NNadir

NNadir's Journal

January 14, 2024

Discovery of Enzymes to Catalyze Pericyclic Reactions.

A couple of days ago I attended a lecture by K.N. Houk which inspired me to look into a subject about which I have not thought for a long time, my days in synthetic chemistry being far behind me; somehow I drifted elsewhere. As a result, partly out of nostalgia, partly out of curiosity, a partly because of my disappointed realization that I could have been, should have been, more, I was inspired to check out this paper pointing to a topic about which I'd only mused casually, this many years ago: Masao Ohashi, Fang Liu, Yang Hai, Mengbin Chen, Man-cheng Tang, Zhongyue Yang, Michio Sato, Kenji Watanabe, K. N. Houk & Yi Tang, SAM-dependent enzyme-catalysed pericyclic reactions in natural product biosynthesis. Nature 549, 502–506 (2017).

The question is that while pericyclic reactions - reactions that feature, in the thermal case, 2n + 2 electrons moving in a quasi aromatic transition state (i.e., 2, 6, 10, 12...electrons, most commonly 6) in such a way that the stereochemistry is tightly controlled - are frequently used in laboratory syntheses of complex natural products, in nature, these types of reactions are not particularly well characterized in biological systems. I sort of mused about this in a half serious way; it never occurred to me to seriously look into the matter. In fact, I never even thought as to whether biological pericyclic reactions were common or even known.

It turns out they are known.

The abstract of the paper points, quite well, to the question I never more than casually asked myself:

Pericyclic reactions—which proceed in a concerted fashion through a cyclic transition state—are among the most powerful synthetic transformations used to make multiple regioselective and stereoselective carbon–carbon bonds1. They have been widely applied to the synthesis of biologically active complex natural products containing contiguous stereogenic carbon centres2,3,4,5,6. Despite the prominence of pericyclic reactions in total synthesis, only three naturally existing enzymatic examples (the intramolecular Diels–Alder reaction7, and the Cope8 and the Claisen rearrangements9) have been characterized. Here we report a versatile S-adenosyl-L-methionine (SAM)-dependent enzyme, LepI, that can catalyse stereoselective dehydration followed by three pericyclic transformations: intramolecular Diels–Alder and hetero-Diels–Alder reactions via a single ambimodal transition state, and a retro-Claisen rearrangement. Together, these transformations lead to the formation of the dihydropyran core of the fungal natural product, leporin10.

From the paper's introduction:

Naturally existing enzymatic pericyclic reactions are rare12,13,14. Indeed, only a handful of enzymes that can catalyse these reactions have been characterized over the past five decades (Fig. 1a)7,8,9,12,13,14, even though pericyclic reactions have been proposed as key transformations in the biosynthesis of many polycyclic natural products12,15,16. We sought an enzyme-catalysed inverse electron demand hetero-Diels–Alder (HDA) reaction17 that constructs heterocycles in natural products (Fig. 1a). The HDA reaction has been proposed as a key biotransformation yielding dihydropyran cores, which are prevalent structural features in natural products that include the cytotoxic leporin B (1) from Aspergillus species (Fig. 1b)10,15,16,18. The biomimetic synthesis of the dihydropyran core in leporin uses the E/Z geometric mixture of the unstable ?-quinone methide19 intermediate 5 generated from the dehydration of alcohol 4. The uncatalysed process gives a mixture of the minor desired HDA adduct leporin C (2) and major other regio- and stereoisomeric intramolecular Diels–Alder (IMDA) and HDA adducts (Fig. 1c)20. It was therefore proposed that an enzyme must be encoded in the biosynthetic pathway of leporins to catalyse the HDA cycloaddition in a stereoselective fashion and to suppress the IMDA reaction to afford the dihydropyran core in 2 (Fig. 1c)14.

