Morphology and genome of a snailfish from the Mariana Trench provide insights into deep-sea adaptation

When organisms (any thing living) are faced with an adverse environment, or when they cope with adversity over long periods of time, their genomes constantly change in order to adapt, improve their survival success (i.e. finding food, avoiding predators, and reproducing). The deepest areas of the ocean (i.e. between 6,000 and 11,000 m) are commonly referred to as the hadal zone, representing about 1–2% of Earth’s benthic region (i.e. ecological zone at the lowest level of any body of water such as an ocean, lake, or stream). These deep-ocean areas are among the most hostile environments on Earth, due to their high hydrostatic pressure, darkness, limited food supply, low temperatures, and hypoxia (low oxygen content). The most conspicuous environmental constraint in the hadal zone is hydrostatic pressure, which increases by 10 atmospheres (atm) per 100 m of depth (thereby reaching ~1,000 atm of pressure in the deepest ocean trenches).

Nevertheless, amazingly, life thrives in these poorly explored realms, which might mimic hostile environments on other planets in our universe. Recent technological advances have prompted a renewed wave of hadal exploration — resulting in discovery of hundreds of deep-dwelling species — including microbes, protists (single-celled organisms like protozoa or simple algae), worms, Porifera (e.g. sponges), Mollusca (e.g. mussel, clam), Echinodermata (coelenterates) Crustacea (e.g. crabs, lobsters, shrimps, krill, barnacles), Cnidaria (e.g. coral, anemones, box jellies, jellyfish) and fishes.

The most common hadal vertebrate species are liparid snailfishes (small tadpole-shaped cold-water fishes with pelvic fins forming a sucker; related to lumpfish and sea snail), which live at the widest depth range of any marine fish family (habitats ranging from intertidal to depths exceeding 8,100 m). Recent studies have shown that snailfish are top predators in the hadal food chain. However, very little is known about the genetic basis and evolutionary history of snailfishes’ adaptation to deep-sea life. Authors [see attached article] sequenced the genome of a snailfish species, Pseudoliparis swirei, found at a depth of 7,415 m. Unlike closely related shallow sea species, P. swirei has transparent, unpigmented skin and scales, thin and incompletely ossified bones, an inflated stomach, and a non-closed skull.

Phylogenetic analyses show that P. swirei diverged from a close relative living near the sea surface about 20 million years ago and has robust genetic diversity. Genomic analyses reveal that: [a] the bone Gla protein (bglap) gene has a frameshift mutation that appears to cause early termination of cartilage calcification; (2) cell membrane fluidity and transport protein activity in P. swirei appear to have been enhanced by changes in protein sequences and gene expansion (i.e. more genes; increased genome size) and (3) the stability of its proteins appear to have been increased by critical mutations in genes encoding the trimethylamine N-oxide-synthesizing enzyme and hsp90 chaperone protein. These data provide insights into morphological, physiological, and molecular evolution of the hadal vertebrates.

DwN

Nature Ecol May 2o19; https://doi.org/10.1038/s41559-019-0864-8

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China’s human-like monkeys spark concerns

This article is just out, from news.com in Australia. These provocative experiments will undoubtedly cause world-wide concern for bioethics meetings and setting up some international rules. 🙁

DwN

China’s human-like monkeys spark concerns

By Natasha Christian news.com.au

A computer scientist — who is credited as a researcher/coauthor on a Chinese medical experiment that saw monkey brains implanted with human genes to make them more human — has slammed the project as ethically unacceptable.

Dr. Martyn Styner, an associate professor at the University of North Carolina, has distanced himself from the experiment after the group of Chinese scientists who led it became the target of a medical ethics debate. Dr. Styner argues the knowledge gained from experimenting with monkey brains in this way was not enough to go through with it.

