Exosomes and the RNA-mediated future of medicine (2)

By: James V. Kohl | Published on: September 11, 2015
Exosomes and the RNA-mediated future of medicine (2)(click to enlarge)

GDNF-Transfected Macrophages Produce Potent Neuroprotective Effects in Parkinson’s Disease Mouse Model
Excerpt:

…genetically-modified macrophages released exosomes with incorporated GDNF that may facilitate GDNF transport into the target cells and preserve it against degradation.

published 9/17/14 and reported on 9/11/15 as:

Smart cells teach neurons damaged by Parkinson’s to heal themselves

Excerpt:

In addition to delivering GDNF, the engineered macrophages can “teach” neurons to make the protein for themselves by delivering both the tools and the instructions needed: DNA, messenger RNA and transcription factor.

MedicalXpress.com suddenly seems interested in reporting on the role of exosomes in RNA-mediated cell type differentiation, which is what I did yesterday in this blog post. Exosomes and the RNA-mediated future of medicine
See also: UNC smart cells teach neurons damaged by Parkinson’s to heal themselves
Excerpt: “By teaching immune system cells to make this protective protein, we harness the natural systems of the body to combat degenerative conditions like Parkinson’s disease,” Batrakova said.
See also: RNA-binding protein influences key mediator of cellular inflammation and stress responses

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3 MIN READ
0
The “great filter” is an epigenetic trap
4 MIN READ
0
Atomic-resolution of cell type signaling
4 MIN READ
0
Information and communication
2 MIN READ
0
Unraveling evolutionary pseudoscience
2 MIN READ
0
Eibi Nevo gets it wrong
3 MIN READ
0
Rs3827760 is Val370Ala and EDARV370A
3 MIN READ
0
From “Blood Music” to Evolution 2.0
5 MIN READ
0
Olfaction & the octopus and human genomes (2)
4 MIN READ
0
Olfaction & the octopus and human genomes
3 MIN READ
0
Protosuns, prebiotic molecules, proteins, and people
4 MIN READ
0
Mammalian-wide interspersed repeats (MIRs)
2 MIN READ
0
Ecological speciation vs revised evolutionary syntheses
6 MIN READ
0
Ecology replaces the extended evolutionary synthesis
4 MIN READ
0
The stability of organized genomes (4)
3 MIN READ
0
The stability of organized genomes (3)
3 MIN READ
0
The stability of organized genomes (2)
5 MIN READ
0
Epimutation.com: a domain of confusion
8 MIN READ
0
Light -induced nucleic acid-mediated gene duplication?
< 1 MIN READ
0
Is the best Chinese research from China?
3 MIN READ
0
The stability of organized genomes
5 MIN READ
0
Viruses, amino acids, and somatic cell types (3)
9 MIN READ
0
Viruses, amino acids, and somatic cell types (2)
5 MIN READ
0
Big Bang Cosmology vs Reality
< 1 MIN READ
0
RNA-mediated terms of virus-induced en-deer-ment
2 MIN READ
0
Domestication via a single amino acid substitution
2 MIN READ
0
Hematopoiesis and practopoiesis
4 MIN READ
0
RNA-mediated morphological AND behavioral phenotypes
2 MIN READ
0
Becoming biologically informed (3)
3 MIN READ
0
Easy editing: Reinventing our RNA world
3 MIN READ
0
Is photic-zone ribosomal diversity linked to all biodiversity?
2 MIN READ
0
Picornaviruses moving between primates (or not)
2 MIN READ
0
Riding the wrong direction
3 MIN READ
0
Decreased phenotypic variation: Faith in Facts
7 MIN READ
1
Faithfully repaired DNA
5 MIN READ
0
RNA-mediated gene duplication, fixation, and ecological adaptation
6 MIN READ
0
MicroRNA controlled growth and brain development
7 MIN READ
0
MicroRNA – controlled ecological adaptations
5 MIN READ
0
Celebrating independence from ridiculous theories
3 MIN READ
0
Is SUMOylation RNA-directed DNA methylation? (revisited)
4 MIN READ
0
“New” epigenetic mechanism for lifelong learning?
3 MIN READ
0
The sum of our RNA-mediated parts
2 MIN READ
0
microRNAs and memory: Why trust a theory?