A figure:

The caption:

a, Examples (ex) of pericyclic reactions and enzymes that can catalyse pericyclic reactions. Known and unknown enzymatic reactions are shown in black and grey arrows, respectively. EDG, electron donating group; EWG, electron withdrawing group; HOMO, highest occupied molecular orbital; LUMO, lowest unoccupied molecular orbital; b, The structures of natural products containing dihydropyran, which would be biosynthesized by HDA reaction. Variecolortide A is naturally racemic; the relative stereochemistry of epipyridone and leporin B are shown. c, The putative leporin biosynthetic gene cluster in A. flavus and the assignment of encoded genes and biosynthetic pathway of leporins. PKS–NRPS, polyketide synthase–non-ribosomal peptide synthetase; TF, transcription factor; MCT, monocarboxylate transporter; SDR, short-chain dehydrogenase/reductase; ER, enoylreductase; OMT, O-methyltransferase. The structures show the relative stereochemistry. d, Analysis of metabolites from the transformants of A. nidulans by HPLC. The peak at 12?min corresponds to the tetramic acid product that is biosynthesized by LepA (PKS–NRPS) and LepG (ER).

Some more text:

The biosynthetic gene cluster of leporin B (1) in Aspergillus flavus has been reported and genetically verified (Fig. 1c)10. However, no clear enzyme candidate that can catalyse the pericyclic reaction was apparent in the cluster. To identify the enzyme responsible for this biotransformation, we heterologously reconstituted the leporin B (1) biosynthetic pathway in Aspergillus nidulans (Fig. 1c, d)21. As shown in Fig. 1d, coexpression of the polyketide synthase?non-ribosomal peptide synthetase (PKS?NRPS) LepA, the partnering enoyl reductase (ER) LepG, and the ring-expansion P45022 LepH led to the biosynthesis of the ketone 3. Additional coexpression with the short chain dehydrogenase/reductase (SDR) LepF, which is hypothesized to reduce 3 to the alcohol 4, led to a mixture of HDA products including the desired dihydropyran 2 as a minor product and the diastereomer 9, as well as the spirocyclic IMDA products 6–8 (Fig. 1c, d). Among these products, 2 and 6 are proposed to be derived from the quinone methide (E)-5, while 7–9 are from (Z)-5 (Fig. 1c). These results are consistent with biomimetic synthetic observations, and indicate that in order to biosynthesize 2 as the desired pericyclic reaction product, enzymatic stereocontrol of dehydration of 4 to (E)-5, as well as control of the subsequent pericyclic reaction, are required.

The only remaining annotated enzyme in the gene cluster is LepI, which is predicted to be an O-methyltransferase (OMT) with a well-conserved SAM binding site even though no O-methylation step is required for leporin B (1) biosynthesis. When lepI was introduced into the A. nidulans strain that produced the various pericyclic products derived from reduction of 3, we were surprised to observe the exclusive production of 2 without any other products (Fig. 1d). Further addition of the P450 lepD yielded the final product 1, thereby completing heterologous pathway reconstitution (Fig. 1c, d). To first verify the function of SDR LepF, recombinant protein was expressed from Saccharomyces cerevisiae and assayed in the presence of 3 and NADPH, which yielded a single product 4 corresponding to the reduced compound (Extended Data Fig. 1). To obtain sufficient 4 for assay with LepI, we reduced 3 with NaBH4 which gave both 4 and diastereomer 4? in a ratio of approximately 1:1 (Extended Data Figs 1, 2). Each isomer was isolated and immediately added to LepI expressed and purified from Escherichia coli. Both 4 and 4? dehydrated spontaneously in the absence of LepI and afforded a mixture of IMDA (6–8) and HDA (2 and 9) products, with 2 being a very minor product (Fig. 2a). However, when LepI was added to 4, complete conversion to 2 was accomplished in the absence of any added cofactors (Fig. 2a). In contrast, addition of LepI to 4? had only a small effect on product profile. The collective in vivo and in vitro data therefore point to LepI being solely responsible for formation of 2 starting from 4, which requires stereoselective dehydration to yield (E)-5 and subsequent HDA reaction to 2...

"SAM" is a nucleoside, adenosine, that has alkylated a methionine, "S-adenosyl methionine," a sulfonium ion. It is a moiety that is often found in biosynthetic methylations. Methionine itself is one of the 20 coded amino acids.

