SARS-CoV-2 exploits angiotensin-converting enzyme 2 (ACE2) as a receptor to invade cells. It has been reported that the UK and South African strains may have higher transmission capabilities, ...eventually in part due to amino acid substitutions on the SARS-CoV-2 Spike protein. The pathogenicity seems modified but is still under investigation. Here we used the experimental structure of the Spike RBD domain co-crystallized with part of the ACE2 receptor, several in silico methods and numerous experimental data reported recently to analyze the possible impacts of three amino acid replacements (Spike K417N, E484K, N501Y) with regard to ACE2 binding. We found that the N501Y replacement in this region of the interface (present in both the UK and South African strains) should be favorable for the interaction with ACE2, while the K417N and E484K substitutions (South African strain) would seem neutral or even unfavorable. It is unclear if the N501Y substitution in the South African strain could counterbalance the K417N and E484K Spike replacements with regard to ACE2 binding. Our finding suggests that the UK strain should have higher affinity toward ACE2 and therefore likely increased transmissibility and possibly pathogenicity. If indeed the South African strain has a high transmission level, this could be due to the N501Y replacement and/or to substitutions in regions located outside the direct Spike-ACE2 interface but not so much to the K417N and E484K replacements. Yet, it should be noted that amino acid changes at Spike position 484 can lead to viral escape from neutralizing antibodies. Further, these amino acid substitutions do not seem to induce major structural changes in this region of the Spike protein. This structure-function study allows us to rationalize some observations made for the UK strain but raises questions for the South African strain.
The Delta SARS-CoV-2 variant has a higher viral load than the Beta and the historical variants in nasopharyngeal samples from newly diagnosed COVID-19 patients
(
) has been implicated in inflammatory acne where highly mutated Christie-Atkins-Munch-Petersen factor (CAMP)1 displays strong toll like receptor (TLR)-2 binding activity. Using specific antibodies, ...we showed that CAMP1 production was independent of
phylotype and involved in the induction of inflammation. We confirmed that TLR-2 bound both mutated and non-mutated recombinant CAMP1, and peptide array analysis showed that seven peptides (A14, A15, B1, B2, B3, C1 and C3) were involved in TLR-2 binding, located on the same side of the three-dimensional structure of CAMP1. Both mutated and non-mutated recombinant CAMP1 proteins induced the production of C-X-C motif chemokine ligand interleukin (CXCL)8/(IL)-8 in vitro in keratinocytes and that of granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor (TNF)-α, IL-1β and IL-10 in ex vivo human skin explants. Only A14, B1 and B2 inhibited the production of CXCL8/IL-8 by keratinocytes and that of (GM-CSF), TNF-α, IL-1β and IL-10 in human skin explants stimulated with rCAMP1 and
. Following pretreatment with B2, RNA sequencing on skin explants identified the 10 genes displaying the strongest differential expression as
,
,
,
,
,
,
, chemokine ligand (
)
,
and colony stimulating factor (
)
. We, thus, identified a new CAMP1-derived peptide as a TLR-2 modulator likely to be a good candidate for clinical evaluation.
Variational steepest descent approximation schemes for the modified Patlak-Keller-Segel equation with a logarithmic interaction kernel in any dimension are considered. We prove the convergence of the ...suitably interpolated in time implicit Euler scheme, defined in terms of the Euclidean Wasserstein distance, associated with this equation for subcritical masses. As a consequence, we recover the recent result about the global in time existence of weak solutions to the modified Patlak-Keller-Segel equation for the logarithmic interaction kernel in any dimension in the subcritical case. Moreover, we show how this method performs numerically in dimension one. In this particular case, this numerical scheme corresponds to a standard implicit Euler method for the pseudoinverse of the cumulative distribution function. We demonstrate its capabilities to reproduce the blow-up of solutions for supercritical masses easily without the need of mesh-refinement.
When patterns are set during embryogenesis, it is expected that they are straightly established rather than subsequently modified. The patterning of the three mouse molars is, however, far from ...straight, likely as a result of mouse evolutionary history. The first-formed tooth signaling centers, called MS and R2, disappear before driving tooth formation and are thought to be vestiges of the premolars found in mouse ancestors. Moreover, the mature signaling center of the first molar (M1) is formed from the fusion of two signaling centers (R2 and early M1). Here, we report that broad activation of Edar expression precedes its spatial restriction to tooth signaling centers. This reveals a hidden two-step patterning process for tooth signaling centers, which was modeled with a single activator-inhibitor pair subject to reaction-diffusion (RD). The study of Edar expression also unveiled successive phases of signaling center formation, erasing, recovering, and fusion. Our model, in which R2 signaling center is not intrinsically defective but erased by the broad activation preceding M1 signaling center formation, predicted the surprising rescue of R2 in Edar mutant mice, where activation is reduced. The importance of this R2-M1 interaction was confirmed by ex vivo cultures showing that R2 is capable of forming a tooth. Finally, by introducing chemotaxis as a secondary process to RD, we recapitulated in silico different conditions in which R2 and M1 centers fuse or not. In conclusion, pattern formation in the mouse molar field relies on basic mechanisms whose dynamics produce embryonic patterns that are plastic objects rather than fixed end points.
•The extent of co-infections of SARS-CoV-2 with other respiratory viruses remains unknown.•Lower respiratory tract samples improved the diagnosis of non-SARS-CoV-2 respiratory infections.•7% of ...SARS-CoV-2-positive patients were co-infected with other respiratory viruses.•The detection of other respiratory viruses could not rule out SARS-CoV-2 co-infection.•Lower respiratory tract samples increased the accuracy of diagnosis of COVID-19.
