NNadir

NNadir's Journal

September 21, 2019

Palladium is a fission product.

The paper I will discuss in this very brief post is this one: Enhancement of Thermoelectric Properties in Pd–In Co-Doped SnTe and Its Phase Transition Behavior. (Wang et al ACS Appl. Mater. Interfaces 2019 11 37 33792-33802)

I don't have time this morning for much more than this.

Thermoelectric devices are well known and have been utilized, most famously in the space program, for the direct conversion of heat into electricity.

As an advocate of the last, best hope of saving the planet, nuclear energy, I follow the science around these devices rather closely.

The historical thermoelectric devices, including those that powered the Voyager spacecraft - with which we are still in contact after many decades - had low energy efficiency: Typically the heat energy converted to electrical energy was less than 10%. The efficiency of these devices is described in science and engineering by a parameter known as the Seeback coefficient, usually referred to by the somewhat confusing symbol "ZT" which is not an algebraic product.

I consider that all of the components of so called "nuclear waste" are valuable and need to be recovered, both as useful radioactive materials and as non-radioactive materials.

It is possible to isolate non-radioactive palladium from fission products in the case where fast separation of ruthenium is undertaken, since ruthenium-106 has a relatively short half-life, roughly a year. This is possible for fluid phased reactors of a type that has been popularly discussed among modern nuclear engineers. Ru-106 decays to stable palladium-106.

However the isolation of palladium from used nuclear fuel that has been foolishly allowed to accumulate without being put to use will contain a long lived radioactive isotope, Pd-107, which decays with a long half life to stable Ag-107. I believe that this palladium is also useful and that the risk associated with its radioactivity is vanishingly small if it is utilized in devices, which is why this paper caught my eye.

In the fast fission of plutonium - which in my view is the key to making nuclear fuel inexhaustible - about 6% of the fission products are palladium. (Natural palladium contains the 102 isotope which is observationally stable but probably radioactive with an a half-life so long as to be undetectable. Used nuclear fuel will contain this mass number in the form of stable ruthenium-102)

Here is figure 10 from the paper:

Here is the caption:

Figure 10. a) ZT values as a function temperature for Sn1.03–2xPdxInxTe; b) ZT contrast

From the conclusion of the paper:

In summary, we first confirmed that the existence of Pd can introduce the valence band convergence of SnTe, proven by first-principles calculation, and then carried out the experiment of doped Pd. In addition to valence band convergence and no deterioration of conductivity, chemical bond softening and grain refinement can also be introduced into SnTe doped with Pd. Moreover, the neutron and synchrotron powder diffraction experiments show that the significant change in the thermal conductivity of the codoped system is caused by local structural distortion. This persistent local structural distortion and the instability strongly affect the high temperature thermal conductivity, which affects overall thermoelectric performance. Therefore, we obtain a low thermal conductivity in this work. For instance, doped 2.5 mol % of In and Pd can reduce the thermal conductivity to 1.13 Wm–1K–1. The purpose of improving thermoelectric performance can be achieved by adjusting local structural distortion. Finally, due to the above synergistic effect, the ZT value of the Sn0.98Pd0.025In0.025Te sample reached 1.51 at 800 K.

This is a very high ZT value. To save the world from climate change, it is necessary to utilize high temperature nuclear reactors with high thermal efficiency in a combined cycle fashion, with some of the energy being utilized to make chemical fuels that can be obtained from hydrogen and carbon oxides, both CO and CO2. CO2 can also be reduced to carbon for use in materials, which is essentially combustion in reverse.

Temperatures of 800 K are readily accessible under these conditions, and may be utilized in the cooling phases necessary in the thermochemical conversion of carbon oxides to economically viable closed cycles approaches to carbon utilization.

It's cool I think.

None of this is likely to happen by the way, since fear and ignorance are obviously triumphant in modern times, but it is feasible that ignorance will fail, both on the right, where it is politically popular, and on the left, where anti-nuclear stupidity is popular.

I hope you will have a wonderful weekend.

September 20, 2019

Carbocations Generated Electrochemically from Carboxylic Acids.

The paper I'll discuss in this post is this one: Hindered dialkyl ether synthesis with electrogenerated carbocations (Baran et al, Nature 573, 398–402 (2019)).

Last year my kid was in France where he was working with some organosilanes and he asked me to scan and email an organic chemistry textbook and some problem solutions so he could teach himself some organic chemistry. He told me he was thinking of taking some organic chemistry courses for one of the minors he was considering.

I said, "Well that's OK with me, but if you take courses in organic chemistry, just don't fall in love with it."

Medicinal chemistry is a dying field in the United States, and with it, the economic value of degrees in chemistry focusing on organic chemistry. That's really terrible, since organic chemistry is such a beautiful science and the history of organic chemistry in the United States is sublime.

It's been some decades since I've worked in the field, but I recall how very much alive I felt in those days, young, newly married to the woman of my dreams and still going to work on the weekends not because I had to do so, not because anyone was paying me to do so, but simply because I loved doing it.

I suppose on a certain level a knowledge of organic chemistry still permeates my day to day life and work, but it's peripheral; I'm sure I've forgotten more than I know.

But today I came across this beautiful and in someways earth shattering beautiful little paper in a major cross disciplinary scientific journal where one doesn't see that much organic synthesis anymore, Nature. (There is a Nature Journal called Nature Chemistry, but I don't read it all that much unless some reference drags me there.)

From the introduction:

Hindered ethers are of high value for various applications; however, they remain an underexplored area of chemical space because they are difficult to synthesize via conventional reactions1,2. Such motifs are highly coveted in medicinal chemistry, because extensive substitution about the ether bond prevents unwanted metabolic processes that can lead to rapid degradation in vivo. Here we report a simple route towards the synthesis of hindered ethers, in which electrochemical oxidation is used to liberate high-energy carbocations from simple carboxylic acids...

I haven't kept up on things, but right off the bat that strikes me as a big deal, carbocations from simple carboxylic acids.

