bluuebunny/crossref_metadata_2025 huggingface dataset:
Low perforin expression in CD8+ T lymphocytes during the acute phase of severe SARS-CoV-2 infection predicts long COVID
Authors: Kundura Lucy , Cezar Renaud , André Sonia , Campos-Mora Mauricio , Lozano Claire , Vincent Thierry , Muller Laurent , Lefrant Jean-Yves , Roger Claire , Claret Pierre-Géraud , Duvnjak Sandra , Loubet Paul , Sotto Albert , Tran Tu-Ahn , Estaquier Jérôme , Corbeau Pierre
Published: October 2022

T cell cytotoxicity plays a major role in antiviral immunity. Anti-SARS-CoV-2 immunity may determine acute disease severity, but also the potential persistence of symptoms (long COVID). We therefore measured the expression of perforin, a cytotoxic mediator, in T cells of patients recently hospitalized for SARS-CoV-2 infection. We recruited 54 volunteers confirmed as being SARS-CoV-2-infected by RT-PCR and admitted to Intensive Care Units (ICUs) or non-ICU, and 29 age- and sex-matched healthy controls (HCs). Amounts of intracellular perforin and granzyme-B, as well as cell surface expression of the degranulation marker CD107A were determined by flow cytometry. The levels of 15 cytokines in plasma were measured by Luminex. The frequency of perforin-positive T4 cells and T8 cells was higher in patients than in HCs (9.9 ± 10.1% versus 4.6 ± 6.4%, p = 0.006 and 46.7 ± 20.6% vs 33.3 ± 18.8%, p = 0.004, respectively). Perforin expression was neither correlated with clinical and biological markers of disease severity nor predictive of death. By contrast, the percentage of perforin-positive T8 cells in the acute phase of the disease predicted the onset of long COVID one year later. A low T8 cytotoxicity in the first days of SARS-CoV-2 infection might favor virus replication and persistence, autoimmunity, and/or reactivation of other viruses such as Epstein-Barr virus or cytomegalovirus, paving the way for long COVID. Under this hypothesis, boosting T cell cytotoxicity during the acute phase of the infection could prevent delayed sequelae.
Prime, shock and kill: BCL-2 inhibition for HIV cure
Authors: Chandrasekar Aswath P. , Badley Andrew D.
Published: October 2022

While modern HIV therapy can effectively suppress viral replication, the persistence of the latent reservoir posits the greatest hurdle to complete cure. The “shock and kill” strategy is under investigation for HIV therapy, aiming to reactivate latent HIV, and subsequently eliminate it through anti-retroviral therapy and host immune function. However, thus far, studies have yielded suboptimal results, stemming from a combination of ineffective latency reversal and poor immune clearance. Concomitantly, studies have now revealed the importance of the BCL-2 anti-apoptotic protein as a critical mediator of infected cell survival, reservoir maintenance and immune evasion in HIV. Furthermore, BCL-2 inhibitors are now recognized for their anti-HIV effects in pre-clinical studies. This minireview aims to examine the intersection of BCL-2 inhibition and current shock and kill efforts, hoping to inform future studies which may ultimately yield a cure for HIV.
Helicobacter pylori-infected human neutrophils exhibit impaired chemotaxis and a uropod retraction defect
Authors: Prichard Allan , Khuu Lisa , Whitmore Laura C. , Irimia Daniel , Allen Lee-Ann H.
Published: October 2022

Helicobacter pylori is a major human pathogen that colonizes the gastric mucosa and plays a causative role in development of peptic ulcers and gastric cancer. Neutrophils are heavily infected with this organism in vivo and play a prominent role in tissue destruction and disease. Recently, we demonstrated that H. pylori exploits neutrophil plasticity as part of its virulence strategy eliciting N1-like subtype differentiation that is notable for profound nuclear hypersegmentation. We undertook this study to test the hypothesis that hypersegmentation may enhance neutrophil migratory capacity. However, EZ-TAXIScan™ video imaging revealed a previously unappreciated and progressive chemotaxis defect that was apparent prior to hypersegmentation onset. Cell speed and directionality were significantly impaired to fMLF as well as C5a and IL-8. Infected cells oriented normally in chemotactic gradients, but speed and direction were impaired because of a uropod retraction defect that led to cell elongation, nuclear lobe trapping in the contracted rear and progressive narrowing of the leading edge. In contrast, chemotactic receptor abundance, adhesion, phagocytosis and other aspects of cell function were unchanged. At the molecular level, H. pylori phenocopied the effects of Blebbistatin as indicated by aberrant accumulation of F-actin and actin spikes at the uropod together with enhanced ROCKII-mediated phosphorylation of myosin IIA regulatory light chains at S19. At the same time, RhoA and ROCKII disappeared from the cell rear and accumulated at the leading edge whereas myosin IIA was enriched at both cell poles. These data suggest that H. pylori inhibits the dynamic changes in myosin IIA contractility and front-to-back polarity that are essential for chemotaxis. Taken together, our data advance understanding of PMN plasticity and H. pylori pathogenesis.
The lymphatic system and COVID-19 vaccines
Authors: Miyasaka Masayuki
Published: October 2022

Understanding the precise mechanism of vaccine-induced protection and the immune correlates of protection against coronavirus disease 2019 (COVID-19) is crucially important for developing next-generation vaccines that confer durable and protective immunity against COVID-19. Similar factors are also important for other infectious diseases. Here, I briefly summarize the mechanism of action of the currently used COVID-19 mRNA vaccines from the viewpoint of the function of the lymphatic system.
Extracellular vesicles as advanced therapeutics for the resolution of organ fibrosis: Current progress and future perspectives
Authors: Lv Ke , Wang Yizhuo , Lou Peng , Liu Shuyun , Zhou Pingya , Yang Li , Lu Yanrong , Cheng Jingqiu , Liu Jingping
Published: October 2022

