Here are the most popular of the 65 posts I’ve made so far in 2018, starting from the earliest:
This 2018 Loma Linda review subject was gestational hypoxia:
“Of all the stresses to which the fetus and newborn infant are subjected, perhaps the most important and clinically relevant is that of hypoxia. This review explores the impact of gestational hypoxia on maternal health and fetal development, and epigenetic mechanisms of developmental plasticity with emphasis on the uteroplacental circulation, heart development, cerebral circulation, pulmonary development, and the hypothalamic-pituitary-adrenal axis and adipose tissue.
An understanding of the specific hypoxia-induced environmental and epigenetic adaptations linked to specific organ systems will enhance the development of target-specific inhibition of DNA methylation, histone modifications, and noncoding RNAs that underlie hypoxia-induced phenotypic programming of disease vulnerability later in life.
A potential stumbling block to these efforts, however, relates to timing of the intervention. The greatest potential effect would be accomplished at the critical period in development for which the genomic plasticity is at its peak, thus ameliorating the influence of hypoxia or other stressors.
With future developments, it may even become possible to intervene before conception, before the genetic determinants of the risk of developing programmed disease are established.”
Table 3 “Antenatal hypoxia and developmental plasticity” column titles were Species | Offspring Phenotypes of Disorders and Diseases | Reference Nos.
This review was really an ebook, with 94 pages and 1,172 citations in the pdf file. As I did with Faith-tainted epigenetics, I read it with caution toward recognizing 1) the influence of the sponsor’s biases, 2) any directed narrative that ignored evidence contradicting the narrative, and 3) any storytelling.
See if you can match the meaning of the review’s last sentence (“intervene before conception” quoted above) with the meaning of any sentence in its cited reference Developmental origins of noncommunicable disease: population and public health implications.
One review topic that was misconstrued was transgenerational epigenetic inheritance of hypoxic effects. The “transgenerational” term was used inappropriately by several of the citations, and no cited study provided evidence for gestational hypoxic effects through the F2 grandchild and F3 great-grandchild generations.
One omitted topic was gestational hypoxic effects of caffeine. The first paper that came up for my PubMed search of “caffeine pregnancy hypoxia” was an outstanding 2017 Florida rodent review Long-term consequences of disrupting adenosine signaling during embryonic development that had this paragraph and figure:
“One substance that fetuses are frequently exposed to is caffeine, which is a non-selective adenosine receptor antagonist. We discovered that in utero alteration in adenosine action leads to adverse effects on embryonic and adult murine hearts. We find that cardiac A1ARs [a type of adenosine receptor] protect the embryo from in utero hypoxic stress, a condition that causes an increase in adenosine levels.
After birth in mice, we observed that in utero caffeine exposure leads to abnormal cardiac function and morphology in adults, including an impaired response to β-adrenergic stimulation. Recently, we observed that in utero caffeine exposure induces transgenerational effects on cardiac morphology, function, and gene expression.”
Why was this review and its studies omitted? It was on target for both gestational hypoxia and transgenerational epigenetic inheritance of hypoxic effects!
It was alright to review smoking, cocaine, methamphetamine, etc., but the most prevalent drug addiction – caffeine – couldn’t be a review topic?
The Loma Linda review covered a lot, but I had a quick trigger due to the sponsor’s bias. I started to lose “faith” in the reviewers after reading the citation for the review’s last sentence that didn’t support the statement.
My “faith” disappeared after not understanding why a few topics were misconstrued and omitted. Why do researchers and sponsors ignore, misrepresent, and not continue experiments through the F3 generation to produce evidence for and against transgenerational epigenetic inheritance? Where was the will to follow evidence trails regardless of socially acceptable beverage norms?
The review acquired the taint of storytelling with the reviewers’ assertion:
“..timing of the intervention. The greatest potential effect would be accomplished at the critical period in development for which the genomic plasticity is at its peak, thus ameliorating the influence of hypoxia or other stressors.”
Contradictory evidence was in the omitted caffeine study’s graphic above which described two gestational critical periods where an “intervention” had opposite effects, all of which were harmful to the current fetus’ development and/or to following generations. Widening the PubMed link’s search parameters to “caffeine hypoxia” and “caffeine pregnancy” returned links to human early life studies that used caffeine in interventions, ignoring possible adverse effects on future generations.
This is my final curation of any paper sponsored by this institution.
https://www.physiology.org/doi/abs/10.1152/physrev.00043.2017 “Gestational Hypoxia and Developmental Plasticity” (not freely available) Thanks to coauthor Dr. Xiang-Qun Hu for providing a copy.
