NNadir
NNadir's JournalIt comes close to my family. My sister-in-law has a high fever and is prostrate at home.
She's been tested and awaits results.
It takes several days as I understand.
She works in a hospital as a social worker. Her nineteen year old son is working his way through college as a food service worker in a nursing home with 9 positive cases as of now.
My sister-in-law, my nephew and niece were taking care of her boyfriend who is recovering from rotator cuff surgery.
My niece is 15 years old. It all falls on her.
They are in Western Massachusetts, a seven or eight hour drive from here; in any case, we're not sure we'd know what to do if we could get there..
I've read that only about 30% of those tested actually have Covid. She at least doesn't have the cough, so maybe it's just a flu.
We feel kind of helpless.
Science on Saturday: 50 years of Mars Exploration: What have we learned?
Here's a way to kill some time while "sheltering in place."
I attended this lecture a few weeks back when the world was still open.
The speaker was Professor Luhendra Ojha, who has a great beard, and a great message for anyone who thinks that after we're done screwing up this planet, we can all move to Mars.
While still an undergraduate at the University of Arizona, Dr. Ojha discovered the existence of liquid water on Mars.
The video is available at this link, scroll down: 50 Years of Mars Exploration: What have learned.
Hoarding in France, as reported to me by a German colleague experiencing German hoarding.
I had a conference call with a German colleague this morning - a friend who I like very much. A few weeks ago he asked me how things were in the US and told me that people were hoarding toilet paper. I responded by saying - which was true then - that I'd not seen or heard of that here.
Here we are today.
We had a conference call this morning and after we completed business the conversation turned to toilet paper, the first time in my professional life where this was a topic of personal interaction.
We laughed about it, and then he asked me why we in the US and in Germany couldn't be more like the French.
The French, he reported, are hoarding red wine and condoms.
Every time I've been to France, and I used to go there quite a bit, I've noticed that the French know how to live.
My nephew is working his way through college doing food service in a nursing home.
Four people there have tested positive for Corona Virus.
All they can do is watch him and take his temperature frequently.
Nature Medicine corrective to some myths about the origins of Covid-19.
The paper I'll discuss in this post is this one: The proximal origin of SARS-CoV-2 (Kristian G. Andersen, Andrew Rambaut, W. Ian Lipkin, Edward C. Holmes & Robert F. Garry, Nature Medicine (2020). https://doi.org/10.1038/s41591-020-0820-9)
The scientific publication community has agreed to make all Covid-19 open sourced so you are encouraged to use the link to read it, as it is a useful corrective to racist conspiracy theorists infesting the White House while the nation experiences a severe shortage of leadership which has led to a severe shortage of toilet paper.
Some excerpts from the paper:
SARS-CoV-2 is the seventh coronavirus known to infect humans; SARS-CoV, MERS-CoV and SARS-CoV-2 can cause severe disease, whereas HKU1, NL63, OC43 and 229E are associated with mild symptoms6. Here we review what can be deduced about the origin of SARS-CoV-2 from comparative analysis of genomic data. We offer a perspective on the notable features of the SARS-CoV-2 genome and discuss scenarios by which they could have arisen. Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus...
...The receptor-binding domain (RBD) in the spike protein is the most variable part of the coronavirus genome1,2. Six RBD amino acids have been shown to be critical for binding to ACE2 receptors and for determining the host range of SARS-CoV-like viruses7. With coordinates based on SARS-CoV, they are Y442, L472, N479, D480, T487 and Y4911, which correspond to L455, F486, Q493, S494, N501 and Y505 in SARS-CoV-27
The letter codes, for example, "Y442," here refer to amino acids in the spike protein which binds to human cells and their position in the amino acid sequnce. For those mentioned as being critical for binding the codes (which you can look up in many places) are Y = tyrosine, L = leucine, N = Asparagine, D = Aspartic Acid, T = Threonine, S = serine.
N, asparagine, is very important in molecular recognition, a feature of metabolism that is exploited by viruses to infect cells, since often on the side chain of this amino acid, which terminates in a structure called an "amide," a carbonyl group bound to an amine, one of the hydrogens in the amine is displaced by a link to a special type of (usually) highly branched sugar polymer called a glycan. Glycans bound to asparagine are called "N-Glycans."