This paper is highly cited. A description of the mechanism and the nature of the SAM cofactor's role in the mechanism can be found here: Min Chang, Yu Zhou, Hao Wang, Zihe Liu, Yi Zhang, Yue Feng, Crystal structure of the multifunctional SAM-dependent enzyme LepI provides insights into its catalytic mechanism, Biochemical and Biophysical Research Communications, Volume 515, Issue 2, 2019, Pages 255-260, and probably elsewhere.

This is a little esoteric, but it made me think a lot outside of the little box in which I live and to reflect a bit on my life and despite much happiness, some regrets.

January 14, 2024

The IEAE Praises Kenya's Progress in Building Nuclear Infrastructure

IAEA sees 'significant progress' in Kenya's research reactor preparations

Subtitle:

Kenya is pursuing the development of the country's first research reactor, a stepping stone towards a future nuclear power programme, and invited an International Atomic Energy Agency (IAEA) mission to review the development of its national nuclear infrastructure.

A brief excerpt of the brief article:

Andrey Sitnikov, who led the Integrated Nuclear Infrastructure Review for Research Reactors Mission and is the technical lead of the IAEA Research Reactor Section, said: "Kenya has demonstrated a sustained and very professional approach to the development of its research reactor programme. We noted that before making the final decision, Kenya did a great job of developing and preparing laws and regulatory documents, actively involving interested stakeholders in the programme, and developing human resources of both the future operator and the regulator."

The eight-member mission team, from India and the USA and six IAEA staff members, conducted the nine-day mission in December, reviewing the status of the country's nuclear infrastructure development against the Phase 1 criteria from the IAEA's Milestones Approach, which provides guidance for the preparation of a research reactor project on 19 issues ranging from nuclear safety and waste managements to financing.

The mission team provide recommendations and suggestions for the further development of nuclear infrastructure. Kenya plans to commission its first research reactor in the early 2030s. In September 2023 the Nuclear Power and Energy Agency (NuPEA) announced a potential project for a 1000 MWe nuclear plant located in either Kilifi or Kwale...

Have a nice day.

January 14, 2024

At the Mauna Loa CO2 Observatory, 2024 Starts With a Fairly Disgusting Bang.

As I've indicated repeatedly in my DU writings, somewhat obsessively I keep a spreadsheet of the weekly data at the Mauna Loa Carbon Dioxide Observatory, which I use to do calculations to record the dying of our atmosphere, a triumph of fear, dogma and ignorance that did not have to be, but nonetheless is, a fact.

Facts matter.

When writing these depressing repeating posts about new records being set, reminiscent, over the years, to the ticking of a clock at a deathwatch, I often repeat some of the language from a previous post on this awful series, as I am doing here with some modifications. It saves time.

As I've been reporting over the years in various contexts, the concentrations of the dangerous fossil fuel waste carbon dioxide which is killing the planet fluctuate sinusoidally over the year, with the rough sine wave superimposed on a quadratic axis:

Monthly Average Mauna Loa CO2

January 1-6 were part of week 52, beginning on 12/31/2003. Here's the data for the first full week on 2024, Week 1:

Week beginning on January 07, 2024: 423.47 ppm
Weekly value from 1 year ago: 419.54 ppm
Weekly value from 10 years ago: 398.26 ppm
Last updated: January 13, 2024

Weekly average CO2 at Mauna Loa (Accessed 01/14/2024)

2024's first full week shows an increase over week 1 of 2023 of 3.93 ppm in the concentration of the dangerous fossil fuel waste CO₂.

As of this writing, 2502 weekly data points are recorded at the Mauna Loa website, and can be accessed from the data pages. The current reading is the 22nd highest. Of the 50 highest, 13 have taken place in the last 5 years, 33 in the last 10 years, and 40 in this century. Of the 10 that occurred in the 20th century, six occurred in 1998 when the rain forests in S.E. Asia caught fire after slash and burn fires set to make palm oil plantations for "renewable biodiesel" for Germany went out of control.

