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1. Bacterial modification of the host glycosaminoglycan heparan sulfate modulates SARS-CoV-2 infectivity

   https://doi.org/https://doi.org/10.1101/2020.08.17.238444  

   Cameron Martino ; Benjamin P Kellman ; Daniel R Sandoval ; Thomas Mandel Clausen ; Clarisse A Marotz ; Se Jin Song ; Stephen Wandro ; Livia S Zaramela ; Rodolfo Antonio Salido Benítez ; Qiyun Zhu ; et al ( August 2020 , bioRxiv)

   The human microbiota has a close relationship with human disease and it remodels components of the glycocalyx including heparan sulfate (HS). Studies of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) spike protein receptor binding domain suggest that infection requires binding to HS and angiotensin converting enzyme 2 (ACE2) in a codependent manner. Here, we show that commensal host bacterial communities can modify HS and thereby modulate SARS-CoV-2 spike protein binding and that these communities change with host age and sex. Common human-associated commensal bacteria whose genomes encode HS-modifying enzymes were identified. The prevalence of these bacteria and the expression of key microbial glycosidases in bronchoalveolar lavage fluid (BALF) was lower in adult COVID-19 patients than in healthy controls. The presence of HS-modifying bacteria decreased with age in two large survey datasets, FINRISK 2002 and American Gut, revealing one possible mechanism for the observed increase in COVID-19 susceptibility with age. In vitro, bacterial glycosidases from unpurified culture media supernatants fully blocked SARS-CoV-2 spike binding to human H1299 protein lung adenocarcinoma cells. HS-modifying bacteria in human microbial communities may regulate viral adhesion, and loss of these commensals could predispose individuals to infection. Understanding the impact of shifts in microbial community composition and bacterial lyases on SARS-CoV-2 infection may lead to new therapeutics and diagnosis of susceptibility. 

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2. Assessment of Complex Flow Patterns in Patients With Carotid Webs, Patients With Carotid Atherosclerosis, and Healthy Subjects Using 4D Flow MRI

   https://doi.org/10.1002/jmri.29013  

   El Sayed, Retta ; Park, Charlie C. ; Shah, Zahraw ; Nahab, Fadi B. ; Haussen, Diogo C. ; Allen, Jason W. ; Oshinski, John N. ( September 2023 , Journal of Magnetic Resonance Imaging)

   Carotid webs (CaWs) are fibromuscular projections in the internal carotid artery (ICA) that cause mild luminal narrowing (<50%), but may be causative in up to one‐third of seemingly cryptogenic strokes. Understanding hemodynamic alterations caused by CaWs is imperative to assessing stroke risk. Time‐Average Wall Shear Stress (TAWSS) and Oscillatory Shear Index (OSI) are hemodynamic parameters linked to vascular dysfunction and thrombosis.

   To test the hypothesis: “CaWs are associated with lower TAWSS and higher OSI than mild atherosclerosis or healthy carotid bifurcation.”

   Prospective study.

   A total of 35 subjects (N = 14 bifurcations with CaW, 11F, age: 49 ± 10, 10 mild atherosclerosis 6F, age: 72 ± 9, 11 healthy 9F, age: 42 ± 13).

   4D flow/STAR‐MATCH/3D TOF/3T MRI, CTA.

   4D Flow velocity data were analyzed in two ways: 1) 3D ROI in the ICA bulbar segment (complex flow patterns are expected) was used to quantify the regions with low TAWSS and high OSI. 2) 2D planes were placed perpendicular to the centerline of the carotid bifurcation for detailed analysis of TAWSS and OSI.

   Independent‐samples Kruskal–Wallis‐H test with 0.05 used for statistical significance.