The importance of glycans in molecular recognition has long been known - differences glycans are the origins of blood types - however the molecular complexity of glycans has made them very difficult to understand. Since it has been technically easier to release glycans from asparagine in proteins they are, despite their complexity, somewhat easier to study than the other class of glycans, "O-Glycans." Glycans are usually studied using high resolution mass spectrometry, and special tools and software have been developed for their analysis, as long as they can be released from the proteins for study.
O-glycans are attached to amino acids having a hydroxyl function on their side chain. These are serine, threonine and tyrosine, all of which are found in the important binding in the SARS-CoV viruses including Covid-19 listed above. It has been historically very difficult to release O-glycans from the amino acids to which they are bound. The technology for doing so has only become prominent in the last few years, and it is still "at the cutting edge" and not widely used. (This event should stimulate wider use however.)
All of this is important because of the following text in the paper:
...The function of the predicted O-linked glycans is unclear, but they could create a mucin-like domain that shields epitopes or key residues on the SARS-CoV-2 spike protein18. Several viruses utilize mucin-like domains as glycan shields involved immunoevasion18.
Some excerpts on origins:
...As many early cases of COVID-19 were linked to the Huanan market in Wuhan1,2, it is possible that an animal source was present at this location. Given the similarity of SARS-CoV-2 to bat SARS-CoV-like coronaviruses2, it is likely that bats serve as reservoir hosts for its progenitor...
...Malayan pangolins (Manis javanica) illegally imported into Guangdong province contain coronaviruses similar to SARS-CoV-221. Although the RaTG13 bat virus remains the closest to SARS-CoV-2 across the genome1, some pangolin coronaviruses exhibit strong similarity to SARS-CoV-2 in the RBD, including all six key RBD residues21 (Fig. 1)...
...Neither the bat betacoronaviruses nor the pangolin betacoronaviruses sampled thus far have polybasic cleavage sites. Although no animal coronavirus has been identified that is sufficiently similar to have served as the direct progenitor of SARS-CoV-2, the diversity of coronaviruses in bats and other species is massively undersampled...
...It is possible that a progenitor of SARS-CoV-2 jumped into humans, acquiring the genomic features described above through adaptation during undetected human-to-human transmission. Once acquired, these adaptations would enable the pandemic to take off and produce a sufficiently large cluster of cases to trigger the surveillance system that detected it1,2.
Viruses, in particular RNA viruses, have a spectacular ability to evolve because 1) their replication machinery is primitive and prone to error and 2) they can produce a huge number of generations in a single day, 3) they produce a lot of descendants, including many whose mutations are not fatal but on the contrary are better adapted than the original virus was in its host.
Again, the article is open sourced, and you are invited to open it. This is, of course, a scientific publication, and not some nonsense dripping off the tongue of a racist poorly educated, very unstable and intellectually impaired spoiled child as is in the White House.
However, it is wise to admit to ignorance if one has it - and I am personally ignorant of many things - so that one can eliminate one's ignorance by asking questions of someone who knows more than one does one's self. This process is called "education." Education differs greatly from making stupid assertions involving "alternate facts" since you definitely have to be some kind of idiot to invent that oxymoron.
It is possible, as I spend most of my time reading scientific publications, that I may be able to answer some questions associated with this paper if one has opened this and has them. I will be happy to try to help in that case.
I certainly hope our country will remedy the critical shortage in leadership by putting an experienced, competent and decent leader in the White House once again, former Vice President, Joe Biden.
Figure 1:
The caption:
Enjoy your Sunday evening.
Katherine Johnson (1918-2020)
From Nature: Katherine Johnson (1918-2020)
It's open sourced, but here's a few excerpts:
Wider fame for Johnson came in 2016 with the publication of my group biography Hidden Figures, and the release of the film based on it. Asked about the challenges of being black in a segregated workplace, or of having upended the no-women policy in her divisions research meetings, she was most likely to reply: I was just doing my job.
A gifted mathematician who always followed her curiosity, Johnson became a powerful symbol of the often-unheralded contributions that women and minority ethnic groups have made to science, technology, mathematics and computing over the course of the twentieth century. Although her fascination with numbers was obvious from childhood she recalled counting dishes, stars, steps, everything the possibility of deploying her talent as a professional mathematician was anything but.
Born Katherine Coleman in White Sulphur Springs, West Virginia, she and her three siblings were sent 200 kilometres away by their parents to be educated, because there was no local school beyond sixth grade for those who were called coloured students in the pre-civil-rights-era United States. Teachers allowed her to skip several grades in school, and she was just 14 when she entered the historically black West Virginia State College in Institute to study mathematics...