BRAIN DEVELOPMENT RESEARCH

The research, funded by the Chinese Academy of Sciences and led by the country’s Kunming Institute of Zoology, saw the creation of 11 transgenic monkeys that carried human copies of the MCPH1 (microcephalin-1) gene. The group wanted to observe how the gene affected monkey brain development. It’s the latest series of mutant monkeys to be born in recent years as a result of Chinese medical research. MCPH1 is considered important for brain development and evolution. It is also linked to brain size.

Of the 11 monkeys, six survived birth and five lived to the study’s publication date in China’s National Science Review on March 27. According to the research, brain imaging and tissue section analysis showed delayed maturation of the neural system similar to developmental delay experienced in humans. In humans, this can see juvenile features carry on into adulthood.

One difference between humans and monkeys is that humans take a lot longer to form their brain’s neural-network (from childhood to adulthood). Slowing down the brain maturing process can lead to improved intelligence during human evolution.

The study also found the gene-altered monkeys displayed improved short-term memory and quicker reaction time, compared to monkeys that did not carry the gene. The Chinese researchers have argued that using monkeys to make this discovery provided an important insight into what makes humans unique in terms of brain development.

A mutated MCPH1 gene can lead to microcephaly in human babies, which means they can be born with unusually small heads due to abnormal brain development.

SIGNIFICANT HARM TO THESE MONKEYS

However, Dr. Styner, who was tasked with developing software tools to measure brain MRI data for the research, said he felt there were ethical implications to this research.

“My lab generates software to help other labs with running their MRI studies, I am only loosely connected to the science of many studies. That certainly was the case here. One could even argue that I probably should not be a co-author given my lack of scientific involvement in this work. I had no input on the science in this project, except for how to best process their MRI data,” he told News Corp.

“The issue is not transgenic animals in general, or even transgenic monkeys. But rather it’s the combination of it all, i.e. a transgenic monkey whose brain is altered by adding a human brain development gene with the goal to make it more human-like.

“There are ethically acceptable uses for transgenic animals (possibly even monkeys) that do not target the brain but with another goal, e.g. making it a potential organ donor for a human. “That’s a very different setting then what we have in this work and one with much less significant ethical implications.”

He said in this study by changing the brain and brain development, the researchers created a monkey that was more human-like — neither human nor monkey. “Quite possibly those transgenic monkeys would not fit with their family/colony anymore. Thus there is significant harm here to these monkeys, though I don’t think we actually learn a lot from this particular study or avenue of research.”

ONLY MONKEYS?

The researchers hope to continue using monkeys to conduct further research on degenerative and social disorders such as Alzheimer disease, Parkinson disease, multiple sclerosis, and autism as they argue their findings could provide important insight that leads to better understanding and treatment. However, critics have argued that implanting monkeys with human genes pushes the ethical boundaries of using animals for medical research.

But their initial research has been compared to sci-fi classic story Planet of the Apes, which sees gene-edited apes go into battle with humans for control of the planet.

The researchers dismiss this claim saying apes are not used at all in their research and never will be.

They argue the rhesus monkeys used in the experiments are distant enough from humans genetically to quash this concern. Monkeys are more closely related to humans genetically than rodents, but they’re not as close as apes are related to humans.

Dr. Styner told NBC News when criticism of the research first surfaced that: “My personal opinion is now that, from an ethical point of view, such research should actually not be done.”

CHINA TRIALS PUSH BOUNDARIES

The Chinese Institute of Neuroscience defended its experiments, saying cloned and gene-altered monkeys will lead to a reduction in the number of monkeys used in medical testing in the future. In January Chinese research saw five macaque monkeys cloned from a single animal that was gene-manipulated to have a sleep disorder.

The study, for the purpose of observing mental illness, led to all five monkeys developing signs of depression, anxiety and behaviors associated with schizophrenia.

