Gene therapy for deafness

It's not a common cause of deafness, but his looks promising. Perhaps one day we will have gene therapy for many developmental disabilities.

ABSTRACT

------------------------------------------------------

Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model

Omar Akil, Frank Dyka, Charlotte Calvet, Alice Emptoz, Ghizlene Lahlou, Sylvie Nouaille, Jacques Boutet de Monvel, Jean-Pierre Hardelin, William W. Hauswirth, Paul Avan, Christine Petit, Saaid Safieddine, and Lawrence R. Lustig

PNAS published ahead of print February 19, 2019 https://doi.org/10.1073/pnas.1817537116

Contributed by Christine Petit, November 27, 2018 (sent for review October 12, 2018; reviewed by Jonathan Gale and Botond Roska)

Significance

In humans, inner ear development is completed in utero, with hearing onset at ∼20 weeks of gestation. However, genetic forms of congenital deafness are typically diagnosed during the neonatal period. Gene therapy approaches in animal models should therefore be tested after the period of hearing onset, to determine whether they can reverse an existing deafness phenotype. Here, we used a mouse model of DFNB9, a human deafness form accounting for 2–8% of all cases of congenital genetic deafness. We show that local gene therapy in the mutant mice not only prevents deafness when administered to immature hearing organs, but also durably restores hearing when administered at a mature stage, raising hopes for future gene therapy trials in DFNB9 patients.

Local Hawaiian music: Britney Paiva on ukulele

Local ukulele virtuoso Britney Paiva performing in church. The second piece (The Prayer) is very inspiring.

Claws across the wolf's blood moon! My spotting telescope, Maryruth's iPhone 6+, and the neighbor's palm tree shadow, as seen from our lanai. There was a lunar eclipse tonight.

Reflections on Gustav Bergmann's "Some Remarks on the Ontology of Ockham"

Here.

The flaw in the simplicity of medieval's metaphysics of substances and properties seems to be their lack of explanation for our understanding of relations between objects. Ockham objects to objectivity of relations by pointing out that, given three dogs sitting together, each has a sitting property, but the "threeness" of the three dogs is not a property of each dog, nor is it held 1/3 by each dog. But this objection can either mean that substances are real and relations less so, or that the idea of substance as basic to our ontology is somehow flawed.

Much of medicine, indeed much of all modern science, is the study of relations. Statistics is the study of the mathematics of relations. In medicine, the isolated case report can be quite useful, and some scientific research, for example of sunspots, can be seen as a time series study of a single subject. However, most modern scientific studies are of the properties of groups of subjects: for example, the epidemiology of morbidity and mortality rates, or statistical comparisons of a repeated measure across a group of subjects under different treatments. Comparing two groups of subjects via correlations within and across groups is a relational measure, similar in its simplest respects to Ockham's counting of a group of dogs.

As opposed to the medieval traditions, I tend to see substance and essence pragmatically, as anything that has a structure or function of interest. So, if we study the population of an island, that population is the substance under study. A sculpture can be a substance of which the art is the form and the clay is the matter, but when we study the silica of that clay, its particles are the form and chemical compounds are the matter. Seen as a essence of sorts, a population has collective properties of the substance of that population. So, considering Anselm's example, the substance of a pack of dogs would then have the property of its number of dogs. Whether we classify what is under study as having relational properties or properties of a substance, in this view, is mostly a matter of scale.

Studying relations sets up for a combinational explosion of ontology, or at least an explosion of the statistics that create an explosive epistomology of those combinations, something Ockham may have tried to avoid. That explosion is where we can use Ockham most: for the razor.

On the reports of human CRISPR research.

What He Jiankui et al., 2018 said was an important ethical principle.	What He Jiankui claims he did by using CRISPR to knock out a receptor for the HIV virus in human embryo.	Was this inconsistency not just hypocrisy, but an ethics violation?
1. Mercy for families in need. A broken gene, infertility, or a preventable disease should not extinguish life or undermine a loving couple's union.	The potential for getting HIV, a generally preventable illness, has no bearing on specifically genetic illnesses.	No. However, the experimentation done required considerable money, time, and effort which could have been used on curative work.
2. Only for serious disease, never for vanity. Gene surgery is a serious medical procedure that should never be used for aesthetics, enhancement, or sex selection purposes -- or in any way that would compromise a child's welfare, joy, or free will. No one has a right to determine a child's genetics except to prevent disease. Gene surgery exposes a child to potential safety risks that can be permanent. Performing gene surgery is only permissible when the risks of the procedure arc outweighcd by a serious medical need.	Becoming resistant to a disease like HIV is a plus and is not just an aesthetic vanity, yet this counts as an enhancement which comes with genuine risk of unknown side effects due to a transmissible mutation of a cell’s receptor. Doctor He’s institutional review board, if there was one involved, seriously needs remedial education.	Yes.
3. Respect a child's autonomy. A life is more than our physical body and its DNA. After gene surgery, a child has equal rights to live life freely, to choose his or her occupation, and to privacy. No obligations exist to to his or her parents or any organization, including paying for the procedure.	No child can give informed consent as an embryo. Parental consent can only go so far.	Yes.
4. Genes do not define you. Our DNA does not predetermine our purpose or what we could achieve. We flourish from our own hard work, nutrition, and support from society and our loved ones. Whatever our genes may be, we are equal in dignity and potential.	Except for increased scrutiny, there seems to be no compromise of rights here. No genetically subservient underclass or supersoldier creation is seen here.	No.
5. Everyone deserves freedom from genetic disease. Wealth should not determine health. Organizations developing genetic cures have a deep moral obligation to serve families of every background.	Infertility clinics that charge large fees not covered by medical insurance already abound. We’ll have to see how this works out.	No.

References: https://www.wired.com/story/he-jiankui-crispr-babies-bucked-own-ethics-policy/

https://www.liebertpub.com/doi/10.1089/crispr.2018.0051

Even light exercise stimulates memory related brain systems.

The evidence for exercise and cognitive health continues to accumulate, including some evidence for increasing blood flow to memory system regions noted here.

-----------------------------------

ABSTRACT

Rapid stimulation of human dentate gyrus function with acute mild exercise

Kazuya Suwabe, Kyeongho Byun, Kazuki Hyodo, Zachariah M. Reagh, Jared M. Roberts, Akira Matsushita, Kousaku Saotome, Genta Ochi, Takemune Fukuie, Kenji Suzuki, Yoshiyuki Sankai, Michael A. Yassa, and Hideaki Soya

PNAS published ahead of print September 24, 2018 https://doi.org/10.1073/pnas.1805668115

Significance

Our previous work has shown that mild physical exercise can promote better memory in rodents. Here, we use functional MRI in healthy young adults to assess the immediate impact of a short bout of mild exercise on the brain mechanisms supporting memory processes. We find that this brief intervention rapidly enhanced highly detailed memory processing and resulted in elevated activity in the hippocampus and the surrounding regions, as well as increased coupling between the hippocampus and cortical regions previously known to support detailed memory processing. These findings represent a mechanism by which mild exercise, on par with yoga and tai chi, may improve memory. Future studies should test the long-term effects of regular mild exercise on age-related memory loss.

Abstract

Physical exercise has beneficial effects on neurocognitive function, including hippocampus-dependent episodic memory. Exercise intensity level can be assessed according to whether it induces a stress response; the most effective exercise for improving hippocampal function remains unclear. Our prior work using a special treadmill running model in animals has shown that stress-free mild exercise increases hippocampal neuronal activity and promotes adult neurogenesis in the dentate gyrus (DG) of the hippocampus, improving spatial memory performance. However, the rapid modification, from mild exercise, on hippocampal memory function and the exact mechanisms for these changes, in particular the impact on pattern separation acting in the DG and CA3 regions, are yet to be elucidated. To this end, we adopted an acute-exercise design in humans, coupled with high-resolution functional MRI techniques, capable of resolving hippocampal subfields. A single 10-min bout of very light-intensity exercise (30%V˙O2peak) results in rapid enhancement in pattern separation and an increase in functional connectivity between hippocampal DG/CA3 and cortical regions (i.e., parahippocampal, angular, and fusiform gyri). Importantly, the magnitude of the enhanced functional connectivity predicted the extent of memory improvement at an individual subject level. These results suggest that brief, very light exercise rapidly enhances hippocampal memory function, possibly by increasing DG/CA3−neocortical functional connectivity.

Do dogs use a left temporal speech area for understanding of human language words?

Here.

---------------------------------------------

Awake fMRI Reveals Brain Regions for Novel Word Detection in Dogs

Ashley Prichard, Peter F. Cook, Mark Spivak, Raveena Chhibber, Gregory Berns

doi: https://doi.org/10.1101/178186

Abstract

How do dogs understand human words? At a basic level, understanding would require the discrimination of words from non-words. To determine the mechanisms of such a discrimination, we trained 12 dogs to retrieve two objects based on object names, then probed the neural basis for these auditory discriminations using awake-fMRI. We compared the neural response to these trained words relative to oddball pseudowords the dogs had not heard before. Consistent with novelty detection, we found greater activation for pseudowords relative to trained words bilaterally in the parietotemporal cortex. To probe the neural basis for representations of trained words, searchlight multivoxel pattern analysis (MVPA) revealed that a subset of dogs had clusters of informative voxels that discriminated between the two trained words. These clusters included the left temporal cortex and amygdala, left caudate nucleus, and thalamus. These results demonstrate that dogs' processing of human words utilizes basic processes like novelty detection, and for some dogs, may also include auditory and hedonic representations.