Loss-of-function mutations in Na
1.7 cause congenital insensitivity to pain (CIP); this voltage-gated sodium channel is therefore a key target for analgesic drug development. Utilizing a multi-modal ...approach, we investigated how Na
1.7 mutations lead to human pain insensitivity. Skin biopsy and microneurography revealed an absence of C-fiber nociceptors in CIP patients, reflected in a reduced cortical response to capsaicin on fMRI. Epitope tagging of endogenous Na
1.7 revealed the channel to be localized at the soma membrane, axon, axon terminals, and the nodes of Ranvier of induced pluripotent stem cell (iPSC) nociceptors. CIP patient-derived iPSC nociceptors exhibited an inability to properly respond to depolarizing stimuli, demonstrating that Na
1.7 is a key regulator of excitability. Using this iPSC nociceptor platform, we found that some Na
1.7 blockers undergoing clinical trials lack specificity. CIP, therefore, arises due to a profound loss of functional nociceptors, which is more pronounced than that reported in rodent models, or likely achievable following acute pharmacological blockade. VIDEO ABSTRACT.
Research in hand surgery: types of study design Peck, Liam J.; Rodrigues, Jeremy N.; Wormald, Justin C. R.
Journal of hand surgery. European volume,
10/2023, Letnik:
48, Številka:
9
Journal Article
The potassium channel Kv1.6 has recently been implicated as a major modulatory channel subunit expressed in primary nociceptors. Furthermore, its expression at juxtaparanodes of myelinated primary ...afferents is induced following traumatic nerve injury as part of an endogenous mechanism to reduce hyperexcitability and pain-related hypersensitivity. In this study, we compared two mouse models of constitutive Kv1.6 knock-out (KO) achieved by different methods: traditional gene trap via homologous recombination and CRISPR-mediated excision. Both Kv1.6 KO mouse lines exhibited an unexpected reduction in sensitivity to noxious heat stimuli, to differing extents: the Kv1.6 mice produced via gene trap had a far more significant hyposensitivity. These mice (
) expressed the bacterial reporter enzyme LacZ in place of Kv1.6 as a result of the gene trap mechanism, and we found that their central primary afferent presynaptic terminals developed a striking neurodegenerative phenotype involving accumulation of lipid species, development of "meganeurites," and impaired transmission to dorsal horn wide dynamic range neurons. The anatomic defects were absent in CRISPR-mediated Kv1.6 KO mice (
) but were present in a third mouse model expressing exogenous LacZ in nociceptors under the control of a Nav1.8-promoted Cre recombinase. LacZ reporter enzymes are thus intrinsically neurotoxic to sensory neurons and may induce pathologic defects in transgenic mice, which has confounding implications for the interpretation of gene KOs using
Nonetheless, in
mice not affected by LacZ, we demonstrated a significant role for Kv1.6 regulating acute noxious thermal sensitivity, and both mechanical and thermal pain-related hypersensitivity after nerve injury.
In recent decades, the expansion of technologies to experimentally manipulate the rodent genome has contributed significantly to the field of neuroscience. While introduction of enzymatic or fluorescent reporter proteins to label neuronal populations is now commonplace, often potential toxicity effects are not fully considered. We show a role of Kv1.6 in acute and neuropathic pain states through analysis of two mouse models lacking Kv1.6 potassium channels: one with additional expression of LacZ and one without. We show that LacZ reporter enzymes induce unintended defects in sensory neurons, with an impact on behavioral data outcomes. To summarize we highlight the importance of Kv1.6 in recovery of normal sensory function following nerve injury, and careful interpretation of data from LacZ reporter models.
Loss-of-function mutations in NaV1.7 cause congenital insensitivity to pain (CIP); this voltage-gated sodium channel is therefore a key target for analgesic drug development. Utilizing a multi-modal ...approach, we investigated how NaV1.7 mutations lead to human pain insensitivity. Skin biopsy and microneurography revealed an absence of C-fiber nociceptors in CIP patients, reflected in a reduced cortical response to capsaicin on fMRI. Epitope tagging of endogenous NaV1.7 revealed the channel to be localized at the soma membrane, axon, axon terminals, and the nodes of Ranvier of induced pluripotent stem cell (iPSC) nociceptors. CIP patient-derived iPSC nociceptors exhibited an inability to properly respond to depolarizing stimuli, demonstrating that NaV1.7 is a key regulator of excitability. Using this iPSC nociceptor platform, we found that some NaV1.7 blockers undergoing clinical trials lack specificity. CIP, therefore, arises due to a profound loss of functional nociceptors, which is more pronounced than that reported in rodent models, or likely achievable following acute pharmacological blockade.
Display omitted
•Patients with CIP due to NaV1.7 mutations have a functional absence of nociceptors•Lack of nociceptive drive is reflected in a reduced cortical response to capsaicin•Patient iPSC nociceptors show reduced excitability, especially to ramp stimuli•Gene-edited iPSC nociceptors represent a valuable analgesic drug screening platform
Gene mutations associated with painless phenotypes offer great insight for analgesic development. Using a multi-modal approach, McDermott et al. show that mutations in the voltage-gated sodium channel NaV1.7 cause congenital insensitivity to pain due to a lack of functional nociceptors.