A year earlier, China announced it was successful in creating the world’s first cloned monkeys Zhong Zhong and Hua Hua. In 2016 China’s Institute of Neuroscience used transgenic monkeys to observe the MECP2 gene, which is related to autism. The monkeys with artificial human MECP2 gene were subject to behavioral tests. Compared to monkeys that did not have the gene, the gene-altered monkeys had autism-like behaviors, metabolism issues, increased stress responses and lower social skills. China’s Institute of neuroscience said they followed strict international guidelines for animal research.

“This research will help to reduce the number of macaque monkeys currently used in biomedical research around the world. Without the interference of a very heterogeneous genetic background, a much smaller number of cloned monkeys carrying disease phenotypes may be sufficient for preclinical tests of the efficacy of therapeutics,” said neuroscientist Dr. Poo Mu-ming, who helped supervise both of these studies. “Researchers used to use more animals for drug test for accuracy, but now we could change the situation with cloning technology,” he said.

Late last year another a Chinese researcher drew condemnation from science peers for successfully gene-altering twin girls to prevent them from contracting HIV. Chinese authorities launched an investigation into this ‘world first’ result and put a stop to the research. China is currently considering new laws which would see stricter requirements and greater scrutiny overseeing medical trials in the country.

It would also require all future medical trials to be approved by an administrative body and ethical panel. In Australia, there are strict guidelines for medical research, which is governed by the Australian Code for Responsible Conduct of Research.

This story originally appeared in news.com.au.

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Genome-wide polygenic score (GPS) — Prediction of weight and obesity trajectories from birth to adulthood

These GEITP pages often discuss genotype-phenotype associations of multifactorial traits. Today’s multifactorial trait is “extreme obesity” (but we might consider it like other complex phenotypes such as height, type-2 diabetes, adverse drug response, or toxic effects of an environmental toxicant). Severe obesity, defined as body mass index (BMI) of 40 kg/ m2 or greater, is a rapidly growing public health issue — currently affecting 8% of American adults. Inherited susceptibility to obesity can, in rare cases, be attributed to a large-effect mutation that perturbs energy homeostasis or fat deposition [e.g. genetic inactivation of the melanocortin-4 receptor (MC4R) gene].

A recent genome-wide association study (GWAS) quantified the relationship between each of 2.1 million common genetic variants and BMI in >300,000 individuals; none of the individual variants accounted for a large proportion of the trait. The strongest association was noted for a common variant at the FTO locus (alpha-ketoglutarate-dependent dioxygenase); the risk allele is associated with a statistically robust, but clinically modest, increase in weight of ~1 kg per inherited risk allele. Obtaining meaningful predictive power — thus requires “an aggregation of information from many common variants into a polygenic score.” However, previous efforts to create an effective polygenic score for obesity have had only modest success. This ‘‘polygenic’’ model paradigm is similar to other complex diseases in which polygenic inheritance (involving many common genetic variants, each having small-effect) accounts for the majority of inherited susceptibility.

Authors [see attached article] used recently developed computational algorithms and large datasets to derive, validate, and test a robust polygenic predictor of BMI and obesity. This genome-wide polygenic score (GPS) integrates all available common variants into a single

quantitative measure of inherited susceptibility. GPS identifies a subset of the adult population that is at substantial risk of severe obesity — in some cases equivalent to rare monogenic mutations.

Authors tested this predictor in >300,000 individuals ranging from birth to middle age. Among middle-aged adults, they observed a 13-kg gradient in weight and a 25-fold gradient in risk of severe obesity across polygenic score deciles (population divided into tenths). In a longitudinal birth cohort, minimal differences in birthweight were noted across score deciles, but a significant GPS gradient emerged in early childhood and reached 12 kg by 18 years of age. This new approach to quantify inherited susceptibility to a complex disease, and other multifactorial traits, appears to afford new opportunities for clinical prevention and automatic assessment. 🙂

DwN

Cell 18 Apr 2o19; 177: 587–596

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A compendium of mutational signatures of environmental agents

It is well known that diverse environmental carcinogens result in distinctly different patterns of genomic responses. Whole-genome sequencing (WGS) of a single malignant melanoma and a single lung cancer cell line in 2010, for example, first illustrated the power of this approach — revealing the characteristic mutational spectra of UV light vs tobacco carcinogens, respectively. Subsequently, WGS of large numbers of other tumors revealed mutational patterns in nearly all tumors that arise from both endogenous (i.e. within the body) and exogenous (outside the body) sources. Global, unbiased depiction provided by WGS has permitted more refined insights into mutational processes of human cancers, facilitating clinical applications of cancer genomics.

