Breakthrough infections with the omicron and delta variants of SARS-CoV-2 result in similar re-activation of vaccine-induced immunity

Background: Results showing that sera from double vaccinated individuals have minimal neutralizing activity against Omicron have been interpreted as indicating the need for a third vaccine dose for protection. However, there is little information about early immune responses to Omicron infection in double vaccinated individuals. Methods: We measured inflammatory mediators, antibodies to the SARS-CoV-2 spike and nucleocapsid proteins, and spike peptide-induced release of interferon gamma in whole blood in 51 double-vaccinated individuals infected with Omicron, in 14 infected with Delta, and in 18 healthy controls. The median time points for the first and second samples were 7 and 14 days after symptom onset, respectively. Findings: Infection with Omicron or Delta led to a rapid and similar increase in antibodies to the receptor-binding domain (RBD) of Omicron protein and spike peptide-induced interferon gamma in whole blood. Both the Omicron- and the Delta-infected patients had a mild and transient increase in inflammatory parameters. <p<Interpretation: The results suggest that two vaccine doses are sufficient to mount a rapid and potent immune response upon infection in healthy individuals of with the Omicron variant

Circulating markers of extracellular matrix remodelling in severe COVID-19 patients

Background Abnormal remodelling of the extracellular matrix (ECM) has generally been linked to pulmonary inflammation and fibrosis and may also play a role in the pathogenesis of severe COVID-19. To further elucidate the role of ECM remodelling and excessive fibrogenesis in severe COVID-19, we examined circulating levels of mediators involved in various aspects of these processes in COVID-19 patients. Methods Serial blood samples were obtained from two cohorts of hospitalised COVID-19 patients (n = 414). Circulating levels of ECM remodelling mediators were quantified by enzyme immunoassays in samples collected during hospitalisation and at 3-month follow-up. Samples were related to disease severity (respiratory failure and/or treatment at the intensive care unit), 60-day total mortality and pulmonary pathology after 3-months. We also evaluated the direct effect of inactivated SARS-CoV-2 on the release of the different ECM mediators in relevant cell lines. Results Several of the measured markers were associated with adverse outcomes, notably osteopontin (OPN), S100 calcium-binding protein A12 and YKL-40 were associated with disease severity and mortality. High levels of ECM mediators during hospitalisation were associated with computed tomography thorax pathology after 3-months. Some markers (i.e. growth differential factor 15, galectin 3 and matrix metalloproteinase 9) were released from various relevant cell lines (i.e. macrophages and lung cell lines) in vitro after exposure to inactivated SARS-CoV-2 suggesting a direct link between these mediators and the causal agent of COVID-19. Conclusion Our findings highlight changes to ECM remodelling and particularly a possible role of OPN, S100A12 and YKL-40 in the pathogenesis of severe COVID-19

Radiographic closure time of appendicular growth plates in the Icelandic horse

<p>Abstract</p> <p>Background</p> <p>The Icelandic horse is a pristine breed of horse which has a pure gene pool established more than a thousand years ago, and is approximately the same size as living and extinct wild breeds of horses. This study was performed to compare the length of the skeletal growth period of the "primitive" Icelandic horse relative to that reported for large horse breeds developed over the recent centuries. This information would provide practical guidance to owners and veterinarians as to when the skeleton is mature enough to commence training, and would be potentially interesting to those scientists investigating the pathogenesis of osteochondrosis. Interestingly, osteochondrosis has not been documented in the Icelandic horse.</p> <p>Methods</p> <p>The radiographic closure time of the appendicular growth plates was studied in 64 young Icelandic horses. The results were compared with previously published closure times reported for other, larger horse breeds. The radiographs were also examined for any signs of developmental orthopaedic diseases. In order to describe further the growth pattern of the Icelandic horse, the total serum alkaline phosphatase (ALP) activity was determined and the height at the withers was measured.</p> <p>Results</p> <p>Most of the examined growth plates were fully closed at the age of approximately three years. The horses reached adult height at this age; however ALP activity was still mildly increased over baseline values. The growth plates in the digits were the first to close at 8.1 to 8.5 months of age, and those in the regions of the distal radius (27.4 to 32.0 months), tuber olecrani (31.5 to 32.2 months), and the stifle (27.0 to 40.1 months) were the last to close. No horse was found to have osteochondrosis type lesions in the neighbouring joints of the evaluated growth plates.</p> <p>Conclusion</p> <p>The Icelandic horse appears to have similar radiographic closure times for most of the growth plates of its limbs as reported for large new breeds of horses developed during the past few centuries. It thus appears that different breeding goals and the intensity of breeding have not altered the length of the growth period in horses. Instead, it can be assumed that the pristine and relatively small Icelandic horse has a slower rate of growth. The appendicular skeleton of Icelandic horses has completed its bone growth in length at approximately 3 years of age, and therefore may be able to enter training at this time.</p

Regulation of immune cells in atherosclerosis and its clinical implications: The role of A-to-I editing and interleukin 6 receptor inhibition