Organ fibrosis is a serious health challenge worldwide, and its global incidence and medical burden are increasing dramatically each year. Fibrosis can occur in nearly all major organs and ultimately lead to organ dysfunction. However, current clinical treatments cannot slow or reverse the progression of fibrosis to end-stage organ failure, and thus advanced anti-fibrotic therapeutics are urgently needed. As a type of naturally derived nanovesicle, native extracellular vesicles (EVs) from multiple cell types (e.g., stem cells, immune cells, and tissue cells) have been shown to alleviate organ fibrosis in many preclinical models through multiple effective mechanisms, such as anti-inflammation, pro-angiogenesis, inactivation of myofibroblasts, and fibrinolysis of ECM components. Moreover, the therapeutic potency of native EVs can be further enhanced by multiple engineering strategies, such as genetic modifications, preconditionings, therapeutic reagent-loadings, and combination with functional biomaterials. In this review, we briefly introduce the pathology and current clinical treatments of organ fibrosis, discuss EV biology and production strategies, and particularly focus on important studies using native or engineered EVs as interventions to attenuate tissue fibrosis. This review provides insights into the development and translation of EV-based nanotherapies into clinical applications in the future.
Liver disease accompanied by enteropathy in common variable immunodeficiency: Common pathophysiological mechanisms
Authors: Lima Fabiana Mascarenhas Souza , Toledo-Barros Myrthes , Alves Venâncio Avancini Ferreira , Duarte Maria Irma Seixas , Takakura Cleusa , Bernardes-Silva Carlos Felipe , Marinho Ana Karolina Barreto Berselli , Grecco Octavio , Kalil Jorge , Kokron Cristina Maria
Published: October 2022

Common variable immunodeficiency (CVID) is one of the inborn errors of immunity that have the greatest clinical impact. Rates of morbidity and mortality are higher in patients with CVID who develop liver disease than in those who do not. The main liver disorder in CVID is nodular regenerative hyperplasia (NRH), the cause of which remains unclear and for which there is as yet no treatment. The etiology of liver disease in CVID is determined by analyzing the liver injury and the associated conditions. The objective of this study was to compare CVID patients with and without liver–spleen axis abnormalities in terms of clinical characteristics, as well as to analyze liver and duodenal biopsies from those with portal hypertension (PH), to elucidate the pathophysiology of liver injury. Patients were divided into three groups: Those with liver disease/PH, those with isolated splenomegaly, and those without liver–spleen axis abnormalities. Clinical and biochemical data were collected. Among 141 CVID patients, 46 (32.6%) had liver disease/PH; 27 (19.1%) had isolated splenomegaly; and 68 (48.2%) had no liver–spleen axis abnormalities. Among the liver disease/PH group, patients, even those with mild or no biochemical changes, had clinical manifestations of PH, mainly splenomegaly, thrombocytopenia, and esophageal varices. Duodenal celiac pattern was found to correlate with PH (p < 0.001). We identified NRH in the livers of all patients with PH (n = 11). Lymphocytic infiltration into the duodenal mucosa also correlated with PH. Electron microscopy of liver biopsy specimens showed varying degrees of lymphocytic infiltration and hepatocyte degeneration, which is a probable mechanism of lymphocyte-mediated cytotoxicity against hepatocytes and enterocytes. In comparison with the CVID patients without PH, those with PH were more likely to have lymphadenopathy (p < 0.001), elevated β2-microglobulin (p < 0.001), low B-lymphocyte counts (p < 0.05), and low natural killer-lymphocyte counts (p < 0.05). In CVID patients, liver disease/PH is common and regular imaging follow-up is necessary. These patients have a distinct immunological phenotype that may predispose to liver and duodenal injury from lymphocyte-mediated cytotoxicity. Further studies could elucidate the cause of this immune-mediated mechanism and its treatment options.
Conformation-stabilizing ELISA and cell-based assays reveal patient subgroups targeting three different epitopes of AGO1 antibodies
Authors: Moritz Christian P. , Do Le-Duy , Tholance Yannick , Vallayer Pierre-Baptiste , Rogemond Véronique , Joubert Bastien , Ferraud Karine , La Marca Coralie , Camdessanché Jean-Philippe , Honnorat Jérôme , Antoine Jean-Christophe
Published: October 2022