...These reactive carbocation intermediates, which are generated with low electrochemical potentials, capture an alcohol donor under non-acidic conditions; this enables the formation of a range of ethers (more than 80 have been prepared here) that would otherwise be difficult to access. The carbocations can also be intercepted by simple nucleophiles, leading to the formation of hindered alcohols and even alkyl fluorides. This method was evaluated for its ability to circumvent the synthetic bottlenecks encountered in the preparation of 12 chemical scaffolds, leading to higher yields of the required products, in addition to substantial reductions in the number of steps and the amount of labour required to prepare them.

Here's the stuff from the world in which I used to live:

The Williamson ether synthesis3,4 is a long-established method by which to synthesize primary alkyl ethers via SN2 substitution (Fig. 1a). However, in contexts involving secondary or tertiary alkyl halides the reaction often derails, leading to elimination byproducts or to no reaction at all. Hindered ether 1, which is a key intermediate in the synthesis of an aurora kinase modulator, exemplifies this commonly faced challenge. Despite the documented utility of hindered ethers1,2, very little progress has been made in facilitating access to them. The alternative workhorse method, the Mitsunobu reaction, also fails in such settings owing to the steric demands of the SN2 process and the pKa requirements of the nucleophile5...

The Mitsunobu reaction is always a favorite, since it involves a reagent known as DEAD, (diethyl azodicarboxylate).

The pictures tell the story:

The caption:

a, The synthesis of hindered ethers is a long-standing challenge in organic synthesis. A; constant-current electrolysis; cat., catalyst; Cbz, carboxybenzyl; LG, leaving group. b, Historical context and previous strategies for decarboxylative etherification. FG, functional group; NHPI, N-hydroxyphthalimide. c, Development and optimization of hindered ether synthesis depicted through electromechanistic analysis. aCompound 3 (0.2 mmol), 3.0 equiv. of alcohol 4 (except where designated). bYield based on gas chromatography. All entries were performed in triplicate. cConditions: acid 3 (0.2 mmol), alcohol 4 (0.6 mmol), AgPF6 (0.3 mmol), 2,4,6-collidine (0.6 mmol), nBu4NPF6 (0.1 M), 3 Å molecular sieves (150 mg), dichloromethane (CH2Cl2; 3 ml), current (I) = 10 mA, 3 h. dIsolated yield. DMF, N,N-dimethylformamide; RT, room temperature; +C/?C represents the graphite electrodes.

Actually, this chemistry is quite old according to the authors:

This class (Fig. 1a, yellow inset) stems from the oldest synthetic organic electrochemical reaction, the Kolbe dimerization, which was discovered9 in 1847. In the so-called interrupted Kolbe variant, known as the Hofer–Moest reaction10, electrolytic oxidation of a carboxylic acid under mildly alkaline conditions generates a carbocation that can be captured by incipient nucleophiles10,11,12,13,14,15,16,17,18. A distinct advantage of this reaction is the non-acidic generation of high-energy carbocations directly from carboxylic acids.

It's chemistry with which I'm unfamiliar, for some reason I've always looked askance at electrochemistry, at least until recently, when I have come to regret my intellectual laziness in this regard.

Some structures they synthesized:

The caption:

See Supplementary Information for literature routes. bAgSbF6 (0.3 mmol) instead of AgPF6. cDBU (1,8-diazabicyclo[5.4.0]undec-7-ene; 0.6 mmol) instead of 2,4,6-collidine. dKSbF6 (0.3 mmol) instead of AgPF6. eAlcohol as limiting reagent, conditions: alcohol (0.15 mmol), carboxylic acid (0.45 mmol), AgClO4 (0.6 mmol), 2,4,6-collidine (0.675 mmol), nBu4NClO4 (0.2 M), 3 Å molecular sieves (100 mg), CH2Cl2 (2 ml), I = 10 mA, 3 h. fAgClO4 (0.6 mmol) instead of AgPF6, nBu4NClO4 (0.1 M) instead of nBu4NPF6. g4.0 or 6.0 equiv. alcohol. h1.5 ml CH2Cl2, I = 7.5 mA, 4 h. i nBu4NClO4 (0.1 M) instead of nBu4NPF6, no AgPF6. jReaction performed in triplicate; yield is average of three runs. kSee Supplementary Information for more examples. Boc, tert-butyloxycarbonyl; d.r., diastereomeric ratio; MS, molecular sieves; Ts, tosyl.

The caption:

See Supplementary Information for literature routes. bSee Supplementary Information for more examples. cH2O (0.1 ml) as nucleophile. dCarboxylic acid or phenylacetonitrile as nucleophile (0.6 mmol, 3 equiv.), conditions: AgClO4 (0.6 mmol, 3 equiv.), 2,4,6-collidine (0.6 mmol, 3 equiv.), nBu4NClO4 (0.1 M), 3 Å molecular sieves (150 mg), CH2Cl2 (3 ml). eKF (0.72 mmol, 3.6 equiv.) as nucleophile, conditions: 18-crown-6 (0.72 mmol, 3.6 eq), AgClO4 (0.6 mmol, 3 equiv.), 2,4,6-collidine (0.6 mmol, 3 equiv.), nBu4NPF6 (0.1 M), 3 Å MS (150 mg), CH2Cl2 (3 ml). fConditions for scale-up to (±)-5 (each reaction): 3 (2.4 mmol), (±)-4 (7.2 mmol), 2,4,6-collidine (3.6 mmol), nBu4NClO4 (0.1 M), 3 Å molecular sieves (450 mg), CH2Cl2 (9 ml) +C/?C (10 mA), RT, 15 h. gConditions for scale-up to 81 (each reaction): 71 (1.2 mmol), H2O (0.1 ml), 2,4,6-collidine (1.8 mmol), nBu4NPF6 (0.02 M), acetone (9 ml), +C/?C (10 mA), RT, 12 h. Nu, nucleophile; pin, pinacolato.

The conclusion of the paper strikes me as something of an understatement:

It is anticipated that the mild electrogeneration of carbocations reported herein will find use in numerous settings in which standard SN2 and carbocation-based approaches are unsuccessful in forming hindered functionalized carbogenic frameworks.

This is by the way, molten salt chemistry, in the extreme, since a key reagent is nBu4NPF6. Electrochemistry in molten salts would be a very big deal in a sane world, not the one we live in, a world where organic chemistry would regain some value.

I know, I know, I know...it's very esoteric...very esoteric...

