The sperm-specific Ca2+ channel CatSper (cation channel of sperm) controls the intracellular Ca2+ concentration and, thereby, the swimming behavior of sperm from many species. The steroidal ...ethylenediamine RU1968 (1) represents a well-characterized, potent, and fairly selective cross-species inhibitor of CatSper. Due to its two additional centers of chirality in the amine-bearing side chain, RU1968 is a mixture of diastereomeric pairs of enantiomers and, thus, difficult to synthesize. This has hampered the use of this commercially not available inhibitor as a powerful tool for research. Here, simplifying both structure and synthesis, we introduced novel stereochemically less complex and enantiomerically pure aminomethyl RU1968 analogues lacking the C-21 CH3 moiety. Starting from (+)-estrone, a five-step synthesis was developed comprising a Wittig reaction as the key step, leading to a diastereomerically pure 17β-configured aldehyde. Subsequent reductive amination yielded diastereomerically and enantiomerically pure amines. Compared to RU1968, the novel ethylenediamine 2d and homologous trimethylenediamine derivative 2e inhibited CatSper with similar and even twofold enhanced potency, respectively. Considering that these aminomethyl analogues are enantiomerically pure and much easier to synthesize than RU1968, we envisage their common use in future studies investigating the physiology of CatSper in sperm.
Background Monogenic causes of isolated dystonia are heterogeneous. Assembling cohorts of affected individuals sufficiently large to establish new gene-disease relationships can be challenging. ...Objective We sought to expand the catalogue of monogenic etiologies for isolated dystonia. Methods After the discovery of a candidate variant in a multicenter exome-sequenced cohort of affected individuals with dystonia, we queried online platforms and genomic data repositories worldwide to identify subjects with matching genotypic profiles. Results Seven different biallelic loss-of-function variants in AOPEP were detected in five probands from four unrelated families with strongly overlapping phenotypes. In one proband, we observed a homozygous nonsense variant (c.1477C>T p.Arg493*). A second proband harbored compound heterozygous nonsense variants (c.763C>T p.Arg255*;c.777G>A p.Trp259*), whereas a third proband possessed a frameshift variant (c.696_697delAG p.Ala234Serfs*5) in trans with a splice-disrupting alteration (c.2041-1G>A). Two probands (siblings) from a fourth family shared compound heterozygous frameshift alleles (c.1215delT p.Val406Cysfs*14;c.1744delA p.Met582Cysfs*6). All variants were rare and expected to result in truncated proteins devoid of functionally important amino acid sequence. AOPEP, widely expressed in developing and adult human brain, encodes a zinc-dependent aminopeptidase, a member of a class of proteolytic enzymes implicated in synaptogenesis and neural maintenance. The probands presented with disabling progressive dystonia predominantly affecting upper and lower extremities, with variable involvement of craniocervical muscles. Dystonia was unaccompanied by any additional symptoms in three families, whereas the fourth family presented co-occurring late-onset parkinsonism. Conclusions Our findings suggest a likely causative role of predicted inactivating biallelic AOPEP variants in cases of autosomal recessive dystonia. Additional studies are warranted to understand the pathophysiology associated with loss-of-function variation in AOPEP. (c) 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
We explore the two-dimensional extended Hubbard model on the triangular lattice in the high doping regime. On-site and nearest-neighbour repulsive interactions are treated in a non-perturbative way ...by means of Extended Dynamical Mean Field Theory. We compute the low-temperature phase diagram, displaying a metallic phase and a symmetry-broken phase for strong intersite repulsions. We describe the correlation effects on both single-particle and two-particle observables in the metallic phase. Whereas single-particle spectra feature a Hubbard satellite typical of strongly correlated systems, local susceptibilities remain close to their non-interacting limit, even for large on-site repulsions. We argue that this behaviour is typical of the strongly doped case. We also report a region in parameter space with negative static local screening.
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