... In 1952 she applied to work at NACAs research outpost in Hampton, Virginia, then called the Langley Aeronautical Laboratory. She began her career in the all-black, all-female West Area Computing Unit, helmed by mathematician Dorothy Vaughan. Vaughan soon sent her to fill an opening in the Flight Research Division, a group that specialized in tests on actual aeroplanes, rather than wind-tunnel simulations. For five years, Johnson was part of an engineering team that investigated phenomena such as wake turbulence, leading to improved safety for military and commercial aviation...
... The Flight Research Division diverted its attention to spacecraft, and by 1958, Johnson had contributed to Notes on Space Technology, the agencys first comprehensive reference document on space flight. By 1959, she had prepared a trajectory analysis for a crewed suborbital flight. The following year, she co-authored the research report Determination of Azimuth Angle at Burnout for Placing a Satellite Over a Selected Earth Position, laying out the equations that would form the basis of that crewed orbital space flight piloted by Glenn.
Her named credit on the report was a first for a woman in her division, and positioned her to play a part in a mission that enabled the United States to draw even with the Soviet Union one of the pivotal moments of the space race. In the days leading up to Glenns flight, the astronaut asked Johnson the girl, as he called her to hand-check the trajectory equations that had been input into the IBM 7090 computer. The flight forever linked a black female mathematician to one of the United States most glorious achievements.
History, mass loss, structure, and dynamic behavior of the Antarctic Ice Sheet
The paper I'll discuss in this post is this one, a review article: History, mass loss, structure, and dynamic behavior of the Antarctic Ice Sheet (Robin E. Bell1, Helene Seroussi, Science, Vol. 367, Issue 6484, pp. 1321-1325)
First, a diversion appropriate to the times:
"An easy way to get to know a town is to look for how one works there, how one loves there, how one dies there. In our small town, these are all done together, an effect of the climate, in an atmosphere that is frenetic and absent..."
(Perhaps our planet is more a smaller town and less a giant world than we know.)
"...One is bored there and one starts to take on habits. Our citizens work a lot, but always to enrich themselves. Above all, their primary interest, as seen in their expressions, is in commerce and in doing business..."
(Well yeah, in our small world...)
"...Naturally, they have a taste for simple joys; they love women, films and swimming in the sea. But quite reasonably they reserve these pleasures for Saturday night, and Sunday; the other days of the week they work to get lots of money. In the evenings, when they leave their offices, they gather at a regular time in cafes, they walk the same streets, or happily set themselves on their balconies. The desires of the young are violent and brief, while those vices of the older ones go little beyond shooting clubs,
friendly banquets, or gambling in high stakes card games."
(Shooting clubs...gambling...high stakes... in our small world.)
Under the circumstances, The Plague has a familiar ring, does it not? In that book, the rats crawl out first, and die, and people wonder to themselves why the authorities don't do something about the rats, while the authorities seek to cover the whole matter up, declaring it unimportant.
The signature of the temporary decline, world wide, in the use of cars will show up in the atmosphere, but the effect will most likely be temporary. At the end of Camus's simultaneously allegorical and observational book, the world goes back to normal when the plague is over, which I assume is going back to being "good for business," but one wonders whether normal is itself a plague.
"Business as usual," as they say time and time again in the IPCC climate reports, report after report after report, a metronome of disaster.
The fact is that we are very much involved in high stakes gambling, with the entire planetary atmosphere, a point made in the paper referenced at the outset. It's a review article discussing papers discussing the Antarctic ice sheets.
From the introduction to the paper:
...Over the past 100 million years or more, Antarctica shifted from a green tree-covered continent (8) to a continent encased in ice as it became tectonically isolated while the global climate cooled (9). The tectonic isolation of the continent began more than 200 million years ago, when it was at the center of the Gondwana supercontinent with a climate similar to that of modern New Zealand. The supercontinent breakup occurred slowly, first with Africa (170 million years ago), then India (145 million years ago), and last, Australia (90 million years ago), shifting away from what today is Antarctica as the Southern Ocean began to form. The final step occurred 34 million years ago as the Drake Passage (10), between South America and the Antarctic Peninsula, and the Tasmanian Gateway, south of Australia, opened. The global oceans thereby were effectively linked. The Antarctic Circumpolar Current, the strongest ocean current on the planet, began to circulate around the continent, and Antarctica was isolated...
