Mouse NRF2 loss recapitulates heritable impacts of paternal cigarette smoke exposure in next-generation offspring

As these GEITP pages have often stated, any trait (phenotype) reflects contributions of: genetics (differences in DNA sequence); epigenetic factors (chromosomal events independent of DNA sequence: DNA methylation, RNA interference, histone modifications, and chromatin remodeling); environmental effects (smoking, diet, lifestyle); endogenous influences (kidney or cardiopulmonary disorders); and each person’s microbiome. The topic today fits well with the theme of gene-environment interactions. The environmental “signal” is cigarette smoke exposure — in the father’s lungs. The genes (actually, in this case, an epigenetic factor = DNA methylation) that “respond to this signal” are in the children — of the offspring that had been exposed in utero (!!). This phenonmenon is called transgenerational imprinting, and there are known examples reported in humans as well as mice.

Paternal cigarette smoking has been linked to increased risk of several diseases in the father’s offspring, as well as his grandchildren (e.g. obesity, cancer, behavioral disorders), but the mechanisms by which this occurs remain unclear. How does cigarette smoke exposure, originating in the father’s lungs, lead to heritable (i.e. passed on to the subsequent generation) health problems from the offspring that had been in the mother’s uterus at the time? Authors [see attached article] found that paternal cigarette smoke exposure causes significant changes in gene expression and DNA methylation in the brains of the unexposed grandchildren.

Authors hypothesized that the observed heritable impacts were likely associated with systemic oxidative stress. When they examined epigenetic and gene expression patterns in mice that were null for the Nfe2l2 (alias = Nrf2) gene (a mouse model known to be hypersensitive to oxidative stress), many of the observed outcomes from paternal cigarette-smoke exposure were reiterated — including impacts on epigenetic marks and gene expression. Male mice comprised two groups (cigarette-smoking exposed vs nonexposed), and the experimental group was exposed to the body mass-adjusted equivalent of 10–20 cigarettes per day, 5 days per week over a period of 60 days (corresponding to two complete cycles of spermatogenesis). The cigarette-smoke-exposed offspring (and control mice) were then bred to unexposed females, and their offspring were analyzed for phenotypic and molecular measures.

The nuclear factor (erythroid-derived-2)-like-2 (NFE2L2) pathway is one of the primary cellular defenses against cytotoxic effects of oxidative stress; thus, to investigate the mode by which cigarette-smoke-induced epigenetic changes occur, authors used the Nfe2l2-null mouse model, which has compromised antioxidant capacity. Consistent with previous papers in the literature, both wild-type (WT) and Nfe2l2(-/-) offspring — whose fathers had been exposed to cigarette smoke — weighed significantly less than non-exposed control animals. Sperm concentration and motility were not significantly affected by cigarette-smoke exposure, but sperm concentration was lower in Nfe2l2(-/-) than WT males, and conception was significantly delayed in cigarette-smoke-exposed Nfe2l2(-/-) mice compared with unexposed

Nfe2l2(-/-) mice.

Authors thus found that paternal smoking is associated with changes in the methylated DNA (DNAme) pattern and gene expression pattern in prefrontal cortex of the offspring’s offspring. Importantly, paternal sperm DNAme changes are distinctly different from the DNAme changes that were detected in prefrontal cortex of the grandchildren, indicating that the observed DNAme changes in sperm are not directly inherited, but rather via additional steps in the process of transgenerational imprinting. In addition, the changes in sperm DNAme associated with cigarette-smoke exposure were not observed in sperm of unexposed offspring — suggesting that the effects are likely not maintained across multiple generations. These results suggest that oxidative stress is an important mechanism by which heritable negative impacts of paternal cigarette smoking arise.

DwN

[P.S. This publication takes the record — in this PLoS Genet journal — for the poorest-ever-written and least-clear descriptions of what these TWELVE authors had actually carried out versus how they explained what they had done.] ☹

Plos Genet June 2020; 16: e1008756

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Origin and the elaboration of a major evolutionary transition in individuality

This topic fits nicely the theme of gene-environment interactions — the “environmental signal” is the life cycle of Camponotini (ant tribe containing two extinct genera and eight extant genera — including the carpenter ant); the “response to the signal” is the symbiotic decision (during evolution) of Biochmannia bacteria to join the ant in an obligate endosymbiosis relationship [“obligate” means that either the endosymbiont or the host cannot survive without the other (e.g. gutless marine worms of the genus Riftia which get nutrition from their endosymbiotic bacteria); the most common examples of obligate endosymbiosis are mitochondria in animal cells and chloroplasts in plant cells] — which is believed to have contributed to the ecological and evolutionary success of these two organisms. This might also be called a form of “adaptation.” Obligate endosymbiosis (in which distantly related species integrate to form a single replicating individual) represents a major evolutionary transition in individuality of an animal or plant.

Phylogenetic evidence suggests that the ancestor of Blochmannia was horizontally transferred from hemipteran bugs (a distantly related order of insects) to the most recent common ancestor of the Camponotini ~51 million years ago(!!). Blochmannia enhances nutrition by increasing amino acid synthesis, which can regulate the size of worker ants; ants, in turn, provide Blochmannia with a protected cellular environment for proliferation and to ensure strict vertical transmission of these bacteria through the germline. Consequently, Blochmannia and Camponotini have co-evolved and their phylogenies are congruent [see Fig. 4a of attached article as an excellent illustration of this evolutionary convergence].

In ants, wasps and flies, the germplasm is a maternally inherited region of cytoplasm — localized to the posterior pole of oocytes and freshly laid eggs — where it has a dual function in specifying the germline and the embryonic posterior. The mRNAs and/or proteins of a group of highly conserved ‘germline genes’ are localized together in the germplasm. To investigate whether integration of Blochmannia into Camponotini influences the germplasm, authors [see attached article] first determined the localization of mRNAs or proteins of germline genes in freshly laid eggs of Lasius niger (an early-branching species that is in the same subfamily as the Camponotini, but that lacks Blochmannia); in L. niger, authors found that three germline genes localize in a single germplasm at the posterior pole (similar to other ants, wasps and flies). These three germline genes in Camponotus floridanus (a species in Camponotini having germplasm surrounded by Blochmannia), also localized in a single germplasm at the posterior pole in oocytes.