Autoantibodies (Abs) are biomarkers for many disease conditions and are increasingly used to facilitate diagnosis and treatment decisions. To guarantee high sensitivity and specificity, the choice of their detection method is crucial. Via cell-based assays, we recently found 21 patients with neurological diseases positive for antibodies against argonaute (AGO), 10 of which having a neuropathy (NP). Here, we established a simple and conformation-sensitive ELISA with the aim to distinguish between AGO1 Abs against conformational epitopes and non-conformational epitopes and to reveal further characteristics of AGO1 antibodies in NP and autoimmune disease (AID). In a retrospective multicenter case/control and observational study, we tested 434 patients with NP, 274 disease controls with AID, and 116 healthy controls (HC) for AGO1 Abs via conformation-stabilizing ELISA. Seropositive patients were also tested for conformation-specificity via comparative denaturing/stabilizing ELISA (CODES-ELISA), CBA positivity, AGO1 titers and IgG subclasses, and AGO2 reactivity. These parameters were statistically compared among different epitope-specific patient groups. We found Abs in 44 patients, including 28/434 (6.5%) NP, 16/274 (5.8%) AID, and 0/116 (0%) HC. Serum reactivity was consistently higher for AGO1 than AGO2. Globally among the 44 AGO1 Abs-positive patients, 42 were also tested in CBA for AGO1 Abs positivity and 15 (35.7%) were positive. Furthermore, 43 were tested for conformation-specificity and 32 (74.4%) bound a conformational epitope. Among the subgroups of highly positive patients (ELISA z-score >14) with sera binding conformational epitopes (n=23), 14 patient sera were also CBA positive and 9 bound a second conformational but CBA-inaccessible epitope. A third, non-conformational epitope was bound by 11/43 (15.6%). Among the epitope-specific patient subgroups, we found significant differences regarding the Abs titers, IgG subclass, and AGO2 reactivity. When comparing AGO1 Abs-positive NP versus AID patients, we found the conformation-specific and CBA inaccessible epitope significantly more frequently in AID patients. We conclude that 1) conformational ELISA was more sensitive than CBA in detecting AGO1 Abs, 2) serum reactivity is higher for AGO1 than for AGO2 at least for NP patients, 3) AGO1 Abs might be a marker-of-interest in 6.5% of NP patients, 4) distinguishing epitopes might help finding different patient subgroups.
Immune-associated pivotal biomarkers identification and competing endogenous RNA network construction in post-operative atrial fibrillation by comprehensive bioinformatics and machine learning strategies
Authors: Zhou Yufei , Wu Qianyun , Ni Gehui , Hong Yulu , Xiao Shengjue , Liu Chunjiang , Yu Zongliang
Published: October 2022

Background

Atrial fibrillation (AF) is the most common arrhythmia. Previous studies mainly focused on identifying potential diagnostic biomarkers and treatment strategies for AF, while few studies concentrated on post-operative AF (POAF), particularly using bioinformatics analysis and machine learning algorithms. Therefore, our study aimed to identify immune-associated genes and provide the competing endogenous RNA (ceRNA) network for POAF.

Methods

Three GSE datasets were downloaded from the GEO database, and we used a variety of bioinformatics strategies and machine learning algorithms to discover candidate hub genes. These techniques included identifying differentially expressed genes (DEGs) and circRNAs (DECs), building protein-protein interaction networks, selecting common genes, and filtering candidate hub genes via three machine learning algorithms. To assess the diagnostic value, we then created the nomogram and receiver operating curve (ROC). MiRNAs targeting DEGs and DECs were predicted using five tools and the competing endogenous RNA (ceRNA) network was built. Moreover, we performed the immune cell infiltration analysis to better elucidate the regulation of immune cells in POAF.

Results

We identified 234 DEGs (82 up-regulated and 152 down-regulated) of POAF via Limma, 75 node genes were visualized via PPI network, which were mainly enriched in immune regulation. 15 common genes were selected using three CytoHubba algorithms. Following machine learning selection, the nomogram was created based on the four candidate hub genes. The area under curve (AUC) of the nomogram and individual gene were all over 0.75, showing the ideal diagnostic value. The dysregulation of macrophages may be critical in POAF pathogenesis. A novel circ_0007738 was discovered in POAF and the ceRNA network was eventually built.

Conclusion

We identified four immune-associated candidate hub genes (C1QA, C1R, MET, and SDC4) for POAF diagnosis through the creation of a nomogram and evaluation of its diagnostic value. The modulation of macrophages and the ceRNA network may represent further therapy methods.
Pan-cancer analyses of classical protein tyrosine phosphatases and phosphatase-targeted therapy in cancer
Authors: Wang Tao , Ba Xinlei , Zhang Xiaonan , Zhang Na , Wang Guowen , Bai Bin , Li Tong , Zhao Jiahui , Zhao Yanjiao , Yu Yang , Wang Bing
Published: October 2022

Protein tyrosine phosphatases function in dephosphorylating target proteins to regulate signaling pathways that control a broad spectrum of fundamental physiological and pathological processes. Detailed knowledge concerning the roles of classical PTPs in human cancer merits in-depth investigation. We comprehensively analyzed the regulatory mechanisms and clinical relevance of classical PTPs in more than 9000 tumor patients across 33 types of cancer. The independent datasets and functional experiments were employed to validate our findings. We exhibited the extensive dysregulation of classical PTPs and constructed the gene regulatory network in human cancer. Moreover, we characterized the correlation of classical PTPs with both drug-resistant and drug-sensitive responses to anti-cancer drugs. To evaluate the PTP activity in cancer prognosis, we generated a PTPscore based on the expression and hazard ratio of classical PTPs. Our study highlights the notable role of classical PTPs in cancer biology and provides novel intelligence to improve potential therapeutic strategies based on pTyr regulation.
Harmonization and qualification of intracellular cytokine staining to measure influenza-specific CD4+ T cell immunity within the FLUCOP consortium
Authors: Begue Sarah , Waerlop Gwenn , Salaun Bruno , Janssens Michel , Bellamy Duncan , Cox Rebecca Jane , Davies Richard , Gianchecchi Elena , Medaglini Donata , Montomoli Emanuele , Pettini Elena , Leroux-Roels Geert , Clement Frédéric , Pagnon Anke
Published: October 2022

