A novel severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) causing COVID-19 pandemic in humans, recently emerged and has exported in more than 200 countries as a result of rapid ...spread. In this study, we have made an attempt to investigate the SARS-CoV-2 genome reported from 13 different countries, identification of mutations in major coronavirus proteins of these different SARS-CoV-2 genomes and compared with SARS-CoV. These thirteen complete genome sequences of SARS-CoV-2 showed high identity (>99%) to each other, while they shared 82% identity with SARS-CoV. Here, we performed a very systematic mutational analysis of SARS-CoV-2 genomes from different geographical locations, which enabled us to identify numerous unique features of this viral genome. This includes several important country-specific unique mutations in the major proteins of SARS-CoV-2 namely, replicase polyprotein, spike glycoprotein, envelope protein and nucleocapsid protein. Indian strain showed mutation in spike glycoprotein at R408I and in replicase polyprotein at I671T, P2144S and A2798V,. While the spike protein of Spain & South Korea carried F797C and S221W mutation, respectively. Likewise, several important country specific mutations were analyzed. The effect of mutations of these major proteins were also investigated using various in silico approaches. Main protease (Mpro), the therapeutic target protein of SARS with maximum reported inhibitors, was thoroughly investigated and the effect of mutation on the binding affinity and structural dynamics of Mpro was studied. It was found that the R60C mutation in Mpro affects the protein dynamics, thereby, affecting the binding of inhibitor within its active site. The implications of mutation on structural characteristics were determined. The information provided in this manuscript holds great potential in further scientific research towards the design of potential vaccine candidates/small molecular inhibitor against COVID19.
Sepsis, including severe sepsis and septic shock, is a major cause of morbidity and mortality. Albumin and C-reactive protein (CRP) are considered as good diagnostic markers for sepsis. Thus, initial ...CRP and albumin levels were combined to ascertain their value as an independent predictor of 180-day mortality in patients with severe sepsis and septic shock.
We conducted a retrospective cohort study involving 670 patients (>18 years old) who were admitted to the emergency department and who had received a standardized resuscitation algorithm (early goal-directed therapy) for severe sepsis and septic shock, from November 2007 to February 2013, at a tertiary hospital in Seoul, Korea. The outcome measured was 180-day all-cause mortality. A multivariate Cox proportional hazard model was used to identify the independent risk factors for mortality. A receiver operating characteristic (ROC) curve analysis was conducted to compare the predictive accuracy of the CRP/albumin ratio at admission.
The 180-day mortality was 28.35% (190/670). Based on the multivariate Cox proportional hazard analysis, age, the CRP/albumin ratio at admission (adjusted HR 1.06, 95% CI 1.03-1.10, p<0.001), lactate level at admission (adjusted HR 1.10, 95% CI 1.05-1.14, p<0.001), and the Sequential Organ Failure Assessment (SOFA) score at admission (adjusted HR 1.12, 95% CI 1.07-1.18, p<0.001) were independent predictors of 180-day mortality. The area under the curve of CRP alone and the CRP/albumin ratio at admission for 180-day mortality were 0.5620 (P<0.001) and 0.6211 (P<0.001), respectively.
The CRP/albumin ratio was an independent predictor of mortality in patients with severe sepsis or septic shock.
The dentate gyrus of the hippocampus continues generating new neurons throughout life. These neurons originate from radial astrocytes within the subgranular zone (SGZ). Here, we find that Sox1, a ...member of the SoxB1 family of transcription factors, is expressed in a subset of radial astrocytes. Lineage tracing using Sox1-tTA;tetO-Cre;Rosa26 reporter mice shows that the Sox1-expressing cells represent an activated neural stem/progenitor population that gives rise to most if not all newly born granular neurons, as well as a small number of mature hilar astrocytes. Furthermore, a subpopulation of Sox1-marked cells have long-term neurogenic potential, producing new neurons 3 months after inactivation of tetracycline transactivator. Remarkably, after 8 weeks of labeling and a 12-week chase, as much as 44% of all granular neurons in the dentate gyrus were derived from Sox1 lineage-traced adult neural stem/progenitor cells. The fraction of Sox1-positive cells within the radial astrocyte population decreases with age, correlating with a decrease in neurogenesis. However, expression profiling shows that these cells are transcriptionally stable throughout the lifespan of the mouse. These results demonstrate that Sox1 is expressed in an activated stem/progenitor population whose numbers decrease with age while maintaining a stable molecular program.