However — as the oocyte transitioned to a freshly laid egg — nine germline genes (mRNAs or proteins) localized in one of four subcellular locations (which authors named “zones 1, 2, 3 and 4”) [see paper for details of these zones]. At a later stage, after the egg cellularizes and has initiated zygotic expression (the cellular blastoderm stage), the products of these nine genes persisted in these four zones. In both freshly laid and later-stage eggs, localization and expression of mRNAs or proteins of germline genes is combinatorial — most are present in all four zones, but nos mRNA is only in two zones, and osk mRNA is only in one zone. Moreover, localization of these mRNAs or proteins is also dynamic (in later-stage eggs, the number of zones in which nos mRNA is present increases to three, and to two for osk mRNA — but the number of zones in which smaug mRNA is present decreases from four to three). This combinatorial and dynamic localization shows that these four zones are not identical and suggests that they have distinct roles in integrating Blochmannia into the ant tissues during embryogenesis; because the freshly laid egg is a single host cell, evolution of these four distinct zones is the result of changes in the subcellular localization of maternally inherited mRNAs and proteins.

Authors therefore provided evidence for the origin and elaboration of developmental integration between Blochmannia and Camponotini in a phylogenetic tree (see Fig. 4b of attached article]. In step 1 (pre-existing capacity), a novel zone (zone 3) evolved to have a role in embryonic patterning — before the origin of this developmental integration; this event led to a pre-existing capacity to localize mRNAs and proteins into novel subcellular locations, which was subsequently co-opted to facilitate integration of Blochmannia into the Camponotini.

The Hox genes Abdominal A (abdA) and Ultrabithorax (Ubx) — which, in arthropods, normally function to differentiate abdominal and thoracic segments after they form — were rewired in the Camponotini also to regulate germline genes early in development. Consequently, the mRNAs and proteins of these Hox genes are expressed maternally and colocalize at a subcellular level with those of germline genes in the germplasm and three novel locations in the freshly laid egg. Blochmannia bacteria then selectively regulate these mRNAs and proteins to make each of these four locations functionally distinct — creating a system of coordinates in the embryo in which each location performs a different function to integrate Blochmannia into the Camponotini (!!). 😊

DwN

Nature 10 Sept 2020; 585: 239-244

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Spontaneous generation of prions and transmissible PrP amyloid in a humanized transgenic mouse model of A117V Gerstmann-Sträussler-Scheinker (GSS)

“Consensus science” is the risky situation whereby “a majority of ‘scientists’ might agree upon a ‘fact’ they fervently believe to be true.” The consensus may or may not turn out to be confirmed by further research, but we should remember that science is never completely irrefutable. For example, “mad cow disease” [and the human equivalent, CJD (Creutzfeldt-Jakob Disease)] — was a degenerative brain disease of unknown cause. After more than a decade of studies, neurologist Stanley Prusiner reported in 1982 that these diseases were caused by a virus-like protein, which he named “prion” (derived from “protein” and “infectious”). He was ridiculed by at least 99% of the scientific world, because “viruses are well known always to comprise DNA or RNA.” Prusiner persisted, however, because he was convinced the consensus was wrong. In 1997 he was awarded the Nobel Prize for Medicine or Physiology for his novel discovery; prions are now realized to affect tissues other than brain and, in fact, are found even in lower organisms — such as yeast…!! ☹

Prions are known to cause other fatal neurodegenerative diseases in mammals, such as scrapie in sheep and goats, and bovine spongiform encephalopathy (BSE) in cattle. Prions are unique pathogens in that they are composed of infectious assemblies of misfolded host-encoded prion protein (PrP). Prions propagate via seeded protein polymerization (a process that involves addition of PrP monomers to an elongating assembly of misfolded PrP chains, followed by fission of the polymer to produce more “seeds”). Human prion diseases are associated with a range of clinical presentations — classified by both clinico-pathological syndrome and etiology. About 15% of cases are associated with autosomal dominant pathogenic mutations in the human prion protein gene (PRNP), and, to date, more than 40 mutations have been described. How pathogenic mutations in PRNP cause inherited prion disease has yet to be resolved (however, in most cases, the mutation is thought to lead to spontaneous conformational change in the expressed protein, leading to the generation of disease-related PrP assemblies that propagate by seeded protein misfolding).

Many studies of acquired or sporadic CJD indicate that a residue-129 polymorphism of human PrP critically dictates thermodynamic preferences for PrP assemblies associated with human distinct prion strains; yet, the full spectrum of effects that different pathogenic PRNP mutations have — remains unclear. Notably, a common feature of PRNP point mutations associated with conspicuous amyloid PrP plaque deposition in brain — is that the expressed full-length mutant PrP forms two distinct disease-related assemblies of misfolded PrP: [a] one assembly forms N-terminally truncated protease-resistant fragments that correspond to those generated from classical PrP 27–30, which is enriched in brain areas showing synaptic PrP deposition, spongiform vacuolation, and neurodegeneration; [b] the other disease-associated assembly forms smaller N- and C-terminally truncated protease-resistant fragments associated with PrP amyloid plaques.

The proposed mechanism is that the mutation predisposes to conformational change in the expressed protein, leading to the generation of disease-related multichain PrP assemblies that propagate by seeded protein misfolding. Despite considerable experimental support for this hypothesis — until now, spontaneous formation of disease-relevant transmissible PrP assemblies in transgenic models expressing only mutant human PrP has not been demonstrated. Authors [see attached article] report findings from transgenic mice that express human PrP 117V on a mouse PrP null background (117VV Tg30 mice), which models the PRNP A117V (alanine-to-valine) mutation causing inherited prion diseases, including the Gerstmann-Sträussler-Scheinker (GSS) disease phenotype in humans.