Despite the knowledge that cell-mediated immunity (CMI) contributes to the reduction of severe influenza infection, transmission, and disease outcome, the correlates of protection for cell-mediated immunity remain still unclear. Therefore, measuring the magnitude and quality of influenza-specific T cell responses in a harmonized way is of utmost importance to improve characterisation of vaccine-induced immunity across different clinical trials. The present study, conducted as part of the FLUCOP project, describes the development of a consensus protocol for the intracellular cytokine staining (ICS) assay, in order to reduce inter-laboratory variability, and its qualification. In order to develop a consensus protocol, the study was divided into different stages. Firstly, two pilot studies evaluated critical parameters in the analytical (read-outs) and post-analytical (gating strategies and data analysis) methods applied by eight different laboratories within the FLUCOP consortium. The methods were then harmonized by fixing the critical parameters and the subsequent consensus protocol was then qualified by one FLUCOP member. The antigen-specific cell population was defined as polypositive CD4+ T cells (i.e. positive for at least two markers among CD40L/IFNγ/IL2/TNFα), which was shown to be the most sensitive and specific read-out. The qualification of this consensus protocol showed that the quantification of polypositive CD4+ T cells was precise, linear and accurate, and sensitive with a lower limit of quantification of 0.0335% antigen-specific polypositive CD4+ T cells. In conclusion, we provide the description of a harmonized ICS assay, which permits quantitative and qualitative evaluation of influenza vaccine-induced T cell responses. Application of this harmonized assay may allow for future comparisons of T cell responses to different influenza vaccines. It may facilitate future assessments of potential correlates of protection with the promise of application across other pathogens.
Traumatized triad of complementopathy, endotheliopathy, and coagulopathy ˗ Impact on clinical outcomes in severe polytrauma patients
Authors: Yang Zhangsheng , Le Tuan D. , Simovic Milomir O. , Liu Bin , Fraker Tamara L. , Cancio Tomas S. , Cap Andrew P. , Wade Charles E. , DalleLucca Jurandir J. , Li Yansong
Published: October 2022

Complementopathy, endotheliopathy, and coagulopathy following a traumatic injury are key pathophysiological mechanisms potentially associated with multiple-organ failure (MOF) and mortality. However, the heterogeneity in the responses of complementopathy, endotheliopathy, and coagulopathy to trauma, the nature and extent of their interplay, and their relationship to clinical outcomes remain unclear. Fifty-four poly-trauma patients were enrolled and divided into three subgroups based on their ISS. Biomarkers in blood plasma reflecting complement activation, endothelial damage, and coagulopathy were measured starting from admission to the emergency department and at 3, 6, 12, 24, and 120 hours after admission. Comparative analyses showed that severely injured patients (ISS>24) were associated with longer days on mechanical ventilation, in the intensive care unit and hospital stays, and a higher incidence of hyperglycemia, bacteremia, respiratory failure and pneumonia compared to mildly (ISS<16) or moderately (ISS=16-24) injured patients. In this trauma cohort, complement was activated early, primarily through the alternative complement pathway. As measured in blood plasma, severely injured patients had significantly higher levels of complement activation products (C3a, C5a, C5b-9, and Bb), endothelial damage markers (syndecan-1, sTM, sVEGFr1, and hcDNA), and fibrinolytic markers (D-dimer and LY30) compared to less severely injured patients. Severely injured patients also had significantly lower thrombin generation (ETP and peak) and lower levels of coagulation factors (I, V, VIII, IX, protein C) than less severely injured patients. Complement activation correlated with endothelial damage and hypocoagulopathy. Logistic regression analyses revealed that Bb >1.57 μg/ml, syndecan-1 >66.6 ng/ml or D-dimer >6 mg/L at admission were associated with a higher risk of MOF/mortality. After adjusting for ISS, each increase of the triadic score defined above (Bb>1.57 µg/ml/Syndecan-1>66.6 ng/ml/D-dimer>6.0mg/L) was associated with a 6-fold higher in the odds ratio of MOF/death [OR: 6.83 (1.04-44.96, P=0.046], and a 4-fold greater in the odds of infectious complications [OR: 4.12 (1.04-16.36), P=0.044]. These findings provide preliminary evidence of two human injury response endotypes (traumatized triad and non-traumatized triad) that align with clinical trajectory, suggesting a potential endotype defined by a high triadic score. Patients with this endotype may be considered for timely intervention to create a pro-survival/organ-protective phenotype and improve clinical outcomes.
Trends in industrialization and commercialization of IgY technology
Authors: Yakhkeshi Saeed , Wu Rao , Chelliappan Brindha , Zhang Xiaoying
Published: October 2022

IgY technology refers to the strategic production process involved in generating avian immunoglobulin (IgY) against target antigens in a much more cost-effective manner with broad applications in the fields of diagnostics, prophylaxis, and therapeutics for both human and veterinary medicine. Over the past decade, promising progress in this research area has been evident from the steep increase in the number of registered manufacturing companies involved in the production of IgY products, the number of patents, and the notable number of clinical trials underway. Hence, it is crucial to conduct a prospective analysis of the commercialization and marketing potential of IgY-based commercial products for large-scale applications. This review revealed that the number of IgY patent applications increased steeply after 2010, with the highest of 77 patents filed in 2021. In addition, 73 industries are reportedly involved in marketing IgY products, out of which 27 were promoting biotherapeutics for human and veterinary medicine and 46 were in the diagnostic field. IgY antibodies are being used as primary and secondary antibodies, with approximately 3729 and 846 products, respectively. Biotherapeutic product consumption has notably increased as a food supplement and as a topical application in human and veterinary medicine, which are under different clinical phases of development to reach the market with around 80 and 56 products, respectively. In contrast, the number of IgY products as parenteral administrations and licensed drugs is not well developed given the lack of technical standards established for IgY registration and industrialization, as well as the restriction of the nature of polyclonal antibodies. However, recent ongoing research on functional IgY fragments indicates a promising area for IgY applications in the near future. Therefore, retrospective analysis with speculations is mandatory for IgY technology maturation toward industrialization and commercialization.
Impaired intratumoral natural killer cell function in head and neck carcinoma
Authors: Mele Dalila , Pessino Greta , Trisolini Giuseppe , Luchena Alberto , Benazzo Marco , Morbini Patrizia , Mantovani Stefania , Oliviero Barbara , Mondelli Mario U. , Varchetta Stefania
Published: October 2022

Natural killer (NK) cells are emerging as unique players in the immune response against cancer; however, only limited data are available on tumor infiltrating NK cells in head and neck squamous cell carcinoma (HNSCC), one of the most common cancer. Occurrence of HNSCC is closely related to the immune microenvironment, and immunotherapy is increasingly being applied to this setting. However, the limited success of this type of treatment in this tumor calls for further investigation in the field.