2 MIN READ
0
Protein folding and Google page rank
2 MIN READ
0
Iron, ferritin, thyroxine
2 MIN READ
0
“Evolution” of sex differences?
2 MIN READ
0
Nutrient stress-induced RNA-mediated pathology
< 1 MIN READ
0
Amino acid substitutions are not mutations
2 MIN READ
0
RNA-mediated events from A to Z
2 MIN READ
0
“First” evidence
5 MIN READ
0
What I cannot create I eliminate from discussion
3 MIN READ
0
RNA-mediated development
2 MIN READ
0
Creating and maintaining the human virome
2 MIN READ
0
Healthy mutants
2 MIN READ
0
Uniquely epigenomic gene regulation
2 MIN READ
0
MicroRNAs and inappropriate functions
2 MIN READ
0
Rejecting pseudoscientific nonsense
6 MIN READ
1
Living the life that randomness created? (Sarcasm alert)
3 MIN READ
0
30 years of theoretical nonsense
3 MIN READ
0
microRNAs, glycosylation, and genomes
4 MIN READ
0
Unknown mechanisms and conclusions
2 MIN READ
0
Alternative splicings: epigenetics meets pharmacogenomics
4 MIN READ
0
Epigenetic regulation of aging by glycine and GnRH
5 MIN READ
0
Physicians who practice evolutionary medicine?
3 MIN READ
0
Pattern recognition: biogeochemical structure and function
5 MIN READ
0
Tweaking the story to fit the theory
5 MIN READ
0
Appetite for ingesting theories (raw)
< 1 MIN READ
0
I forgot. How do mutations cause evolution?
4 MIN READ
0
One amino acid substitution, genes, and brain activity
3 MIN READ
0
Batch effect vs epigenetic effects
3 MIN READ
0
Gene expression, immortality, and cancer
6 MIN READ
0
Missing a fact: microRNAs are genomic biomarkers
4 MIN READ
1
Bee-birthed epigenetics and primate cell types
5 MIN READ
0
A lighting requirement for life
11 MIN READ
3
Scientists lose. A sci-fi author gains credibility
2 MIN READ
0
Vitamin B3 and DNA repair
4 MIN READ
0
Bees and primates automagically evolve
3 MIN READ
0
Ignoring systems complexity (it’s too complicated)
3 MIN READ
0
Five years of Ferguson
2 MIN READ
0
Computing via phosphorylation and fixation
3 MIN READ
0
Virus-driven cancer treatment and prevention
2 MIN READ
0
The microbiome, pharmacogenetics, and privacy
< 1 MIN READ
0
Retinoic acid + one receptor regulate the genome
3 MIN READ
0
Epigenetics: microRNAs effect an integrative pathway
4 MIN READ
0
Protein isoforms do not evolve
3 MIN READ
0
Tissue type variation and expression of genes
< 1 MIN READ
0
From gut bacteria to breast milk and back
5 MIN READ
0
Chance mutations — not natural selection
5 MIN READ
0
Viruses in gut microbes
4 MIN READ
0
How to find a “holy grail” under your nose
3 MIN READ
0
Physics, chemistry, light, and life
2 MIN READ
0
Finding odor and taste receptors everywhere
6 MIN READ
0
Linking the origin of birds to dinosaurs
< 1 MIN READ
0
An epigenetic mark links algae, worms, and flies
2 MIN READ
0
Effect and affect of a single base-pair change
4 MIN READ
0
Tet3 regulation of nutrient-dependent cell type differentiation
4 MIN READ
0
Thermodynamics and protein folding landscapes
2 MIN READ
0
RNA-mediated silencing of a chromosome
3 MIN READ
0
Viruses, proteins, and gut metagenomes do not evolve
< 1 MIN READ
0
Pathology constrains X-linked evolution
2 MIN READ
0
Feedback loops link insects to human brains
2 MIN READ
0
Viruses and cell type differentiation
3 MIN READ
0
RNA-mediated cell types and precision medicine
5 MIN READ
0
DNA Methylation and organized genomes (2)
10 MIN READ
0
DNA Methylation and organized genomes
7 MIN READ
0
Misunderstanding cancer
7 MIN READ
0
Amino acid-dependent cell type differentiation
8 MIN READ
0
Nutrient-dependent RNA interference (2)
4 MIN READ
0
The Darwin Code by Greg Bear
13 MIN READ
0
Nutrient-dependent RNA interference
4 MIN READ
0
Mutisensory integration: watching the paradigm shift
12 MIN READ
0
Origin of life and cancer (1,2,3)
2 MIN READ
0
A genetic variant refutes neo-Darwinism
6 MIN READ
0
MicroRNAs and invasive phenotypes
< 1 MIN READ
0
Silencing genes and serious scientists
3 MIN READ
0
The miRNA/mRNA balance: a suboptimal strategy?