The comparator with the value 10 years ago is 25.21 ppm higher than that of the first week of 2014. Of the 50 highest 10 year comparators, this is 23rd highest, out of 2046 pieces of such data. All of the top 50 in this category have taken place since 2019.

There are people here who believe that the reactionary return to 19th century dependence on the weather for energy supplies - abandoned for a reason - is about addressing climate change.

This has never been true. Enthusiasm for so called "renewable energy" was originally not about addressing climate change, for which it is clearly inadequate. It's clearly not working and never had a chance of doing so. The land and material intensity of so called "renewable energy" are unsustainable.

Things are getting worse faster than ever.

Enthusiasm for so called "renewable energy" was always about attacking the only sustainable scalable form carbon minimized clean energy, nuclear energy. In this, it was successful, arresting progress in nuclear energy in its tracks by popularizing bad thinking, selective attention and by sweeping the consequences of this anti-progressive scheme to entrench fossil fuels under the rug by diverting attention from it.

The antinuke scheme of ignoring fossil fuels, the death toll, the environmental destruction, and collapse of the atmosphere, is unraveling; nuclear energy is no longer a pariah. Almost certainly it's too little, too late. The planet is burning.

Have a nice Sunday afternoon.

January 13, 2024

Head on Over to the Women's Rights Forum and Kick This One Up Big Time With Recs.

I don't do this sort of thing often, but I'd like to ask for recs for this one:

Barefoot and Pregnant, Gwen Levey and the Breakdown (Official)

There would be nothing better for this country than for this video to go mainstream.

January 13, 2024

The Verge of Crisis in US Nuclear Fuel: A Gorgonian Knot

I hear a lot from dumb assed antinukes about "peak uranium," the wishful thinking of their asinine and frankly deadly enthusiasm for the status quo coupled with a reactionary fantasy that we should return to a practice of depending on the weather for energy which was abandoned in the early 19th century for a reason.

It is impossible to consume all of the uranium on Earth; there is simply too much of it, which should be obvious if one considers that uranium, and to a lesser extent, thorium and radioactive potassium, powers plate tectonics. It moves the continents around.

Nevertheless, in the short term, in current industrial practices in the nuclear fuel industry - which I personally believe need to be changed - there is a problem.

An article on the topic from earlier in the last year:

On the verge of a crisis: The U.S. nuclear fuel Gordian knot

Some excerpts:

The naturalist John Muir is widely quoted as saying, “When we try to pick out anything by itself, we find it hitched to everything else in the Universe.” While he was speaking of ecology, he might as well have been talking about nuclear fuel.

At the moment, by most accounts, nuclear fuel is in crisis for a lot of reasons that weave together like a Gordian knot. Today, despite decades of assertions from nuclear energy supporters that the supply of uranium is secure and will last much longer than fossil fuels, the West is in a blind alley. We find ourselves in conflict with Russia with ominous implications for uranium, for which Russia holds about a 14 percent share of the global market, and for two processes that prepare uranium for fabrication into reactor fuel: conversion (for which Russia has a 27 percent share) and enrichment (a 39 percent share).

No one really knows whether Russian exports will survive the war in Ukraine. Rosatom, Russia’s state-owned atomic energy corporation and the successor to the Soviet Minatom, is deeply tied to the war effort, and the U.S. government has already sanctioned three Rosatom subsidiaries as well as one person involved in Russia’s control of the Zaporizhzhia reactor complex. But this has not spurred efforts at self-sufficiency; so far, the effect has been paralysis.

This could be called a failure of the market, but it is really a failure of governments, here and abroad. “The uranium market was never an actual market,” said William D. Magwood IV, director general of the Nuclear Energy Agency. “It’s always been a government creature,” he said.

In hindsight, Congress and the Department of Energy have made some major miscalculations, the biggest being the assumption that imports from Russia would meet U.S. national security objectives and financial needs. Those imports included Soviet stocks of weapons-grade uranium downblended to meet civil reactor needs and a lot of inexpensive enrichment. But it now appears that the imports have allowed almost every step in the domestic fuel supply chain—from mining and milling to conversion and enrichment—to wither...