Yet, human cancers result from environmental and endogenous exposures that are uncontrolled and in highly variable genetic backgrounds. Although mathematical methods have been applied to deconstruct mutation profiles into individual mutational signatures, these approaches are complex and fraught with issues of interpretation — due to lack of experimental controls. Therefore, an important next step is to examine systematically mutational patterns associated with a broad selection of environmental or therapeutic mutagens, generated under highly-controlled conditions. Authors [see attached article] used a human induced pluripotent stem cell (iPSC) line, having the advantages of being normal, undifferentiated, fast-growing, and easy to clone. Most of the agents tested are classified by the International Agency for Research on Cancer (IARC) as “known, probable, or possible human carcinogens.”

Authors examined mutational signatures in 324 WGS human iPSC lines exposed to 79 known or suspected environmental carcinogens. Forty-one yielded characteristic substitution mutational signatures; some were similar to signatures found in human tumors. In addition, six agents produced double-substitution (altering two base-pairs) signatures, and eight agents produced insertion-deletion (indel) signatures. The mutation patterns included fully functional mismatch- and transcription-coupled repair pathways, resulting in an assortment of signature outcomes — even for a single agent. This compendium of experimentally induced mutational signatures will now permit further exploration of roles of environmental agents in cancer etiology and underscores how human stem cell DNA (when the cells are in a culture dish) is directly vulnerable to environmental agents. [It is known that, in intact pregnant animals, however, stem cell DNA appears to be extremely resistant to such environmental damage.] 🙂

DwN

Cell 2 May 2o19; 177: 1–16

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Autism spectrum disorder (ASD) mouse model — improved by gut bacteria ???

Autism spectrum disorder (ASD) is a great example of a gene-environment interactions topic — i.e. fitting in perfectly to these GEITP pages. Clearly there are hundreds, if not thousands, of small-effect genes that contribute to genetic susceptibility (to be afflicted with ASD), but it is likely there are epigenetic effects and environmental factors that play a role. Any participation of endogenous conditions (normal physiology or abnormal pathophysiology), or influence by one’s microbiome, is something that must also be considered. ASD in Western societies, just like obesity and type-2 diabetes, continues to be on the rise. Why? What the heck is going on?

Defined as a heterogeneous neurodevelopmental disorder, ASD is characterized by social deficits, repetitive behaviors, and language difficulties. In addition to these core symptoms — ASD patients often suffer from gastrointestinal (GI) issues; in fact, children with ASD are 3.5 times more likely to suffer from GI disorders than children without developmental disorders. Moreover, GI problems have been associated with changes in the microbial communities inhabiting the gut of ASD individuals. Studies in animal models have shown that gut microbes can modulate central nervous system (CNS)-driven behaviors in very powerful ways.

Authors [of the attached article] recently found that the bacterial species — Lactobacillus reuteri — reverses social deficits in maternal high-fat-diet mouse offspring. However, whether the effect of L. reuteri on social behavior is generalizable to other ASD models, and its mechanism(s) of action, remains unknown. [In the attached article], authors show that L. reuteri treatment selectively rescues social deficits in genetic, environmental, and idiopathic ASD models. Interestingly, effects of L. reuteri on social behavior are not mediated by restoring the composition of the host’s gut microbiome (which was found to be altered in all of these ASD models). Instead, L. reuteri acts via the vagus nerve, and rescues social interaction-induced synaptic plasticity in the ventral tegmental area of the brains of ASD mice, but not in oxytocin receptor-deficient [Oxtr(-/-)] mice. These studies therefore suggest that L. reuteri treatment emerges as a promising non-invasive microbial-based avenue to combat ASD-related social dysfunction..!! 🙂