A picture:
The caption:
(Top) Global CO2. (Bottom) Ocean surface temperature. Onset of East Antarctic ice occurred 34 million years ago as ocean temperatures and CO2 dropped (53, 54). Development of West Antarctica marine ice sheet at 14 million years ago began with the next major drop in global temperature. Two extreme modes of Antarctic ice have occurred since the onset of glaciation in West Antarctica was first covered with ice: ice extending all the way to the continental shelf during cold periods, such as the Last Glacial Maximum 25,000 years ago, and retreat beyond the present extent, with partial collapse of marine portions of Antarctica during some past warm periods (16).
Later on the authors say:
...East Antarctica is the largest ice sheet on the planet, with thicknesses greater than 4600 m (19). In some areas, the bedrock underlying the ice is above sea level, but extensive portions are below sea level. The top of the ice sheet, Dome A, is at 4200 m over the Gamburtsev Mountains (Figs. 2 and 3), whereas the deepest point, carved by erosion during successive advance and retreat of an ice stream, is located more than 3500 m below sea level under Denman Glacier (19). Beneath the thick ice are large lakesVostok (21), 90°E, and Sovietskaya (22)with up to 1000 m of water (Figs. 2 and 3). These systems have been sealed from the atmosphere for ~34 million years since the onset of Antarctic glaciation. The iconic ice core records of temperature and CO2 come from the deep cores at Vostok [400,000 years (14)], Dome C [800,000 years (23)], and Dome F [720,000 years (24)].
The bold is mine.
Figure 2:
The caption:
(A) East and (B) West Antarctic cross section profiles. (C and D) Location of profiles are shown on (C) surface velocity and (D) subglacial bed topography (17). West Antarctica maximum elevation of 2200 m is nested in the deep Byrd Subglacial Basin, with depths 2500 m below sea level. The East Antarctic Ice Sheet nucleated on the high Gamburtsev Mountains, with the maximum elevation at Dome A reaching 4200 m, covers deep subglacial lakes such as Lake Vostok and has portions that are marine. The portions of the ice sheets with bedrock elevation below sea level are shaded blue.
Figure 3:
The caption:
(Top) Gamburtsev Mountains. (Middle) Lake Vostok. (Bottom) West Antarctica. Location of profiles are approximately along the profiles shown in Fig. 2. Radar layers indicate ice stratigraphy. Ice is deformed as it flows over mountains, but layers remain flat as the ice flows over Lake Vostok, the location of the first deep ice core. The color shading highlights the age of the ice sheets. Basal freeze-on is observed in the Gamburtsev Mountain profile
The evidence for recent changes of Antarctic ice is quantified by three independent measurements primarily derived from satellite and airborne systems: decreasing mass from gravity, dropping surface elevation, and increased surface velocities (Fig. 4).
Changes in ice mass are measured from space with the pair of GRACE (Gravity Recovery and Climate Experiment) satellites, which capture changes in the gravity field experienced by each spacecraft as they orbit Earth together (28). The original pair of satellites resolved monthly changes in Antarctic ice mass from 2002 to 2017 (Fig. 4), and a new pair of satellites, GRACE Follow-On, was launched in 2018 to continue the record of the Earth and Antarctic mass changes. The observed changes must be corrected for modeled changes in motion of the solid Earth to include the crust and the mantle rebound owing to past and ongoing ice mass changes. Determining both the Earth structure and the history of past ice sheet changes are the greatest challenges in separating the observed mass changes into the solid Earth component and the changes in ice mass. The GRACE data (28) show mass loss in West Antarctica, focused in the Amundsen and Bellingshausen Sea sectors, and mass gain in some regions of East Antarctica and along Kamb Ice Stream (Fig. 4).