The article goes into some detail. One short term solution is the development, discussed in the article, via the focus on the materials science of nuclear fuels, to rely on fuels enriched above 5% to around 10% using recently developed accident tolerant fuels. These will be used in the new Vogtle reactors, as I discussed here: The Vogtle 4 Nuclear Reactor Will Feature the First Use of 6% Enriched Uranium in a LWR

Personally, I have long felt that we need to do away with uranium enrichment all together, and move toward reprocessing of used nuclear fuel. The US, still the world's largest supplier of commercial nuclear energy despite the serious efforts of antinuke ignoramuses, has about 80,000 metric tons of used nuclear fuel. About 1%, roughly of this fuel is plutonium by mass, with an energy content of about 65 exajoules, or about 65% roughly, in the "percent talk" used by antinuke reactionaries to defend useless and fossil fuel dependent so called "renewable energy," of annual US energy demand from all sources, including the coal, oil and gas about which antinukes couldn't care less. Since plutonium forms in used nuclear fuels, running MOX fuels in reactors means that the plutonium will not be entirely consumed. If we partner with the Canadians and their CANDU systems, in theory at least, we could do away entirely with enrichment facilities.

If we add a little thorium to plutonium/uranium based fuels we can extend burn ups - in nuclear fuels "burn ups" are the rough equivalent of gas mileage - to very high levels, especially given the robustness of fuels even in US light water reactors.

One thing is certain. We need to cut the Russians out of the supply chain.

I trust you'll have a nice weekend.

January 13, 2024

Wow, Democrats and Republicans Agreeing on a Climate Related Issue.

One doesn't see this sort of thing very often any more, real bipartisanship:

Lawmakers urge federal funding for Palisades restart.

A bipartisan group of nine House members is calling on the Department of Energy to give “fair, full, and swift consideration” to Holtec International’s application for DOE Loan Programs Office funding to restart the company’s Palisades nuclear plant, closed last year by the facility’s previous owner, Entergy.

Holtec submitted its application in late February of this year, having earlier sought, unsuccessfully, financial assistance for resurrecting the Covert, Mich., plant through the DOE’s Civil Nuclear Credit (CNC) Program.

The pitch: “Repowering Palisades could significantly grow the region’s economy, strengthen our domestic energy security, and return safe, reliable, and carbon-free generation back to the electrical grid,” wrote the lawmakers in a December 15 letter to energy secretary Jennifer Granholm and Nuclear Regulatory Commission chair Christopher Hanson. “Restoring Palisades’ 800 megawatts of baseload generation, which is sufficient to reliably power more than 800,000 homes with clean energy, would be critical to addressing our nation’s fast-growing energy needs. In addition to clear energy benefits, Palisades has the potential to directly drive economic growth and create hundreds of highly skilled jobs, including a union workforce and long-term opportunities in STEM fields. Having only been off line since mid-2022, the plant remains in workable condition . . . .”

Letter signatories included Reps. Jack Bergman (R., Mich.), Bill Huizenga (R., Mich.), John Moolenaar (R., Mich.), Donald Norcross (D., N.J.), Hillary Scholten (D., Mich.), Elissa Slotkin (D., Mich.), Haley Stevens (D., Mich.), Jeff Van Drew (R., N.J.) and Tim Walberg (R., Mich.)...

Governor Whitmer is also in support of the effort.

January 13, 2024

A Weakness in the "Death Star" Protein, KRAS.

This little bit came in on my Nature News Newsfeed with a link to a popular article:

Death Star’ protein has a weak spot

Researchers have identified a second weakness in a cancer-promoting protein called KRAS. An analysis of 26,000 mutations revealed two vulnerable spots in the protein: one that has already been exploited by existing KRAS inhibitors, and a novel location called cavity 3. Like the Death Star from Star Wars, the KRAS was thought to be impenetrable — but a complete blueprint of the spherical protein has helped researchers to find a rare weak point.