By studying brain samples from uninoculated groups of mice, authors discovered that some elderly mice (> 475 days old) spontaneously generated abnormal PrP assemblies, which — after inoculation into further groups of 117VV Tg30 mice — produced a molecular and neuropathological phenotype consistent with that seen after transmission of brain isolates from inherited prion disease A117V patients to the same mice. Authors believe this 117VV Tg30 mouse line is the first transgenic model expressing only mutant human PrP to show spontaneous generation of transmissible PrP assemblies that directly mirror those generated in an inherited clinical prion disease. 😊😊

DwN

PLoS Biol June 2020; 18: e3000725

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Combined Utility of Many Disease and Risk Factor Polygenic Risk Scores (PRS) for Stratifying Risk of All-Cause Mortality; and of Colorectal Cancer

This topic involves heavy population genetics and genomics, so bear with me. Genome-wide association studies (GWAS) first began in ~2005, and the number of GWAS has exploded ever since. Fundamentally, researchers choose a phenotype (trait) and then sequence the genomes of thousands of subjects having the trait, and compare those data with genomes of thousands of controls without the trait. Usually, the phenotype is a gradient (e.g. height, body mass index, IQ) in which a quantitative trait exhibits a distribution (often a bell-shaped curve) between two extremes.

GWAS have been performed for studies of genetic differences in drug response, and in response to environmental toxicants — as well as studies of single-nucleotide variants (SNVs) associated with complex diseases (multifactorial traits such as obesity, heart disease, cancer, schizophrenia). Consequently, increasingly large sample sizes have led to discovery of thousands of SNVs associated with individual traits, including complex diseases and risk factors for disease. Analyses of polygenicity of a variety of traits have further indicated that many individual traits are likely to be associated with thousands, to tens of thousands, of SNVs (located in and near genes) — each having a very small-effect contribution on the phenotype.

Thus, in the latest advancement in this field of population genomics, much attention has been paid to the usefulness of polygenic risk scores (PRS) — which represent the genetic burden of a given trait; the long-term (highly optimistic) plan is to develop strategies for risk-based intervention through lifestyle modification, screening, and drug therapy. A PRS for a given trait is typically defined as “a weighted sum of a set of germline SNVs, in which the weight for each SNV corresponds to an estimate of the strength of association between the SNV and the trait.”

Recent studies indicate that, whereas PRS tend to have “modest predictive capacity overall”, they have the potential to offer “substantial stratification of a population” into distinct levels of risk for some common diseases (e.g. coronary artery disease, autism spectrum disorder, breast cancer). Clearly there is ongoing debate regarding the utility of PRS in clinical practice. However, PRS can be more robust, and with more cost-efficient tools for risk stratification, than other biomarkers and risk factors; in particular, PRS do not change over time (they measure germline SNVs and thus need to be measured only once). In addition, the risk associated with PRS for different traits — appears in many cases to be fairly consistent over an individual’s life course, and time-varying lifestyle and clinical factors tend to act in a multiplicative way on baseline genetic risk. Furthermore, if genome-wide genotype and/or sequencing data are available on an individual, those same data can be used to evaluate the PRS for a large number of traits simultaneously. Thus, beyond the use of PRS for prevention of specific diseases, it is important to evaluate their utility for broad health outcomes, particularly if PRS are to be used in routine health care.

The two studies [see attached] both deal with PRS; the first one describes SNVs that contribute to “all-cause mortality” and the second one concerns “colorectal cancer.”

While a small number of SNVs associated with lifespan have been identified, no study to date has systematically evaluated the ability of emerging PRS for life-threatening diseases and mortality risk factors to predict mortality. Using data from the UK Biobank to combine PRS for 13 diseases and 12 mortality risk factors into sex-specific composite PRS (cPRS), authors [see first paper] estimated differences in life expectancy — between the top and bottom 5% of the cPRS — to ~4.79 years and ~6.75 years for women and men, respectively. These associations were substantially attenuated, after adjusting for non-genetic mortality risk factors measured at study entry (i.e. middle-age for most participants). Authors naïvely suggest that “the cPRS may be useful in counseling younger individuals at higher genetic risk of mortality on modification of non-genetic factors.” [Hah. ☹]

Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low versus high risk of developing CRC, because they can then be offered targeted screening and interventions to address risks of developing disease (if they are in a high-risk group) versus avoid unnecessary screening and interventions (if they are in a low-risk group). Authors [see second paper] compared 55,105 CRC-affected patients with 65,079 control subjects of European ancestry. Their PRS was built in three ways — using [a] 140 previously identified and validated CRC loci; [b] SNV selection based on linkage disequilibrium (LD = the non-random association of alleles at different loci in a given population) clumping, followed by machine-learning approaches; and [c] LDpred (a Bayesian approach for genome-wide risk prediction). Authors also tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected patients. The discriminatory accuracy — calculated by the age- and sex-adjusted area-under-the-(receiver operating characteristics)-curve (AUC), was highest for the LDpred-derived PRS (AUC ~0.654) including nearly 1.2 million SNVs (the proportion of causal genetic SNVs for CRC assumed to be 0.003), whereas the PRS of the 140 known SNVs identified from GWAS had the lowest AUC (~0.629).

Based on the LDpred-derived PRS, authors were able to identify 30% of individuals without a family history (i.e. having risk for CRC similar to those with a family history of CRC) — whereas the PRS, based on known GWAS SNVs identified only the top 10% as having a similar relative risk; therefore, ~90% of these individuals have no family history and would have been considered “average risk” under current screening guidelines, but might benefit from earlier screening…!! This breakthrough study demonstrates to these GEITP pages that PRS might actually offer a valuable method for risk-stratified CRC screening. Might other targeted interventions be demonstrated soon…?? 😊

DwN

Am J Hum Genet Sept 2020; 107: 418-431 & 432-444

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Interesting New COVID-19 Theory Emerging from Supercomputer Analysis: the Bradykinin Hypothesis

Interesting New COVID-19 Theory Emerging from Supercomputer Analysis
A closer look at the Bradykinin hypothesis
Thomas Smith
Aug 31· 2020

3d rendering of multiple coronavirus.