DwN

Neuron 2o19; 101: 246-259

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New Homo subline discovered? “Homo luzonensis” in the Philippines

Because evolution of modern man is a topic covered by gene-environment interactions, these GEITP pages have kept up-to-date on the latest advances in how we Homo sapiens got here, today. The first of our “close relatives” Homo neaderthalensis was first discovered as a fossil in the Neander Valley (Germany) in the 1850s, and the first publication of Neaderthal DNA was from mitochondria (mtDNA) in 1997. Since these GEITP pages have begun in 2008 — there have been additional sublines identified and DNA sequenced: Homo denisova, Homo floresiensis (small hobbitt-sized humans from Flores island in Indonesia), and now Homo luzonensis (from island of Luzon in The Phillippines).

Hominins are members of the human family tree who are more closely related to each other than they are to chimpanzees and bonobos (divergence of 6-7 million years ago). Most extinct hominin species are not our direct ancestors, whereas our close relatives (divergence 600,000-850,000 years ago) had an evolutionary history that took only slightly different paths from ours. Authors [see attached article] identified this new close relative, named Homo luzonensis after Luzon; specimens of H. luzonensis were dated to minimum ages of 50,000 and 67,000 years old — which suggests that this species was alive at the same time as H. sapiens, H. neaderthalensis, H. denisova, and H. floresiensis.

Hominins appear in the fossil record ~6 million to 7 million years ago in southeast Africa, and the earliest hominin fossils found in Eurasia are about 1.8 million years old. Explanations for the earliest hominin dispersals from Africa fall under what is known as the “Out of Africa I paradigm.” Modern humans only come into focus in the “Out of Africa II paradigm,” which refers to the early dispersals of H. sapiens from Africa to Eurasia that first occurred in the past 200,000 to 300,000 years. Homo erectus (discovered in Indonesia on island of Java) is commonly believed to be the only early hominin that was part of the Out of Africa I dispersal ~1.5 to 2 million years ago, spreading across Africa and Eurasia. Meanwhile, other hominin species (2 to 7 million years ago) — e.g. Homo habilis, the australopiths, and more than a dozen others — had smaller brains and anatomy less similar to that of modern humans and died out, while remaining in Africa.

Authors [see attached report] describe specimens from Luzon that display a combination of primitive and derived morphological features that is different from the combination of features found in other species in the genus Homo (including Homo floresiensis and Homo sapiens) and authors believe “warrants their attribution to a new species,” which they name Homo luzonensis. This publication, however, DOES NOT INCLUDE WHOLE-GENOME SEQUENCING and therefore much more will be understood about this subline, and where it fits (in the Greater Realm of Things) when WGS has been completed — which will undoubtedly happen very soon. 🙂

DwN

Nature 11 Apr 2o19; 568: 181-186 & News’N’Views editorial pp 176-178

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Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions

These GEITP pages have often discussed epigenetic effects — which, as you recall, includes DNA-methylation, RNA-interference, histone modifications, and chromatin remodeling. In contrast to genetic effects (in which alterations in DNA sequence contribute to the phenotype), epigenetic effects represent non-DNA-sequence events that can be heritable, as well as caused by environmental factors. There are now available assays to screen genome-wide for DNA-methylation and RNA-interference (miRNAs) associations of any trait, whereas histone modifications and chromatin remodeling still require more studies before any commercial assays can be developed. The attached article focuses on the screening and diagnosis of NeuroDevelopmental syndromes with or without Congenital Anomalies (ND/CA).