Surgical HNSSC specimens of 32 consecutive patients were mechanically and enzymatically dissociated. Tumor cells were separated from infiltrating cells by short centrifugation and infiltrating NK cells were phenotypically and functionally characterized by multiple antibody staining and flow cytometry. Tumor infiltrating NK cells in HNSCC showed a peculiar phenotype predominantly characterized by increased NKG2A and reduced Siglec-7, NKG2D, NKp30 and CD16 expression. This phenotype was associated with a decreased ability to perform antibody-dependent cellular cytotoxicity (ADCC). However, NK, CD4 and CD8 shared an increment of glucocorticoid-induced tumor necrosis factor-related (GITR) costimulatory receptor which could be exploited for immunotherapy with agonistic anti-GITR antibodies combined with checkpoint inhibitors.
Early suppression of antiviral host response and protocadherins by SARS-CoV-2 Spike protein in THP-1-derived macrophage-like cells
Authors: Miltner Noémi , Linkner Tamás Richárd , Ambrus Viktor , Al-Muffti Aya S. , Ahmad Hala , Mótyán János András , Benkő Szilvia , Tőzsér József , Mahdi Mohamed
Published: October 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease-19 (COVID-19). The spike protein (S) of SARS-CoV-2 plays a crucial role in mediating viral infectivity; hence, in an extensive effort to curb the pandemic, many urgently approved vaccines rely on the expression of the S protein, aiming to induce a humoral and cellular response to protect against the infection. Given the very limited information about the effects of intracellular expression of the S protein in host cells, we aimed to characterize the early cellular transcriptomic changes induced by expression of the S protein in THP-1-derived macrophage-like cells. Results showed that a wide variety of genes were differentially expressed, products of which are mainly involved in cell adhesion, homeostasis, and most notably, antiviral and immune responses, depicted by significant downregulation of protocadherins and type I alpha interferons (IFNAs). While initially, the levels of IFNAs were higher in the medium of S protein expressing cells, the downregulation observed on the transcriptomic level might have been reflected by no further increase of IFNA cytokines beyond the 5 h time-point, compared to the mock control. Our study highlights the intrinsic pathogenic role of the S protein and sheds some light on the potential drawbacks of its utilization in the context of vaccination strategies.
An update on the interaction between COVID-19, vaccines, and diabetic kidney disease
Authors: Yang Yang , Zou Shubiao , Xu Gaosi
Published: October 2022

Up to now, coronavirus disease 2019 (COVID-19) is still affecting worldwide due to its highly infectious nature anrapid spread. Diabetic kidney disease (DKD) is an independent risk factor for severe COVID-19 outcomes, and they have a certain correlation in some aspects. Particularly, the activated renin–angiotensin–aldosterone system, chronic inflammation, endothelial dysfunction, and hypercoagulation state play an important role in the underlying mechanism linking COVID-19 to DKD. The dipeptidyl peptidase-4 inhibitor is considered a potential therapy for COVID-19 and has similarly shown organ protection in DKD. In addition, neuropilin-1 as an alternative pathway for angiotensin-converting enzyme 2 also contributes to severe acute respiratory syndrome coronavirus 2 entering the host cells, and its decreased expression can affect podocyte migration and adhesion. Here, we review the pathogenesis and current evidence of the interaction of DKD and COVID-19, as well as focus on elevated blood glucose following vaccination and its possible mechanism. Grasping the pathophysiology of DKD patients with COVID-19 is of great clinical significance for the formulation of therapeutic strategies.
Cardiometabolic characterization in metabolic dysfunction–associated fatty liver disease
Authors: Perdomo Carolina M. , Núñez-Córdoba Jorge M. , Ezponda Ana , Mendoza Francisco J. , Ampuero Javier , Bastarrika Gorka , Frühbeck Gema , Escalada Javier
Published: October 2022

Background

To better understand the patient's heterogeneity in fatty liver disease (FLD), metabolic dysfunction–associated fatty liver disease (MAFLD) was proposed by international experts as a new nomenclature for nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the cardiovascular risk, assessed through coronary artery calcium (CAC) and epicardial adipose tissue (EAT), of patients without FLD and patients with FLD and its different subtypes.

Methods

Cross sectional study of 370 patients. Patients with FLD were divided into 4 groups: FLD without metabolic dysfunction (non-MD FLD), MAFLD and the presence of overweight/obesity (MAFLD-OW), MAFLD and the presence of two metabolic abnormalities (MAFLD-MD) and MAFLD and the presence of T2D (MAFLD-T2D). MAFLD-OW included two subgroups: metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUHO). The patients without FLD were divided into 2 groups: patients without FLD and without MD (non-FLD nor MD; reference group) and patients without FLD but with MD (non-FLD with MD). EAT and CAC (measured through the Agatston Score) were determined by computed tomography.

