as a small but scalable process to offer an immediately available treatment option that would simultaneously be harmonized with an increased availability of convalescent plasma over the viral outbreak time-course. Concerning the ongoing pandemic status of the COVID-19, the proof of concept was demonstrated on anti-SARS-CoV-2 convalescent plasma but is likely applicable to any other type depending on the current needs. It was guided by the idea of persistent keeping of IgG molecules in the solution, so that protection of their native structure could be assured. Our manufacturing procedure provided a high-quality IgG product of above the average recovery whose composition profile was analyzed by mass spectrometry as quality control check. It was proved free from IgA and IgM as mediators of adverse transfusion reactions, as well as of any other residual impurities, since only IgG fragments were identified. The proportion of S protein-specific IgGs remained unchanged relative to the convalescent plasma. Undisturbed IgG subclass composition was accomplished as well. However, the fractionation principle affected the final product’s capacity to neutralize wild-type SARS-CoV-2 infectivity, reducing it by half. Decrease in neutralization potency significantly correlated with the amount of IgM in the starting material.
Depth-Dependent Genetic Structuring of a Depth-Generalist Coral and Its Symbiodiniaceae Algal Communities at Campeche Bank, Mexico
Authors: Sturm Alexis B. , Eckert Ryan J. , Carreiro Ashley M. , Simões Nuno , Voss Joshua D.
Published: May 2022

Depth-generalist coral holobionts inhabit shallow (0–30 m) and mesophotic (30–150 m) reef zones but may exhibit genetic specialization as a result of adaptations to environmental shifts and/or due to a lack of dispersal across depth. The level of depth-dependent genetic structuring varies across reef locations which may impact the roles mesophotic populations play in the persistence and recovery of metapopulations. A depth-generalist coral species, Montastraea cavernosa, was sampled across a shallow to mesophotic gradient at 10, 15, 25, and 35 m at Alacranes and Bajos del Norte reefs on Campeche Bank, Mexico. Both 2bRAD and ITS2 sequencing were used to quantify genetic differentiation of the coral hosts and community structure of their algal endosymbionts (Family Symbiodiniaceae) across depth zones and between these reefs. Significant levels of M. cavernosa genetic differentiation were identified across depth at both reefs, especially between the shallow (10, 15, and 25 m) and mesophotic (35 m) zones. While Symbiodiniaceae hosted by these corals were predominantly Cladocopium species, both depth and reef location were significant factors driving ITS2 type profiles found within each population. The magnitude of depth-dependent genetic structuring of both the coral and Symbiodiniaceae was much greater at Alacranes, relative to Bajos del Norte, suggesting that the refugia potential of mesophotic communities at Alacranes is limited. However, relatively high levels of horizontal coral connectivity between the two reefs, and Bajos del Norte’s location at the entrance to the Gulf of Mexico suggests that it may play an important role in the maintenance of the coral’s regional metapopulation and should be considered in future assessments of this species’ connectivity dynamics and management.
Changes in the Skin Proteome and Signs of Allostatic Overload Type 2, Chronic Stress, in Response to Repeated Overcrowding of Lumpfish (Cyclopterus lumpus L.)
Authors: Patel Deepti M. , Brinchmann Monica F. , Hanssen Anna , Iversen Martin H.
Published: May 2022

Lumpfish (Cyclopterus lumpusL) is a North Atlantic species harvested for its roe and increasingly used as a cleanerfish in Atlantic salmon (Salmo salarL.) farming to remove salmon louse (Lepeophtheirus salmonis). In aquaculture, the health and welfare of fish depends on optimal levels of several biotic and abiotic factors. Crowding, a common abiotic stress factor in aquaculture practice, can affect the welfare and survival of fish. In this study, lumpfish was exposed to crowding stress daily at random timepoints for one month (stress group) or no crowding (control group). Blood and skin were sampled weekly for physiological parameter analysis and proteomics, respectively. Adrenocorticotropic hormone (ACTH) stimulation and dexamethasone (DEX) suppression test were conducted at the sampling timepoints. Gel-based proteomics coupled with liquid chromatography and tandem mass spectrometry (LC-MS/MS) was used to identify protein changes in skin tissues of lumpfish under crowding. The results indicated that the stress group showed signs of allostatic overload type 2 (chronic stress) due to oversensitivity to ACTH, and a reduced negative feedback system with increased baseline levels of cortisol. These chronic changes in the endocrine system promoted changes in secondary and tertiary stress responses as reduced osmoregulatory capacity and stunted growth, after 14 days of stress and onward. Calmodulin, guanine nucleotide binding protein subunit beta 2, glutathione-S-transferase Mu 3, fatty acid binding protein, heat shock cognate 70 kDa protein, keratin, histone H4 and 14-3-3 alpha/beta showed protein spot intensity changes compared with controls in lumpfish skin at one or several time points during the one month period of crowding stress. The differentially expressed proteins are related to several metabolic pathways and are involved in stress and immune responses. Overall, the study shows that lumpfish can suffer from chronic stress with possible dire consequences for the animal welfare.
Perineural Administration of Dexmedetomidine in Axillary Brachial Plexus Block Provides Safe and Comfortable Sedation: A Randomized Clinical Trial
Authors: Rocans Rihards P. , Ozolina Agnese , Andruskevics Mareks , Narchi Patrick , Ramane Diana , Mamaja Biruta
Published: May 2022