Lowering of the surface elevation has been measured with altimeters from space and aircraft in the same regions where mass loss is observed. Both radar (Cryosat and European Remote Sensing satellites) and laser altimeters [Ice, Cloud, and land Elevation Satellite 1 (ICESat1) and ICESat2 satellites, Operation IceBridge airborne] are used to measure ice surface elevation. Laser observations are impeded by cloud cover, whereas radar measurements penetrate into the upper portions of the snowpack, introducing some ambiguity. Dropping elevation over the 25-year altimetry period is pronounced in the Amundsen and Bellingshausen Sea sectors of West Antarctica and Wilkes Land in East Antarctica (3). Pine Island, Thwaites, and Smith-Pope-Kohler Glaciers experienced the greatest elevation drop over this period, with changes of up to 9 m/year (Fig. 4). Supporting the observed GRACE mass gain, some margins of East Antarctica are increasing in elevation because of increased snowfall (Fig. 4) (29). Along the Siple Coast, the interior of Kamb Ice Stream has thickened at a rate of ~0.65 m/year over the past 20 years because of its stagnation (Fig. 4) (3). Velocity measurements based on interferometric synthetic aperture radar (SAR) measurements and speckle tracking (4) allow the flow of large regions to be observed with accuracies of several tens of meters per year. The changes in ice sheet velocity are striking in the Peninsula, where a substantial acceleration of glaciers feeding the Larsen ice shelves was observed after their collapse, as well as in the Amundsen Sea sector. In this region, Pine Island Glaciers velocity doubled from the 1990s to the 2010s (Fig. 4), while its grounding line position, accurately estimated by differential interferometric SAR, retreated by more than 30 km (7). The velocity observations are used to calculate the flux of ice discharge into the ocean and, combined with modeled surface accumulation, to estimate the ice mass gain or loss for the different catchment basins. Through an international collaboration, the scientific community has demonstrated the robust agreement between these three different methods and highlighted the ongoing changes of the Antarctic Ice Sheet (5).
Between 1950 and 2000, the average air temperature in the Peninsula increased by 4°C (30). During this warming period, the Larsen A and B ice shelves collapsed in 1995 and 2002, respectively (Fig. 4). The glaciers feeding the Larsen B Ice Shelf sped up after the loss of the backward stress or buttressing (6, 31). Before the Larsen B collapse, the surface of the ice shelf surface was covered by lakes, indicating that warming air temperatures and surface meltwater can destabilize ice shelves, leading to faster flow of Antarctic ice into the global oceans and highlighting the protecting role of ice shelves (32)...
They continue:
These remote sensing observations allow scientists to observe ice sheet changes and decipher the causes of such changes. Both the ocean surrounding Antarctica and the atmosphere, especially in the Peninsula region, have warmed over the 25-year observational record of ice change (33, 34). Antarctica is losing most of its mass through increased ice flow of the outlet glaciers and ice streams. This contrasts with the Greenland Ice Sheet, where half of the loss is due to faster ice flow and half is due to increased melting of the ice sheet surface (35). Surface melt is not yet a major contributor to ice loss in Antarctica, and global climate models suggest that an increase in snowfall in East Antarctica could partially offset the dynamic mass loss (36). Although these changes have been ongoing for the past three decades, more rapid and dramatic mass loss cannot be excluded...
...The concentration of changes in West Antarctica points to the dominant role the warming ocean plays in recently observed change (39, 40). At the base of the outlet glaciers in the Amundsen Sea, the topography beneath the ice either rises inland or drops. A bed topography dropping inland with ice getting thicker is referred to as a reverse slope. This reverse slope for a marine ice sheet has long been at the core of a concept called the marine ice sheet instability (37). As a glacier retreats across a reverse slope, glacier retreat means thicker ice at the grounding line, and therefore, more ice is leaving the ice sheet, while the region that accumulates snow is reduced. The ice sheet is out of balance. The greater flux of ice results in thinning and additional retreat until a region with an inland rising slope is encountered to stabilize the grounding line (38). In addition to this, ice dynamics imbalance on a reverse slope; the thicker ice at the grounding line means more ice is exposed to warming ocean waters (40). A perturbation can nudge an outlet glacier off a stable point into a region with a reverse slope and have consequences for decades (39, 41). An extreme El Nino event in the 1940s appears to have triggered the grounding line retreat still ongoing in the Pine Island catchment in West Antarctica (42)
Another trigger for rapid and sustained increased ice flux is the collapse of buttressing ice shelves. This concept was widely debated in the science community until the acceleration of the ice flow in the glaciers feeding the Larsen B ice shelf after its collapse in 2003 was observed (6, 31). Shortly before the collapse, this ice shelf surface was covered with lakes, leading to the hypothesis that hydrofracture and loading from lakes can damage an ice shelf sufficiently to induce a catastrophic collapse (32). This mechanism has been incorporated into some ice sheet models (41) but assumes that meltwater is stationary and that little water is transported across an ice shelf. It is now clear that surface water can flow from the grounded ice onto ice shelves (43) and coalesce into rivers atop the ice surface that end as waterfalls at their front (44). Hydrology could therefore have a stabilizing impact on ice sheet mass balance as the distribution of meltwater increases...