It's very esoteric, but in a time of so much tragedy, children in cages, a destructive nutcase running the country, it is well worth finding some peace in the knowledge that there still are wonderful and beautiful things left, even in this country.

I hope you will enjoy a very pleasant up coming weekend.

September 19, 2019

Structural basis of nucleosome recognition and modification by MLL methyltransferases

The paper I'll discuss in this post has the title I've used for the post itself: Structural basis of nucleosome recognition and modification by MLL methyltransferases (Jing Huang et al Nature 573, 445–449 (2019))

Last night I had the pleasure of attending a lecture by Dr. Benjamin Garcia who is a world expert in the structure of chromatin, specifically, the epigenetic implications of particular post translational modifications of histones. Histones are the proteins that wrap DNA, choreographing the way they and the genes that constitute them turn on and off, to simplify the matter somewhat. The histones - there are four of them - are extremely basic proteins, inasmuch as they are rich in arginine and lysine, and it is the chemistry of the latter amino acid, lysine, that is a controlling factor in how histones behave and function.

(As aside, the evening was an embarrassment of riches, Dr. Garcia's lecture was followed by one by Dr. Vicki Wysocki - in the picture of her lab group she is in the back row on the far left, partially obscured by one of her students. Dr. Wysocki is a world leader in the use of mass spectrometry to study protein complex structures, that is how proteins interact with one another to conduct the business of metabolism. She showed work where she defined the structure of an hexameric protein by mass spectrometry that was later confirmed by cryo EM imagining (the imaging was problematic so her group took a shot at it by mass spec) - no small trick.)

Anyway, about histones: As they control the operation of DNA, they are obviously involved in many processes involving cell division, both normal cell division and abnormal cell division, notably cancer. It is known that specific residues, in particular the ?-amino group in lysine, in the protein sequences of the histones are modified generally (but not always) in one of two ways, by acetylation or methylation. A bit of nomenclature: The term "H3K4" refers to histone 3, "H3" having a lysine residue (K in peptide language) in the 4 position in the amino acid sequence. The term "H2BK120" refers to histone 2B's lysine in the 120th residue of the sequence.

The histones in turn can also choreograph or allow the chemical modification of DNA itself - DNA can be methylated - this is the area of "epigenetics" which controls many areas of cell function and behavior, including, it seems, aging.

I've played in this space professionally. It's fascinating.

Before producing excerpts of the texts, it is probably useful to produce a graphic from the paper showing what this chromatin complex of histones and DNA looks like:

The caption:

a, Schematic of the domain organizations of the human MLL1 catalytic module. The colour scheme is the same as that of the MLL1–ubNCP structural model shown in c. DBM, DPY30 binding motif; PHD-WH, plant homeodomain and winged-helix domain; WIN-AS, WDR5-interacting motif and activation segment. b, Atomic model of human MLL1 catalytic module, shown from the cryo-EM structure of human MLL1–ubNCP complex. c, d, Cryo-EM density map (c) and atomic model (d) of human MLL1–ubNCP complex, shown from two orthogonal views. The cryo-EM map is segmented and coloured according to the components of the MLL1–ubNCP complex. Ub, ubiquitin.

The abstract and introduction describes what some of these abbreviations mean:

Methyltransferases of the mixed-lineage leukaemia (MLL) family—which include MLL1, MLL2, MLL3, MLL4, SET1A and SET1B—implement methylation of histone H3 on lysine 4 (H3K4), and have critical and distinct roles in the regulation of transcription in haematopoiesis, adipogenesis and development1,2,3,4,5,6. The C-terminal catalytic SET (Su(var.)3-9, enhancer of zeste and trithorax) domains of MLL proteins are associated with a common set of regulatory factors (WDR5, RBBP5, ASH2L and DPY30) to achieve specific activities7,8,9. Current knowledge of the regulation of MLL activity is limited to the catalysis of histone H3 peptides, and how H3K4 methyl marks are deposited on nucleosomes is poorly understood. H3K4 methylation is stimulated by mono-ubiquitination of histone H2B on lysine 120 (H2BK120ub1), a prevalent histone H2B mark that disrupts chromatin compaction and favours open chromatin structures, but the underlying mechanism remains unknown10,11,12. Here we report cryo-electron microscopy structures of human MLL1 and MLL3 catalytic modules associated with nucleosome core particles that contain H2BK120ub1 or unmodified H2BK120. ...

This is a paper about the epigenetics of leukemia.

...The human MLL1 catalytic module, which is composed of full-length WDR5, RBBP5, ASH2L and DPY30 (WRAD) proteins and MLL1 (residues 3754–3969), formed complexes with unmodified nucleosome core particles (NCPs) or NCPs containing mono-ubiquitinated H2BK120 (hereafter, ubNCPs) in electrophoretic mobility shift assays (Fig. 1a, Extended Data Fig. 1a, b). Cryo-electron microscopy (cryo-EM) single-particle analysis yielded a global density map of the MLL1–ubNCP complex at an overall resolution of 3.2 Å (Extended Data Figs. 1c, 2, Extended Data Table 1). Another cryo-EM dataset of the MLL1–ubNCP complex was processed to an overall resolution of 4.0 Å, and revealed electron microscopy density immediately N-terminal to SPRY domain of the ASH2L region (known as the pre-SPRY domain) as well as the conformational dynamics of ubiquitin within the complex (Extended Data Fig. 3a). We generated an atomic model of the MLL1–ubNCP complex by docking available high-resolution structures of human MLL1 subunits, the nucleosome and ubiquitin9,13,14,15,16 into the electron microscopy map, followed by manual building (Fig. 1b–d).

The "complexes" here are what Dr. Wysocki's group studies, not by imaging (Cryo-EM) but be interference from mass spectrometry data. Very cool.

Anyway, some more text.