Although microRNAs (miRNAs) are among the most intensively studied molecules of the past 20 years, determining what is and what is not a miRNA has not been straightforward. Here, we present a uniform ...system for the annotation and nomenclature of miRNA genes. We show that less than a third of the 1,881 human miRBase entries, and only approximately 16% of the 7,095 metazoan miRBase entries, are robustly supported as miRNA genes. Furthermore, we show that the human repertoire
of miRNAs has been shaped by periods of intense miRNA innovation and that mature gene products show a very different tempo and mode of sequence evolution than star products. We establish a new open access database-MirGeneDB (
http: mirgenedb.org
)-to catalog this set of miRNAs, which complements the efforts of miRBase but differs from it by annotating the mature versus star products and by imposing an evolutionary hierarchy upon this curated and consistently named repertoire.
Psilocybin is being studied for use in treatment-resistant depression.
In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of ...a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits).
A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval CI, -10.2 to -2.9; P<0.001) and between the 10-mg group and 1-mg group was -2.5 (95% CI, -6.2 to 1.2; P = 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups.
In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.).
Atopic dermatitis imposes a significant burden on patients, families and healthcare systems. Management is difficult, due to disease heterogeneity, co‐morbidities, complexity in care pathways and ...differences between national or regional healthcare systems. Better understanding of the mechanisms has enabled a stratified approach to the management of atopic dermatitis, supporting the use of targeted treatments with biologicals. However, there are still many issues that require further clarification. These include the definition of response, strategies to enhance the responder rate, the duration of treatment and its regimen (in the clinic or home‐based), its cost‐effectiveness and long‐term safety. The EAACI Guidelines on the use of dupilumab in atopic dermatitis follow the GRADE approach in formulating recommendations for each outcome and age group. In addition, future approaches and research priorities are discussed.
Body condition is commonly used in ecology to assess the physiological health of an organism or population and can be used to predict individual survival or breeding success. Waterfowl have been the ...focus of much research on body condition, and we studied body condition via carcass composition and using a scaled mass index (SMI) in American Black Ducks (Anas rubripes Brewster, 1902) wintering in coastal, agricultural, and urban areas of Atlantic Canada. Carcass composition varied between sexes and body mass decreased through winter as fat reserves depleted. Carcass composition was compared with American Black Ducks wintering in the United States, and American Black Ducks wintering in Atlantic Canada were structurally smaller yet proportionally fatter than those wintering in the United States, likely as a mechanism to survive Atlantic Canada’s harsher winters. SMI did not differ between coastal, agricultural, or urban American Black Ducks, indicating that despite known differences in the diets of the Black Ducks from these three areas, they can maintain similar body conditions capable of surviving the winter. We show that the SMI is a nondestructive alternative to study body condition in waterfowl. Our research highlights the adaptability and hardiness of American Black Ducks at the northern limit of their winter range.
American black ducks, native to eastern North America, have been the focus of significant international conservation and management programs. The combined USA and Canadian population has ...traditionally been managed as a single population; however black duck demographics may vary by region. To help understand potential regional differences in black ducks, we used satellite telemetry to assess migratory chronology and movements of black ducks wintering near Windsor, Nova Scotia, Canada, near the northern limits of their wintering range where numbers are increasing. Wintering black ducks from Nova Scotia did not leave the Atlantic Flyway and included both longer‐distance migrants (~ 1500 km north) and locally‐breeding individuals. None of our tracked ducks travelled south of Nova Scotia during any part of the annual cycle, indicating a population segment that never leaves Canada and is subject solely to Canadian harvest pressures. Band recovery data revealed that a small portion (2.4%) of black ducks originally banded during winter in Nova Scotia were recovered south along the east coast of the USA, indicating that some of these black ducks are subject to international harvest pressures. Our results show that there are differences in annual black duck movements even within a small part of their range, adding to the growing evidence that black duck populations show fine‐scale temporal and spatial structure. This structure will need to be considered in future interprovincial and international harvest management plans of this important species.
Atlantic Canada is the northern limit of the American black duck
(Anas rubripes
) wintering range, and more recently, the mallard (
A. platyrhynchos
) wintering range. Atlantic Canada has experienced ...considerable urban and agricultural development over the last century, and wintering black ducks and mallards appear to be using these habitats, in addition to traditional coastal habitat to survive the winters. This paper combines digestive tract content and stable isotope analysis to provide a comprehensive analysis of winter black duck and mallard diet in Atlantic Canada, and compares mallard and black duck winter diet in agricultural and coastal areas. Coastal black ducks wintering in Atlantic Canada had a diet consisting mainly of marine invertebrates and wild plant matter, while coastal mallards appeared to rely less on invertebrates and more on plant matter through winter. As winter progressed, the agricultural black ducks relied more on the feed provided by the farmer at our study site, indicated by a significant decline in their δ
15
N ratios. Mallards at the agricultural site maintained a low and steady δ
15
N ratio through winter, indicating a less diverse winter diet than sympatrically-wintering black ducks. Urban black ducks had a diet consisting entirely of vegetation and anthropogenic food supplies, which appeared to meet their nutritional requirements for winter survival. Our research highlights the importance of agricultural and urban habitats for wintering black ducks and mallards in Atlantic Canada.
PDF
