Search

The contribution of domestic cattle in human societies is enormous, making cattle, along with other essential benefits, the economically most important domestic animal in the world today. To expand existing knowledge on cattle domestication and mitogenome diversity, we performed a comprehensive complete mitogenome analysis of the species (802 sequences, 114 breeds). A large sample was collected in Southeast Europe, an important agricultural gateway to Europe during Neolithization and a region rich in cattle biodiversity. We found 1725 polymorphic sites (810 singletons, 853 parsimony-informative sites and 57 indels), 701 unique haplotypes, a haplotype diversity of 0.9995 and a nucleotide diversity of 0.0015. In addition to the dominant T-3 and several rare haplogroups (Q, T-5, T-4, T-2 and T-1), we have identified maternal line in Austrian Murbodner cattle that possess surviving aurochs' mitochondria haplotype P-1 that diverged prior to the Neolithization process. This is convincing evidence for rare female-mediated adaptive introgression of wild aurochs into domesticated cattle in Europe. We revalidated the existing haplogroup classification and provided Bayesian phylogenetic inference with a more precise estimated divergence time than previously available. Occasionally, classification based on partial mitogenomes was not reliable; for example, some individuals with haplogroups P and T-5 were not recognized based on D-loop information. Bayesian skyline plot estimates (median) show that the earliest population growth began before domestication in cattle with haplogroup T-2, followed by Q (-10.0-9.5 kyBP), whereas cattle with T-3 (similar to 7.5 kyBP) and T-1 (similar to 3.0-2.5 kyBP) expanded later. Overall, our results support the existence of interactions between aurochs and cattle during domestication and dispersal of cattle in the past, contribute to the conservation of maternal cattle diversity and enable functional analyses of the surviving aurochs P-1 mitogenome.

This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple oral doses of enpatoran (formerly named M5049), a new toll‐like receptor (TLR) 7 and 8 dual antagonist, and the effect of food on a single dose in healthy participants. In this single phase 1, randomized (3:1), double‐blind, placebo‐controlled study, 96 participants received single and multiple ascending oral doses of enpatoran. Participants in single‐dose cohorts received one dose of enpatoran (1, 3, 9, 25, 50, 100, or 200 mg) or placebo using a sentinel dosing strategy. Multiple‐dose cohorts received enpatoran (9, 25, or 200 mg once daily, or 25 or 50 mg twice daily) or placebo for 14 days. Safety, tolerability, PK, and PD (ex vivo‐stimulated cytokine secretion) were assessed in both parts. The effect of food was assessed in an open‐label, one‐way crossover study in the 25 mg single‐dose cohort. Single‐ and multiple‐oral doses of enpatoran up to 200 mg were well tolerated and no significant dose‐limiting adverse events or safety signals were observed under fasting or fed conditions. PK parameters were linear and dose‐proportional across the dose range evaluated, with a slightly delayed absorption and lower peak concentration observed at 25 mg with food. Exposure‐dependent inhibition of ex vivo‐stimulated interleukin‐6 secretion was observed, with maximum inhibition at 200 mg. Enpatoran was well tolerated at doses up to 200 mg. Further investigation of enpatoran is warranted as a potential treatment for diseases driven by TLR7/8 overactivation, such as systemic lupus erythematosus and COVID‐19 pneumonia., The graphical abstract shows the study design and key outcomes from the study.

For future retinal tissue engineering, it is essential to understand formation of retinal tissue in a 'cell-by-cell' manner, as can be best studied in retinal reaggregates. In avians, complete laminar spheres can be produced, with ganglion cells internally and photoreceptors at the surface; a similar degree of retinal reconstruction has not been achieved for mammals. Here, we have studied self-organizing potencies of retinal cells from neonatal gerbil retinae to form histotypic spheroids up to 15 days in culture (R-spheres). Shortly after reaggregation, a first sign of tissue organization was detected by use of an amacrine cell (AC)-specific calretinin (CR) antibody. These cells sorted out into small clusters and sent unipolar processes towards the centre of each cluster. Thereby, inner cell-free spaces developed into inner plexiform layer (IPL)-like areas with extended parallel CR(+) fibres. Occasionally, IPL areas merged to combine an 'inner half retina', whereby ganglion cells (GCs) occupied the outer sphere surface. This tendency was much improved in the presence of supernatants from retinal pigmented cells (RPE-spheres), e.g. cell organization and proliferation was much increased, and cell death shortened. As shown by several markers, a perfect outer ring was formed by GCs and displaced ACs, followed by a distinct IPL and 1-2 rows of ACs internally. The inner core of RPE spheres consisted of horizontal and possibly bipolar cells, while immunostaining and RT-PCR analysis proved that photoreceptors were absent. This shows that (1) mammalian retinal histogenesis in reaggregates can be brought to a hitherto unknown high level, (2) retinal tissue self-organizes from the level of the IPL, and (3) RPE factors promote formation of almost complete retinal spheres, however, their polarity was opposite to that found in respective avian spheroids.

2-Methylcyclohexyl- or 2-methylcyclopentylamines are obtained as mixtures of trans- and cis-diastereomers.

Blinding diseases can be assigned predominantly to genetic defects of the photoreceptor/pigmented epithelium complex. As an alternative, we show here for an acetylcholinesterase (AChE) knockout mouse that photoreceptor degeneration follows an impaired development of the inner retina. During the first 15 postnatal days of the AChE-/- retina, three major calretinin sublaminae of the inner plexiform layer (IPL) are disturbed. Thereby, processes of amacrine and ganglion cells diffusely criss-cross throughout the IPL. In contrast, parvalbumin cells present a nonlaminar IPL pattern in the wild-type, but in the AChE-/- mouse their processes become structured within two 'novel' sublaminae. During this early period, photoreceptors become arranged regularly and at a normal rate in the AChE-/- retina. However, during the following 75 days, first their outer segments, and then the entire photoreceptor layer completely degenerate by apoptosis. Eventually, cells of the inner retina also undergo apoptosis. As butyrylcholinesterase (BChE) is present at a normal level in the AChE-/- mouse, the observed effects must be solely due to the missing AChE. These are the first in vivo findings to show a decisive role for AChE in the formation of the inner retinal network, which, when absent, ultimately results in photoreceptor degeneration.