Summary
By studying healthy women who do not request analgesia during their first delivery, we investigate genetic effects on labor pain. Such women have normal sensory and psychometric test results, except for significantly higher cuff pressure pain. We find an excess of heterozygotes carrying the rare allele of SNP rs140124801 in
KCNG4
. The rare variant K
V
6.4-Met419 has a dominant-negative effect and cannot modulate the voltage dependence of K
V
2.1 inactivation because it fails to traffic to the plasma membrane.
In vivo
,
Kcng4
(K
V
6.4) expression occurs in 40% of retrograde-labeled mouse uterine sensory neurons, all of which express K
V
2.1, and over 90% express the nociceptor genes
Trpv1
and
Scn10a
. In neurons overexpressing K
V
6.4-Met419, the voltage dependence of inactivation for K
V
2.1 is more depolarized compared with neurons overexpressing K
V
6.4. Finally, K
V
6.4-Met419-overexpressing neurons have a higher action potential threshold. We conclude that K
V
6.4 can influence human labor pain by modulating the excitability of uterine nociceptors.
Reconstructing dense 3D anatomical coordinates from 2D projective measurements has become a central problem in digital pathology for both animal models and human studies. We describe a new family of diffeomorphic mapping technologies called Projective LDDMM which generate diffeomorphic mappings of dense human MRI atlases at tissue scales onto sparse measurements at micron scales associated with histological and more general optical imaging modalities. We solve the problem of dense mapping surjectively onto histological sections by incorporating new technologies for crossing modalities that use non-linear scattering transforms to represent multiple radiomic-like textures at micron scales and incorporating a Gaussian mixture-model frame-work for modelling tears and distortions associated to each section. We highlight the significance of our method through incorporation of neuropathological measures and MRI, as relevant to the development of biomarkers for Alzheimer’s disease and one instance of the integration of imaging data across the scales of clinical imaging and digital pathology.
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