Recruitment of immune cells to the developing atherosclerotic plaques is a hallmark in the atherosclerotic process. Immune cell recruitment is also a major factor following acute cardiovascular events in atherosclerosis, such as myocardial infarction and stroke, where there is massive recruitment to the site of injury. To identify treatment targets, there is a need to better understand the immunopathogenic mechanism in the atherosclerotic process and its related clinical implications. In this thesis, we aimed to: (i) assess the impact of Endonuclease V (EndoV), an enzyme known to cleave adenosine-to-inosine (A-to-I) modified RNA, on the immune cell response in atherogenesis and stroke, and (ii) investigate the effect of tocilizumab, an interleukin-6 (IL-6) receptor inhibitor, on the immune cell levels and responses in patients during ST-elevation myocardial infarction (STEMI). In human carotid atherosclerotic plaques, we found higher levels of EndoV and A-to-I editing than in non-atherosclerotic arteries. Absence of EndoV gave a reduced atherosclerotic plaque burden, both in lipid content and lesion size, with reduced monocyte recruitment in mice. In addition, abolishment of EndoV seemed to have protective effects on brain damage in a murine hypoxia-ischemic stroke model. Inhibition of the IL-6 signaling pathway in STEMI patients is beneficial for the patient outcome. This thesis shows that tocilizumab reduced neutrophil and monocyte counts without affecting lymphocyte counts in the circulation following STEMI. Tocilizumab dampened the inflammatory responses in neutrophils with neutrophil degranulation, while monocytes had an upregulation of several cytokine signaling pathways with potential beneficial effects on myocardial remodeling and inflammation. These changes might contribute to the observed improved outcome for the tocilizumab treated patients

Mediator of DNA Damage Checkpoint Protein 1 Facilitates V(D)J Recombination in Cells Lacking DNA Repair Factor XLF

DNA double-strand breaks (DSBs) trigger the Ataxia telangiectasia mutated (ATM)-dependent DNA damage response (DDR), which consists of histone H2AX, MDC1, RNF168, 53BP1, PTIP, RIF1, Rev7, and Shieldin. Early stages of B and T lymphocyte development are dependent on recombination activating gene (RAG)-induced DSBs that form the basis for further V(D)J recombination. Non-homologous end joining (NHEJ) pathway factors recognize, process, and ligate DSBs. Based on numerous loss-of-function studies, DDR factors were thought to be dispensable for the V(D)J recombination. In particular, mice lacking Mediator of DNA Damage Checkpoint Protein 1 (MDC1) possessed nearly wild-type levels of mature B and T lymphocytes in the spleen, thymus, and bone marrow. NHEJ factor XRCC4-like factor (XLF)/Cernunnos is functionally redundant with ATM, histone H2AX, and p53-binding protein 1 (53BP1) during the lymphocyte development in mice. Here, we genetically inactivated MDC1, XLF, or both MDC1 and XLF in murine vAbl pro-B cell lines and, using chromosomally integrated substrates, demonstrated that MDC1 stimulates the V(D)J recombination in cells lacking XLF. Moreover, combined inactivation of MDC1 and XLF in mice resulted in synthetic lethality. Together, these findings suggest that MDC1 and XLF are functionally redundant during the mouse development, in general, and the V(D)J recombination, in particular

The relationship between height at the withers and age of 63 Icelandic horses

<p><b>Copyright information:</b></p><p>Taken from "Radiographic closure time of appendicular growth plates in the Icelandic horse"</p><p>http://www.actavetscand.com/content/49/1/19</p><p>Acta Veterinaria Scandinavica 2007;49(1):19-19.</p><p>Published online 17 Jul 2007</p><p>PMCID:PMC1950711.</p><p></p> The fitted curve is a geometric model

The relationship between alkaline phosphatase (ALP, in U/L) and age (in months) of 64 Icelandic horses with a fitted geometric curve

<p><b>Copyright information:</b></p><p>Taken from "Radiographic closure time of appendicular growth plates in the Icelandic horse"</p><p>http://www.actavetscand.com/content/49/1/19</p><p>Acta Veterinaria Scandinavica 2007;49(1):19-19.</p><p>Published online 17 Jul 2007</p><p>PMCID:PMC1950711.</p><p></p> The dotted line at the ALP-level of 242.5 U/L represents the mean ALP value of the control group of 11 horses, which were 7 to 16 years of age

Radiographic closure time of appendicular growth plates in the Icelandic horse-2

<p><b>Copyright information:</b></p><p>Taken from "Radiographic closure time of appendicular growth plates in the Icelandic horse"</p><p>http://www.actavetscand.com/content/49/1/19</p><p>Acta Veterinaria Scandinavica 2007;49(1):19-19.</p><p>Published online 17 Jul 2007</p><p>PMCID:PMC1950711.</p><p></p>alanx, proximal first phalanx and distal metacarpus. B) Horse aged 50.8 months. Fully closed growth plates at the proximal radius and distal humerus. Note the absence of any radiolucency and diffuse opacity in the region of the previous growth plate

Generation of a Mouse Model Lacking the Non-Homologous End-Joining Factor Mri/Cyren

Classical non-homologous end joining (NHEJ) is a molecular pathway that detects, processes, and ligates DNA double-strand breaks (DSBs) throughout the cell cycle. Mutations in several NHEJ genes result in neurological abnormalities and immunodeficiency both in humans and mice. The NHEJ pathway is required for V(D)J recombination in developing B and T lymphocytes, and for class switch recombination in mature B cells. The Ku heterodimer formed by Ku70 and Ku80 recognizes DSBs and facilitates the recruitment of accessory factors (e.g., DNA-PKcs, Artemis, Paxx and Mri/Cyren) and downstream core factor subunits X-ray repair cross-complementing group 4 (XRCC4), XRCC4-like factor (XLF), and DNA ligase 4 (Lig4). Accessory factors might be dispensable for the process, depending on the genetic background and DNA lesion type. To determine the physiological role of Mri in DNA repair and development, we introduced a frame-shift mutation in the Mri gene in mice. We then analyzed the development of Mri-deficient mice as well as wild type and immunodeficient controls. Mice lacking Mri possessed reduced levels of class switch recombination in B lymphocytes and slow proliferation of neuronal progenitors when compared to wild type littermates. Human cell lines lacking Mri were as sensitive to DSBs as the wild type controls. Overall, we concluded that Mri/Cyren is largely dispensable for DNA repair and mouse development