It refers to this popular science article:

Researchers discover the weak points of the protein that causes one in 10 cancers

Subtitle:

Four scientists from Barcelona have created the first map of the vulnerable sites of the KRAS gene, whose mutations, often associated with smoking, cause millions of tumors

Some excerpts from the popular article:

One in two men and almost one in three women will have cancer during their lifetime. In at least one in 10 cases, the tumor will be driven by mutations in the KRAS gene, discovered in 1982, but so devilishly complex that the scientific community has spent four decades trying to find its Achilles. Mutations in KRAS are behind almost 90% of pancreatic cancer cases, 40% of colon cancers and 35% of lung cancers. A team from the Center for Genomic Regulation in Barcelona has finally managed to create a complete map of its weaknesses. A preview of the research was published Monday in the journal Nature, a showcase of the best world science.

Genes are stretches of DNA with the instructions for making a protein. The KRAS gene is the manual for generating the KRAS protein, a kind of switch that causes the cell to divide. Uncontrolled activation of KRAS causes cells to run amok, multiply and cause cancer. For decades, it seemed impossible to target this protein with drugs. However, in 2021, the U.S. pharmaceutical company Amgen received FDA approval for sotorasib, an effective drug against lung cancer in people who have a specific mutation in the KRAS gene, which is associated with damage caused by smoking. Biochemist Ray Deshaies, scientific vice-president of Amgen, explained at a press conference that “[the delay of over four decades] wasn’t because we didn’t know what we wanted to do, which was inhibit the mutation in KRAS, it’s just that we had no idea how to do it...”

...The authors of the new study explain that the KRAS protein is like the Death Star, the unconquerable space station from the Star Wars film saga. “The protein is quite spherical and has very few sites that you could imagine as binding points for a drug,” says South African bioinformatician André Faure, who works at the Barcelona institution. “It was considered to be impenetrable,” emphasizes his colleague Albert Escobedo. In the movie Star Wars, the good guys got a blueprint of the Death Star and the hero Luke Skywalker managed to hit its only weak point. The Center for Genomic Regulation team has now obtained the complete blueprint of KRAS...

The full scientific paper, which is not in a finalized form but is provided on an "ASAP" basis, referring to allosteric sites is here: Weng, C., Faure, A.J., Escobedo, A. et al. The energetic and allosteric landscape for KRAS inhibition. Nature (2023)

January 13, 2024

...the rooms of the house called Science. . . . One thing we find throughout the house--there are no locks...

After 70 years, J. Robert Oppenheimer’s legacy is being rewritten

Our research has turned up a December date that is perhaps less significant, but still poignant. On December 20, 1953, just one day before he was informed his security clearance had been suspended, the BBC broadcast the last of six lectures by Oppenheimer in his series Science and the Common Understanding.

In a recording available on the BBC’s website, Oppenheimer can be heard delivering the sixth lecture, titled “The Sciences and Man’s Community.” In it he says:

Some moments during these lectures we have looked together into one of the rooms of the house called Science. . . . One thing we find throughout the house—there are no locks. There are no shut doors. Wherever we go, there are signs and usually the words of welcome. It is an open house, open to all comers.

The discoveries of science, the new rooms in this great house, have changed the way men think of things outside its walls. We have some glimmering now—the depth in time and the vastness in space of the physical world we live in. An awareness of how long our history, how immense our cosmos—touches us, even in simple earthly deliberations. . . .

What is new, what was not anticipated a half century ago, is that though to an atomic system there was a potential applicability of one or another of these ideas in any real situation, only some of these ways of description could be actual. This is because we need to take into account not merely the atomic system we are studying but the means we use in observing it, and the fitness of these experimental means for defining and measuring selected properties of the system. All such ways of observing are needed for the whole experience of the atomic world. All but one are excluded in any actual experience. . . .