Earlier this summer, the Summit supercomputer at Oak Ridge National Lab in Tennessee set about crunching data on more than 40,000 genes from 17,000 genetic samples in an effort to better understand Covid-19. Summit is the second-fastest computer in the world, but the process — which involved analyzing 2.5 billion genetic combinations — still took more than a week.

When Summit was done, researchers analyzed the results. It was, in the words of Dr. Daniel Jacobson, lead researcher and chief scientist for computational systems biology at Oak Ridge, a “eureka moment.” The computer had revealed a new theory about how Covid-19 impacts the body: the bradykinin hypothesis. The hypothesis provides a model that explains many aspects of Covid-19, including some of its most bizarre symptoms. It also suggests 10-plus potential treatments, many of which are already FDA approved. Jacobson’s group published their results in a paper in the journal eLife in early July.

According to the team’s findings, a Covid-19 infection generally begins when the virus enters the body through ACE2 receptors in the nose (the receptors, which the virus is known to target, are abundant there). The virus then proceeds through the body, entering cells in other places where ACE2 is also present: the intestines, kidneys, and heart. This likely accounts for at least some of the disease’s cardiac and GI symptoms.

But once Covid-19 has established itself in the body, things start to get really interesting. According to Jacobson’s group, the data Summit analyzed shows that Covid-19 isn’t content to simply infect cells that already express lots of ACE2 receptors. Instead, it actively hijacks the body’s own systems, tricking it into up-regulating ACE2 receptors in places where they’re usually expressed at low or medium levels, including the lungs.

In this sense, Covid-19 is like a burglar who slips in your unlocked second-floor window and starts to ransack your house. Once inside, though, they don’t just take your stuff — they also throw open all your doors and windows so their accomplices can rush in and help pillage more efficiently.

The renin–angiotensin system (RAS) controls many aspects of the circulatory system, including the body’s levels of a chemical called bradykinin, which normally helps to regulate blood pressure. According to the team’s analysis, when the virus tweaks the RAS, it causes the body’s mechanisms for regulating bradykinin to go haywire. Bradykinin receptors are resensitized, and the body also stops effectively breaking down bradykinin. (ACE normally degrades bradykinin, but when the virus downregulates it, it can’t do this as effectively.)

The end result, the researchers say, is to release a bradykinin storm — a massive, runaway buildup of bradykinin in the body. According to the bradykinin hypothesis, it’s this storm that is ultimately responsible for many of Covid-19’s deadly effects. Jacobson’s team says in their paper that “the pathology of Covid-19 is likely the result of bradykinin storms rather than cytokine storms,” which had been previously identified in Covid-19 patients, but that “the two may be intricately linked.” Other papers had previously identified bradykinin storms as a possible cause of Covid-19’s pathologies.

As bradykinin builds up in the body, it dramatically increases vascular permeability. In short, it makes your blood vessels leaky. This aligns with recent clinical data, which increasingly views Covid-19 primarily as a vascular disease, rather than a respiratory one. But Covid-19 still has a massive effect on the lungs. As blood vessels start to leak due to a bradykinin storm, the researchers say, the lungs can fill with fluid. Immune cells also leak out into the lungs, Jacobson’s team found, causing inflammation.

And Covid-19 has another especially insidious trick. Through another pathway, the team’s data shows, it increases production of hyaluronic acid (HLA) in the lungs. HLA is often used in soaps and lotions for its ability to absorb more than 1,000 times its weight in fluid. When it combines with fluid leaking into the lungs, the results are disastrous: It forms a hydrogel, which can fill the lungs in some patients. According to Jacobson, once this happens, “it’s like trying to breathe through Jell-O.”

This may explain why ventilators have proven less effective in treating advanced Covid-19 than doctors originally expected, based on experiences with other viruses. “It reaches a point where regardless of how much oxygen you pump in, it doesn’t matter, because the alveoli in the lungs are filled with this hydrogel,” Jacobson says. “The lungs become like a water balloon.” Patients can suffocate even while receiving full breathing support.

The bradykinin hypothesis also extends to many of Covid-19’s effects on the heart. About one in five hospitalized Covid-19 patients have damage to their hearts, even if they never had cardiac issues before. Some of this is likely due to the virus infecting the heart directly through its ACE2 receptors. But the RAS also controls aspects of cardiac contractions and blood pressure. According to the researchers, bradykinin storms could create arrhythmias and low blood pressure, which are often seen in Covid-19 patients.

The bradykinin hypothesis also accounts for Covid-19’s neurological effects, which are some of the most surprising and concerning elements of the disease. These symptoms (which include dizziness, seizures, delirium, and stroke) are present in as many as half of hospitalized Covid-19 patients. According to Jacobson and his team, MRI studies in France revealed that many Covid-19 patients have evidence of leaky blood vessels in their brains.

Bradykinin — especially at high doses — can also lead to a breakdown of the blood-brain barrier. Under normal circumstances, this barrier acts as a filter between your brain and the rest of your circulatory system. It lets in the nutrients and small molecules that the brain needs to function, while keeping out toxins and pathogens and keeping the brain’s internal environment tightly regulated.

If bradykinin storms cause the blood-brain barrier to break down, this could allow harmful cells and compounds into the brain, leading to inflammation, potential brain damage, and many of the neurological symptoms Covid-19 patients experience. Jacobson told me, “It is a reasonable hypothesis that many of the neurological symptoms in Covid-19 could be due to an excess of bradykinin. It has been reported that bradykinin would indeed be likely to increase the permeability of the blood-brain barrier. In addition, similar neurological symptoms have been observed in other diseases that result from an excess of bradykinin.”

Increased bradykinin levels could also account for other common Covid-19 symptoms. ACE inhibitors — a class of drugs used to treat high blood pressure — have a similar effect on the RAS system as Covid-19, increasing bradykinin levels. In fact, Jacobson and his team note in their paper that “the virus… acts pharmacologically as an ACE inhibitor” — almost directly mirroring the actions of these drugs.