Results

Compared with the reference group (non-FLD nor MD), regarding EAT, patients with MAFLD-T2D and MAFLD-MUHO had the highest risk for CVD (OR 15.87, 95% CI 4.26-59.12 and OR 17.60, 95% CI 6.71-46.20, respectively), patients with MAFLD-MHO were also at risk for CVD (OR 3.62, 95% CI 1.83-7.16), and patients with non-MD FLD did not have a significantly increased risk (OR 1.77; 95% CI 0.67-4.73). Regarding CAC, patients with MAFLD-T2D had an increased risk for CVD (OR 6.56, 95% CI 2.18-19.76). Patients with MAFLD-MUHO, MAFLD-MHO and non-MD FLD did not have a significantly increased risk compared with the reference group (OR 2.54, 95% CI 0.90-7.13; OR 1.84, 95% CI 0.67-5.00 and OR 2.11, 95% CI 0.46-9.74, respectively).

Conclusion

MAFLD–T2D and MAFLD–OW phenotypes had a significant risk for CVD. MAFLD new criteria reinforced the importance of identifying metabolic phenotypes in populations as it may help to identify patients with higher CVD risk and offer a personalized therapeutic management in a primary prevention setting.
Outcomes of critically ill coronavirus disease 2019 patients requiring kidney replacement therapy: A retrospective cohort study
Authors: Braunsteiner Josephine , Jarczak Dominik , Schmidt-Lauber Christian , Boenisch Olaf , de Heer Geraldine , Burdelski Christoph , Frings Daniel , Sensen Barbara , Nierhaus Axel , Hoxha Elion , Huber Tobias B. , Wichmann Dominic , Kluge Stefan , Fischer Marlene , Roedl Kevin
Published: October 2022

Background

Coronavirus disease 2019 (COVID-19) has resulted in high hospitalization rates worldwide. Acute kidney injury (AKI) in patients hospitalized for COVID-19 is frequent and associated with disease severity and poor outcome. The aim of this study was to investigate the incidence of kidney replacement therapy (KRT) in critically ill patients with COVID-19 and its implication on outcome.

Methods

We retrospectively analyzed all COVID-19 patients admitted to the Department of Intensive Care Medicine at the University Medical Center Hamburg-Eppendorf (Germany) between 1 March 2020 and 31 July 2021. Demographics, clinical parameters, type of organ support, length of intensive care unit (ICU) stay, mortality and severity scores were assessed.

Results

Three-hundred critically ill patients with COVID-19 were included. The median age of the study population was 61 (IQR 51–71) years and 66% (n = 198) were male. 73% (n = 219) of patients required invasive mechanical ventilation. Overall, 68% (n = 204) of patients suffered from acute respiratory distress syndrome and 30% (n = 91) required extracorporeal membrane oxygenation (ECMO). We found that 46% (n = 139) of patients required KRT. Septic shock (OR 11.818, 95% CI: 5.941–23.506, p < 0.001), higher simplified acute physiology scores (SAPS II) (OR 1.048, 95% CI: 1.014–1.084, p = 0.006) and vasopressor therapy (OR 5.475, 95% CI: 1.127–26.589, p = 0.035) were independently associated with the initiation of KRT. 61% (n = 85) of patients with and 18% (n = 29) without KRT died in the ICU (p < 0.001). Cox regression found that KRT was independently associated with mortality (HR 2.075, 95% CI: 1.342–3.208, p = 0.001) after adjusting for confounders.

Conclusion

Critically ill patients with COVID-19 are at high risk of acute kidney injury with about half of patients requiring KRT. The initiation of KRT was associated with high mortality.
Trends in management and outcomes of pregnant women living with HIV between 2008–2013 and 2014–2019: A retrospective cohort study
Authors: Brandon Olivia , Chakravarti Sujay , Hemelaar Joris
Published: October 2022

Background

Despite major advances in the care of pregnant women living with HIV (WLHIV), they remain at increased risk of adverse pregnancy outcomes. This study assesses recent developments in management and outcomes of pregnant WLHIV at a tertiary obstetric unit in the United Kingdom.

Methods

We conducted a retrospective cohort study of WLHIV delivering at the John Radcliffe Hospital, Oxford, during 2008–2019. Detailed data was collected for maternal, virological, obstetric, and perinatal characteristics. To determine changes over time, data from the periods 2008–13 and 2014–19 were compared.

Results

We identified 116 pregnancies in 94 WLHIV. Between 2008–2013 and 2014–2019, the rate of preconception HIV diagnosis increased from 73 to 90% (p = 0.021) and the proportion of WLHIV on combination ART (cART) at conception increased from 54 to 84% (p = 0.001). The median gestation at which cART was initiated antenatally decreased from 22+1 to 17+1 weeks (p = 0.003). In 2014-2019, 41% of WLHIV received non-nucleoside reverse transcriptase inhibitor-based cART, 37% protease inhibitor-based cART, and 22% of cART regimens contained an integrase inhibitor. The proportion of WLHIV with a viral load <50 copies/mL at delivery rose from 87 to 94% (p = 0.235). Sixty-six percent of WLHIV delivered by Cesarean section, with a significant decrease over time in the rate of both planned (62–39%, p = 0.016) and actual (49–31%, p = 0.044) elective Cesarean. Perinatal outcomes included one case of perinatal HIV transmission (0.86%), 11% preterm birth, 15% small-for-gestational-age, and 2% stillbirth. There was an association between a viral load >50 copies/mL at delivery and preterm delivery (p = 0.0004).