Atomic theory is then in part an account of these descriptions and in part an understanding of the circumstances to which one applies or another or another. And so it is with man's life. He may be any one of a number of things, but he will not be all of them. He may be well versed. He may be a poet. He may be a creator in one, or more than one science. He will not be all kinds of man, or all kinds of scientist even. He will be lucky if he has a bit of familiarity outside that room in which he works.

Today I went to a nice lecture including a discussion of putative enzymes for catalyzing pericyclic reactions, "Diels-Alderases" which featured discussions of a number of DFT calculations, all of which, at their root, rely on the Born-Oppenheimer Approximation, and I thought I'd post this.

January 12, 2024

It took 8 exchanges with a robot to confirm I had a parking space at an event I'm attending tomorrow.

It kept sending me the same text, over and over and over, telling me to use the automated system without confirming I had a space.

After the eighth a human finally logged in and confirmed the space. The automated system collected all my information, then refused to let me click "accept." There was a note with an email address for me to notify if I was having a problem, and the solution was an email telling me to use the system that was not working.

I'm running out of time on the planet, but I sort of wonder what the hell it will be like for future generations.

January 11, 2024

My wife and I were surprised to find ourselves at what, in another time, would be porno movie.

On Sunday my wife woke up in a bad mood about stuff at her job.

At times like this, I like to suggest that she come home (psychologically) from work. It's very hard to get her to do so, though. I decided to see if I could divert her attention by taking her to lunch and a movie.

Of course, we really don't follow the latest and greatest in films without prodding - like, for instance, the Barbieheimer phenomenon - so I looked to see what was at the Princeton Garden Theater, a nonprofit theater that sometimes shows films that are mainstream, although in general I wouldn't know what mainstream films are "out."

What was showing was Poor Things

The description of the movie was this:

Yorgos Lathimos (The Lobster, The Favourite) returns with this highly praised “dark comedy.” Emma Stone is a young woman brought back to life by an unorthodox scientist played by Willem Dafoe. Set in the Victorian era, POOR THINGS follows Stone’s character on a Candide journey of self-discovery. It’s a visually stunning film, which features a “Steampunk” set, high fashion costuming, and eye-popping cinematography. Yes, it’s a “comedy,” but with very candid sexual discovery. It’s also equal parts surreal, grotesque, beautiful, and dramatic - a typical Lathimos offering, in other words. Also with Mark Ruffalo.

We seem to have not noticed "very candid sexual discovery" in the description.

It is a visually stunning film by the way. The sets and the highly stylized depictions of cities, of boats, etc. are beautiful. The plot and the acting (I hope it's acting) are rather interesting. It's decidedly not a cookie cutter movie, and features considerable originality.

But there is a lot, a great deal, of sex in the film, some of it certainly bordering on sordid.

Overall, we found the Victorian Era science fiction stuff, which by the way involves some medical type gore, to be creative, but, um, um, um, there was a lot of sex in the film.

After the film we agreed that in the 1980s it would have been considered a porno film.

This recalled something of my wife's youth when, on campus, there was going to be a "discussion" with the porno star Harry Reems of what pornography is and is not - free speech, objectivization, art, all that stuff that was under discussion then - and controversially, as part of the "discussion" they were showing the porno movie "Deep Throat" in which Reems appeared. My (future) wife and her girlfriends decided to go see the movie, a kind of late adolescence giggly curiosity sort of thing. (In those days one could still be "curious" about that sort of thing as a college Freshwoman.) My future wife, then the campus hottie, found that those men who saw her there suddenly became more infatuated with her.

It blew over and nothing bad happened to her as a result of her attendance.

Hormones are a weird thing; mine too, at least back then, when "Deep Throat" could have some value of shock. Nothing is shocking now, I think. I'm not sure the "Deep Throat" "debate" was worth much, although apparently it was well attended but I suspect the audience was adolescent. (My wife and girlfriends did not sit through the whole thing.) I didn't go, but I heard about it.

As for my wife and I, we have a very different life now in which the spirit - that ineffable quality - has transcended the physical nature of our love, very happy memories notwithstanding.

We were suitably amused.

By the way, my wife was shaken out of her bad mood; that was a good thing.

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