Hypercytokinemia is a critically fatal factor in COVID-19. However, underlying pathogenic mechanisms are unknown. Here we show that brinogen and leukotriene-A4 hydrolase (LTA4H), two of the most potent in ammatory contributors, are elevated by 67.7 and astonishing 227.7% in the plasma of patients infected by SARS-CoV-2 and admitted to intensive care unit in comparison with healthy control, respectively. Conversely, transferrin identi ed as a brinogen immobilizer in our recent work and Spink6 are down-regulated by 40.3 and 25.9%, respectively. Furthermore, we identify Spink6 as the rst endogenous inhibitor of LTA4H, a pro-in ammatory enzyme catalyzing nal and rating limited step in biosynthesis of leukotriene-B4 that is an extremely in ammatory mediator and a target to design superior anti-in ammatory drugs. Additionally, virus Spike protein is found to evoke LTA4H and brinogen expression in vivo. Collectively, these ndings identify the imbalance between in ammatory drivers and antagonists, which likely contributes to hypercytokinemia in COVID-19. Spink6 may have superior antiin ammatory function because it speci cally targets epoxide hydrolase of LTA4H to inhibit leukotriene-B4 biosynthesis without effecting LTA4H's aminopeptidase activity.

Background: Since December 2019, acute respiratory disease (ARD) due to 2019 novel coronavirus (2019-nCoV) emerged in Wuhan city and rapidly spread throughout China. We sought to delineate the clinical characteristics of these cases. Methods:We extracted the data on 1,099 patients with laboratory-confirmed 2019-nCoV ARD from 552 hospitals in 31 provinces/provincial municipalities through January 29 th , 2020. Results:The median age was 47.0 years, and 41.90% were females. Only 1.18% of patients had a direct contact with wildlife, whereas 31.30% had been to Wuhan and 71.80% had contacted with people from Wuhan. Fever (87.9%) and cough (67.7%) were the most common symptoms. Diarrhea is uncommon. The median incubation period was 3.0 days (range, 0 to 24.0 days). On admission, ground-glass opacity was the typical radiological finding on chest computed tomography (50.00%).Significantly more severe cases were diagnosed by symptoms plus reverse-transcriptase polymerase-chain-reaction without abnormal radiological findings than non-severe cases (23.87% vs. 5.20%, P<0.001). Lymphopenia was observed in 82.1% of patients. 55 patients (5.00%) were . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10. 1101 /2020 admitted to intensive care unit and 15 (1.36%) succumbed. Severe pneumonia was independently associated with either the admission to intensive care unit, mechanical ventilation, or death in multivariate competing-risk model (sub-distribution hazards ratio, 9.80; 95% confidence interval, 4.06 to 23.67). Conclusions:The 2019-nCoV epidemic spreads rapidly by human-to-human transmission. Normal radiologic findings are present among some patients with 2019-nCoV infection. The disease severity (including oxygen saturation, respiratory rate, blood leukocyte/lymphocyte count and chest X-ray/CT manifestations) predict poor clinical outcomes. Abstract: 249 words; main text: 2677 words : medRxiv preprint Clinical outcomesThe percentages of patients being admitted to the ICU, requiring invasive ventilation and death were 5.00%, 2.18% and 1.36%, respectively. This corresponded to 67 (6.10%) of patients having reached to the composite endpoint ( Table 3).Results of the univariate competing risk model are shown in Table E1 in Supplementary Appendix. Severe pneumonia cases (SDHR, 9.803; 95%CI, 4.06 to 23.67), leukocyte count greater than 4,000/mm 3 (SDHR, 4.01; 95%CI, 1.53 to 10.55) and interstitial abnormality on chest X-ray (SDHR, 4.31; 95%CI, 1.73 to 10.75) were associated with the composite endpoint (Fig. 2, see Table E2 in Supplementary Appendix). Sensitivity analyses are shown in Figure E2 in Supplementary Appendix. DiscussionThis study has shown that fever occurred in only 43.8% of patients with 2019-nCoV ARD on presentation but developed in 87.9% following hospitalization. Severe pneumonia occurred in 15.7% of cases. No radiolo...