2 MIN READ
0
Nutrient-dependent microRNAs control cell types
6 MIN READ
0
Deeply ingrained thoughts
< 1 MIN READ
0
Graphic misrepresentations of ecological adaptation
2 MIN READ
0
Too many targets for theories
3 MIN READ
0
Methylation maintains cell type differences (2)
2 MIN READ
0
Methylation maintains cell type differences
3 MIN READ
0
Creating nothing but a theory (3)
4 MIN READ
3
Creating nothing but a theory (2)
4 MIN READ
0
Creating nothing but a theory
4 MIN READ
0
Viruses and ecologically adapted animals
2 MIN READ
0
2 genes in 2 species (too expensive and too insignificant)
11 MIN READ
0
The quantum / classical RNA-mediated ‘tipping point’
3 MIN READ
0
Epigenetic effects of soil bacteria on plants
< 1 MIN READ
0
Epigenetic switch links MicroRNAs to RNA-protein interactions
4 MIN READ
0
Quantum correlations/pseudoscience
3 MIN READ
0
Anti-entropic solar energy
5 MIN READ
0
Mimicking claims and ignoring facts
4 MIN READ
0
Correctly modeling life on this planet
3 MIN READ
0
Correctly modeling ecological adaptation
4 MIN READ
0
Behavior (4): All responses are RNA-mediated in birds
4 MIN READ
0
Questions about life’s diversity
21 MIN READ
0
UV-light mutations and gene loss (not gain)
5 MIN READ
0
Virus-driven origin of life
2 MIN READ
0
Luis P. Villarreal tells it like it is
3 MIN READ
0
RNA-directed gene choice
5 MIN READ
0
Walk towards the light
< 1 MIN READ
0
Two types of microRNA are not double agents
2 MIN READ
0
Epigenetics Skeptism
5 MIN READ
0
Assembling yourself: Molecular self / other recognition
4 MIN READ
0
What about birds?
5 MIN READ
0
Virus-driven cell type differentiation
2 MIN READ
0
RNA directed DNA methylation and cell types
4 MIN READ
0
Implicating microRNAs in cancer
2 MIN READ
0
Rejecting what is known about viral microRNAs and nutrient-dependent microRNAs
2 MIN READ
0
Reverse phosphorylation
7 MIN READ
0
RNA-mediated repurposing in microbes and adaptations in primate brains
2 MIN READ
0
RNA-mediated “repurposing” is nutrient-dependent and pheromone-controlled
3 MIN READ
0
RNA-mediated "repurposing" is nutrient-dependent and pheromone-controlled
3 MIN READ
0
From 3-D to epigenetically-effected 4-D genome make-up
5 MIN READ
0
Let there be anti-entropic light (1)
11 MIN READ
0
An epigenetic trap (the prequel)
5 MIN READ
0
Imagining that data historically supports evolutionary theory
7 MIN READ
0
Atheism: Arrogant, useless, and divisive ignorance
7 MIN READ
0
The anti-entropic force of "Nature"
2 MIN READ
0
Nutritional epigenetics, exercise, and immune system integrity
4 MIN READ
0
What if Darwin was not still dead?
2 MIN READ
0
Military combat training to fight disease (2)
3 MIN READ
0
Military combat training to fight disease
3 MIN READ
0
Theoretical physics and molecular biology
5 MIN READ
0
Atoms to ecosystems is not almost a molecular ecology
3 MIN READ
0
Epigenetic effects of viruses on cellular homeostasis (2)
2 MIN READ
0
RNA-mediated epigenetic modification via DNA-methylation
4 MIN READ
0
Quantum physics, quantum biology, and quantum consciousness
4 MIN READ
0
How fast can evolutionary theory be changed?