Innate lymphoid cells (ILCs) are important regulators of early infection at mucosal barriers. ILCs are divided into three groups based on expression profiles, and are activated by cytokines and ...neuropeptides. Yet, it remains unknown if ILCs integrate other signals in providing protection. We show that signaling through herpes virus entry mediator (HVEM), a member of the tumor necrosis factor (TNF) receptor superfamily, in ILC3 is important for host defense against oral infection with the bacterial pathogen Yersinia enterocolitica. HVEM stimulates protective interferon-γ (IFN-γ) secretion from ILCs, and mice with HVEM-deficient ILC3 exhibit reduced IFN-γ production, higher bacterial burdens and increased mortality. In addition, IFN-γ production is critical as adoptive transfer of wild-type but not IFN-γ-deficient ILC3 can restore protection to mice lacking ILCs. We identify the TNF superfamily member, LIGHT, as the ligand inducing HVEM signals in ILCs. Thus HVEM signaling mediated by LIGHT plays a critical role in regulating ILC3-derived IFN-γ production for protection following infection.
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•ILC3 are required for early host defense during Y. enterocolitica infection•IFN-γ from CCR6− ILC3 is essential for protection of mice from Yersinia•HVEM expression by ILC3 is important for IFN-γ production following infection•LIGHT is the ligand for HVEM signaling in regulating ILC3-derived IFN-γ production
Seo et al. find that IFN-γ-producing ILC3 in the small intestine are required for host protection against Yersinia enterocolitica infection. HVEM signaling in ILC3, mediated by the ligand LIGHT, is critical for regulating IFN-γ production for protection following infection.
Trichosporon is an emerging yeast that causes invasive infections in immunocompromised patients experiencing prolonged hospitalisation, indwelling venous catheters and neutropenia.
This retrospective ...observational cohort study analysed invasive Trichosporon infections (ITIs) occurring between January 2005 and December 2022 at three tertiary hospitals and compared the clinical characteristics and prognostic factors of ITIs caused by Trichosporon asahii and non-T. asahii spp. After evaluating 1067 clinical isolates, we identified 46 patients with proven ITIs, defined as cases in which Trichosporon was isolated from blood, cerebrospinal fluid, or sterile tissues.
The patients were separated into T. asahii and non-T. asahii groups containing 25 and 21 patients, respectively, all of which except one were immunocompromised. During this period, both the number of clinical isolates and patients with ITIs (mainly T. asahii) increased; whereas, cases involving non-T. asahii spp. decreased. Compared with the non-T. asahii group, the T. asahii group had more patients with multiple catheters (84% vs. 33%, p = .001) and those receiving renal replacement therapy (48% vs. 14%, p = .005). The all-cause 28-day mortality rate after ITI in the T. asahii group (44%) was significantly higher than in the non-T. asahii group (10%, Log-rank p = .014). The multivariate Cox regression model revealed that T. asahii (reference, non-T. asahii spp.; aHR = 4.3; 95% CI = 1.2-15.2, p = .024) and neutropenia for 5 days or more (aHR = 2.2, 95% CI = 1.5-3.6, p = .035) were independent factors in the 28-day mortality after ITI.
The proven ITIs due to T. asahii produced more unfavourable outcomes compared with ITIs caused by non-T. asahii spp.
Abstract
Kikuchi-Fujimoto disease (KFD) is usually self-limiting, but prolonged systemic symptoms often result in frequent hospital visits, long admission durations, or missed workdays. We ...investigated the role of fluorine-18 fluoro-2-deoxy-D-glucose (
18
F-FDG) positron emission tomography/computed tomography (PET/CT) in assessing KFD severity. We reviewed the records of 31 adult patients with pathologically confirmed KFD who underwent
18
F-FDG PET/CT between November 2007 and April 2018 at a tertiary-care referral hospital. Disease severity was assessed using criteria based on clinical manifestations of advanced KFD. Systemic activated lymph nodes and severity of splenic activation were determined using semi-quantitative and volumetric PET/CT parameters. The median of the mean splenic standardized uptake value (SUV
mean
) was higher in patients with severe KFD than those with mild KFD (2.38 ± 1.18 vs. 1.79 ± 0.99,
p
= 0.058). Patients with severe KFD had more systemically activated volume and glycolytic activity than those with mild KFD (total lesion glycolysis: 473.5 ± 504.4 vs. 201.6 ± 363.5,
p
= 0.024). Multivariate logistic regression showed that myalgia (odds ratio OR 0.035; 95% confidence interval CI 0.001–0.792;
p
= 0.035), total lymph node SUV
max
(cutoff 9.27; OR 24.734; 95% CI 1.323–462.407;
p
= 0.032), and spleen SUV
mean
(cutoff 1.79; OR 37.770; 95% CI 1.769–806.583;
p
= 0.020) were significantly associated with severe KFD.