Figure 4:
The caption:
(A) Spatial ice mass loss (m.w.e.) estimated from GRACE-collected data over the 20022017 period (28). Gray areas show the extension of the floating ice shelves that do not contribute directly to sea level rise. (B) Ice front retreat in the Antarctic Peninsula for the Larsen A, B, and C ice shelves between 1995 and 2017 (6, 31). (C) Change in ice velocity between 2005 and 2017 (meters per year) for glaciers in the Amundsen Sea Sector (4). Black lines represent the ice front and grounding lines. (D) Time series of mass loss (gigatons) and associated uncertainties estimated from GRACE-collected data (28).
...Increasingly, communities around the globe are asking how much the sea level will rise in the coming decades. Although we now know that the answer for each community must incorporate knowledge of local processes, such as isostatic uplift from unloading of ice at the end of the last glacial period and subsidence owing to sediment compaction, changing ocean volume from Antarctic mass loss remains one of the largest contributors to communities unknown future. Gaps in our fundamental knowledge of the bathymetry close to the ice sheet and in regions covered by sea ice and ice shelves, the temperature of the deep water masses, the fate of surface meltwater, and the basal conditions beneath the ice sheets introduce limits into our ability to project the future. It is essential that we refine our projections through expanded observational efforts and improved ice sheet models.
Protecting individual cities with walls and barriers only protects those living behind the protection. An ice sheetbased solution might be more equitable...
The review's conclusion:
Over the 200 years since Antarctica was first spotted, our knowledge of the continent has shifted from the notion of a stagnant piece of ice to a constantly evolving continent interacting with the ocean around, the atmosphere above, and the solid Earth under it and affected by human activities. Advancing our knowledge of the basic history and fundamental processes that control the ice sheet evolution is crucial to future generations...
My feeling is that we don't care all that much for future generations any more than to despise them.
The plague will end, and "Naturally, [we will] have a taste for simple joys; they love women, films and swimming in the sea. But quite reasonably they reserve these pleasures for Saturday night, and Sunday; the other days of the week they work to get lots of money. In the evenings, when they leave their offices, they gather at a regular time in cafes, they walk the same streets, or happily set themselves on their balconies. The desires of the young are violent and brief, while those vices of the older ones go little beyond shooting clubs, friendly banquets, or gambling in high stakes card games."
Business as usual, but our problems will still be here.
This issue of Science is the Antarctic issue.
Times are hard, but I hope you will still make the best of the weekend.
So my son sends me a text...
"Me and my brother are going for a walk..."
I send back a text saying, "I'm sure you mean, 'My brother and I...'" and sign it "Dad, the Grammar Nazi."
He responds, "Where's the grammar Eisenhower when you need him?"
Good point.
Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide.
The paper I'll reference is this one: Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved ?-ketoamide inhibitors (Linlin Zhang1,2, Daizong Lin1,3, Xinyuanyuan Sun1,2, Ute Curth4, Christian Drosten5, Lucie Sauerhering6,7, Stephan Becker6,7, Katharina Rox8,9, Rolf Hilgenfeld, Science 20 Mar 2020: eabb3405)
The world's scientific publishing community, in recognition of the crisis affecting all humanity, has made all Covid-19 related papers open sourced.
Here's an excerpt any way, and a few comments on the picture below:
One of the best characterized drug targets among coronaviruses is the main protease (Mpro, also called 3CLpro) (4). Along with the papain-like protease(s), this enzyme is essential for processing the polyproteins that are translated from the viral RNA (5). The Mpro operates at no less than 11 cleavage sites on the large polyprotein 1ab (replicase 1ab, ~790 kDa); the recognition sequence at most sites is Leu-Gln? Ser,Ala,Gly) (? marks the cleavage site). Inhibiting the activity of this enzyme would block viral replication. Since no human proteases with a similar cleavage specificity are known, inhibitors are unlikely to be toxic.