The regulation of mitochondrial DNA (mtDNA) expression is crucial for mitochondrial biogenesis during development and differentiation. We have disrupted the mouse gene for mitochondrial transcription factor A (Tfam; formerly known as m-mtTFA) by gene targetting of loxP-sites followed by cre-mediated excision in vivo. Heterozygous knockout mice exhibit reduced mtDNA copy number and respiratory chain deficiency in heart. Homozygous knockout embryos exhibit a severe mtDNA depletion with abolished oxidative phosphorylation. Mutant embryos proceed through implantation and gastrulation, but die prior to embryonic day (E)10.5. Thus, Tfam is the first mammalian protein demonstrated to regulate mtDNA copy number in vivo and is essential for mitochondrial biogenesis and embryonic development.

Membrane-type matrix metalloproteinase I (MT1-MMP)-deficient mice were found to have severe defects in skeletal development and angiogenesis. The craniofacial, axial, and appendicular skeletons were severely affected, leading to a short and domed skull, marked deceleration of postnatal growth, and death by 3 wk of age. Shortening of bones is a consequence of decreased chondrocyte proliferation in the proliferative zone of the growth plates. Defective vascular invasion of cartilage leads to enlargement of hypertrophic zones of growth plates and delayed formation of secondary ossification centers in long bones. In an in vivo corneal angiogenesis assay, null mice did not have angiogenic response to implanted FGF-2, suggesting that the defect in angiogenesis is not restricted to cartilage alone. In tissues from null mice, activation of latent matrix metalloproteinase 2 was deficient, suggesting that MT1-MMP is essential for its activation in vivo. Matrix metalloproteinases (MMPs) are a family of Zndependent enzymes that are essential for extracellular matrix (ECM) turnover in normal and pathological conditions (1, 2). The MMPs are produced as latent proenzymes, and can be inhibited by specific tissue inhibitors of metalloproteinases (TIMPs). The enzymes can be divided into two structurally distinct subgroups, i.e., membrane-type (MT-MMP) and secreted MMPs. The secreted MMPs include interstitial collagenases (MMP-1, -8, and -13), which degrade fibrillar collagens, gelatinases (type IV collagenases, MMP-2 and -9) with high activity against gelatin and type IV collagen, and stromelysins (MMP-3, -10, and -11), which degrade a variety of collagenous and noncollagenous ECM proteins. Although the secreted MMPs have different expression patterns, there seems to be considerable redundancy and overlap between them with respect to function. Thus, mice deficient for MMP-2 (3), MMP-3 (4), MMP-7 (5), MMP-9 (6), MMP-10 (7), or MMP-12 (8) are all viable. Of these, only the MMP-9-deficient mice have been reported to show developmental abnormalities, which involve the growth plate and endochondral ossification (6).To date, five genetically distinct MT-MMPs (Mmp14-17, Mmp 21) have been identified (9-14). These enzymes (except MMP-17, which is glycosylphosphatidylinositol anchored) are singlepass type I membrane proteins with an extracellular N terminus containing the catalytic domain and a short C-terminal cytoplasmic domain. The prototypic MT-MMP, MT1-MMP (also termed MMP-14), was first identified as a cellular receptor and activator for pro-MMP-2 (9), but both MT1-MMP and MT2-MMP (MMP-15) have also been shown to have activity against a variety of ECM proteins, including gelatin, fibronectin, vitronectin, fibrillar collagens, and aggrecan (15, 16). MT1-MMP is widely expressed in cultured cells and tissues during development (17), but its strictly regulated spatial and temporal expression indicates more specific roles for this enzyme (17, 18). A crucial role for MT1-MMP for bone growth was recently demonstrated in MT1-MMP-deficient mi...