This 2018 UK review subject was colored-hearing experiences from music:
“Music-colour synaesthesia has a broad scope encompassing not only tone-colour synaesthesia elicited on hearing individual tones, but a complex and idiosyncratic mixture of phenomenological experiences often mediated by timbre, tempo, emotion and differing musical style.
The possession of synaesthesia or absolute pitch was shown to have very little effect on the actual colours chosen for each of the musical excerpts, but it might be reasonable to expect that music that elicits a strong emotional response may be more likely to induce synaesthesia than music that does not.
The examination of eight neuroimaging studies were found to be largely inconclusive in respect of confirming the perceptual nature of music-colour synaesthesia. Neither the hyperconnectivity nor the disinhibited feedback theory currently holds as a single categorical explanation for synaesthesia.
Theories promoting the notion of ‘ideaesthesia’ have highlighted the importance of the role of concept and meaning in the understanding of synaesthesia..and a replacement definition: Synaesthesia is a phenomenon in which a mental activation of a certain concept or idea is associated consistently with a certain perception-like experience.”
Much of the review was philosophizing and casting around for clues. The review cited interesting studies and reviews, including The Merit of Synesthesia for Consciousness Research.
One relevant element missed by the underlying research and the review was critical periods of human development. A cited reference in How brains mature during critical periods was Sensitive periods in human development: Evidence from musical training (not freely available) which illuminated some aspects of the research:
“In contrast to a critical period, where a function cannot be acquired outside the specific developmental window, a sensitive period denotes a time where sensory experience has a relatively greater influence on behavioral and cortical development. Sensitive periods may also be times when exposure to specific stimuli stimulates plasticity, enhancing changes at the neuronal and behavioral levels.
The developmental window for absolute pitch may be more similar to a critical than a sensitive period.
The auditory cortex appears to have an unusually long period of developmental plasticity compared with other sensory systems; changes in its cellular organization and connectivity continue into late childhood.
The effects of musical training have been shown to impact auditory processing in the brainstem as well.”
Let’s say that a researcher wanted – as one cited study did – to examine absolute pitch, a rare trait, present in a subset of synesthetes – music-color, another rare trait. The study as designed would probably be underpowered due to an insufficient number of subjects, and it would subsequently find “very little effect.”
Let’s say another researcher focused on brain areas in the cerebrum, and like the eight cited studies, ignored the nuclei in the pons part of the brainstem which are the first brain recipients of sound and equilibrium information from the inner ear via the eighth cranial nerve. Like those studies, the researcher was also biased against including limbic brain areas that would indicate “a strong emotional response.” A study design that combined leaving out important brain-area participants in the synesthesia process with a few number of synesthetes would be unlikely to find conclusive evidence.
The reviewer viewed the lack of evidence from “eight neuroimaging studies” as indicating something about the “perceptual nature of music-colour synaesthesia.” An alternative view is that the “inconclusive” evidence had more to do with study designs that:
- Had a small number of subjects;
- Omitted brain areas relevant to the music-color synesthesia process;
- Didn’t investigate likely music-color synesthesia development periods; and
- Didn’t investigate associations of music-color synesthesia with epigenetic states.
Consider the magnitude of omitting the thalamus from synesthesia studies as one “perceptual nature” example. Just the background information of Thalamus gating and control of the limbic system and cerebrum is a form of memory indicated its relevance to synesthesia:
“Despite the fundamental differences between visual, auditory and somatosensory signals, the basic layouts of the thalamocortical systems for each modality are quite similar.
For a given stimulus, the output neural response will not be static, but will depend on recent stimulus and response history.
Sensory signals en route to the cortex undergo profound signal transformations in the thalamus. A key thalamic transformation is sensory adaptation in which neural output adjusts to the statistics and dynamics of past stimuli.”
One of this study’s researchers described ways that an individual’s “stimulus and response history” became unconscious memories with the thalamus. Including the thalamus in synesthesia studies may also have findings that involve reliving or re-experiencing a memory, possibly an emotional memory.
In such future research, it could be a design element to ask synesthetes before and after the experiment to identify feelings and memories accompanying synesthesia experiences.
It shouldn’t be a requirement, however, to insist that memories and emotions be consciously identified in order to be included in the findings. Human studies, for example, Unconscious stimuli have a pervasive effect on our brain function and behavior have found:
“Pain responses can be shaped by learning that takes place outside conscious awareness.