Dexmedetomidine prolongs the duration of regional block while its systemic sedative effect when administered perineurally is unknown. We aimed to evaluate the systemic sedative effect of perineural dexmedetomidine in patients after axillary brachial plexus block (ABPB). This single-blinded prospective randomized control trial included 80 patients undergoing wrist surgery receiving ABPB. Patients were randomized into two groups – Control group (CG, N = 40) and dexmedetomidine group (DG, N = 40). Both groups received ABPB with 20 ml of 0.5% Bupivacaine and 10 ml of 2% Lidocaine. Additionally, patients in DG received 100 mcg of dexmedetomidine perineurally. Depth of sedation was evaluated using Narcontrend Index (NI) and Ramsay Sedation Scale (RSS) immediately after ABPB and in several time points up to 120 min. Duration of block as well as patient satisfaction with sedation was evaluated using a postoperative survey. Our results showed that NI and RSS statistically differed between groups, presenting a deeper level of sedation during the first 90 min in DG compared to controls, P < 0.001. In the first 10 to 60 min after ABPB the median RSS was 4 (IQR within median) and median NI was 60 (IQR 44–80) in DG group, in contrast to CG patients where median RSS was 2 (IQR within median) and median NI was 97 (IQR 96–98) throughout surgery. The level of sedation became equal in both groups 90 and 120 min after ABPB when the median NI value was 98 (97–99) in DG and 97.5 (97–98) in CG, P = 0.276, and the median RSS was 2 (IQR within median) in both groups, P = 0.128. No significant intergroup differences in hemodynamic or respiratory parameters were found. Patients in DG expressed satisfaction with sedation and 86.5% noted that the sensation was similar to ordinary sleep. In DG mean duration of motor block was 13.5 ± 2.1 h and sensory block was 12.7 ± 2.8 h which was significantly longer compared to CG 6.3 ± 1.5 h, P < 0.001 and 6.4 ± 1.8 h, P < 0.001. We found that beside prolongation of analgesia, perineural administration of dexmedetomidine might provide rather safe and comfortable sedation with no significant effect on hemodynamic or respiratory stability and yields a high level of patient satisfaction.
Global Research Trends of Gender-Related Artificial Intelligence in Medicine Between 2001–2020: A Bibliometric Study
Authors: Yoon Ha Young , Lee Heisook , Yee Jeong , Gwak Hye Sun
Published: May 2022