The WD40 domain of RBBP5 (hereafter, RBBP5WD40) is sandwiched between the H2BK120-conjugated ubiquitin and core histones, and confers both nucleosome and ubiquitin recognition (Fig. 2a). The RBBP5WD40 is wedged into the H2B–H4 cleft, which represents a histone surface that is exploited by other nucleosome-binding proteins (such as Sir3 and 53BP114,20) (Fig. 2a, b). Two loops, which connect the WD40 propeller blades 5, 6 and 7, mediate direct interactions with nucleosome (Fig. 2b). One of these loops is accommodated between the C-terminal helix of H2B and nucleosome DNA adjacent to this helix, with the hydrophobic residues Leu248 and Val249 facing the C-terminal helix of H2B and the positively charged Arg251 pointing to the phosphate backbone of the DNA (Fig. 2b, Extended Data Fig. 4a). The other loop adheres to residues Lys79 and Thr80 of histone H3, which further stabilizes the association of RBBP5WD40 with the H2B–H4 cleft (Fig. 2b, Extended Data Fig. 4b). Removal of RBBP5WD40 severely impaired the methyltransferase activities of MLL1 towards nucleosomal H3K4 (Fig. 2d), which emphasizes that the recognition of a specific histone surface through RBBP5WD40 is required for efficient H3K4 methylation on the nucleosome.

RBBP5 is a retinoblastoma binding protein that is important in cell division; it is a tumor suppressor gene. (One of the interesting points of Dr. Garcia's talk last night concerned the interaction of histone tails with protein sequences that seem to be involved in immune function - the immunology of cancer is another interesting topic.)

I recognize that this is all very esoteric, and I produce it because of the high the lectures gave me, so let me limit the rest of this post to some pretty pictures of chromatin histone/DNA complexes with captions.

The caption:

a, Overview of the RBBP5–ubNCP interactions, showing that RBBP5WD40 is sandwiched between the histone H2B–H4 cleft and H2BK120ub1. b, Detailed view of the recognition interface between RBBP5WD40 and the histone H2B–H4 cleft. H2B?C, C-terminal ?-helix of H2B. c, Interface between the ?-helix-containing loop of RBBP5WD40 and H2BK120ub1 in the major RBBP5–ubiquitin binding mode, shown in front and back views. d, End-point histone methyltransferase (HMT) assays of equal amount of wild-type (WT) complexes and mutant MLL1 complexes (deletion of RBBP5WD40). Each assay was repeated at least three times with similar results. n = 3 independent experiments. Data are mean ± s.d. The input of the HMT reactions is shown in Extended Data Fig. 4f. e, Overview of the interactions of MLL1SET–ASH2L with the nucleosome, shown in front and back views. The ASH2L pre-SPRY domain (ASH2Lpre-SPRY) is shown with its electron microscopy density map. ASH2LSPRY, SPRY domain of ASH2L; C-ter, C terminus; RBBP5AS-ABM, activation segment and ASH2L-binding motif of RBBP5. f, Interaction between the N-terminal motif of MLL1SET (SET-N) and the C-terminal helical region of histone H2A. ?2 and ?3 denote ?-helices 2 and 3 of histone H2A, respectively. g, HMT assays of an equal amount of MLL1 complexes with wild-type or truncated ASH2L. Each assay was repeated at least three times with similar results. n = 3 independent experiments. Data are mean ± s.d. The input of the HMT reactions is shown in Extended Data Fig. 5c. h, Electrophoretic mobility shift assays of MLL1 complexes bearing ASH2L truncations with NCPs at molar ratios of 1:1, 2:1 and 4:1. Each assay was repeated at least three times with similar results. The input of the assays is shown in Extended Data Fig. 5d. Numbers on the left represent the number of base pairs (converted from molecular mass). i, Alanine-scanning mutagenesis of the ASH2L pre-SPRY domain to identify residues that are critical for the activity of MLL1. Each assay was repeated at least three times with similar results. n = 3 independent experiments. Data are mean ± s.d. The input of the HMT reactions is shown in Extended Data Fig. 5e.

The caption:

a, Cryo-EM density maps and atomic models of the two binding modes of the human MLL1–NCP complex, in the dyad view of the nucleosome. b, Superposition of the two MLL1–NCP structures from a, showing the rotation of the MLL1 complex on the nucleosome surface between the binding modes. c, Detailed view of the recognition interface between RBBP5WD40 and SHL2-adjacent regions of the nucleosome from MLL1–NCP binding mode 2, shown with electron microscopy densities of key residues of the interface. d, Michaelis–Menten kinetic analysis of activities of human MLL1 on NCP and ubNCP. Data are mean ± s.d. n = 3 independent experiments. The kcat and Km of human MLL1 on ubNCP and NCP are shown with their standard errors.

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The caption:

a, Cryo-EM density map and atomic model of human MLL3–ubNCP complex, shown from two orthogonal views. The colour scheme is the same as that of the MLL1–ubNCP complex, except that MLL3 is coloured in teal. b, Structural comparison of human MLL1 (coloured in orange) and MLL3 (coloured in teal) catalytic modules, based on structural superposition of MLL1SET and MLL3SET. c, Overall structural organization of the interface between WDR5, MLL1 and RBBP5 subunits. The WIN and activation segment motifs of MLL1 are shown with electron microscopy density maps. d, Detailed view of the interface between WDR5, MLL1 and RBBP5, highlighting a cluster of hydrophobic residues of MLL1AS and RBBP5AS that flank the insertion motif (labelled SET-I) and the SAH-binding pocket of MLL1SET. e, HMT assays performed with wild-type MLL1 complex and mutant MLL1 complex with deletions of both MLL1AS and RBBP5AS. Each assay was repeated at least three times with similar results. n = 3 independent experiments. Data are mean ± s.d. The input of the HMT reactions is shown in Extended Data Fig. 8c. f, Overview of the interface between WDR5, MLL3 and RBBP5 subunits. g, HMT assays of equal amount of MLL1 complex (MLL1–WRAD), MLL3 complexes with or without WDR5 (MLL3–WRAD and MLL3–RAD, respectively) and an MLL3 chimaera composed of the MLL1WIN-AS motif and the MLL3SET domain (MLL1AS–MLL3–WRAD) on the substrate of the nucleosome. Each assay was repeated at least three times with similar results. n = 3 independent experiments. Data are mean ± s.d. The input of the HMT reactions is shown in Extended Data Fig. 9b. h, A working model shows the different structural organizations at the interface between WDR5, MLL1SET (or MLL3SET) and RBBP5 that contribute to activity specificity in MLL1 (or MLL3) complexes. SAM, S-adenosyl-L-methionine.