5 MIN READ
0
Biological energy and a microbiome model of a light-driven time machine
3 MIN READ
0
The biologically-based origin of the mammalian placenta (2)
6 MIN READ
0
Quantum Superpositions: let there be light
4 MIN READ
0
Are viruses microRNAs? (2)
5 MIN READ
0
Are viruses microRNAs?
3 MIN READ
0
Sneaking up from behind (2)
3 MIN READ
0
Sneaking up from behind
4 MIN READ
0
Quantum entanglement, mass, and biomass
4 MIN READ
0
Physicists: Desperate Acts
16 MIN READ
0
An epigenetic trap (the sequel)
10 MIN READ
0
Mute points: most are afraid to mention them
6 MIN READ
0
All of “like kind” (Part 2)
2 MIN READ
0
All of "like kind" in the (bigger) family
6 MIN READ
1
Environment epigenetically shapes the immune system
3 MIN READ
0
Beneficial microbes kill beneficial mutations
4 MIN READ
0
Constrained evolution is ecological adaptation
5 MIN READ
0
A single amino acid substitution differentiates cell types of E. coli
3 MIN READ
0
Unconstrained evolutionary innovability
4 MIN READ
0
RNA-protein interactions reveal biophysical to ecological landscapes
2 MIN READ
0
Mutagenesis: Replacing facts with theories
5 MIN READ
0
ISHE's human ethology group
2 MIN READ
0
Amino acid homeostasis for a Happy New Year!
6 MIN READ
0
Understanding cell type differentiation
3 MIN READ
0
From Hydra to humans vs a Lakatosian research program
4 MIN READ
0
Unified nutritional and molecular mechanisms
9 MIN READ
0
Removing natural selection; reshaping the horse; adjusting evolutionary theory
4 MIN READ
0
Communication, not mutations
2 MIN READ
0
Models by evolutionary biologists are not models
2 MIN READ
0
The future of physics predicts no future for evolutionary theory
3 MIN READ
0
Model organisms: the birds and the bees
3 MIN READ
0
Chemical ecology and RNA-mediated control of DNA loops
< 1 MIN READ
0
Atoms to ecosystems: Evolutionary theory vs the coelacanth
6 MIN READ
0
Jumping back: Science or Pseudoscience? (2)
2 MIN READ
0
Jumping back: Science or Pseudoscience?
6 MIN READ
0
Single-cell level assay of protein biosynthesis and degradation
2 MIN READ
0
Glycine and GnRH: Am I being pedantic?
4 MIN READ
0
Extensive molecular evidence vs ridiculous theories
2 MIN READ
0
Dual genomes: exposing the evolution industry
5 MIN READ
0
One test of bioenergetic health?
2 MIN READ
0
Meaningful dialogue, anonymous fools and idiot minions
4 MIN READ
0
Epigenetic pharmacology and RNA-mediated transciptional landscapes
3 MIN READ
0
RNA-mediated events and "The Theory of Everything"
4 MIN READ
0
Sackler Colloquium: Effects or AFFECTS on Behavior
2 MIN READ
0
Thermodynamic constraints and ecological adaptations sans evolution
6 MIN READ
0
Eliminating correlations from evolutionary ecology
6 MIN READ
0
RNA-mediated species specificity
2 MIN READ
0
Are mutations beneficial?
4 MIN READ
0
The key to science: experimental evidence
5 MIN READ
0
Ecological adaptations reported as evolution in insects and mammals
4 MIN READ
0
There’s a model for that!
5 MIN READ
0
Biologists puzzled by evolved RNAs and decaying DNA
6 MIN READ
0
SNPs and millions of small variations in the human genome
3 MIN READ
0
More than a bag of chemicals?
2 MIN READ
0
Achiral GnRH: no prophesy, just prediction
9 MIN READ
0
Nothing new under the sun, except pseudoscientific nonsense
6 MIN READ
0
Making sense of quotes scattered across disciplines
2 MIN READ
0
Intelligent viruses and cancers?
10 MIN READ
0
Complex behaviors of cell types in cancer
6 MIN READ
0
De novo DNA methylation?
3 MIN READ
0
RNA eclipses the importance of DNA to cell type differentiation
4 MIN READ
0
We need pattern recognition, not proclamations
3 MIN READ
0
Pharmacogenomics
3 MIN READ
0
Sexual differentiation of cell types in plants
2 MIN READ
0
A model of MHC 'evolution'
2 MIN READ
0
From deep time into real time: What evolutionary processes?