This study aimed to assess the research on medical Artificial intelligence (AI) related to sex/gender and explore global research trends over the past 20 years. We searched the Web of Science (WoS) for gender-related medical AI publications from 2001 to 2020. We extracted the bibliometric data and calculated the annual growth of publications, Specialization Index, and Category Normalized Citation Impact. We also analyzed the publication distributions by institution, author, WoS subject category, and journal. A total of 3,110 papers were included in the bibliometric analysis. The number of publications continuously increased over time, with a steep increase between 2016 and 2020. The United States of America and Harvard University were the country and institution that had the largest number of publications. Surgery and urology nephrology were the most common subject categories of WoS. The most occurred keywords were machine learning, classification, risk, outcomes, diagnosis, and surgery. Despite increased interest, gender-related research is still low in medical AI field and further research is needed.
Screening and Whole Genome Sequencing of SARS-CoV-2 Circulating During the First Three Waves of the COVID-19 Pandemic in Libreville and the Haut-Ogooué Province in Gabon
Authors: Lekana-Douki Sonia Etenna , N'dilimabaka Nadine , Levasseur Anthony , Colson Philippe , Andeko Julia Cyrielle , Zong Minko Ornella , Banga Mve-Ella Octavie , Fournier Pierre-Edouard , Devaux Christian , Ondo Bertrand Mve , Akombi Falone Larissa , Yacka Mouele Bolo Laurianne , Ngonga Dikongo Audrey Michel , Diané Abdoulaye , Mabika Mabika Arsène , Mathouet Jenny Francine , Dzembo Cresh , Atiga Nick Chenis , Mouity Matoumba Anicet , Ndjangangoye Nal Kennedy , Bréchard Ludivine , Bedotto-Buffet Marielle , Mangombi Pambou Joa Braithe , Kandet Yattara Marisca , Mbongo Nkama Elvire Anita , Mintsa Ndong Armel , Adegnika Ayola Akim , Raoult Didier , Fenollar Florence , Lekana-Douki Jean-Bernard
Published: May 2022

Since the onset of the COVID-19 pandemic, the SARS-CoV-2 viral dynamics in Africa have been less documented than on other continents. In Gabon, a Central African country, a total number of 37,511 cases of COVID-19 and 281 deaths have been reported as of December 8, 2021. After the first COVID-19 case was reported on March 12, 2020, in the capital Libreville, the country experienced two successive waves. The first one, occurred in March 2020 to August 2020, and the second one in January 2021 to May 2021. The third wave began in September 2021 and ended in November 2021. In order to reduce the data gap regarding the dynamics of SARS-CoV-2 in Central Africa, we performed a retrospective genotyping study using 1,006 samples collected from COVID-19 patients in Gabon from 2020 to 2021. Using SARS-CoV-2 variant screening by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR) and whole genome sequencing (WGS), we genotyped 809 SARS-CoV-2 samples through qRT-PCR and identified to generated 291 new genomes. It allowed us to describe specific mutations and changes in the SARS-CoV-2 variants in Gabon. The qRT-PCR screening of 809 positive samples from March 2020 to September 2021 showed that 119 SARS-CoV-2 samples (14.7%) were classified as VOC Alpha (Pangolin lineage B.1.1.7), one (0.1%) was a VOC Beta (B.1.351), and 198 (24.5 %) were VOC Delta (B.1.617.2), while 491 samples (60.7%) remained negative for the variants sought. The B1.1 variant was predominant during the first wave while the VOC Alpha dominated the second wave. The B1.617.2 Delta variant is currently the dominant variant of the third wave. Similarly, the analysis of the 291 genome sequences indicated that the dominant variant during the first wave was lineage B.1.1, while the dominant variants of the second wave were lineages B.1.1.7 (50.6%) and B.1.1.318 (36.4%). The third wave started with the circulation of the Delta variant (B.1.617). Finally, we compared these results to the SARS-CoV-2 sequences reported in other African, European, American and Asian countries. Sequences of Gabonese SARS-CoV-2 strains presented the highest similarities with those of France, Belgium and neighboring countries of Central Africa, as well as West Africa.
Programmed Cell Death in Sepsis Associated Acute Kidney Injury
Authors: Wu Zhifen , Deng Junhui , Zhou Hongwen , Tan Wei , Lin Lirong , Yang Jurong
Published: May 2022

Sepsis-associated acute kidney injury (SA-AKI) is common in patients with severe sepsis, and has a high incidence rate and high mortality rate in ICU patients. Most patients progress to AKI before drug treatment is initiated. Early studies suggest that the main mechanism of SA-AKI is that sepsis leads to vasodilation, hypotension and shock, resulting in insufficient renal blood perfusion, finally leading to renal tubular cell ischemia and necrosis. Research results in recent years have shown that programmed cell death such as apoptosis, necroptosis, pyroptosis and autophagy play important roles. In the early stage of sepsis-related AKI, autophagy bodies form and inhibit various types of programmed cell death. With the progress of disease, programmed cell death begins. Apoptosis promoter represents caspase-8-induced apoptosis and apoptosis effector represents caspase-3-induced apoptosis, however, caspase-11 and caspase-1 regulate gasdermin D-mediated pyroptosis. Caspase-8 and receptor interacting kinase 1 bodies mediate necroptosis. This review focuses on the pathophysiological mechanisms of various programmed cell death in sepsis-related AKI.
Myeloperoxydase and CD15 With Glycophorin C Double Staining in the Evaluation of Skin Wound Vitality in Forensic Practice
Authors: Gauchotte Guillaume , Bochnakian Agathe , Campoli Philippe , Lardenois Emilie , Brix Muriel , Simon Etienne , Colomb Sophie , Martrille Laurent , Peyron Pierre-Antoine
Published: May 2022

