Early expression of hypocretin/orexin in the chick embryo brain.

Hypocretin/Orexin (H/O) neuropeptides are released by a discrete group of neurons in the vertebrate hypothalamus which play a pivotal role in the maintenance of waking behavior and brain state control. Previous studies have indicated that the H/O neuronal development differs between mammals and fish; H/O peptide-expressing cells are detectable during the earliest stages of brain morphogenesis in fish, but only towards the end of brain morphogenesis (by ∼ 85% of embryonic development) in rats. The developmental emergence of H/O neurons has never been previously described in birds. With the goal of determining whether the chick developmental pattern was more similar to that of mammals or of fish, we investigated the emergence of H/O-expressing cells in the brain of chick embryos of different ages using immunohistochemistry. Post-natal chick brains were included in order to compare the spatial distribution of H/O cells with that of other vertebrates. We found that H/O-expressing cells appear to originate from two separate places in the region of the diencephalic proliferative zone. These developing cells express the H/O neuropeptide at a comparatively early age relative to rodents (already visible at 14% of the way through fetal development), thus bearing a closer resemblance to fish. The H/O-expressing cell population proliferates to a large number of cells by a relatively early embryonic age. As previously suggested, the distribution of H/O neurons is intermediate between that of mammalian and non-mammalian vertebrates. This work suggests that, in addition to its roles in developed brains, the H/O peptide may play an important role in the early embryonic development of non-mammalian vertebrates

Distribution of H/O neurons (red dots) in the hypothalamus of E20 chick embryos (left column) and P21 chicks (right column).

<p>The most cranial level is shown on top and the most caudal one on the bottom. The distance between consecutive levels is indicated on the side. 3v: 3^rd ventricle; lv: lateral ventricle; ot: optic tract; ox: optic chiasm; P: pallium; T: tectum. Scale bar is the same for both columns and is 1 mm.</p

Distribution of H/O neurons (red dots) in the hypothalamus of E10 (left column) and E16 chick embryos (right column).

<p>The most cranial level is shown on top and the most caudal one on the bottom. The distance between consecutive levels is indicated on the side. 3v: 3^rd ventricle; lv: lateral ventricle; ot: optic tract; ox: optic chiasm; P: pallium; T: tectum. Scale bars are 1 mm.</p

Mean number of H/O neurons (A) and their cranio-caudal spatial extent (in µm) (B) in the brains of embryos at different ages.

<p>Bars represent ± 1 SEM and n = 4 for all ages, except for incubation periods of 8 days or less, where n = 3. For each graph, points that do not share symbols above them are significantly different from each other at the <i>p</i><0.05 level, two-tailed, corrected for multiple comparisons (Kruskal-Wallis ANOVA; H = 15.96, df = 6, <i>p</i> = 0.014 in A; H = 33.05, df = 10, <i>p</i> = 0.0003 in B).</p

H/O neurons in E10 and E20 chicken embryos.

<p>H/O neurons appear brown. Coronal sections of the caudal portions of the hypothalamus show the distribution of labeled neurons in a representative E10 embryo at low (A) and at high magnification (C) and in a representative E20 embryo at low (B) and at high magnification (D). The sections from the E10 embryo were counterstained with Cresyl Violet to better identify the brain structures. The inverted V-shape distribution of H/O neurons is evident at both ages. Labeled neurons appear bigger and more strongly labeled at E20 than E10. 3v: 3^rd ventricle. Scale bars are 200 µm (A, B) and 10 µm (C, D).</p

Total number (mean per animal) of H/O positive cells found in the entire hypothalamus, and cranio-caudal spatial extent (in µm) of the hypothalamic area containing H/O cells at different ages.

<p>n: number of animals; nc: not collected; SEM: Standard Error of the Mean.</p><p>Total number (mean per animal) of H/O positive cells found in the entire hypothalamus, and cranio-caudal spatial extent (in µm) of the hypothalamic area containing H/O cells at different ages.</p

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease