Virus propagation methods generally use transformed cell lines to grow viruses from clinical specimens, which may force viruses to rapidly adapt to cell culture conditions, a process facilitated by high viral mutation rates. Upon propagation in VeroE6 cells, SARS-CoV-2 may mutate or delete the multibasic cleavage site (MBCS) in the spike protein. Previously, we showed that the MBCS facilitates serine protease-mediated entry into human airway cells (Mykytyn et al., 2021). Here, we report that propagating SARS-CoV-2 on the human airway cell line Calu-3 – that expresses serine proteases – prevents cell culture adaptations in the MBCS and directly adjacent to the MBCS (S686G). Similar results were obtained using a human airway organoid-based culture system for SARS-CoV-2 propagation. Thus, in-depth knowledge on the biology of a virus can be used to establish methods to prevent cell culture adaptation.
P681 mutation has little impact on transmissibility in the SARS-CoV-2 UK variant, finds study
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A new preprint, recently released on the bioRxiv * server, explores the impact of a single mutation, the P681H mutation, on the transmissibility of the virus.
The virus depends on its spike protein to engage the target host cell receptor, the angiotensin-converting enzyme 2 (ACE2), and achieve cell entry. The spike has undergone a number of point and grouped mutations.
Towards the end of 2020, the so-called UK variant of SARS-CoV-2 was detected as it led to failure to detect the target spike gene in spike-based diagnostic polymerase chain reaction tests, though the subjects were reported positive by PCR tests detecting other viral protein targets like the nucleocapsid.
Sequencing led to its being termed variant of concern (VOC) B.1.1.7/501Y.V1, and it rapidly spread over the south of England and then to the rest of the UK and the world. Interestingly, this VOC has 23 point mutations in its genome, especially nine in the spike protein.
These include a 69-70 deletion (the cause of S-gene target failure), Y144 del, N501Y, A570D, D614G, P681H, T716I, S982A, and D118H. Seven of these are found only in the UK strain.
The D614G and jN501Y mutations are found in all the three VOCs currently circulating, namely, the UK, South African (B.1.351) and Brazil (B.1.1.28.1 (P.1), variants, respectively. Both these mutations enhance the binding affinity of the spike to the ACE2 receptor.
The virus spike is made up of S1 and S2 subunits, at the interface of which there is a furin cleavage site. This is not found in other Sarbecoviruses.
This interface in SARS-CoV-2 shows the sequence 681-P-R-R-A-R|S-686, and cleavage occurs between the arginine and serine residues, termed the P1|P1’ residues. In this case, the P681H mutation in the UK strain occurs at the P5 cleavage position.
Furin is a serine protease that requires a polybasic motif-containing paired arginine residues, at least R-xx-R (P4-x-x-P1), but prefers that the P2 also be basic. The presence of a furin cleavage site in SARS-CoV-2 makes it more transmissible.
Allogene Therapeutics (ALLO), SpringWorks Therapeutics (SWTX) Report First Patient Dosing in
"We are pleased to have initiated this portion of the UNIVERSAL trial and look forward to investigating ALLO-715 in combination with nirogacestat as part of our comprehensive anti-BCMA strategy aimed at bringing an off-the-shelf cell therapy to patients with relapsed or refractory multiple myeloma," said David Chang, M.D., Ph.D., President, CEO and Co-Founder of Allogene Therapeutics.
Gamma secretase inhibition prevents the cleavage and shedding of BCMA from the surface of multiple myeloma cells. In preclinical models, nirogacestat has been shown to increase the cell surface density of BCMA and reduce levels of soluble BCMA, which may enhance the activity of BCMA-targeted therapies.1 In addition, emerging clinical data suggest that a GSI may increase antitumor efficacy of BCMA-targeted autologous CAR T therapy in patients with relapsed and refractory multiple myeloma.2,3
ALLO-715 utilizes the TALEN® gene-editing technology pioneered and owned by Cellectis. Allogene has an exclusive license to the Cellectis technology for allogeneic products directed at the BCMA target. Allogene holds the global development and commercial rights for this investigational candidate.