Our results support the notion that nonconscious stimuli have a pervasive effect on human brain function and behavior and may affect learning of complex cognitive processes such as psychologically mediated analgesic and hyperalgesic responses.”
Does an orangy twilight of aging sunflowers help you feel?
https://www.sciencedirect.com/science/article/pii/S1053810017305883 “Music-colour synaesthesia: Concept, context and qualia” (not freely available)
This 2018 Nevada rodent study was on acetyl-L-carnitine’s action in the brainstem:
“We examined age-related changes in the efficiency of synaptic transmission at the calyx of Held, from juvenile adults (1-month old) and late middle-age (18- to 21-month old) mice. The calyx of Held synapse has been exploited as a model for understanding excitation-secretion coupling in central glutamatergic neurons, and is specialized for high-frequency transmission as part of a timing circuit for sound localization.
Our observations suggest that during aging, there is neuronal cell loss in the MNTB [Medial nucleus of the trapezoid body, a collection of brainstem nuclei in an area that’s the first recipient of sound and equilibrium information], similar to previous reports. In remaining synapses of the MNTB, we observed severe impairments in transmission timing and SV [synaptic vesicle] recycling, resulting in timing errors and increased synaptic depression in the calyx of Held synapse. These defects reduce the efficacy of this synapse to encode temporally sensitive information and are likely to result in diminished sound localization.
We orally administered ALCAR for 1 month and found that it reversed transmission defects at the calyx of Held synapse in the older mice.
These results support the concept that facilitators of mitochondrial metabolism and antioxidants may be an extremely effective therapy to increase synaptic function and restore short-term plasticity in aged brains, and provide for the first time a clear mechanism of action for ALCAR on activity-dependent synaptic transmission.“
Human brainstem research is neglected, as noted by Advance science by including emotion in research. Evidence from such research doesn’t play well with beliefs in the popular models and memes of human cerebral dominance.
Do you know any “late middle-age” people who have obvious auditory and synaptic deficits? What if some of the neurobiological causes of what’s wrong in their brains could be “reversed by ALCAR?”
Before using this study as a guide, however, I asked the study’s researchers to calculate the human-equivalent dosage. When I translated the “daily dose of ~2.9 g/kg/d” it worked out to several hundred times the 500 mg to 1 g dietary supplement dosage of acetyl-L-carnitine.
The study’s corresponding coauthor replied:
“This is indeed much larger than that normally consumed by humans via dietary supplementation. We are currently working to determine the effective ‘minimal’ dose of ALCAR and alpha lipoic acid, to better assist guidelines for human application of this supplement.”
https://www.researchgate.net/publication/323941877_Age-related_defects_in_short-term_plasticity_are_reversed_by_acetyl-L-carnitine_at_the_mouse_calyx_of_Held “Age-related defects in short-term plasticity are reversed by acetyl-L-carnitine at the mouse calyx of Held”
This 2018 US Veterans Administration review subject was resiliency and stress responses:
“Neurobiological and behavioral responses to stress are highly variable. Exposure to a similar stressor can lead to heterogeneous outcomes — manifesting psychopathology in one individual, but having minimal effect, or even enhancing resilience, in another.
We highlight aspects of stress response modulation related to early life development and epigenetics, selected neurobiological and neurochemical systems, and a number of emotional, cognitive, psychosocial, and behavioral factors important in resilience.”
The review cited studies I’ve previously curated:
- The truth about complex traits and GWAS that I curated yesterday;
- Conscious mental states should not be the first-choice explanation of behavior on the first day of this blog, February 1, 2015; and
- Manufacturing PTSD evidence with machine learning, but I had a different view of the study than the reviewers’ favorable one.
There were two things I didn’t understand about this review. The first was why the paper isn’t freely available. It’s completely paid for by the US taxpayer, and no copyright is claimed. I recommend contacting the authors for a copy.
The second was why the VA hasn’t participated in either animal or human follow-on studies to the 2015 Northwestern University GABAergic mechanisms regulated by miR-33 encode state-dependent fear. That study’s relevance to PTSD, this review’s subject, and the VA’s mission is too important to ignore. For example:
“Fear-inducing memories can be state dependent, meaning that they can best be retrieved if the brain states at encoding and retrieval are similar.
“It’s difficult for therapists to help these patients,” Radulovic said, “because the patients themselves can’t remember their traumatic experiences that are the root cause of their symptoms.”