From the paper's conclusion:

In summary, cryo-EM structures of human MLL1–ubNCP, MLL1–NCP and MLL3–ubNCP complexes provide a structural framework for nucleosome recognition and activity specificity of methyltransferases of the MLL family. The association between MLL proteins and nucleosomes ensures the proper deposition of H3K4-methyl marks in euchromatin regions, in which the open chromatin structures favour the access of MLL enzymes to the nucleosome surface. This association also allows the regulation of the activities of MLL enzymes by pre-existing histone marks or chromatin-binding factors, as exemplified in the trans-histone crosstalk between H2BK120ub1 and H3K4 methylation. These findings—together with recently reported cryo-EM structures of other histone modifiers (DOT1L and PRC2) in complex with nucleosomes25,26,27,28,29,30—highlight the importance of structural characterizations of histone-tail modifications in the context of nucleosomes and chromatin, which will shed light on the molecular mechanism(s) that underlie the complex and integrated regulation of histone modifications by chromatin structures and other epigenetic signals. Future studies are required to further investigate how an intact MLL complex works in the context of hierarchical chromatin structures.

Well, to each his own; I guess you had to be there.

Even cancer can have its own magnificence.

Evenings like last evening make my life worth living, such beautiful science albeit in a sadly dying world.

I hope your work week has had as many moments of transcendent joy as mine has had.

September 17, 2019

Electricity Prices Around the World 2017

Source: IEA Electricity Information 2018, Page IV.8

September 15, 2019

An Interactive Map of Severely PFAS Contaminated Sites in the US.

These are the perfluoralkanoates, widely used persistent organic chemicals where all, or most of the hydrogens have been replaced with fluorine. It appears that their physiology of these compounds is problematic.

There are probably no human beings who are not contaminated with them at some level, but some are far more contaminated than others. (The dose makes the poison.)

I was able to click on sites near my home, and found that a small commercial airport for commuter traffic and served by at least one commuter airline was a former military base that has profound PFAS contamination.

https://www.ewg.org/interactive-maps/2019_pfas_contamination/map/

September 15, 2019

Today's Google Doodle Honors an Important and Unsung Type of Scientist, the "Amateur" Scientist.

There are scientists, very important scientists in fact, who do their science as something other as a job. Some of these are autodidacts, who teach themselves what they need to know and go on to advance their fields greatly, often in obscurity that outlives their physical lives, with fame coming after their deaths.

These kinds of people are invaluable.

Gregor Mendel was such a scientist; his job was "Monk," but he did science that survived him and helped pave the way for modern genetics.

Today's Google Doodle is about another such scientist: Ynes Mexia

I personally love the Google Doodles; they teach me things I didn't know.

September 14, 2019

Electricity Prices Around the World 2013.

Excuse this experiment in software management. I am working to gain better use of graphics in blog posts as I consider starting a private blog of my own.

This test graphic comes from an article I've been writing for some time on why negative electricity prices are economically and environmentally destructive. It will contain this graphic from a report by the interesting energy thinker at MIT, whose work I follow closely, Charles Forsberg. For the record, he is not nearly as hostile to so called "renewable energy" as I am - I think of it as an expensive sacred cow that is speeding the destruction of the planet - but despite this disagreement, he is an important realistic thinker on decarbonization with broad multidisciplinary insights.

The full report is here: MIT-ANP-TR-162

This post is just a test, and if it annoys anyone, I apologize.

September 14, 2019

It's unusual, but a pundit actually cause me to change my sig line here.

I have no use for pundits, or for journalists in general, since they have played too large a role in normalizing the reprehensible.

But I came across some punditry that was actually, in my cynical view, quite thoughtful in its appeal to FDR, and took a quote from it as my new sig line.

The pundit's remarks, from CNN, are here: The History Lesson 2020 Democrats Cannot Afford to Ignore.

The text therein is my new sig line for the time being. (I do change it frequently.)

September 13, 2019

Genetic Sequencing of Mahi Mahi to Determine the Exposure Level From the Deep Horizon Oil Disaster.

The paper I'll discuss in this relatively brief post is this one: Whole-Transcriptome Sequencing of Epidermal Mucus as a Novel Method for Oil Exposure Assessment in Juvenile Mahi-Mahi (Coryphaena hippurus) (Justin B. Greer,*,† Nicolette E. Andrzejczyk,*,† Edward M. Mager,‡ John D. Stieglitz,§ Daniel Benetti,§ Martin Grosell,∥ and Daniel Schlenk†,?, Environ. Sci. Technol. Lett. 2019, 6, 538?544)

One of the joys of writing posts in this "sleepy little DU science forum" - as I've heard it described - is the privilege of learning things as I write. Over the last few weeks, I've been writing a somewhat involved post comparing two recently published scientific papers about two radioactive contamination events, one of which is everyone's favorite with the possible exception of Chernobyl, Fukushima, and the other involving radioactive contamination of a San Joaquin oil field in California. Writing this rather long post has stimulated me to do some interesting reading on the human physiology of certain radioactive nuclides, including two that surely killed a rather famous scientist.

One of the side notes I found myself going down is the case of the famous scientific paper about the "Fukushima Tuna Fish" which received vast international attention, much to the chagrin of the paper's authors, and believe me, when a scientist gets a paper with an international attention all over the news media, "chagrin" is not usually the word associated with the attention.

Anyway, this is not that post. I'm still working on it and it isn't done.

It proves to timely: The recent Fukushima attention concerns the proposal to dump "radioactive" seawater into the sea - it happens that there is no such thing, and never has been such a thing as seawater that isn't radioactive - the dumping is perfectly OK with me. If one supports nuclear energy as I do, one has to greet such ignorance with a mixture of amusement and despair. If the Fukushima "radioactive seawater" is dumped, we can expect the morons at Greenpeace to have a festival of clownish trivializing stupidity featuring dressing up and cruising around in diesel powered boats in their ongoing efforts to be sure the planet commits a suicide worthy of the Darwin Award.

I'm sure the reactions will be as stupid as the reaction I experienced here some time ago when a correspondent dug up one of my old posts to announce that the world was ending because a tunnel collapsed on the radioactively contaminated Hanford Nuclear Weapons Complex in Washington State, a collapse also widely reported in the media, albeit not as actively as the famous Fukushima tuna fish.