By acting like a natural ACE inhibitor, Covid-19 may be causing the same effects that hypertensive patients sometimes get when they take blood pressure–lowering drugs. ACE inhibitors are known to cause a dry cough and fatigue, two textbook symptoms of Covid-19. And they can potentially increase blood potassium levels, which has also been observed in Covid-19 patients. The similarities between ACE inhibitor side effects and Covid-19 symptoms strengthen the bradykinin hypothesis, the researchers say.

ACE inhibitors are also known to cause a loss of taste and smell. Jacobson stresses, though, that this symptom is more likely due to the virus “affecting the cells surrounding olfactory nerve cells” than the direct effects of bradykinin.

Though still an emerging theory, the bradykinin hypothesis explains several other of Covid-19’s seemingly bizarre symptoms. Jacobson and his team speculate that leaky vasculature caused by bradykinin storms could be responsible for “Covid toes,” a condition involving swollen, bruised toes that some Covid-19 patients experience. Bradykinin can also mess with the thyroid gland, which could produce the thyroid symptoms recently observed in some patients.

The bradykinin hypothesis could also explain some of the broader demographic patterns of the disease’s spread. The researchers note that some aspects of the RAS system are sex-linked, with proteins for several receptors (such as one called TMSB4X) located on the X chromosome. This means that “women… would have twice the levels of this protein than men,” a result borne out by the researchers’ data. In their paper, Jacobson’s team concludes that this “could explain the lower incidence of Covid-19 induced mortality in women.” A genetic quirk of the RAS could be giving women extra protection against the disease.

The bradykinin hypothesis provides a model that “contributes to a better understanding of Covid-19” and “adds novelty to the existing literature,” according to scientists Frank van de Veerdonk, Jos WM van der Meer, and Roger Little, who peer-reviewed the team’s paper. It predicts nearly all the disease’s symptoms, even ones (like bruises on the toes) that at first appear random, and further suggests new treatments for the disease.

As Jacobson and team point out, several drugs target aspects of the RAS and are already FDA approved to treat other conditions. They could arguably be applied to treating Covid-19 as well. Several, like danazol, stanozolol, and ecallantide, reduce bradykinin production and could potentially stop a deadly bradykinin storm. Others, like icatibant, reduce bradykinin signaling and could blunt its effects once it’s already in the body.

Interestingly, Jacobson’s team also suggests vitamin D as a potentially useful Covid-19 drug. The vitamin is involved in the RAS system and could prove helpful by reducing levels of another compound, known as REN (this gene codes for renin). Again, this could stop potentially deadly bradykinin storms from forming. The researchers note that vitamin D has already been shown to help those with Covid-19. The vitamin is readily available over the counter, and around 20% of the population is deficient. If indeed the vitamin proves effective at reducing the severity of bradykinin storms, it could be an easy, relatively safe way to reduce the severity of the virus.

Other drugs could treat symptoms associated with bradykinin storms. Hymecromone, for example, could reduce hyaluronic acid levels, potentially stopping deadly hydrogels from forming in the lungs. And timbetasin could mimic the mechanism that the researchers believe protects women from more severe Covid-19 infections. All of these potential treatments are speculative, of course, and would need to be studied in a rigorous, controlled environment before their effectiveness could be determined and they could be used more broadly.

Covid-19 stands out for both the scale of its global impact and the apparent randomness of its many symptoms. Physicians have struggled to understand the disease and come up with a unified theory for how it works. Though as of yet unproven, the bradykinin hypothesis provides such a theory. And like all good hypotheses, it also provides specific, testable predictions — in this case, actual drugs that could provide relief to real patients.

The researchers are quick to point out that “the testing of any of these pharmaceutical interventions should be done in well-designed clinical trials.” As to the next step in the process, Jacobson is clear: “We have to get this message out.” His team’s finding won’t cure Covid-19. But if the treatments it points to pan out in the clinic, interventions guided by the bradykinin hypothesis could greatly reduce patients’ suffering — and potentially save lives.

https://elemental.medium.com/a-supercomputer-analyzed-covid-19-and-an-interesting-new-theory-has-emerged-31cb8eba9d63

COMMENT:
After sending this GEITP email yestereday — I downloaded the paper [https://elifesciences.org/articles/59177] to examine for more details (not mentioned in the lay article). The RNA-Seq (transcriptomics) expression data are derived from the bronchoalveolar lavage (BAL) of nine symptomatic (i.e. quite ill) COVID-19 patients, compared with that of 40 controls (i.e. COVID-19 negative). The patient metadata can be found in Suppl. Table 1.

Suppl. Table 2 [see attached Excel File] lists the differential gene expression values for 50 genes discussed in this paper. Stimulation of eicosanoid production should include one or more of the arachidonate lipoxygenase (ALOX) genes — which I don’t see among these “most-interesting 50 genes” listed, George. ☹ But, perhaps one can find genes involved in eicosanoid biosynthesis among the raw data not reported here. Among the genes listed in Suppl. Table 2, there is enough information that someone, looking for a research direction, could probably spend many years studying. 😊

DwN

Dan

We published a study on bradykinin’s effects on the airway epithelium in 1985. BK stimulates eicosanoid production in the nanoMolar range. We also used autoradiography to demonstrate epithelial bradykinin-binding sites. I was so pleased to read this information in your latest GEITP email. Also, we were able to inhibit some effects with indomethacin. So—that might be why steroids seem to help with COVID-19, whereas they don’t seem to work in other forms of acute lung injury.

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These GEITP pages often cover topics of evolution, including the Great Human Diaspora (i.e. the multiple Homo sapiens migrations out of Africa, between 25,000 and more than 100,000 years ago; these migrations resulted in the five major geographically-isolated subgroups — Africans, East Asians, Oceanians, Europeans and Amerindians). A longstanding controversy about Oceanian history concerns the possibility of prehistoric admixture (i.e. hanky-panky) between Polynesian and Amerindian populations. The early peopling of Polynesia attracted worldwide interest in 1947, when the Norwegian explorer Thor Heyerdahl set sail on the Kon-Tiki expedition to test his migration theory; the crew left Peru on a wooden raft and — after 101 days and a voyage of more than 7,000 kilometers — they reached Polynesian shores, thus proving the possibility of early travel from South America westward to these Pacific islands. Heyerdahl challenged the scientific community’s view that evidence pointed instead to populating Polynesia by people traveling east from Asia; his idea that Polynesia was initially populated by South Americans was generally criticized by scholars. However, the sweet potato (a South American plant) has a long history of cultivation in eastern Polynesia. Previous scientists — investigating this question through genetics — had focused on Easter Island (Rapa Nui). As the Polynesian island closest to the Americas, and the one having the most elaborate megalithic culture (giant heads made of stone), Rapa Nui has been considered a likely locus for contact. High-resolution analyses of human leukocyte antigen (HLA) alleles had revealed an Amerindian component in modern individuals with self-identified Rapanui ancestry. However, in the only two whole-genome sequencing (WGS) studies of Rapanui variation — only one of eight modern individuals, and one of five skeletal remains — was Amerindian DNA found. Thus, these studies reached opposing conclusions about pre-European contact between Polynesian individuals on Rapa Nui and Amerindian individuals. To date, no WGS studies have considered the possibility of pre-European Amerindian contact on other Polynesian islands. Authors [see attached article & editorial] first analyzed 807 individuals from 17 island populations, and 15 Pacific coast Amerindian groups, searching for signs of admixture. Authors then performed high-density WGS analyses of a smaller data set (166 Rapanui and 188 additional individuals from islands spanning the eastern Pacific). They found conclusive evidence for prehistoric contact of Polynesian individuals with Amerindian individuals (~1200 AD) simultaneously with individuals in remote Oceania. This study therefore strongly suggests that a single contact event occurred in eastern Polynesia — before the settlement of Rapa Nui — between Polynesian individuals and an Amerindian group most closely related to the indigenous inhabitants of present-day Colombia. In other words, Thor Heyerdahl’s theory was correct…!! 😊 DwN Nature 23 Jul 2020; 583: 572-577 & Editorial pp 524-525

This paper (in press, Journal of Medical Virology) — provides a very succinct accurate analysis of the structure of the SARS-CoV-2 virus’ mRNA-encoded gene products. Without going overboard with political accusations, authors give several types of evidence for the likelihood that the proximal origin of this virus is not from any animal vector. Follow-up independent analyses of these, and related, data should be interesting to follow closely. 😊

From the URL below, one can download the manuscript.

DwN

LETTER TO THE EDITOR

Open Access
Questions concerning the proximal origin of SARS‐CoV‐2
Murat Seyran et al. (Total of 18 authors)
First published: 03 September 2020
https://doi.org/10.1002/jmv.26478
This article has been accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/jmv.26478
Abstract

There is a consensus that Severe Acute Respiratory Syndrome Coronavirus-2 (SARS‐CoV‐2) originated naturally from bat coronaviruses (CoVs), in particular, RaTG13. However, the SARS‐CoV‐2 host tropism/adaptation pattern has significant discrepancies compared to other CoVs, raising questions concerning the proximal origin of SARS‐CoV‐2.

https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.26478

COMMENT:
I am no virologist, but it seems clear that studies of the evolutionary origins of any organism must focus on nucleic acid sequences, not protein topology. Protein topology might explain WHY a DNA or RNA sequence variant might prove favorable or not, but such studies say little about evolutionary origins.

The bat virus origin of SARS-CoV-2 is strongly supported by sequence similarities with bat and other coronaviruses. The suggestion of a laboratory origin is beguiling to those who favor conspiracy theories, but the SARS-CoV-2 sequence shows no signs of genetic manipulation. Like most ‘conspiracy theories’, these are actually ‘conspiracy hypothesies’, as they never are backed by sufficient data to rise to the level of a true scientific theory (such as evolution or gravity).

Posted in Center for Environmental Genetics | Comments Off on These GEITP pages often cover topics of evolution, including the Great Human Diaspora (i.e. the multiple Homo sapiens migrations out of Africa, between 25,000 and more than 100,000 years ago; these migrations resulted in the five major geographically-isolated subgroups — Africans, East Asians, Oceanians, Europeans and Amerindians). A longstanding controversy about Oceanian history concerns the possibility of prehistoric admixture (i.e. hanky-panky) between Polynesian and Amerindian populations. The early peopling of Polynesia attracted worldwide interest in 1947, when the Norwegian explorer Thor Heyerdahl set sail on the Kon-Tiki expedition to test his migration theory; the crew left Peru on a wooden raft and — after 101 days and a voyage of more than 7,000 kilometers — they reached Polynesian shores, thus proving the possibility of early travel from South America westward to these Pacific islands. Heyerdahl challenged the scientific community’s view that evidence pointed instead to populating Polynesia by people traveling east from Asia; his idea that Polynesia was initially populated by South Americans was generally criticized by scholars. However, the sweet potato (a South American plant) has a long history of cultivation in eastern Polynesia. Previous scientists — investigating this question through genetics — had focused on Easter Island (Rapa Nui). As the Polynesian island closest to the Americas, and the one having the most elaborate megalithic culture (giant heads made of stone), Rapa Nui has been considered a likely locus for contact. High-resolution analyses of human leukocyte antigen (HLA) alleles had revealed an Amerindian component in modern individuals with self-identified Rapanui ancestry. However, in the only two whole-genome sequencing (WGS) studies of Rapanui variation — only one of eight modern individuals, and one of five skeletal remains — was Amerindian DNA found. Thus, these studies reached opposing conclusions about pre-European contact between Polynesian individuals on Rapa Nui and Amerindian individuals. To date, no WGS studies have considered the possibility of pre-European Amerindian contact on other Polynesian islands. Authors [see attached article & editorial] first analyzed 807 individuals from 17 island populations, and 15 Pacific coast Amerindian groups, searching for signs of admixture. Authors then performed high-density WGS analyses of a smaller data set (166 Rapanui and 188 additional individuals from islands spanning the eastern Pacific). They found conclusive evidence for prehistoric contact of Polynesian individuals with Amerindian individuals (~1200 AD) simultaneously with individuals in remote Oceania. This study therefore strongly suggests that a single contact event occurred in eastern Polynesia — before the settlement of Rapa Nui — between Polynesian individuals and an Amerindian group most closely related to the indigenous inhabitants of present-day Colombia. In other words, Thor Heyerdahl’s theory was correct…!! 😊 DwN Nature 23 Jul 2020; 583: 572-577 & Editorial pp 524-525