The findings imply that in response to traumatic stress, some individuals, instead of activating the glutamate system to store memories, activate the extra-synaptic GABA system and form inaccessible traumatic memories.”
I curated the research in A study that provided evidence for basic principles of Primal Therapy. These researchers have published several papers since then. Here are the abstracts from three of them:
“Pharmacological treatments for psychiatric illnesses are often unsuccessful. This is largely due to the poor understanding of the molecular mechanisms underlying these disorders. We are particularly interested in elucidating the mechanism of affective disorders rooted in traumatic experiences.
To date, the research of mental disorders in general has focused on the causal role of individual genes and proteins, an approach that is inconsistent with the proposed polygenetic nature of these disorders. We recently took an alternative direction, by establishing the role of miRNAs in the coding of stress-related, fear-provoking memories.
Here we describe in detail our work on the role of miR-33 in state-dependent learning, a process implicated in dissociative amnesia, wherein memories formed in a certain brain state can best be retrieved if the brain is in the same state. We present the specific experimental approaches we apply to study the role of miRNAs in this model and demonstrate that miR-33 regulates the susceptibility to state-dependent learning induced by inhibitory neurotransmission.”
“State-dependent learning (SDL) is a phenomenon relating to information storage and retrieval restricted to discrete states. While extensively studied using psychopharmacological approaches, SDL has not been subjected to rigorous neuroscientific study.
Here we present an overview of approaches historically used to induce SDL, and highlight some of the known neurobiological mechanisms, in particular those related to inhibitory neurotransmission and its regulation by microRNAs (miR).
We also propose novel cellular and circuit mechanisms as contributing factors. Lastly, we discuss the implications of advancing our knowledge on SDL, both for most fundamental processes of learning and memory as well as for development and maintenance of psychopathology.”
“Retrieval of fear memories can be state-dependent, meaning that they are best retrieved if the brain states at encoding and retrieval are similar. Such states can be induced by activating extrasynaptic γ-aminobutyric acid type A receptors (GABAAR) with the broad α-subunit activator gaboxadol. However, the circuit mechanisms and specific subunits underlying gaboxadol’s effects are not well understood.
Here we show that gaboxadol induces profound changes of local and network oscillatory activity, indicative of discoordinated hippocampal-cortical activity, that were accompanied by robust and long-lasting state-dependent conditioned fear. Episodic memories typically are hippocampus-dependent for a limited period after learning, but become cortex-dependent with the passage of time.
In contrast, state-dependent memories continued to rely on hippocampal GABAergic mechanisms for memory retrieval. Pharmacological approaches with α- subunit-specific agonists targeting the hippocampus implicated the prototypic extrasynaptic subunits (α4) as the mediator of state-dependent conditioned fear.
Together, our findings suggest that continued dependence on hippocampal rather than cortical mechanisms could be an important feature of state-dependent memories that contributes to their conditional retrieval.”
Here’s an independent 2017 Netherlands/UC San Diego review that should bring these researchers’ efforts to the VA’s attention:
“Post-traumatic stress disorder (PTSD) is a psychiatric disorder that can develop following exposure to or witnessing of a (potentially) threatening event. A critical issue is to pinpoint the (neuro)biological mechanisms underlying the susceptibility to stress-related disorder such as PTSD, which develops in the minority of ~15% of individuals exposed to trauma.
Over the last few years, a first wave of epigenetic studies has been performed in an attempt to identify the molecular underpinnings of the long-lasting behavioral and mental effects of trauma exposure. The potential roles of non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) in moderating or mediating the impact of severe stress and trauma are increasingly gaining attention. To date, most studies focusing on the roles of miRNAs in PTSD have, however, been completed in animals, using cross-sectional study designs and focusing almost exclusively on subjects with susceptible phenotypes.
Therefore, there is a strong need for new research comprising translational and cross-species approaches that use longitudinal designs for studying trajectories of change contrasting susceptible and resilient subjects. The present review offers a comprehensive overview of available studies of miRNAs in PTSD and discusses the current challenges, pitfalls, and future perspectives of this field.”
Here’s a 2017 Netherlands human study that similarly merits the US Veterans Administration’s attention:
“Posttraumatic stress disorder (PTSD) affects many returning combat veterans, but underlying biological mechanisms remain unclear. In order to compare circulating micro RNA (miRNA) of combat veterans with and without PTSD, peripheral blood from 24 subjects was collected following deployment, and isolated miRNA was sequenced.