10 MIN READ
0
In theory, or supported by experimental evidence?
5 MIN READ
0
It’s cell type differention, not cell fate determination (2)
3 MIN READ
0
Are evolutionary theorists 'nob ends'?
5 MIN READ
2
ALPHA GENOMIX
7 MIN READ
2
No excuses: Creation and the meaning of organismal complexity
7 MIN READ
0
Nutrient-dependent gene duplication in plants (but not animals?)
4 MIN READ
0
Evolutionary theorists justify fear of the Ebola viruses
2 MIN READ
0
Evolutionary theorists and evolutionary theists live under rocks
< 1 MIN READ
0
No understanding of biodiversity
2 MIN READ
0
Understanding physical forces of ecological variation and adaptation
< 1 MIN READ
0
Eliminating evolutionary theory
3 MIN READ
0
Behavioral ecology: please continue to believe in our fantasies
3 MIN READ
0
2014 and 2004 Nobel Prize in Medicine
3 MIN READ
0
RNA-mediated events: chromosomal rearrangements and genomic rearrangements
2 MIN READ
2
How much good can be attributed to social science theories?
< 1 MIN READ
0
RNA-mediated genetic engineering (Part 3)
< 1 MIN READ
0
RNA-mediated genetic engineering (Part 2)
3 MIN READ
0
RNA-mediated genetic engineering
2 MIN READ
0
RNA-mediated events are not a matter of faith
2 MIN READ
0
Color vision refutes the evolutionary dogma of gene duplication
4 MIN READ
0
Unassailable evidence vs assumptions
4 MIN READ
0
Forces of "Nature" limit dissemination of information
4 MIN READ
0
Genomic surveillance ends our world of RNA-mediated ecological adaptations
2 MIN READ
0
Systems biology and memory disorders
3 MIN READ
0
RNA-mediated cell type differentiation and behavior
3 MIN READ
0
Different physical locations and different molecular mechanisms of health and disease
2 MIN READ
0
Metabolism, fixation, health or neurodegerative disorder
2 MIN READ
0
Physics, Chemistry, and Molecular biology (PCMb)
2 MIN READ
0
Physics denied; pseudoscientific nonsense accepted
2 MIN READ
0
Ecological variation and niche construction: 1, 2, 3
6 MIN READ
0
Epigenetically-effected metabolic shifts and ecological adaptations
3 MIN READ
0
Evolving DNA before RNA
4 MIN READ
0
Stop evolutionary theorists. Kill cancers
3 MIN READ
0
Did our adapted mind evolve? (Revisited)
2 MIN READ
0
De novo gene Creation sans evolution of genes via mutations
4 MIN READ
0
Did our adapted mind evolve?
6 MIN READ
0
RNA-directed DNA methylation and RNA-mediated events
5 MIN READ
1
Miracles are not miracles to evolutionary theorists
2 MIN READ
0
Mathematical model: microRNA and epigenetic regulation
2 MIN READ
0
Seemingly futile cycles are not thermodynamically futile
3 MIN READ
0
Do bacterial proteins evolve?
3 MIN READ
0
“Kardashians” in science
< 1 MIN READ
0
Probable changes in connectivity
2 MIN READ
0
New technique used in report of atomic-level ecological adaptations
3 MIN READ
0
Can epigenetic inheritance occur without concurrent changes in morphology AND behavior?
3 MIN READ
0
Memory of repression and memory of behavior (2)
< 1 MIN READ
0
Memory of repression and memory of behavior
2 MIN READ
0
Quantum physics meets Evolutionary Psychology News
2 MIN READ
0
Nutrient-dependent pheromone-controlled exercise-induced physiques
< 1 MIN READ
0
Watching and waiting for more retractions
2 MIN READ
0
RNA-mediated ecological adaptations of teeth
4 MIN READ
0
A molecular visualizer of worthwhile molecular biology
2 MIN READ
0
RNA-mediated species diversification from microbes to primates
3 MIN READ
0
RNA-mediated events found everywhere
2 MIN READ
0
Reseachers think copy number variation is genetically determined
< 1 MIN READ
0
Some neuroscientists think a mutation led to human language development
< 1 MIN READ
0
Genotype, observed phenotype, and distinctly disordered behaviors
3 MIN READ
0
Is the problem an internet echo or Feierman's ethics?