About Nirogacestat Nirogacestat is an investigational, oral, selective, small molecule gamma secretase inhibitor in Phase 3 clinical development for desmoid tumors, which are rare and often debilitating and disfiguring soft-tissue tumors. Gamma secretase cleaves multiple transmembrane protein complexes, including Notch, which is believed to play a role in activating pathways that contribute to desmoid tumor growth.
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IL-6: A Pivotal Pleiotropic Inflammatory Cytokine | Lab Equipment | Technology Networks
Early menopausal women could have ovarian function restored - BioNews
Additionally, the treatment may only be viable for pre-menopausal women of a certain age. Dr Wu stated that 'Most older patients will have a very hard time getting pregnant, and even if they do get pregnant, they often will have an abnormal pregnancy that doesn't end well'.
However, these findings provide hope for the approximately 12.2 percent of women who experience early menopause, which is defined as menopause before 45 years of age. Due to many women having children later, the impact of this will only increase.
The abstract for the study was published in the journal Menopause ahead of publication of the paper.
Boron insertion into alkyl ether bonds via zinc/nickel tandem catalysis | Science
Juhl: Want to end sexism? Start with taking a hard look at school dress codes | Montreal Gazette
What do those things have in common? You're more likely to see them on girls, and they're listed as prohibited on the websites of an alarming number of Quebec elementary and high schools.
Here are some more: No rolled-up pants, skirts shorter than knee length, cleavage or "outlandish hair," whatever that means.
When children are told they must not show too much shoulder or have any belly showing, we are teaching them their bodies are a distraction and should be hidden. It sets a tone that they are being or could be sexualized and that the onus is on them to prevent it. A girl shouldn't be told not to have a bra strap showing in case a boy snaps it. Boys should be told to keep their hands off.
These regulations effectively target girls and gender-fluid children and are incredibly subjective. While one school employee might stop to measure a child's clothing, another might not notice, making the entire system unfair. There is a grand imbalance between protecting some students from the "distraction" of a child in spaghetti straps and protecting one student from the disruption of being singled out for wearing a halter top in the summertime. Put the ruler away and don't take it out till math class.
Why are we wasting our time telling girls they can be anything they want if we're simultaneously telling them they can't do it while wearing leggings?
Dress codes aren't about teaching kids about workplace expectations. School already teaches them work happens during the day and that it's normal to bring work home with them. But workplaces are changing, and how we present ourselves in a professional setting is something they are likely to see modelled at home.
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NBS: Petrol, used vehicles major imports to Nigeria in Q4 2020 | TheCable
The National Bureau of Statistics (NBS) says major imports to Nigeria in the fourth quarter of 2020 (Q4) were motor spirits, better known as petrol, used vehicles, motorcycles and antibiotics.
This is contained in NBS recent report, titled: ‘Commodity Price Indices and Terms of Trade (Q4 2020)’.
It said these major imports were from the top major export and import market of Nigeria in Q4 2020, which were India, Spain, the Netherlands, United States and China.
The bureau also said the top major exports from Nigeria to these countries were crude petroleum and natural gas.
According to the report, the all-commodity group import index increased by 0.13 percent in Q4 2020.
It said: "This was driven mainly by an increase in the prices of base metals and articles of base metals (1.0 percent); boilers, machinery and appliances; parts thereof (1.03 percent); and products of the chemical and allied industries (0.75 percent).
"However, the index was negatively affected by animal and vegetable fats and oils and other cleavage products (1.06 percent), prepared foodstuffs; beverages, spirits and vinegar; tobacco (0.66 percent) and plastic, rubber and articles thereof (0.37 percent)".
NBS said this was due to decreases in the prices of wood and articles of wood, wood charcoal and articles (0.49 percent); vehicles, aircraft and parts (0.44 percent); base metals and articles of base metals (0.41 percent).
Lasso Wins Presidential Elections in Ecuador – Escambray
Guillermo Lasso’s presidential victory in Ecuador is described here today as the beginning of a new stage of deepening neoliberalism in that country.
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