God bless the ignore list.

Anyway, the paper here is about another kind of fish, a fish contaminated by petroleum leaks, in this case, oil from the Deepwater Horizon Oil.

From the introduction to the paper:

Large-scale oil spills such as the 2010 Deepwater Horizon (DWH) spill in the Gulf of Mexico can have significant ecological impacts on marine populations, for example, via exposure to polycyclic aromatic hydrocarbons (PAHs). The DWH oil spill resulted in extensive oiling of spawning regions for commercially important pelagic species in the Gulf of Mexico, including mahi-mahi (Coryphaena hippurus). Sublethal exposure to environmentally relevant concentrations of crude oil-derived PAHs has been shown to impair cardiac development, swimming performance, craniofacial development, and behavior, leading to reduced fitness and increased mortality risk.1?4 Therefore, there is a need for the development of monitoring tools that can estimate environmental exposure and monitor the health status of individuals following a spill in a noninvasive manner to minimize further population disruptions.

As biological barriers go, the one with which I am most familiar is human skin, with particular focus on its molecular biology, human skin a fascinating organ, but the authors here are concerned with another complex biological barrier, the mucus layer coating fish, also a fascinating organ with fascinating molecular biology which, as the authors note...

Epidermal mucus provides the first line of defense against pathogens and toxicants and is secreted by goblet cells, sacciform cells, and club cells located throughout the epidermis.6 Mucus contains a wide range of molecules such as proteins, lipids, carbohydrates, mRNA, and DNA, with the most well-characterized being antimicrobial and immunerelated (sic) molecules.7,8 Furthermore, mucosal composition has been shown to be altered by a variety of stress conditions. For example, oil exposure in dusky splitfin (Goodea gracilis) elicited antioxidant responses in the epidermal mucus that were greater than those found in the liver, brain, and muscle.9 Other studies focused on aquaculture applications have demonstrated that immune-related proteins such as lectins, heat shock proteins, and complement factors are highly abundant and dynamically regulated following bacterial infection, food deprivation, and overcrowding stress.10?13 Thus, changes in mucosal composition could be used to identify biomarkers of exposure for environmental contaminants or stressors.

The authors focus on an usually studied subclass of biological barrier molecules, specifically RNA.

Recently there has been increased interest in what is called the "exposome" which is the molecular signatures of exposure to external molecules and stresses, many of which ultimately show up in toxicological syndromes. This is a relatively new undertaking and is proving to be quite fascinating. Here, for example is a link to a recent paper upon which I stumbled, the expsome associated with Alzheimer's disease: The Alzheimer's Disease Exposome. Publication of this paper, by the way, does not "prove" anything at all about Alzheimer's disease, but it offers an important area of inquiry worthy of study.

As they are sometimes and somewhat naively interpreted, the nucleic acids represent something like a computer program of life, and these "programs" are of two types, the germline type - that which is heritable - and the somatic type, that which is involved in the control and feedback loops of the molecular biology of living things. In somatic nucleic acids, a number of changes accumulate normally during life, these are called "epigenetic changes" and as such represent the exposome. These somatic changes are known to control normal and abnormal processes like, in the former case, aging and development, in the latter case, diseases like cancer and autoimmune diseases like lupus and rheumatoid arthritis.

The oil utilized in this study to examine the effects of Deepwater Horizon spill was real Deepwater Horizon Oil, collected from the sea and stored as such:

Oil Preparation and Exposures. High-energy water accommodated fractions (HEWAFs) were prepared from crude oil obtained during surface skimming (OFS) following the DWH oil spill and transferred to the University of Miami under the chain of custody (sample ID OFS-20100719- Juniper-001 A00884). The HEWAF solutions were prepared according to established methods and were diluted to nominal concentrations of 5% or 10% using ultraviolet-sterilized seawater for testing (Supplemental Methods).2 Juvenile mahi-mahi raised from captive wild mahi-mahi broodstock fish16 [F1 generation, ?28 days of age, mass of 4.89 ± 0.14 g (standard error of the mean)] were placed into 10 L glass aquaria containing 8 L of either fresh seawater (control), 5% HEWAF (low), or 10% HEWAF (high) for 48 h. Four individuals were placed in each tank, with four replicate tanks in each treatment group. An 80% water change with fresh seawater or HEWAF dilution was performed on each aquarium ?24 h after the beginning of exposure. Exposures were performed in a temperature-controlled environment at 27 °C with a 16 h:8 h light:dark photoperiod. None of the exposure concentrations elicited acute mortality.

Cool, I think. I'm glad scientists collected "DWH" oil samples and stored them for study years after the fact. Excellent scientific forethought!

Some graphics from the paper:

Figure 1. Results from RNA sequencing of mahi-mahi epidermal mucus, including (A) a heat map of Euclidean distances between samples in the control, low-HEWAF (?PAH = 16.55 ?g/L), and high-HEWAF (?PAH = 23.03 ?g/L) exposure groups calculated from DEseq2 variance stabilizing transformation of the RSEM count data, (B) a volcano plot of differentially expressed transcripts within the low- and high-HEWAF exposure groups, and (C) the top canonical pathways, physiological system development and function (D & F) pathways, and toxicity functions predicted to be altered in the low-oil exposure group by Ingenuity Pathway Analysis. Full lists of all pathways for both low- and high-HEWAF exposures can be found in Tables S8–S12.

Figure 2. (A) Immune system and (B) cardiovascular system and Ca2+ homeostasis functions, as well as associated genes, that were predicted to be altered in mahi-mahi epidermal mucus following low-HEWAF (?PAH = 16.55 ?g/L) exposure based on analysis with IPA.

The authors studied, using modern technology, 194,282 fish genes in the mucus barrier.