2 MIN READ
0
Behavior (3): All responses are RNA-mediated in bees
3 MIN READ
0
RNA-mediated ecological adaptation is not evolution
2 MIN READ
0
Exploding genomes and chromosomal rearrangements via RNA-mediated events
2 MIN READ
0
Behavior (2): All responses are RNA-mediated not genetically-determined
4 MIN READ
0
Behavior: The first response is RNA-mediated not genetically-determined
3 MIN READ
0
Mechanisms that are not understood increase clarity
4 MIN READ
2
Pattern recognition and conserved receptors (TAARs)
5 MIN READ
0
Nutrient-dependent erythropoiesis and anemia
6 MIN READ
0
Evolutionary heritage or ecological adaptation? Racism versus reality
4 MIN READ
0
A relatively young branch of science called epigenetics
4 MIN READ
0
Insect homology and diversity attributed to mutations
2 MIN READ
0
Biophysically constrained beginnings of RNA and DNA
4 MIN READ
0
Baby talk: More misrepresentations of ecological adaptations
2 MIN READ
0
Comparing divergent model organisms
2 MIN READ
1
A microRNA-mediated mechanism that is epigenetically inherited
2 MIN READ
0
Epimutations: Attacking pseudoscientific dogmas
4 MIN READ
0
Order and disorder: Ecological adaptations not mutations
6 MIN READ
0
microRNAs and species relationships
3 MIN READ
0
Drunks and Monkeys: Pseudoscientific nonsense
2 MIN READ
0
The quantum biology of consciousness
3 MIN READ
0
Behavior is receptor-mediated
10 MIN READ
0
Genes and Race: Human History?
2 MIN READ
0
Soft atheism: a case for Creation
< 1 MIN READ
0
Nutrition, pheromones and cancer (2)
2 MIN READ
0
Ecologically linked adapted ants and brains
2 MIN READ
0
MiRNAs methylation and ecological adaptation sans mutations
2 MIN READ
0
Not focused and self-aggrandizing
2 MIN READ
0
Nutrient-dependent cooperation vs cannibalism (video)
2 MIN READ
0
Another powerful refutation of mutation-initiated natural selection
4 MIN READ
0
The new light of chromosomal rearrangements
3 MIN READ
0
Darwinian theories vs Darwin's facts
2 MIN READ
0
Chromosomal rearrangements and ecological adaptations
4 MIN READ
0
The wrong picture of our evolution
4 MIN READ
0
96 fixed amino acid substitutions, not 96 genes
6 MIN READ
0
Jay R. Feierman
3 MIN READ
0
Don't tell the Creationists
2 MIN READ
0
Targeting a cancer gene
2 MIN READ
0
Alternative splicings (very technical)
2 MIN READ
0
Pulses of olfactory/pheromonal input
2 MIN READ
0
Social experiences epigenetically effect gene networks
2 MIN READ
0
Pheromone-controlled thermodynamics and cancer
2 MIN READ
0
Seeds of life: astrobiological theory and mutations theory
3 MIN READ
0
Your comment is awaiting moderation
2 MIN READ
0
Nutrient-dependent pheromone-controlled stickleback evolution
2 MIN READ
0
Functional coding variants are not mutations
2 MIN READ
0
Mirror neurons and microRNA: theory vs biological facts
4 MIN READ
0
Understanding the role of mutations and evolution
4 MIN READ
0
Alzheimer's, microRNAs, and olfaction
< 1 MIN READ
0
Evolution: innovations may have non-adaptive origins (sans mutations)
2 MIN READ
0
Are pheromones responsible for human body odour assessment?
2 MIN READ
0
Epigenetic effects underlie sexual preferences IV
< 1 MIN READ
0
MicroRNA binds messenger RNA: Adaptive Evolution
< 1 MIN READ
0
A key mutational event? That’s not very likely.
3 MIN READ
0
Disorders of development: altered microRNA / messenger RNA balance
< 1 MIN READ
0
Evolution at work sans random mutations
2 MIN READ
0
Sex differences in Alzheimer's and everything else
2 MIN READ
0
CB Nemeroff: Off Restriction
< 1 MIN READ
0
A thought experiment
3 MIN READ
0
Honeybees, food odors, and perfume
< 1 MIN READ
0