Conclusion

Virological, obstetric, and perinatal outcomes of WLHIV improved during the study period. Implementation of national guidance has led to an increase in preconception diagnosis and treatment, earlier initiation of antenatal treatment, a reduction in the number of women with a detectable viral load at delivery, and an increase in vaginal deliveries.
Effects of amikacin, polymyxin-B, and sulbactam combination on the pharmacodynamic indices of mutant selection against multi-drug resistant Acinetobacter baumannii
Authors: Zhu Shixing , Song Chu , Zhang Jiayuan , Diao Shuo , Heinrichs Tobias M. , Martins Frederico S. , Lv Zhihua , Zhu Yuanqi , Yu Mingming , Sy Sherwin K. B.
Published: October 2022

Amikacin and polymyxins as monotherapies are ineffective against multidrug-resistant Acinetobacter baumannii at the clinical dose. When polymyxins, aminoglycosides, and sulbactam are co-administered, the combinations exhibit in vitro synergistic activities. The minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined in 11 and 5 clinical resistant isolates of A. baumannii harboring OXA-23, respectively, in order to derive the fraction of time over the 24-h wherein the free drug concentration was within the mutant selection window (fTMSW) and the fraction of time that the free drug concentration was above the MPC (fT>MPC) from simulated pharmacokinetic profiles. The combination of these three antibiotics can confer susceptibility in multi-drug resistant A. baumannii and reduce the opportunity for bacteria to develop further resistance. Clinical intravenous dosing regimens of amikacin, polymyxin-B, and sulbactam were predicted to optimize fTMSW and fT>MPC from drug exposures in the blood. Mean fT>MPC were ≥ 60% and ≥ 80% for amikacin and polymyxin-B, whereas mean fTMSW was reduced to <30% and <15%, respectively, in the triple antibiotic combination. Due to the low free drug concentration of amikacin and polymyxin-B simulated in the epithelial lining fluid, the two predicted pharmacodynamic parameters in the lung after intravenous administration were not optimal even in the combination therapy setting.
Morphology and phylogeny of ascomycetes associated with walnut trees (Juglans regia) in Sichuan province, China
Authors: Xu Xiu-Lan , Wang Fei-Hu , Liu Chao , Yang Han-Bo , Zeng Zhen , Wang Bao-Xin , Liu Ying-Gao , Yang Chun-Lin
Published: October 2022

In Sichuan province, walnuts, consisting of Juglans regia, Juglans sigillata, and the hybrid J. regia × J. sigillata, are commercially important edible nuts, and J. regia is the most widespread plant. To date, the diversity and distribution of fungi inhabiting on Juglans have not received enough attention, although there have been studies focusing on pathogens from fruit and stem. In order to update the checklist of fungi associated with Sichuan walnuts, a survey on fungi associated with the three Juglans species from 15 representative regions in Sichuan was conducted. In this article, ten fungi distributed in two classes of Ascomycota (Dothideomycetes and Sordariomycetes) were described based on morpho-molecular analyses, and two novel species, Neofusicoccum sichuanense and Sphaerulina juglandina, a known species of Ophiognomonia leptostyla, and seven new hosts or geographical records of Cladosporium tenuissimum, Diatrypella vulgaris, Helminthosporium juglandinum, Helminthosporium velutinum, Loculosulcatispora hongheensis, Periconia byssoides, and Rhytidhysteron subrufulum were included. Morphological descriptions and illustrations of these fungi are provided.
Biological functions of sialic acid as a component of bacterial endotoxin
Authors: Dudek Bartłomiej , Rybka Jacek , Bugla-Płoskońska Gabriela , Korzeniowska-Kowal Agnieszka , Futoma-Kołoch Bożena , Pawlak Aleksandra , Gamian Andrzej
Published: October 2022

Lipopolysaccharide (endotoxin, LPS) is an important Gram-negative bacteria antigen. LPS of some bacteria contains sialic acid (Neu5Ac) as a component of O-antigen (O-Ag), in this review we present an overview of bacteria in which the presence of Neu5Ac has been confirmed in their outer envelope and the possible ways that bacteria can acquire Neu5Ac. We explain the role of Neu5Ac in bacterial pathogenesis, and also involvement of Neu5Ac in bacterial evading the host innate immunity response and molecular mimicry phenomenon. We also highlight the role of sialic acid in the mechanism of bacterial resistance to action of serum complement. Despite a number of studies on involvement of Neu5Ac in bacterial pathogenesis many aspects of this phenomenon are still not understood.
Regulation of Yujin Powder alcoholic extracts on ILC3s-TD IgA-colonic mucosal flora axis of DSS-induced ulcerative colitis
Authors: Wen Yanqiao , Zhang Wangdong , Yang Rong , Jiang Lidong , Zhang Xiaosong , Wang Baoshan , Hua Yongli , Ji Peng , Yuan Ziwen , Wei Yanming , Yao Wanling
Published: October 2022

The intestinal flora maintained by the immune system plays an important role in healthy colon. However, the role of ILC3s-TD IgA-colonic mucosal flora axis in ulcerative colitis (UC) and whether it could become an innovative pathway for the treatment of UC is unknown. Yujin Powder is a classic prescription for treatment of dampness-heat type intestine disease in traditional Chinese medicine and has therapeutic effects on UC. Hence, the present study aimed to investigate the regulatory mechanism of Yujin Powder alcoholic extracts (YJP-A) on UC via ILC3s-TD IgA-colonic mucosal flora axis. The UC mouse model was induced by drinking 3.5% dextran sodium sulfate (DSS), meanwhile, YJP-A was given orally for prevention. During the experiment, the clinical symptoms of mice were recorded. Then the intestinal injury and inflammatory response of mice about UC were detected after the experiment. In addition, the relevant indicators of ILC3s-TD IgA-colonic mucosal flora axis were detected. The results showed that YJP-A had good therapy effects on DSS-induced mice UC: improved the symptoms, increased body weight and the length of colon, decreased the disease activity index score, ameliorated the intestinal injury, and reduced the inflammation etc. Also, YJP-A significantly increased the ILC3s proportion and the expression level of MHC II; significantly decreased the proportion of Tfh cells and B cells and the expression levels of Bcl6, IL-4, Aicda in mesenteric lymph nodes of colon in UC mice and IgA in colon. In addition, by 16S rDNA sequencing, YJP-A could restore TD IgA targets colonic mucus flora in UC mice by decreasing the relative abundance of Mucispirillum, Lachnospiraceae and increasing the relative abundance of Allprevotella, Alistipes, and Ruminococcaceae etc. In conclusion, our results demonstrated that the ILC3s-TD IgA-colonic mucosal flora axis was disordered in UC mice. YJP-A could significantly promote the proliferation of ILC3s to inhibit Tfh responses and B cells class switching through MHC II, further to limit TD IgA responses toward colonic mucosal flora. Our findings suggested that this axis may be a novel and promising strategy to prevent UC.
Emergence of a NDM-1-producing ST25 Klebsiella pneumoniae strain causing neonatal sepsis in China
Authors: Zhao Junhui , Zheng Beiwen , Xu Hao , Li Junfeng , Sun Tengfei , Jiang Xiawei , Liu Wenhong
Published: October 2022