They found:

Analysis of differentially expressed transcripts showed that the mucosal transcriptome was significantly altered following PAH exposure. There were 501 differentially expressed transcripts in the low-HEWAF exposure (227 upregulated, 274 downregulated) and 196 differentially expressed transcripts in the high-HEWAF exposure (121 downregulated, 75 upregulated) (Figure 1B). The low and high treatments shared 136 of the same differentially expressed transcripts (Figure S1), suggesting common transcriptional responses occur within the range of PAH concentrations tested. Cytochrome P450 enzymes (cyp1a1 and cyp1b1) are well-established biomarkers of PAH exposure27 and were among the most highly upregulated transcripts in both the low- and high-HEWAF exposures (Table S7). The efficacy of cyp1a1 induction as a biomarker for PAH exposure has also been examined with other nonlethal sampling methods, with greater cyp1a1 upregulation observed in the caudal fin than in the liver of marine diesel-exposed juvenile coho salmon (Oncorhynchus kisutch).28 Thus, upregulation of cyp1a1 appears to show a robust molecular response using nonlethal sampling methods and may be a useful biomarker candidate for PAH exposure...

... Together, our data suggest that mucosal mRNA abundance may be indicative of whole-animal changes in immune-related function in PAH-exposed fish. IPA also predicted alterations in toxicity functions induced by oil exposure. The top-ranked toxicity functions in the low- HEWAF exposure were liver fibrosis, liver hyperplasia, congenital heart anomaly, and cardiac enlargement (Figure 1C and Table S12). Similarly, liver enlargement, pulmonary hypertension, liver hyperbilirubinemia, and liver hyperplasia were the top-ranked toxicity functions in the high-HWAF exposure. Of all toxicity functions, 17 cardiac functions were predicted to be altered in the low-HEWAF exposure and 11 in the high-HEWAF exposure, with many overlapping categories such as cardiac enlargement, cardiac arrhythmia, cardiac fibrosis, and cardiac necrosis/cell death (Table S12). In addition, there was a predicted inhibition of cardiac muscle function, cardiac muscle contractility, and abnormality of the heart ventricle (Figure 2B), which are cardiac phenotypes known to be altered by crude oil-derived PAH exposure in fish.37,38 Alterations in Ca2+ homeostasis were also predicted from the mucus transcriptional profile, such as decreased mobilization of Ca2+ and an increased quantity of Ca2+ (Figure 2B). Transcripts of ryanodine receptor 2 (ryr2), the primary mediator of calcium-induced Ca2+ release required for cardiomyocyte contraction, were upregulated in the mucus and have also been shown to be dysregulated in oil-exposed mahi-mahi and Atlantic haddock (Melanogrammus aeglef inus) embryos (Table S11).39,40

IPA here refers to "Ingenuity Pathway Analysis" a bioinformatics software tool. IPA, Qiagen

The authors state that to their knowledge, this is the first paper to look at this particular pathway in determining the exposome of oil spills on marine life.

This paper will get no attention from our distracted media with its selective attention, the same media that gave the intellectually and morally challenged awful criminal Donald J. Trump the White House, "...because...her emails..."

In reality the "election" of Donald J. Trump is a trivial, if wholly unfortunate, blip in world history. The destruction of the planetary atmosphere and oceans by dangerous fossil fuels like, but not limited to, petroleum, "...because...Fukushima..." is not trivial.

I wish you a pleasant and safe Friday the 13th.

September 8, 2019

Unexpectedly Increased Particle Emissions from the Steel Industry Using Desulfurization Technology.

The paper I'll discuss briefly in this post is this one: Unexpectedly Increased Particle Emissions from the Steel Industry Determined by Wet/Semidry/Dry Flue Gas Desulfurization Technologies (Li et al, Environ. Sci. Technol. 2019, 53, 17, 10361-10370)

Although extreme weather is likely to overtake it in the near future, the deadliest component of dangerous fossil fuel waste has been air pollution, which kills 7 million people per year, a portion of the death toll resulting not from the combustion of dangerous fossil fuels, although they dominate air pollution, but from the combustion of biomass. The chief component of air pollution that kills people is particulate matter, although the acid gases (sulfur oxides and nitrogen oxides) and ozone also contribute on a fairly grand scale.

There are many technologies for addressing sulfur oxides and I've written about some here recently. Not all dangerous fossil fuels are consumed for power plants and transport devices; some are consumed for material usage. The paper under current discussion suggests that there is no free lunch, using one technology can impact others.

From the introduction:

Severe haze pollution associated with fine particulate matter (PM), i.e., PM2.5 (PM with an aerodynamic diameter less than 2.5 ?m), has frequently occurred in China in the past 2 decades.(1?3) Aiming to reduce PM emissions from anthropogenic sources and improve air quality, the Chinese government has promulgated strict regulations and standards for most major emission sources and updated them every few years. The strictest regulation, also called the “ultralow-emission” standard, has been implemented for pollutant emissions from coal-fired power plants (CFPPs) since 2014.(4) By the end of 2017, approximately 71% of CFPPs had already met the ultralow-emission standard (PM < 10 mg/Nm3, SO2 < 35 mg/Nm3, and NOx < 50 mg/Nm3) by employing various ultralow-emission technologies. Ultralow-emission technologies for high-capacity CFPPs mainly include selective catalytic reduction (SCR), electrostatic precipitators (ESPs), and flue gas desulfurization (FGD) combined with wet ESPs, while air pollution control devices (APCDs) for low-capacity CFPPs are more diverse, including circulating fluidized bed (CFB)-FGD, selective noncatalytic reduction (SNCR), electrostatic fabric filters (FFs), and semidry limestone FGD.(5?9) As a benefit of the ultralow-emission standard, the amounts of the pollutants PM, SO2, and NOx emitted from CFPPs in 2017 were approximately 18.6, 70.0, and 46.8% less than those in 2013, respectively.(10)

Pollutant emissions from the nonpower industry have recently attracted increasing attention as CFPPs have significantly reduced their emissions, especially those from one of the major industrial sources, i.e., steel plants.(11?13) A total of 17.1–36.9% of the atmospheric PM2.5 in many industrial cities has been attributed to emissions from steel plants, as suggested by source apportionment investigations.(14?16) China has been the largest steel producer in the world since 1996 (837.7 Mt in 2017, approximately 49.2% of the total production in the world).(17,18)Figure S1 shows that the relative contribution of primary PM2.5 emissions from the steel industry to total anthropogenic emissions grew from 5.4 to 8.2% from 2005 to 2014 in mainland China, while the relative contribution from CFPPs decreased from 9.5 to 5.1% in the same period, mainly attributed to the ultralow-emission requirement. Because steel emission standards lagged behind those for CFPPs during this period, the steel industry has emitted more PM2.5 than CFPPs since 2008.(17,18) Aiming to improve local air quality, Hebei Province in North China has implemented an ultralow-emission standard for steel plants starting in 2019.(19) The emission parameters for sinter flue gas in the Hebei ultralow-emission standard are the same as those for CFPPs. Although there is still no national standard for steel plants similar to the ultralow-emission standard for CFPPs deployed in mainland China, the detailed requirements of pollutant emissions for the steel industry have recently been under discussion with regard to standard feasibility and flue gas complexity.