Background

The determination of skin wound vitality based on tissue sections is a challenge for the forensic pathologist. Histology is still the gold standard, despite its low sensitivity. Immunohistochemistry could allow to obtain a higher sensitivity. Upon the candidate markers, CD15 and myeloperoxidase (MPO) may allow to early detect polymorphonuclear neutrophils (PMN). The aim of this study was to evaluate the sensitivity and the specificity of CD15 and MPO, with glycophorin C co-staining, compared to standard histology, in a series of medicolegal autopsies, and in a human model of recent wounds.

Methods

Twenty-four deceased individuals with at least one recent open skin wound were included. For each corpse, a post-mortem wound was performed in an uninjured skin area. At autopsy, a skin sample from the margins of each wound and skin controls were collected (n = 72). Additionally, the cutaneous surgical margins of abdominoplasty specimens were sampled as a model of early intravital stab wound injury (scalpel blade), associated with post-devascularization wounds (n = 39). MPO/glycophorin C and CD15/glycophorin C immunohistochemical double staining was performed. The number of MPO and CD15 positive cells per 10 high power fields (HPF) was evaluated, excluding glycophorin C—positive areas.

Results

With a threshold of at least 4 PMN/10 high power fields, the sensitivity and specificity of the PMN count for the diagnostic of vitality were 16 and 100%, respectively. With MPO/glycophorin C as well as CD15/glycophorin C IHC, the number of positive cells was significantly higher in vital than in non-vital wounds (p < 0.001). With a threshold of at least 4 positive cells/10 HPF, the sensitivity and specificity of CD15 immunohistochemistry were 53 and 100%, respectively; with the same threshold, MPO sensitivity and specificity were 28 and 95%.

Conclusion

We showed that combined MPO or CD15/glycophorin C double staining is an interesting and original method to detect early vital reaction. CD15 allowed to obtain a higher, albeit still limited, sensitivity, with a high specificity. Confirmation studies in independent and larger cohorts are still needed to confirm its accuracy in forensic pathology.
A Mouse-Adapted Model of HCoV-OC43 and Its Usage to the Evaluation of Antiviral Drugs
Authors: Xie Peifang , Fang Yue , Baloch Zulqarnain , Yu Huanhuan , Zhao Zeyuan , Li Rongqiao , Zhang Tongtong , Li Runfeng , Zhao Jincun , Yang Zifeng , Dong Shuwei , Xia Xueshan
Published: May 2022

The human coronavirus OC43 (HCoV-OC43) is one of the most common causes of common cold but can lead to fatal pneumonia in children and elderly. However, the available animal models of HCoV-OC43 did not show respiratory symptoms that are insufficient to assist in screening antiviral agents for respiratory diseases. In this study, we adapted the HCoV-OC43 VR-1558 strain by serial passage in suckling C57BL/6 mice and the resulting mouse-adapted virus at passage 9 (P9) contained 8 coding mutations in polyprotein 1ab, spike (S) protein, and nucleocapsid (N) protein. Pups infected with the P9 virus significantly lost body weight and died within 5 dpi. In cerebral and pulmonary tissues, the P9 virus replication induced the production of G-CSF, IFN-γ, IL-6, CXCL1, MCP-1, MIP-1α, RANTES, IP-10, MIP-1β, and TNF-α, as well as pathological alterations including reduction of neuronal cells and typical symptoms of viral pneumonia. We found that the treatment of arbidol hydrochloride (ARB) or Qingwenjiere Mixture (QJM) efficiently improved the symptoms and decreased n gene expression, inflammatory response, and pathological changes. Furthermore, treating with QJM or ARB raised the P9-infected mice’s survival rate within a 15 day observation period. These findings suggested that the new mouse-adapted HCoV-OC43 model is applicable and reproducible for antiviral studies of HCoV-OC43.
Characterization of a Novel Esterase Est33 From an Antarctic Bacterium: A Representative of a New Esterase Family
Authors: Liu Xiaoyu , Zhou Mingyang , Sun Rui , Xing Shu , Wu Tao , He Hailun , Chen Jianbin , Bielicki John Kevin
Published: May 2022