Kon Tiki — revisited: South American genes found in Polynesia

These GEITP pages often cover topics of evolution, including the Great Human Diaspora (i.e. the multiple Homo sapiens migrations out of Africa, between 25,000 and more than 100,000 years ago; these migrations resulted in the five major geographically-isolated subgroups — Africans, East Asians, Oceanians, Europeans and Amerindians). A longstanding controversy about Oceanian history concerns the possibility of prehistoric admixture (i.e. hanky-panky) between Polynesian and Amerindian populations. The early peopling of Polynesia attracted worldwide interest in 1947, when the Norwegian explorer Thor Heyerdahl set sail on the Kon-Tiki expedition to test his migration theory; the crew left Peru on a wooden raft and — after 101 days and a voyage of more than 7,000 kilometers — they reached Polynesian shores, thus proving the possibility of early travel from South America westward to these Pacific islands. Heyerdahl challenged the scientific community’s view that evidence pointed instead to populating Polynesia by people traveling east from Asia; his idea that Polynesia was initially populated by South Americans was generally criticized by scholars. However, the sweet potato (a South American plant) has a long history of cultivation in eastern Polynesia.

Previous scientists — investigating this question through genetics — had focused on Easter Island (Rapa Nui). As the Polynesian island closest to the Americas, and the one having the most elaborate megalithic culture (giant heads made of stone), Rapa Nui has been considered a likely locus for contact. High-resolution analyses of human leukocyte antigen (HLA) alleles had revealed an Amerindian component in modern individuals with self-identified Rapanui ancestry. However, in the only two whole-genome sequencing (WGS) studies of Rapanui variation — only one of eight modern individuals, and one of five skeletal remains — was Amerindian DNA found. Thus, these studies reached opposing conclusions about pre-European contact between Polynesian individuals on Rapa Nui and Amerindian individuals.

To date, no WGS studies have considered the possibility of pre-European Amerindian contact on other Polynesian islands. Authors [see attached article & editorial] first analyzed 807 individuals from 17 island populations, and 15 Pacific coast Amerindian groups, searching for signs of admixture. Authors then performed high-density WGS analyses of a smaller data set (166 Rapanui and 188 additional individuals from islands spanning the eastern Pacific). They found conclusive evidence for prehistoric contact of Polynesian individuals with Amerindian individuals (~1200 AD) simultaneously with individuals in remote Oceania. This study therefore strongly suggests that a single contact event occurred in eastern Polynesia — before the settlement of Rapa Nui — between Polynesian individuals and an Amerindian group most closely related to the indigenous inhabitants of present-day Colombia. In other words, Thor Heyerdahl’s theory was correct…!! 😊

DwN

Nature 23 Jul 2020; 583: 572-577 & Editorial pp 524-525

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Impact of Environmental Chemicals on the Gut Microbiome

As these GEITP pages continue to emphasize, a trait (phenotype; e.g. height, weight, green eyes, blood pressure, a disease such as schizophrenia or obesity, adverse response to a drug) reflects the contribution of: genetics (DNA sequence differences in genes), epigenetic effects (DNA-sequence independent RNA-interference, DNA-methylation, histone modifications, chromatin remodeling), environmental factors (e.g. diet, lifestyle, smoking history), endogenous influences (e.g. cardiopulmonary or kidney disease), and each person’s unique microbiome. This comprehensive review [attached] updates some of the massive literature on the interaction of environmental factors and the microbiome.

Authors state that humans are exposed to hundreds of chemicals — as evidenced by the fact that more than 300 environmental chemicals and/or their metabolites have been measured in human biological samples. Human exposure to these environmental chemicals is constant, and some of these chemicals have long half-lives in the body and environment. Chemicals such as bisphenols, phthalates, pesticides, persistent organic pollutants (POPs; e.g. polychlorinated biphenyls, polycyclic aromatic hydrocarbons, dioxins), and heavy metals (e.g. lead, mercury, arsenic) have endocrine-disrupting effects that can alter hormonal metabolism. Many of these environmental chemicals are associated with adverse health outcomes, including male and female reproductive and developmental defects, type-2 diabetes, cardiovascular disease, liver disease, obesity, thyroid disorders, and immune dysfunction. Because the gut microbiome influences host metabolism, authors suggest these parent chemicals and metabolites may mediate some of the toxic effects of environmental chemicals by way of the microbiome. With chronic exposure to a mixture of environmental chemicals, authors suggest that it is vital to understand how the gut microbial community might be altered — in response to environmental chemical exposures, and the implications of such changes on health outcomes. Reviewing the literature, authors state that the effects of the environmental chemicals on gut microbiota highly depend on sex and age.

These GEITP pages would conclude that, although it is a wide-ranging review, “importance of the dose” of chemicals is not emphasized. In other words, the fact that “more than 300 environmental chemicals have been measured in human biological samples” largely reflects the ability of new instrumentation to detect such chemicals at increasingly lower levels of concentration. Detection of a chemical in a patient — and associating that with a clinical effect — are two different things. Most of the >160 references cited are studies in various animals using large doses. As Paracelsus wrote (in 1538 AD), “Alle Dinge sind Gift, und nichts ist ohne Gift; allein die dosis machts, daß ein Ding kein Gift sei.” (“All things are poison (toxic) and there is nothing that is not toxic; it is the dose alone that makes something toxic or not toxic”). 😊

DwN

Toxicol Sci Aug 2020; 176: 253–284

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An Estimate of Climate Sensitivity

An Estimate of Climate Sensitivity

Charles Rotter / August 31, 2020

Reposted from edmhdotme

Assuming the logarithmic diminution premise to be appropriate, this diagram indicates:

there is no direct, straight-line relationship between atmospheric CO2 concentration and its influence on temperature
the “Greenhouse” warming effectiveness of CO2 diminishes logarithmically with increasing concentrations, which, as a result, implies:

· at 20 ppmv, ~42% of CO2 warming effectiveness is already taken up

· at 100 ppmv, ~67% of CO2 warming effectiveness is taken up

· at 150 ppmv, the CO2 level of plant / planet viability, ~72% of CO2 warming effectiveness is taken up

· at 280 ppmv, the approximate pre-industrial CO2 level, ~82% of CO2 warming effectiveness is taken up

· at the current level of atmospheric CO2, 410 ppmv, ~88% of CO2 warming effectiveness is taken up

Equilibrium Climate Sensitivity, (ECS), is assessed as the further temperature increase that arises from a doubling of CO2 in the atmosphere
the logarithmic diminution graph shows that a doubling of CO2 from 410 ppmv to 820 ppmv should result in a temperature increase of about +0.35°C, because the warming capability of CO2 is now so close to saturation: this calculation takes no account of feedbacks, which are undeterminable

a rise of +0.35°C would be so marginal as to be undetectable within the noise of Global temperature measurements

such a further doubling of atmospheric CO2 to ~820 ppmv would take more than 150 years at the present rate of CO2 emissions
cooling of the Oceans, again re-absorbing CO2 from the atmosphere — is the only way that atmospheric CO2 levels will decrease; that will only happen in the next coming ~100,000-year glaciation period

life on Earth is dependent on its atmospheric CO2 used by plants via photosynthesis to release oxygen and generate organic compounds
as the present Holocene interglacial epoch advanced the planet warmed, so have warmer Oceans out-gassed CO2 to reach a pre-industrial level of about 280 ppmv
that slow CO2 out-gassing process from warmer Oceans is continuing, and has been supplemented largely by human-caused CO2 emissions since the 1850s from the burning of fossil fuels; thus, the measured CO2 level has now reached about 410 ppmv
Water vapour and clouds in the atmosphere are responsible for the greatest part of the Greenhouse effect
CO2 is a significant “Greenhouse Gas”, even though it is only present in trace amounts, (now ~410 parts per million by volume)
CO2 is considered to be responsible for roughly 10% of the total +~33°C “Greenhouse” effect, or about +3.3°C
plant productivity improves radically with increasing atmospheric CO2, and NASA has reported about +15% more green growth worldwide over the last 50 years — which has enhanced agricultural productivity and enabled greater food supply for a growing global population
plant productivity is hampered by colder weather, and any cooling will lead to agricultural losses.

photosynthesis stops, and plants and therefore life on Earth, can no longer survive — if atmospheric CO2 levels fall below 150 ppmv

When plants first flourished (~400,000 years ago), atmospheric CO2 levels were ~10- to 20-times higher than at present, and no runaway global warming occurred; “20 times higher” would have been 8,200 ppmv.

those high levels of CO2 atmosphere have progressively diminished, with CO2 both being absorbed by the oceans to be sequestered as limestone by ocean life, or converted into fossil fuels
about 20,000 years ago, in the depths of the Last Ice Age, Life on Earth came very close to total annihilation when atmospheric CO2 concentration fell to 180 ppmv, which was only ~15% above its terminal value:

this process is driven by colder oceans being able to absorb more atmospheric CO2 and thatby carbonate being progressively sequestered by marine life as limestone.

This is the way that all life on Earth might be extinguished — during some future ice age — due to atmospheric CO2 starvation.

Therefore, all extra CO2 in the atmosphere today — extends the viability of Life on Earth.

This arithmetic shows that human-made additions of CO2 to the atmosphere can only have very marginal further temperature effect into the next century and beyond.

Climate modellers assert that there is substantial positive temperature feedback from the warming induced by added CO2 which could increase the level of water vapour in the atmosphere. In order to reach the much feared +2°C temperature increase, that feedback from water vapour and clouds would have to be at least 5-fold, or even more, to achieve their higher predictions. There is no evidence of such positive feedbacks and observations show feedback is likely to be marginally negative.

This simple math, and the fact that the warming effect of CO2 is already close to being saturated, shows that any level of future atmospheric CO2 — increased by humankind’s burning of fossil fuels — can never cause Catastrophic Anthropogenic Global Warming.

An estimate of Climate Sensitivity

COMMENT:
Hmm… I thought plant life (as in algae in the sea) happened about a billion years ago??
COMMENT:
Good point. I think the better terminology would be — “When plants first flourished ~400,000 years ago, …”

DwN

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Genetics Steps In — to Help Tell the Story of Human Origins

This very recent article (Sept 2020) from The Scientist was offered to me to share on these GEITP pages. Written in semi-layman terms, the history of Homo sapiens evolution is detailed — which gives some continuity to the various articles that have appeared these past 12+ years in these GEITP pages. For those interested, this will make for enjoyable holiday weekend reading. [Unfortunately, the right edge of the print is missing, so one must guess at the furthest-right words on some lines.] ☹

The article begins with geochronologist Rainer Grün from Australia, and then expands to include hundreds of thousands of years of Homo evolution — including discovery of the Neaderthal and Denisovan sublines of hominids. Whereas the figure on the page “Our History in Africa” shows nine sublines, there is actually fossil evidence for at least 22 known sublines. These “fits and starts” of hominids that arose in various geographical regions, survived for 25,000 or 100,000 years, only to become extinct.

What is already abundantly clear in 2020 is that human evolution was far more complex than previously appreciated by

anthropologists. It was not a streamlined process of australopiths steadily evolving into modern humans, but a messy and haphazard journey that includes interwoven ancestries of many groups, some of which have never been discovered — other than through the genetic traces they left in ancient and modern genomes. Human evolution has a long history; a lot of things happened, and a lot of ancestors have contributed to our genomes today. It’s not going to be a simple story and, in all likelihood, many more intriguing information and surprises are yet to come. 😊

DwN

This exciting article can also be downloaded and printed from the internet:

https://www.the-scientist.com/features/genetics-steps-in-to-help-tell-the-story-of-human-origins-67871?utm_campaign=TS_DAILY%20NEWSLETTER

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