This study was performed during the early outbreak period of coronavirus disease 2019 (COVID-19) and the seasonal epidemics of other respiratory viral infections, in order to describe the extent of co-infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with other respiratory viruses. It also compared the diagnostic performances of upper respiratory tract (URT) and lower respiratory tract (LRT) samples for SARS-CoV-2 infection.
From 25 January to 29 March 2020, all URT and LRT samples collected from patients with suspected COVID-19 received in the virology laboratory of Pitié-Salpêtrière University Hospital (Paris, France) were simultaneously tested for SARS-CoV-2 and other respiratory viruses.
A total of 1423 consecutive patients were tested: 677 (47.6%) males, 746 (52.4%) females, median age 50 (range, 1–103) years. Twenty-one (1.5%) patients were positive for both SARS-CoV-2 and other respiratory viruses. The detection rate of SARS-CoV-2 was significantly higher in LRT than in URT (53.6% vs. 13.4%; p<0.0001). The analysis of paired samples from 117 (8.2%) patients showed that SARS-CoV-2 load was lower in URT than in LRT samples in 65% of cases.
The detection of other respiratory viruses in patients during this epidemic period could not rule out SARS-CoV-2 co-infection. Furthermore, LRT samples increased the accuracy of diagnosis of COVID-19.
This article is devoted to the analysis of the classical Keller-Segel system over ℝ
d
, d ≥ 3. We describe as much as possible the dynamics of the system characterized by various criteria, both in ...the parabolic-elliptic case and in the fully parabolic case. The main results in the parabolic-elliptic case are: local existence without smallness assumption on the initial density and a quantified blow-up rate, global existence under an improved smallness condition and comparison of blow-up criteria. A new concentration phenomenon for the fully parabolic case is also given.
We report the discovery of a new orthobunyavirus, Cristoli virus, by means of shotgun metagenomics. The virus was identified in an immunodepressed patient with fatal encephalitis. Full-length genome ...sequencing revealed high-level expression of a virulence factor, possibly explaining the severity of the infection. The patient's recent history suggests circulation in France.
Resistance to the integrase strand transfer inhibitors raltegravir and elvitegravir is often due to well-identified mutations in the integrase gene. However, the situation is less clear for patients ...who fail dolutegravir treatment. Furthermore, most
experiments to select resistance to dolutegravir have resulted in few mutations of the integrase gene. We performed an
dolutegravir resistance selection experiment by using a breakthrough method. First, MT4 cells were infected with human immunodeficiency virus type 1 (HIV-1) Lai. After integration into the host cell genome, cells were washed to remove unbound virus and 500 nM dolutegravir was added to the cell medium. This high concentration of the drug was maintained throughout selection. At day 80, we detected a virus highly resistant to dolutegravir, raltegravir, and elvitegravir that remained susceptible to zidovudine. Sequencing of the virus showed no mutations in the integrase gene but highlighted the emergence of five mutations, all located in the
region, of which four were clustered in the 3' polypurine tract (PPT). Mutations selected
by dolutegravir, located outside the integrase gene, can confer a high level of resistance to all integrase inhibitors. Thus, HIV-1 can use an alternative mechanism to develop resistance to integrase inhibitors by selecting mutations in the 3' PPT region. Further studies are required to determine to what extent these mutations may explain virological failure during integrase inhibitor therapy.
Integrase strand transfer inhibitors (INSTIs) are increasingly used both as first-line drugs and in rescue therapy because of their low toxicity and high efficacy in both treatment-naive and treatment-experienced patients. Until now, resistance mutations selected by INSTI exposure have either been described in patients or selected
and involve the integrase gene. Most mutations selected by raltegravir, elvitegravir, or dolutegravir exposure are located inside the catalytic site of the integrase gene, but mutations outside the catalytic site of the integrase gene have also been selected with dolutegravir. Following
selection with dolutegravir, we report, for the first time, a virus with selected mutations outside the HIV-1 integrase gene that confer resistance to all integrase inhibitors currently used to treat patients, such as raltegravir, elvitegravir, and dolutegravir. Our observation may explain why some viruses responsible for virological failure in patients treated with dolutegravir did not show mutations in the integrase gene.
Abstract Background Propionibacterium acnes ( P. acnes ) has been implicated in the inflammatory phase of acne vulgaris. It has been shown to activate interleukin-8 (IL-8) secretion by interacting ...with Toll-like receptor 2 (TLR-2) on the surface of keratinocytes. Nicotinamide has been shown to be an effective treatment for skin inflammation in various conditions, including acne vulgaris. Objective To investigate the molecular mechanisms underlying the anti-inflammatory properties of nicotinamide in keratinocytes stimulated by P. acnes. Methods HaCaT cells and primary keratinocyte cell lines were stimulated by P. acnes in the presence of nicotinamide. IL-8 production was monitored by ELISA on the cell culture supernatant and by qRT-PCR on total RNA extract. A luciferase reporter system assay was used to assess nicotinamide activity with the IL-8 promoter in transfected keratinocytes. We used western blotting to analyze the effect of nicotinamide on activation of the NF-κB and MAPK pathways. Results Nicotinamide significantly decreased IL-8 production in a dose-dependent manner, decreasing both mRNA and protein levels for this chemokine in immortalized HaCaT cells and primary keratinocytes. P. acnes -induced IL-8 promoter activation seemed to be downregulated by nicotinamide, which inhibited IκB degradation and the phosphorylation of ERK and JNK MAP kinases. Conclusion Our results indicate that nicotinamide inhibits IL-8 production through the NF-κB and MAPK pathways in an in vitro keratinocytes/ P. acnes model of inflammation. Keratinocytes involved in the innate immune response may be a suitable target for treatment during the early phase of inflammation.
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