Studies of microorganisms from extreme environments can sometimes reveal novel proteins with unique properties. Here, we identified a novel esterase gene (Est33) from an Antarctic bacterium. The protein was expressed and purified for biochemical characterizations. Site-mutation variants including S94A, D205A, and H233A were constructed to explore the structure–function relationship of the catalytic triad of Est33, and we found mutating Ser94, Asp205, and His233 residues lead to a complete loss of enzyme activity. In addition, the catalytic Ser94 located in a conserved pentapeptide motif GVSWG. Phylogenetic analysis showed that Est33 and its closely related homologs belonged to an independent group apart from other known family members, indicating that Est33 represented a new family of esterase. The Est33 enzyme was found to be a cold-active esterase retaining 25%–100% activity from 10°C to 30°C and to have optimal catalytic activity toward p-nitrophenol acetate (30°C and pH7.5). The serine modifying reagent phenylmethylsulfonyl fluoride inhibited the activity of Est33 by 77.34%, while thiol reagents such as dithiol threitol (DTT) activated the enzyme by 3-fold. Metal chelating reagents EDTA had no effects, indicating that Est33 is not a metalloenzyme. Collectively, these results indicate that Est33 constitutes the first member of a novel esterase family XXI that has been identified.
Rapid Detection of Bacterial Pathogens and Antimicrobial Resistance Genes in Clinical Urine Samples With Urinary Tract Infection by Metagenomic Nanopore Sequencing
Authors: Zhang Lei , Huang Wenhua , Zhang Shengwei , Li Qian , Wang Ye , Chen Ting , Jiang Hua , Kong Decong , Lv Qingyu , Zheng Yuling , Ren Yuhao , Liu Peng , Jiang Yongqiang , Chen Ying
Published: May 2022

Urinary tract infections (UTIs) are among the most common acquired bacterial infections in humans. The current gold standard method for identification of uropathogens in clinical laboratories is cultivation. However, culture-based assays have substantial drawbacks, including long turnaround time and limited culturability of many potential pathogens. Nanopore sequencing technology can overcome these limitations and detect pathogens while also providing reliable predictions of drug susceptibility in clinical samples. Here, we optimized a metagenomic nanopore sequencing (mNPS) test for pathogen detection and identification in urine samples of 76 patients with acute uncomplicated UTIs. We first used twenty of these samples to show that library preparation by the PCR Barcoding Kit (PBK) led to the highest agreement of positive results with gold standard clinical culture tests, and enabled antibiotic resistance detection in downstream analyses. We then compared the detection results of mNPS with those of culture-based diagnostics and found that mNPS sensitivity and specificity of detection were 86.7% [95% confidence interval (CI), 73.5–94.1%] and 96.8% (95% CI, 82.4–99.9%), respectively, indicating that the mNPS method is a valid approach for rapid and specific detection of UTI pathogens. The mNPS results also performed well at predicting antibiotic susceptibility phenotypes. These results demonstrate that our workflow can accurately diagnose UTI-causative pathogens and enable successful prediction of drug-resistant phenotypes within 6 h of sample receipt. Rapid mNPS testing is thus a promising clinical diagnostic tool for infectious diseases, based on clinical urine samples from UTI patients, and shows considerable potential for application in other clinical infections.
Characterizing the Piezosphere: The Effects of Decompression on Microbial Growth Dynamics
Authors: Cario Anaïs , Oliver Gina C. , Rogers Karyn L.
Published: May 2022