The whole iron and steel producing process, mainly including sintering/pelletizing facilities, blast furnaces, basic oxygen furnaces, electric arc furnaces, and steelmaking furnaces, can generate pollutant emissions.(20,21) The sintering process is the major emission source of most pollutants, including PM, SO2, and NOx, with relative contributions of approximately 30–45, 70, and 90%, respectively, in the whole process.(13,22) Sintering flue gases are generally much more complex than those of CFPPs, exhibiting traits such as variable concentrations/compositions of pollutants, including SO2 and unknown corrosive gases, large temperature fluctuations ranging from 80 to 180 °C, and high variations in oxygen content ranging from approximately 10 to 15%...

It appears that desulfurization technologies designed to address acid gases have had an effect on the particulate emissions.

The wet flue gas desulfurization discussed herein involves the use of limestone and ammonia.

Some pictures from the text:

The caption:

Figure 1. Schematic configuration of APCDs and sampling sites. (a) Limestone and ammonia WFGD system combined with a WESP. (b) Semidry CFB-FGD system combined with an FF. (c) Activated coke dry FGD system

The caption:

Figure 2. Mass concentrations of PMs (a) and species concentrations in PM2.5. WSIs (b), elements (c), and carbonaceous components (d) at the FGD inlets/outlets of the five tested sinters. Note: “Other” WSIs include F–, Br–, NO3–, Na+, and Mg2+; HMs include Mn, Cd, V, Cr, Ni, Cu, Zn, As, and Pb; OC1-3 is the sum of OC1, OC2, and OC3; other elements include P, Sn, Sb, Sc, Ti, Co, Se, and Br.

The caption:

Figure 3. PSDs of PM sampled at the inlets (black line) and the outlets of the five tested FGD systems via high-temperature DLPI+.

The caption:

Figure 4. Chemical composition of segregated-size PMs collected at (a) the FGD inlet (S-1,2,3) and 3 stacks after different FGD systems: (b) limestone, (c) ammonia, and (d) activated coke. The PM was sampled via high-temperature DLPI+.

The caption:

Figure 5. Relative contributions of desulfurization byproducts with major chemical compositions and primary PMs from various FGD processes ((a) limestone, (b) ammonia, (c) activated coke, and (d) CFB) in averaged PM2.5 emissions in flue gases at stacks.

It must be said however, that the authors state that it is not clear that the particulates involved desulfurization technology while contributing to Chinese haze, are not the normal carcinogens associated with coking.

Some text:

The FGD system, an end-of-pipe technology before the stack currently used in the steel and iron industry, determines the emission characteristics of PM to different degrees. WFGD systems carry part of the desulfurization slurry and the water-soluble byproducts, which contribute to the emitted PM concentration after desulfurization and subsequent WESP treatment. Compared to the limestone WFGD, the ammonia WFGD system contributes a higher mass ratio of emitted PMs after desulfurization due to the high solubility of its byproducts and slurry, as well as the heterogeneous byproducts from the reaction between the desulfurizers and acid gaseous species. The semidry and dry FGD systems remove pre-existing particles from the FGD inlets with high efficiency, mainly via physical processes of collision and filtration, while the number of new particles in the FGD devices is directly increased by powders of the desulfurizers and their byproducts.

Figure 5 summarizes the relative contributions of the newly generated components from the FGD systems to PM emissions in the stack. The estimation of newly generated components originating from FGD systems is estimated based on the assumption of the most abundant metal elements (i.e., K and Fe), which are increased by FGD desulfurizers and their byproducts (see the description in the Supporting Information text). Relative mass ratios of 16.5, 63.4, 59.4, and 70.7% in the emitted PM2.5 components are replaced by FGD desulfurizers and their byproducts for limestone WFGD, ammonia WFGD, semidry CFB-GFD, and activated coke dry FGD systems, respectively. The 16.5% replaced components of PM2.5 in the limestone WFGD outlet are occupied by SO42– (9.1%) and Ca (2.3%), while the 63.4% in the ammonia WFGD outlet are dominated by SO42– (43.1%) and NH4+ (14.2%). The 59.4% increase in components in the CFB semidry FGD outlet was mainly attributed to Ca (22.6%) and SO42– (13.1%), and the higher proportions of other compounds may be derived from impurities of the desulfurizer itself or unreacted hydrated lime. The PM2.5 in the activated coke dry FGD outlet possesses a high ratio of EC (39.9%), OC (14.4%), and NH4+ (14.2%). The proportion of byproducts in PM2.5 in the ammonia WFGD, activated coke dry FGD and CFB semidry FGD is over 60%, but this is not the case in the limestone WFGD. The smaller effect on PM2.5 component characteristics at the limestone WFGD outlet could be attributed to its relatively mature desulfurization process (optimal size of spraying slurry droplets) and the efficiency of removing entrained droplets of enriched byproducts by its demister and WESP. Limestone WFGD is the dominated technology (about 90%) for reducing SO2 in CFPPs. Since the concentration of PM is greatly influenced by the scouring intensity of desulfurization slurry and the effect of flue gas carrying. High-efficiency WESP has been commonly installed in front of the stack to effectively reduce the final PM emission to meet the “ultralow-emission standard” in CFPPs recently.(5) Compared to that of CFPPs, more attention about the newly generated components from the FGD systems to PM emissions should be paid for the steel industry.

Interesting.

In any case, the steel industry is an environmental problem that is not generally addressed in some of the wishful thinking we hear about climate change.

Have a pleasant Sunday evening.

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