Previously, we designed and synthesized peptidomimetic ?-ketoamides as broad-spectrum inhibitors of the main proteases of betacoronaviruses and alphacoronaviruses as well as the 3C proteases of enteroviruses (6). The best of these compounds (11r; Fig. 1) showed an EC50 of 400 picomolar against MERS-CoV in Huh7 cells as well as low micromolar EC50 values against SARS-CoV and a whole range of enteroviruses in various cell lines, although the antiviral activity seemed to depend to a great extent on the cell type used in the experiments (6). In order to improve the half-life of the compound in plasma, we modified 11r by hiding the P3 - P2 amide bond within a pyridone ring (Fig. 1, green circles), in the expectation that this might prevent cellular proteases from accessing this bond and cleaving it. Further, to increase the solubility of the compound in plasma and to reduce its binding to plasma proteins, we replaced the hydrophobic cinnamoyl moiety by the somewhat less hydrophobic Boc group (Fig. 1, red circles) to give 13a (see scheme S1 for synthesis).
Figure 1:
The caption:
These test compounds are in a class known as "peptidomimetics." That is they are designed to approximate the shape of peptides without actually being peptides. (Formally all of them have one peptide bond, but none of the structures represent a codon natural amino acid. In two of the structures a precursor has been made by hydrogenating the natural amino acid phenylalanine.
In general, an antiviral drug must be designed to cross a membrane, and thus it is necessary to avoid structures that can ionize wherever possible. It must also possess some "lipophilicity" - a liking for lipids, the main constituents of fats. (An oral drug may have to cross more than one or more membranes.) For many peptide drugs this is done by cyclization; here it is done by chemical modification.)
With the due lack of respect due the orange moron, there is a lot between here and a viable drug. (The multistep chemical sequence can be found in the supplementary material: Doing these sorts of thing on an industrial, rather than a lab, scale is a huge chemical engineering challenge in itself.)
But the good news, in viral drug design, we have tools we have never had before and our pharmaceutical scientists, learning from the days of AIDS, are a damned powerful rapid response team.
Why did nearly a million king penguins vanish without a trace?
A news item from Science, I think it's open sourced: Why did nearly a million king penguins vanish without a trace?
In case it's not open sourced, some excerpts:
...King penguins should be relatively easy to study. Unlike their ice-bound cousins, such as emperor penguins, king penguins live on islands dotting the subantarctic region. That means they can be reliably and repeatedly counted in satellite images over time, and scientists can camp alongside their breeding colonies to observe them. (Other ice-dependent species, like emperor penguins, are more peripatetic.) During the lengthy breeding season, the parents trade off tasks, with one incubating eggs or rearing fluffy brown chicks while the other heads to sea to catch fish and other sea creatures. These foraging round-trips can cover 500 kilometers or more, electronic tags attached to the birds have shown.
...REAMS OF DATA remain to be digested. But the researchers have already ruled out some possible explanations for the massive penguin decline. Land predators, for instance, dont seem to have played a role. Examinations of chicks and adult penguins, as well as excavated bones, revealed no signs of cat or mouse bites, and the teams cameras recorded no attacks. (Rabbits, seen on previous expeditions, were curiously missing.)Nor, it seems, had the penguins simply moved somewhere nearby. A second smaller colony on the island, a natural site for relocation, had just an estimated 17,000 pairs, not enough to explain the massive drop-off in the main group. And Bost says theres no obvious indicationin satellite images, for instancethat the colony relocated to some other island.
That leaves one main explanation, Bost says: If the penguins are not here, they died. But what killed them?
Not disease, apparently. The team is waiting on final blood analyses, but they saw few ailing birds or fresh corpses. We thought wed see carrion, individuals in bad condition, Chaigne says. But the birds looked healthy...
...Evidence that a warming ocean could threaten the penguins comes from a 2015 study that Bost and his colleagues did at a smaller king penguin colony, on Possession Island, some 160 kilometers west of Île aux Cochons... The study, published in Nature Communications, analyzed 124 foraging routes taken by 120 tagged birds over 16 years. It found that in years when the polar front moved south, the penguins had to travel hundreds of kilometers farther. During these very unfavorable environmental conditions, the researchers wrote, the penguin breeding population experienced a 34% decline.
Building on that study, a 2018 paper published in Nature Climate Change forecast that warming seas and other environmental changes could cut king penguin numbers by half by the end of the century.
Whether that scenario explains the Île aux Cochons crash may never be entirely clear...
Profile Information
Gender: MaleCurrent location: New Jersey
Member since: 2002
Number of posts: 33,582