The extent to which the full diversity of the subsurface microbiome can be captured via cultivation is likely hindered by the inevitable loss of cellular viability from decompression during sampling, enrichment, and isolation. Furthermore, the pressure tolerance of previously isolated strains that span surface and subsurface ecosystems can shed light into microbial activity and pressure adaptation in these transition zones. However, assessments of the effects of elevated pressure on the physiology of piezotolerant and piezosensitive species may be biased by high-pressure enrichment techniques. Here, we compared two high-pressure cultivation techniques—one that requires decompression of the whole cultures during sampling and one that employs the previously described isobaric PUSH devices—to explore the effects of repeated decompression during incubations performed to characterize isolates from deep environments. Two model sulfate-reducing prokaryotes were used to test the effects of decompression/repressurization cycles on growth rates, cell yields, and pressure tolerance. The mesophilic bacterium Desulfovibrio salexigens was cultivated from 0.1 to 50 MPa, and the hyperthermophilic archaeon Archaeoglobus fulgidus was tested from 0.1 to 98 MPa. For both cultivation methods, D. salexigens showed exponential growth up to 20 MPa, but faster growth rates were observed for isobaric cultivation. Furthermore, at 30 MPa minor growth was observed in D. salexigens cultures only for isobaric conditions. Isobaric conditions also extended exponential growth of A. fulgidus to 60 MPa, compared to 50 MPa when cultures were decompressed during subsampling. For both strains, growth rates and cell yields decreased with increasing pressures, and the most pronounced effects of decompression were observed at the higher end of the pressure ranges. These results highlight that repeated decompression can have a significant negative impact on cell viability, suggesting that decompression tolerance may depend on habitat depth. Furthermore, sampling, enrichment, and cultivation in isobaric devices is critical not only to explore the portion of the deep biosphere that is sensitive to decompression, but also to better characterize the pressure limits and growth characteristics of piezotolerant and piezosensitive species that span surface and subsurface ecosystems.
Machine Learning Based Microbiome Signature to Predict Inflammatory Bowel Disease Subtypes
Authors: Liñares-Blanco Jose , Fernandez-Lozano Carlos , Seoane Jose A. , López-Campos Guillermo
Published: May 2022

Inflammatory bowel disease (IBD) is a chronic disease with unknown pathophysiological mechanisms. There is evidence of the role of microorganims in this disease development. Thanks to the open access to multiple omics data, it is possible to develop predictive models that are able to prognosticate the course and development of the disease. The interpretability of these models, and the study of the variables used, allows the identification of biological aspects of great importance in the development of the disease. In this work we generated a metagenomic signature with predictive capacity to identify IBD from fecal samples. Different Machine Learning models were trained, obtaining high performance measures. The predictive capacity of the identified signature was validated in two external cohorts. More precisely a cohort containing samples from patients suffering Ulcerative Colitis and another from patients suffering Crohn's Disease, the two major subtypes of IBD. The results obtained in this validation (AUC 0.74 and AUC = 0.76, respectively) show that our signature presents a generalization capacity in both subtypes. The study of the variables within the model, and a correlation study based on text mining, identified different genera that play an important and common role in the development of these two subtypes.
The Old Yellow Enzyme OfrA Fosters Staphylococcus aureus Survival via Affecting Thiol-Dependent Redox Homeostasis
Authors: Ibrahim Eslam S. , Ohlsen Knut
Published: May 2022

Old yellow enzymes (OYEs) are widely found in the bacterial, fungal, and plant kingdoms but absent in humans and have been used as biocatalysts for decades. However, OYEs’ physiological function in bacterial stress response and infection situations remained enigmatic. As a pathogen, the Gram-positive bacterium Staphylococcus aureus adapts to numerous stress conditions during pathogenesis. Here, we show that in S. aureus genome, two paralogous genes (ofrA and ofrB) encode for two OYEs. We conducted a bioinformatic analysis and found that ofrA is conserved among all publicly available representative staphylococcal genomes and some Firmicutes. Expression of ofrA is induced by electrophilic, oxidative, and hypochlorite stress in S. aureus. Furthermore, ofrA contributes to S. aureus survival against reactive electrophilic, oxygen, and chlorine species (RES, ROS, and RCS) via thiol-dependent redox homeostasis. At the host–pathogen interface, S. aureusΔofrA has defective survival in macrophages and whole human blood and decreased staphyloxanthin production. Overall, our results shed the light onto a novel stress response strategy in the important human pathogen S. aureus.
Mir-4728 is a Valuable Biomarker for Diagnostic and Prognostic Assessment of HER2-Positive Breast Cancer
Authors: Rui Tao , Xiang Aizhai , Guo Jufeng , Tang Ning , Lin Xia , Jin Xin , Liu Jian , Zhang Xiaobing
Published: May 2022