PTSD was associated with 8 differentially expressed miRNA. Pathway analysis shows that PTSD is related to the axon guidance and Wnt signaling pathways, which work together to support neuronal development through regulation of growth cones. PTSD is associated with miRNAs that regulate biological functions including neuronal activities, suggesting that they play a role in PTSD symptomatology.”
See the below comments for reasons why I downgraded this review’s rating.
https://link.springer.com/article/10.1007/s11920-018-0887-x “Stress Response Modulation Underlying the Psychobiology of Resilience” (not freely available)
Ponder this drone photo of “a flying human tethered to a monkey” ground drawing made over 1,000 years ago as reported by National Geographic and excerpted by the Daily Star:
1) Aren’t the geoglyph and its description pretty good expressions of our evolved condition? Especially since it’s the interpretation of people who lived more a millennium ago?
With so many information sources freely available now, one couldn’t successfully argue that the ancients understood the world better than we do, though. The price paid for figuring things out today is our “flying human” time and efforts, without which we’re as ignorant as our “monkey.”
2) A few aspects of the current comprehension of the differences between our two pictured primates are in Genetic imprinting, sleep, and parent-offspring conflict:
“I remain skeptical of a tendency to ascribe most modern woes to incongruence between our evolved nature and western cultural practices. We did not evolve to be happy or healthy but to leave genetic descendants, and an undue emphasis on mismatch risks conflating health and fitness [genetic rather than physical fitness].”
Our “flying human” can make happiness and health choices that our “monkey” can’t:
“Our genetic adaptations often try to fool us into doing things that enhance fitness at costs to our happiness.
Our genes do not care about us and we should have no compunction about fooling them to deliver benefits without serving their ends.
Contraception, to take one obvious example, allows those who choose childlessness to enjoy the pleasures of sexual activity without the fitness-enhancing risk of conception.”
3) Another aspect of our two primates’ differences is illuminated in a reference to A study of DNA methylation and age:
“Aging is not and cannot be programmed. Instead, aging is a continuation of developmental growth, driven by genetic pathways.
Genetic programs determine developmental growth and the onset of reproduction. When these programs are completed, they are not switched off.
Aging has no purpose (neither for individuals nor for group), no intention. Nature does not select for quasi-programs. It selects for robust developmental growth.”
The epigenetic clock theory of aging cited the same author, and modified his point to say:
Aging decisions are examples of our “flying human” making choices that aren’t available to our “monkey” concerning the structure, direction, and duration of our one precious life. So:
My 400th blog post curates a 2018 US/UK paper by two of the coauthors of Using an epigenetic clock to distinguish cellular aging from senescence. The authors reviewed the current state of epigenetic clock research, and proposed a new theory of aging:
“The proposed epigenetic clock theory of ageing views biological ageing as an unintended consequence of both developmental programmes and maintenance programmes, the molecular footprints of which give rise to DNAm [DNA methylation] age estimators.
It is best to interpret epigenetic age estimates as a higher-order property of a large number of CpGs much in the same way that the temperature of a gas is a higher-order property that reflects the average kinetic energy of the underlying molecules. This interpretation does not imply that DNAm age simply measures entropy across the entire genome.
To date, the most effective in vitro intervention against epigenetic ageing is achieved through expression of Yamanaka factors, which convert somatic cells into pluripotent stem cells, thereby completely resetting the epigenetic clock. In vivo, haematopoietic stem cell therapy resets the epigenetic age of blood of the recipient to that of the donor.
Future epidemiological studies should consider other sources of DNA (for example, buccal cells), because more powerful estimates of organismal age can be obtained by evaluating multiple tissues. Other types of epigenetic modifications such as adenine methylation or histone modifications may lend themselves for developing epigenetic age estimators.”
- The cerebellum ages more slowly than other body and brain areas
- Using an epigenetic clock with older adults
- Using an epigenetic clock with children
- The degree of epigenetic DNA methylation may be used as a proxy to measure biological age
The challenge is: do you want your quality of life to be under or over this curve?
What are you doing to reverse epigenetic processes and realize what you want? Do you have ideas and/or behaviors that interfere with taking constructive actions to change your phenotype?
If you aren’t doing anything, are you honest with yourself about the personal roots of beliefs in fate/feelings of helplessness? Do beliefs in technological or divine interventions provide justifications for inactions?
https://www.nature.com/articles/s41576-018-0004-3 “DNA methylation-based biomarkers and the epigenetic clock theory of ageing” (not freely available)