Some ND/CA have shown associations with copy number variants (CNVs; segments of the genome [which often include a gene or genes] are repeated, and the number of repeats varies between individual genomes in the human population), or with some rare DNA sequence variant. However, in a large proportion of cases, the underlying genetic etiology is not identified and/or there is no clinical diagnosis. In fact, a large proportion of genetic changes identified through genetic testing in a potentially relevant gene often are not clinically interpretable; these have been termed “Variants of Unknown clinical Significance” (VUS). Authors [see attached article] therefore have chosen DNA-methylation, in an attempt to explain the etiology for some of these ND/CA patients.

DNA-methylation (genetic variants that involve a change in DNA methylation patterns of a limited number of CpGs at a specific locus) is the most commonly studied epigenetic phenomena, and genome-wide screening assays are now commercially available. DNA-methylation has long been known to be involved in causation of a certain group of syndromes — such as imprinting conditions (e,g, Prader-Willi, Angelman,Silver-Russell, and Beckwith-Weidemann syndromes; Albright hereditary osteodystrophy, and uniparental disomy) and trinucleotide repeat expansion disorders (e.g. Huntington Disease, Spinobulbar Muscular Atrophy, at least six of the Spinocerebellar Ataxia types, Dentatorubro-Pallidoluysian Atrophy, Fragile X Syndrome, Fragile XE Mental Retardation, and Friedreich Ataxia).

Authors [in attached article] investigated genome-wide DNA-methylation analysis of peripheral blood in a cohort of 965 ND/CA-affected subjects without a previous diagnostic assumption and a separate assessment of rare epi-variants (DNA-methylation differences) in this cohort. They identified 15 subjects with syndromic Mendelian disorders, 12 subjects with imprinting and trinucleotide repeat expansion disorders; most importantly, they identified 106 subjects with rare epi-variants — a portion of which involved genes clinically or functionally linked to the subjects’ phenotypes. These data show that genomic DNA-methylation analysis can facilitate the molecular diagnosis of unresolved clinical cases and highlight the potential value of epigenomic testing in the routine clinical assessment of ND/CA patients. It is possible that epigenomic testing of this type, in a study of drug response or environmental toxicant toxicity, can also be successfully performed. 🙂

DwN

Am J Hum Genet 4 Apr 2o19; 104: 685-700

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PAIN ain’t the same in boys as it is in girls

The basic theme of these GEITP emails is gene-environment interactions. In the case of this topic, the gene differences occur in males vs females, whereas the environmental signal is induction of PAIN to the individual (mouse or human). At first, studies in mice indicated that pain hypersensitivity results from remarkably different pathways in males and females — reflecting distinct immune-cell types and hormones that contribute to the “discomfort” signal. It has been suggested that no other field of science has identified such striking sex differences; this research could open the door for new medical (and pharmacological) advances.

For example, about 20% of people worldwide experience chronic pain — and the majority are women. Today, the pharmaceutical market offers the same pain drugs to everyone. However, if the roots of pain are different, some drugs might work better in some people than in others. Moreover, people might require different pain medications when hormone levels fluctuate throughout life. It is predicted that future pain medications will be tailored to individuals — and that gender will be a key factor in those personalized prescriptions.

Pain occurs when neural sensors in the skin, muscles, joints or organs register a potentially harmful sensation, such as heat or tissue damage.

They send signals through peripheral nerves to the spinal cord, activating other nerves that send signals to the brainstem and on to the cerebral cortex, which interprets those signals as “ouch!” or “not so ouch!” But pain happens in many ways, and diverse chemical pathways contribute. Some pain types are distinguished by timing. There is the acute response to something hot, sharp or otherwise noxious, and there is long-term, chronic pain that might persist even after the initial injury has healed.