Breast cancer remains one of the most common malignancies in female cancer patients. The rapid and accurate diagnosis of human epidermal growth factor receptor 2 (HER2) status is indispensable for breast cancer patients. The pre-miR-4728 (mir-4728) is encoded within an intron of the HER2 gene. We showed here that mir-4728 was the most significantly upregulated pre-miRNA in HER2-positive breast cancer patients (fold-change: 4.37), and it could serve as a strong diagnostic factor for the HER2 status in breast cancer patients (p < 0.0001). Moreover, mir-4728 was positively correlated with tumor recurrence and appeared to be a critical independent risk factor of tumor recurrence in patients with high tumor burden (HR: 7.558, 95% CI:1.842-31.006, p = 0.005). Remarkably, HER2-positive patients with higher mir-4728 expression levels had better drug responses to targeted therapies. Furthermore, estrogen receptor (ESR), the predictive marker for endocrine therapies, was found to be the direct target of miR-4728-3p. Taken together, our results supported the potential role of mir-4728 in the diagnosis of HER2 status and the prognostic assessment of HER2-positive patients in response to targeted therapies.
Concurrent Structural and Functional Patterns in Patients With Amnestic Mild Cognitive Impairment
Authors: Liu Li , Wang Tenglong , Du Xiangdong , Zhang Xiaobin , Xue Chuang , Ma Yu , Wang Dong
Published: May 2022

Amnestic mild cognitive impairment (aMCI) is a clinical subtype of MCI, which is known to have a high risk of developing Alzheimer’s disease (AD). Although neuroimaging studies have reported brain abnormalities in patients with aMCI, concurrent structural and functional patterns in patients with aMCI were still unclear. In this study, we combined voxel-based morphometry (VBM), amplitude of low-frequency fluctuations (ALFFs), regional homogeneity (Reho), and resting-state functional connectivity (RSFC) approaches to explore concurrent structural and functional alterations in patients with aMCI. We found that, compared with healthy controls (HCs), both ALFF and Reho were decreased in the right superior frontal gyrus (SFG_R) and right middle frontal gyrus (MFG_R) of patients with aMCI, and both gray matter volume (GMV) and Reho were decreased in the left inferior frontal gyrus (IFG_L) of patients with aMCI. Furthermore, we took these overlapping clusters from VBM, ALFF, and Reho analyses as seed regions to analyze RSFC. We found that, compared with HCs, patients with aMCI had decreased RSFC between SFG_R and the right temporal lobe (subgyral) (TL_R), the MFG_R seed and left superior temporal gyrus (STG_L), left inferior parietal lobule (IPL_L), and right anterior cingulate cortex (ACC_R), the IFG_L seed and left precentral gyrus (PRG_L), left cingulate gyrus (CG_L), and IPL_L. These findings highlighted shared imaging features in structural and functional magnetic resonance imaging (MRI), suggesting that SFG_R, MFG_R, and IFG_L may play a major role in the pathophysiology of aMCI, which might be useful to better understand the underlying neural mechanisms of aMCI and AD.
Advancements in Bioelectricity Generation Through Nanomaterial-Modified Anode Electrodes in Microbial Fuel Cells
Authors: Dessie Yilkal , Tadesse Sisay
Published: May 2022

The use of nanotechnology in bioelectrochemical systems to recover bioelectricity and metals from waste appears to be a potentially appealing alternative to existing established procedures. This trend exactly characterizes the current renewable energy production technology. Hence, this review focuses on the improvement of the anode electrode by using different functional metal oxide-conducting polymer nanocomposites to enhance microbial fuel cell (MFC) performance. Enhancement of interfacial bioelectrocatalysis between electroactive microorganisms and hierarchical porous nanocomposite materials could enhance cost-effective bioanode materials with superior bioelectrocatalytic activity for MFCs. In this review, improvement in efficiency of MFCs by using iron oxide- and manganese oxide-based polypyrrole hybrid composites as model anode modifiers was discussed. The review also extended to discussing and covering the principles, components, power density, current density, and removal efficiencies of biofuel cell systems. In addition, this research review demonstrates the application of MFCs for renewable energy generation, wastewater treatment, and metal recovery. This is due to having their own unique working principle under mild conditions and using renewable biodegradable organic matter as a direct fuel source.
Factors Influencing the Outcome of Symptomatic Intracranial Artery Stenosis With Hemodynamic Impairment After Short and Long-Term Stent Placement
Authors: Gong Wentao , Zhang Xianjun , Meng Zhen , Liu Feifei , Li Guangwen , Xiao Juan , Liu Peng , Sun Yujie , Liu Tonghui , Wang Hongxia , Zhang Yong , Wang Naidong
Published: May 2022

Objective

Stent placement is a feasible approach worldwidely for patients with symptomatic intracranial artery stenosis (sICAS) and hemodynamic impairment (HI) who are at high risk of recurrent stroke after medical treatment. Exploration of factors associated with poor outcomes after stent placement could help develop better individualized therapeutic strategies.