18
F-FDG PET/CT could be useful in assessing KFD severity.
C-reactive protein (CRP) or procalcitonin (PCT) alone has limitations in the early detection of infection or inflammation due to shortcomings in specificity and varied cut-off values. Recently, ...interleukin (IL)-6 has been assessed, but it is not known to what extent the three values are homogeneous in reality. This retrospective study was conducted with two large datasets (discrepancy set with results within 24 h of admission 7149 patients and follow-up set until 2 weeks of hospital stay 5261 tests) consisting of simultaneous examinations of CRP, PCT, and IL-6 between January 2015 and August 2021. The specific discrepant group (n = 102, 1.4%) with normal CRP (<10 mg/L) and PCT (<0.1 ng/mL) and high IL-6 (≥100 pg/mL) values was extracted from the discrepancy set. Dimensionality reduction and visualization were performed using Python. The three markers were not clearly clustered after t-distributed stochastic neighbor embedding. Pearson’s correlation coefficients between two markers were substantially low (0.23−0.55). Among the high normalized IL-6 levels (≥0.5) (n = 349), 17.8% and 38.7% of CRP and PCT levels were very low (≤0.01). 9.2% and 13.4% of normal CRP (n = 1522) had high PCT (≥0.5 ng/mL) and IL-6 (≥100 pg/mL) values, respectively. Infection and bacteremia among 102 patients occurred in 36 (35.3%) and 9 (8.8%) patients, respectively. In patients with bacteremia, IL-6 was the first to increase, followed by PCT and CRP. Our study revealed that CRP, PCT, and IL-6 levels were considerably discrepant, which could be misinterpreted if only CRP tests are performed.
Lactoferrin (LF) is known to possess anti-inflammatory activity, although its mechanisms of action are not well-understood. The present study asked whether LF affects the commitment of inducible ...regulatory T cells (Tregs). LF substantially promoted Foxp3 expression by mouse activated CD4
T cells, and this activity was further enhanced by TGF-β1. Interestingly, blocking TGF-β with anti-TGF-β Ab completely abolished LF-induced Foxp3 expression. However, no significant amount of soluble TGF-β was released by LF-stimulated T cells, suggesting that membrane TGF-β (mTGF-β) is associated. Subsequently, it was found that LF binds to TGF-β receptor III, which induces reactive oxygen species production and diminishes the expression of mTGF-β-bound latency-associated peptide, leading to the activation of mTGF-β. It was followed by phosphorylation of Smad3 and enhanced Foxp3 expression. These results suggest that LF induces Foxp3
Tregs through TGF-β receptor III/reactive oxygen species-mediated mTGF-β activation, triggering canonical Smad3-dependent signaling. Finally, we found that the suppressive activity of LF-induced Tregs is facilitated mainly by CD39/CD73-induced adenosine generation and that this suppressor activity alleviates inflammatory bowel disease.
Unfortunately, the options for treating multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) infections are extremely limited. Recently, fosfomycin and minocycline were newly introduced ...as a treatment option for MDR A. baumannii infection. Therefore, we investigated the efficacy of the combination of colistin with fosfomycin and minocycline, respectively, as therapeutic options in MDR A. baumannii pneumonia. We examined a carbapenem-resistant A. baumannii isolated from clinical specimens at Severance Hospital, Seoul, Korea. The effect of colistin with fosfomycin, and colistin with minocycline on the bacterial counts in lung tissue was investigated in a mouse model of pneumonia caused by MDR A. baumannii. In vivo, colistin with fosfomycin or minocycline significantly (p < 0.05) reduced the bacterial load in the lungs compared with the controls at 24 and 48 h. In the combination groups, the bacterial loads differed significantly (p < 0.05) from that with the more active antimicrobial alone. Moreover, the combination regimens of colistin with fosfomycin and colistin with minocycline showed bactericidal and synergistic effects compared with the more active antimicrobial alone at 24 and 48 h. This study demonstrated the synergistic effects of combination regimens of colistin with fosfomycin and minocycline, respectively, as therapeutic options in pneumonia caused by MDR A. baumannii.
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