One study involved injury to the animals’ sciatic nerves (which run from the lower back down each hindleg); this led to a form of chronic pain that

happens when the body’s pain-detecting system is damaged or malfunctioning — causing both male and female mice to become extra-sensitive to touch. Yet, even in this case, there were sex differences: microglia (glial cells that function as macrophages (scavengers) in the central nervous system and form part of the reticuloendothelial system) appeared to have a prominent role in the pain of males, but not in that of female mice. Scientists found that, no matter how they blocked microglia, this eliminated pain hypersensitivity in males alone.

By studying the same nerve injury in female mice lacking T cells, they still became pain-hypersensitive, but now the mechanism seemed to occur through microglia. In females lacking T cells, blocking the activity of microglia prevented this pain response, just as it did in males. And when the researchers transferred T cells back to female mice that were lacking them, the females stopped using microglia in nerve-injury pain [see the figure in the attached editorial]. This entire article [attached] makes for fascinating bedtime reading. 🙂

DwN

Nature 28 Mar 2o19; 567: 448-450

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A Weaning Reaction to Microbiota Is Required for Resistance to Immunopathologies in the Adult

From time to time, these GEITP pages have covered articles on the gut microbiome. It is now appreciated that — if our entire body were examined for total DNA content — more than 90% of all DNA would be found to be derived from the bacteria that live on and in us! This remarkable bacterial community participates in metabolism of food and the production of essential compounds [including vitamins, short-chain fatty acids (SCFAs), and secondary bile acids], as well as playing a role in the immune response and host-mediated defense against pathogens. It has been proposed that the intestinal microbiota behaves like an organ, producing microbial components and metabolites that are involved in many processes of the animal host; this includes influencing the metabolism of drugs and other environmental toxicants.

Shortly after birth, the colonizing microbiota is known to be shaped — by the dietary and immunological components of the milk, which includes maternal-derived immunoglobulin A (IgA), and follows a developmental process characterized by the presence of age-specific

bacterial species. During weaning, introduction of solid foods into the infant’s diet leads to a new phase in the development of the microbiota — characterized by a large increase in bacterial numbers, and evolution toward the composition (profile) that will be associated with adult individuals, and further influenced by ethnicity, gender, diet, drugs (especially antibiotics) being taken, climate, and individual genetic architecture of related family members.

The period between birth and weaning also witnesses important changes in the intestinal immune system. Populations of fetus-derived T cells, innate lymphoid cells (ILCs), and myeloid cells are progressively replaced by cells generated in the bone marrow and thymus after birth. Moreover, the colonizing microbiota induces the generation and expansion of effector and regulatory T cells (Tregs) and ILCs, as well as formation of isolated lymphoid follicles that produce antimicrobial IgA (i.e. important changes in the intestine occur after birth and during weaning, changes that link the development of the microbiota with the development of the immune system).

Authors [see attached article] examined the reactivity of the mouse intestinal immune system during the first weeks after birth, and into adulthood. At weaning, the intestinal microbiota induced a vigorous immune response — a ‘‘weaning reaction’’ — that was programmed in time. Inhibition of the weaning reaction led to pathological imprinting and increased susceptibility to colitis, allergic inflammation, and cancer later in life. Prevention of this pathological imprinting was associated with the generation of RORgt+ regulatory T cells, which required bacterial and dietary metabolites — short-chain fatty acids and retinoic acid. Therefore, the weaning reaction to microbiota is required for immune ontogeny, perturbation of which leads to increased susceptibility to immunopathologies later in life. Wow. Although these studies were performed in mice, it is likely that very similar events occur in the human.

DwN

Immunity 21 May 2o19; 50: 1-13

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Acute and Chronic Effects Associated With Cannabis Use — Is Partly Dependent on Route of Exposure

Legalization of cannabis in a growing number of States — coupled with the perception that “marijuana is an innocuous drug” — has led to significant increases in cannabis consumption, both for its recreational properties and for its alleged medicinal properties. Not emphasized [in the attached article and editorial], however, is the extremely serious “unintended (unexpected?) use of marijuana among individuals from ages 25 down to 12- and 10-year-olds” — at the time “when their brains are still being hard-wired for adulthood.” The result is the brain is irreversibly damaged.