   The percent surface area where low TAWSS was present in the ICA bulb was 12.3 ± 8.0% (95% CI: 7.6–16.9) in CaW subjects, 1.6 ± 1.9% (95% CI: 0.2–2.9) in atherosclerosis, and 8.5 ± 7.7% (95% CI: 3.6–13.4) in healthy subjects, all differences were statistically significant (ƞ² = 0.3 [95% CI: 0.05–0.5],P‐value CaW vs. healthy = 0.2). OSI had similar values in the CCA between groups (ƞ² = 0.07 [95% CI: 0.0–0.2],P‐value = 0.5), but OSI was significantly higher downstream of the bifurcation in CaW subjects compared to atherosclerosis and normal subjects. OSI returned to similar values between groups 1.5 diameters distal to the bifurcation (ƞ² = 0.03 [95% CI: 0.0–0.2],P‐value = 0.7).

   Lower TAWSS and higher OSI are present in the ICA bulb in patients with CaW when compared to patients with atherosclerotic or healthy subjects.

   2

   Stage 2

    

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3. Bone Marrow-Derived Cells Restore Functional Integrity of the Gut Epithelial and Vascular Barriers in a Model of Diabetes and ACE2 Deficiency

   https://doi.org/10.1161/CIRCRESAHA.119.315743  

   Duan, Yaqian ; Prasad, Ram ; Feng, Dongni ; Beli, Eleni ; Li Calzi, Sergio ; Longhini, Ana Leda ; Lamendella, Regina ; Floyd, Jason L. ; Dupont, Mariana ; Noothi, Sunil K. ; et al ( November 2019 , Circulation Research)

   null (Ed.)

   Rationale: There is incomplete knowledge of the impact of bone marrow cells on the gut microbiome and gut barrier function. Objective: We postulated that diabetes mellitus and systemic ACE2 (angiotensin-converting enzyme 2) deficiency would synergize to adversely impact both the microbiome and gut barrier function. Methods and Results: Bacterial 16S rRNA sequencing and metatranscriptomic analysis were performed on fecal samples from wild-type, ACE2 −/y , Akita (type 1 diabetes mellitus), and ACE2 −/y -Akita mice. Gut barrier integrity was assessed by immunofluorescence, and bone marrow cell extravasation into the small intestine was evaluated by flow cytometry. In the ACE2 −/y -Akita or Akita mice, the disrupted barrier was associated with reduced levels of myeloid angiogenic cells, but no increase in inflammatory monocytes was observed within the gut parenchyma. Genomic and metatranscriptomic analysis of the microbiome of ACE2 −/y -Akita mice demonstrated a marked increase in peptidoglycan-producing bacteria. When compared with control cohorts treated with saline, intraperitoneal administration of myeloid angiogenic cells significantly decreased the microbiome gene expression associated with peptidoglycan biosynthesis and restored epithelial and endothelial gut barrier integrity. Also indicative of diabetic gut barrier dysfunction, increased levels of peptidoglycan and FABP-2 (intestinal fatty acid-binding protein 2) were observed in plasma of human subjects with type 1 diabetes mellitus (n=21) and type 2 diabetes mellitus (n=23) compared with nondiabetic controls (n=23). Using human retinal endothelial cells, we determined that peptidoglycan activates a noncanonical TLR-2 (Toll-like receptor 2) associated MyD88 (myeloid differentiation primary response protein 88)-ARNO (ADP-ribosylation factor nucleotide-binding site opener)-ARF6 (ADP-ribosylation factor 6) signaling cascade, resulting in destabilization of p120-catenin and internalization of VE-cadherin as a mechanism of deleterious impact of peptidoglycan on the endothelium. Conclusions: We demonstrate for the first time that the defect in gut barrier function and dysbiosis in ACE2 −/y -Akita mice can be favorably impacted by exogenous administration of myeloid angiogenic cells. 

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4. Copper deficiency is an independent risk factor for mortality in patients with advanced liver disease

   https://doi.org/10.1097/HC9.0000000000000076  

   Yu, Lei ; Yousuf, Sarim ; Yousuf, Shahrukh ; Yeh, Jeffrey ; Biggins, Scott W. ; Morishima, Chihiro ; Shyu, Irene ; O’Shea-Stone, Galen ; Eilers, Brian ; Waldum, Annie ; et al ( March 2023 , Hepatology Communications)

   Copper is an essential trace metal serving as a cofactor in innate immunity, metabolism, and iron transport. We hypothesize that copper deficiency may influence survival in patients with cirrhosis through these pathways.