Methods

This study conducted a post-hoc analysis of a prospective, multicenter registry study of stent use for sICAS with HI in China. Patient and clinical demographics, and stenotic lesion images were analyzed using univariate and multivariate Cox regression to the time until any endpoints or the end of the follow-up period. The short-term endpoint included any transient ischemic attack (TIA), stroke, or death within 1 month after stent placement. The long-term endpoints included the short-term endpoints and any TIA or stroke in the region of the affected artery that occurred more than 1 month after stent placement.

Results

Two hundred and ninety two patients were included, with 13 short-term and 39 long-term endpoints. Multivariate Cox regression analysis revealed that lesions at the arterial origin or bifurcation (Hazard Ratio (HR) = 7.52; 95% CI, 1.89–29.82; p = 0.004) were significantly associated with higher short-term risk. Baseline renal insufficiency reduced the risk (HR = 0.08; 95% CI: 0.01–0.68; p = 0.021). Factors significantly associated with higher long-term risk included irregular or ulcerated plaques at the lesion (HR = 2.15; 95% CI: 1.07–4.33; p = 0.031). Subgroup analyses indicated that higher risk occurred in the older age group (age>59 years, HR = 3.73, 95% CI: 1.27–10.97, p = 0.017), and not in the younger group (age≤59 years, HR = 1.12, 95% CI: 0.42–3.03, p = 0.822).

Conclusion

Irregular or ulcerated plaques in older patients and lesions at the arterial opening or bifurcation were more likely to result in adverse endpoints for stent placement during long or short -term follow-up. Investigation of these factors might facilitate the development of individualized therapeutic strategies for this population.

Clinical Trial Registration

http://www.clinicaltrials.gov, identifier: NCT01968122.
Unusual Histopathological Findings in Mechanically Removed Stroke Thrombi – A Multicenter Experience
Authors: Aspegren Oskar , Staessens Senna , Vandelanotte Sarah , Desender Linda , Cordonnier Charlotte , Puy Laurent , Bricout Nicolas , De Meyer Simon F. , Andersson Tommy , Arnberg Fabian
Published: May 2022

Background

Several studies have investigated the histopathology of mechanically retrieved thrombi from stroke patients. Thrombi with unusual components constitute about 1–2% of all stroke thrombi in clinical practice. Knowledge about these rare components is limited.

Objectives

To characterize the histopathology of unusual stroke thrombi from a real-world setting with relation to clinical presentation, patient characteristics and procedural aspects of mechanical thrombectomy.

Methods

One-thousand and eight thrombi retrieved from stroke patients with mechanical thrombectomy at three different hospitals were retrospectively reviewed for unusual histological components. Fifteen thrombi were included in the study for further histopathological analysis. Clinical data and data on procedural aspects were collected.

Results

We identified six cases with large amounts of extracellular DNA, of which three were calcified. All six cases except one received anticoagulant therapy. We describe two types of calcifications that differ with respect to general calcification morphology, von Kossa staining pattern, macrophage immunophenotype and presence of multinucleated giant cells. Cholesterol-rich (n = 3), adipocyte-like pattern-rich (n = 2), collagen-rich (n = 2) and myxomatous (n = 1) thrombi were also identified and are discussed with regard to pathogenesis and clinical and intervention characteristics. Finally, a thrombus with parts of a vascular wall is described. Suggestions for future studies are made and clinical and technical aspects of the management for these rare but important patients are discussed.

Conclusion

In our retrospective multicenter study, we characterized stroke thrombi histopathologically and found subgroups of thrombi defined by presence of rarely seen components. These defined subgroups showed relation to underlying cardiovascular disease, patient characteristics, and mechanical thrombectomy technique. Knowledge about these components may increase our understanding of stroke pathophysiology and influence interventional procedures.