It is well known that cannabis use is associated with adverse health effects, more cannabis-related emergency department (ED) visits, and cannabis-related increased hospital admissions. In the attached article, authors reviewed health records from patients presenting to the University of Colorado Health Emergency Dept from 2012 to 2016; they found a more-than-3-fold increase in cannabis-associated ED visits over this period. Authors also examined the proportions of ED visits associated with inhalable versus edible cannabis — in light of the sales of both product types in Colorado between 2014 and 2016. Their analysis showed that, although 10.7% of ED visits were attributable to edible cannabis, only 0.32% of total cannabis sales [in kilograms of tetrahydrocannabinol (THC)] represented edible products (i.e. EATING THC is more dangerous than smoking it).

Gastrointestinal (GI) symptoms were the most frequent cause of ED visits (30.7%). Cannabinoid hyper-emesis syndrome (throwing up, wretching uncontrollably) was the most common GI adverse event (and it was also the reason for most hospital admissions). In contrast, intoxication (48.3% vs 27.8%), acute psychiatric symptoms (18.0% vs. 10.9%), and cardiovascular symptoms (8.0% vs. 3.1%) were more common in patients eating THC, compared to those smoking it. The higher-than-expected number of adverse events associated with edible cannabis products — considering the frequency of sales — is consistent with prior findings, including a 2017 Poison Control Center report in which edible products accounted for 17% of cannabis-related visits to health care facilities among adults.

Route-of-administration influences effects of a drug by affecting its bioavailability, peak blood concentrations, and speed at which these two factors are achieved. For drugs with abuse potential, the rate at which they enter the brain and the speed at which they exert their

pharmacologic effects influence addictiveness. The slow rate of absorption of orally-ingested THC (peak blood levels achieved in 3 hrs) compared with inhaled THC (peak blood levels achieved within 30 min) makes it harder for users of edible cannabis to titrate the doses required to achieve the desired drug effects. Further, the slower clearance of oral (12 hrs) vs inhaled (4 hrs) THC can lead to drug accumulation — if users take additional doses when they do not experience the desired effects as quickly as expected. In addition, the wide variety of innocuous-looking edible preparations can lead to over-consumption — particularly when consumers (especially children) do not understand what they are eating. This problem can be compounded by inaccurate labeling of cannabinoid content [THC vs cannabidiol (CBD)] in edible products.

Lastly, but probably most importantly, there are large genetic interindividual differences in oral THC absorption and metabolic response — which also contributes to the unpredictability of drug effects and adverse outcomes. Some of this is due to the fat content of food ingested at the time that THC is eaten. Because THC is highly lipophilic, fatty foods increase THC absorption, but it might also affect its “first-pass” metabolism (phenomenon whereby the drug concentration is substantially decreased — before it reaches the systemic circulation) in the liver. Another factor is that sugars and amino acids are released directly into the mesenteric portal blood on its way to the liver, where they are metabolized before reaching the systemic circulation (first-pass effect), whereas fats are packaged into chylomicrons — which are then diverted into the mesenteric lymphatic system and to the brachial vein, where it first reaches the systemic circulation (thus bypassing first-pass metabolism). This phenomenon might help explain some of the serious side-effects of THC after being taken orally. 🙁

DwN

Ann Intern Med 16 Apr 2019; 170: doi:10.7326/M18-2809 & 2-page editorial

Below is a layman’s summary, recently on NBC News [click on title, if you wish to read that article]:

ER visits linked to marijuana increased at Colorado hospital after legalization, study finds

NBC News—March 25, 2019

After marijuana use was legalized in Colorado in 2012, ER visits linked to cannabis use tripled over the next five years at one of the state’s largest hospitals, according to a new analysis. Psychiatric ER visits were more common after people consumed marijuana edibles, compared to smoking or inhaling cannabis products.

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