   We performed a retrospective cohort study involving 183 consecutive patients with cirrhosis or portal hypertension. Copper from blood and liver tissues was measured using inductively coupled plasma mass spectrometry. Polar metabolites were measured using nuclear magnetic resonance spectroscopy. Copper deficiency was defined by serum or plasma copper below 80 µg/dL for women or 70 µg/dL for men.

   The prevalence of copper deficiency was 17% (N=31). Copper deficiency was associated with younger age, race, zinc and selenium deficiency, and higher infection rates (42% vs. 20%,p=0.01). Serum copper correlated positively with albumin, ceruloplasmin, hepatic copper, and negatively with IL-1β. Levels of polar metabolites involved in amino acids catabolism, mitochondrial transport of fatty acids, and gut microbial metabolism differed significantly according to copper deficiency status. During a median follow-up of 396 days, mortality was 22.6% in patients with copper deficiency compared with 10.5% in patients without. Liver transplantation rates were similar (32% vs. 30%). Cause-specific competing risk analysis showed that copper deficiency was associated with a significantly higher risk of death before transplantation after adjusting for age, sex, MELD-Na, and Karnofsky score (HR: 3.40, 95% CI, 1.18–9.82,p=0.023).

   In advanced cirrhosis, copper deficiency is relatively common and is associated with an increased infection risk, a distinctive metabolic profile, and an increased risk of death before transplantation.

    

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5. Recombinant human plasma gelsolin reverses increased permeability of the blood–brain barrier induced by the spike protein of the SARS-CoV-2 virus

   https://doi.org/10.1186/s12974-022-02642-4  

   Suprewicz, Łukasz ; Tran, Kiet A. ; Piktel, Ewelina ; Fiedoruk, Krzysztof ; Janmey, Paul A. ; Galie, Peter A. ; Bucki, Robert ( December 2022 , Journal of Neuroinflammation)

   Abstract Background Plasma gelsolin (pGSN) is an important part of the blood actin buffer that prevents negative consequences of possible F-actin deposition in the microcirculation and has various functions during host immune response. Recent reports reveal that severe COVID-19 correlates with reduced levels of pGSN. Therefore, using an in vitro system, we investigated whether pGSN could attenuate increased permeability of the blood–brain barrier (BBB) during its exposure to the portion of the SARS-CoV-2 spike protein containing the receptor binding domain (S1 subunit). Materials and methods Two- and three-dimensional models of the human BBB were constructed using the human cerebral microvascular endothelial cell line hCMEC/D3 and exposed to physiologically relevant shear stress to mimic perfusion in the central nervous system (CNS). Trans-endothelial electrical resistance (TEER) as well as immunostaining and Western blotting of tight junction (TJ) proteins assessed barrier integrity in the presence of the SARS-CoV-2 spike protein and pGSN. The IncuCyte Live Imaging system evaluated the motility of the endothelial cells. Magnetic bead-based ELISA was used to determine cytokine secretion. Additionally, quantitative real-time PCR (qRT-PCR) revealed gene expression of proteins from signaling pathways that are associated with the immune response. Results pGSN reversed S1-induced BBB permeability in both 2D and 3D BBB models in the presence of shear stress. BBB models exposed to pGSN also exhibited attenuated pro-inflammatory signaling pathways (PI3K, AKT, MAPK, NF-κB), reduced cytokine secretion (IL-6, IL-8, TNF-α), and increased expression of proteins that form intercellular TJ (ZO-1, occludin, claudin-5). Conclusion Due to its anti-inflammatory and protective effects on the brain endothelium, pGSN has the potential to be an alternative therapeutic target for patients with severe SARS-CoV-2 infection, especially those suffering neurological complications of COVID-19. 

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