Carbapenem-resistant Klebsiella pneumoniae (CRKP) seriously threaten the efficacy of modern medicine with a high associated mortality rate and unprecedented transmission rate. In this study, we isolated a clinical K. pneumoniae strain DY1928 harboring blaNDM-1 from a neonate with blood infection. Antimicrobial susceptibility testing indicated that DY1928 was resistant to various antimicrobial agents, including meropenem, imipenem, ceftriaxone, cefotaxime, ceftazidime, cefepime, piperacillin-tazobactam, and amoxicillin-clavulanate. S1 nuclease-pulsed field gel electrophoresis (S1-PFGE), southern blot and conjugation experiment revealed that the blaNDM-1 gene was located on a conjugative plasmid of IncA/C2 type with a 147.9 kb length. Whole-genome sequencing showed that there was a conservative structure sequence (blaNDM-1-ble-trpF-dsbD) located downstream of the blaNDM-1 gene. Multilocus sequence typing (MLST) classified DY1928 as ST25, which was a hypervirulent K. pneumoniae type. Phylogenetic analysis of genomic data from all ST25 K. pneumoniae strains available in the NCBI database suggested that all blaNDM-1 positive strains were isolated in China and had clinical origins. A mouse bloodstream infection model was constructed to test the virulence of DY1928, and 11 K. pneumoniae strains homologous to DY1928 were isolated from the feces of infected mice. Moreover, we found that DY1928 had a tendency to flow from the blood into the intestine in mice and caused multiple organ damage. To our knowledge, this is the first study to report an infection caused by blaNDM-1-positive ST25 K. pneumoniae in the neonatal unit. Our findings indicated that stricter surveillance and more effective actions were needed to reduce the risk of disseminating such K. pneumoniae strains in clinical settings, especially in neonatal wards.
Drosophila melanogaster as a model to study innate immune memory
Authors: Arch Marta , Vidal Maria , Koiffman Romina , Melkie Solomon Tibebu , Cardona Pere-Joan
Published: October 2022

Over the last decades, research regarding innate immune responses has gained increasing importance. A growing body of evidence supports the notion that the innate arm of the immune system could show memory traits. Such traits are thought to be conserved throughout evolution and provide a survival advantage. Several models are available to study these mechanisms. Among them, we find the fruit fly,Drosophila melanogaster. This non-mammalian model has been widely used for innate immune research since it naturally lacks an adaptive response. Here, we aim to review the latest advances in the study of the memory mechanisms of the innate immune response using this animal model.
Identification of essential genes in Mycobacterium avium subsp. paratuberculosis genome for persistence in dairy calves
Authors: Eshraghisamani Razieh , Mirto Amanda J. , Wang Joyce , Behr Marcel A. , Barkema Herman W. , De Buck Jeroen
Published: October 2022

To cause disease Mycobacterium avium subsp. paratuberculosis needs to enter mammalian cells, arrest phagosomal maturation and manipulate the host immune system. The genetic basis of the bacterial capacity to achieve these outcomes remains largely unknown. Identifying these genes would allow us to gain a deeper understanding of MAP’s pathogenesis and potentially develop a live attenuated Johne’s disease vaccine by knocking out these genes. MAP genes demonstrated to be essential for colonization in the natural host, ruminants, are unknown. Genome-wide transposon mutagenesis and high-throughput sequencing were combined to evaluate the essentiality of each coding region in the bacterial genome to survive in dairy calves. A saturated library of 3,852 MAP Tn mutants, with insertions in 56% of TA sites, interrupting 88% of genes, was created using a MycoMarT7 phagemid containing a mariner transposon. Six calves were inoculated with a high dose of a library of MAP mutants, 1011 CFUs, (input) at 2 weeks of age. Following 2 months of incubation, MAP cells were isolated from the ileum, jejunum, and their associated lymph nodes of calves, resulting in approximately 100,000 colonies grown on solid media across 6 animals (output). Targeted next-generation sequencing was used to identify the disrupted genes in all the mutants in the input pool and the output pool recovered from the tissues to identify in vivo essential genes. Statistical analysis for the determination of essential genes was performed by a Hidden Markov Model (HMM), categorizing genes into essential genes that are devoid of insertions and growth-defect genes whose disruption impairs the growth of the organism. Sequence analysis identified 430 in vivo essential and 260 in vivo growth-defect genes. Gene ontology enrichment analysis of the in vivo essential and growth-defect genes with the highest reduction in the tissues revealed a high representation of genes involved in metabolism and respiration, cell wall and cell processing, virulence, and information pathway processes. This study has systematically identified essential genes for the growth and persistence of MAP in the natural host body.