Staalkrog0140

Human mutations in the CACNA1A gene that encodes the pore-forming α1A subunit of the voltage-gated CaV2.1 (P/Q-type) Ca2+ channel cause multiple neurological disorders including sporadic and familial hemiplegic migraine, as well as cerebellar pathologies such as episodic ataxia, progressive ataxia, and early-onset cerebellar syndrome consistent with the definition of congenital ataxia (CA), with presentation before the age of 2 years. Such a pathological role is in accordance with the physiological relevance of CaV2.1 in neuronal tissue, especially in the cerebellum. This review deals with the report of the main clinical features defining CA, along with the presentation of an increasing number of CACNA1A genetic variants linked to this severe cerebellar disorder in the context of Ca2+ homeostasis alteration. MV1035 mouse Moreover, the review describes each pathological mutation according to structural location and known molecular and cellular functional effects in both heterologous expression systems and animal models. In view of this information in correlation with the clinical phenotype, we take into consideration different pathomechanisms underlying the observed motor dysfunction in CA patients carrying CACNA1A mutations. Present therapeutic management in CA and options for the development of future personalized treatment based on CaV2.1 dysfunction are also discussed.Large quantities of ammonia (NH3 or NH4+) are absorbed from the gut, associated with encephalitis in hepatic disease, poor protein efficiency in livestock, and emissions of nitrogenous climate gasses. Identifying the transport mechanisms appears urgent. Recent functional and mRNA data suggest that absorption of ammonia from the forestomach of cattle may involve TRPV3 channels. The purpose of the present study was to sequence the bovine homologue of TRPV3 (bTRPV3), localize the protein in ruminal tissue, and confirm transport of NH4+. After sequencing, bTRPV3 was overexpressed in HEK-293 cells and Xenopus oocytes. An antibody was selected via epitope screening and used to detect the protein in immunoblots of overexpressing cells and bovine rumen, revealing a signal of the predicted ~ 90 kDa. In rumen only, an additional ~ 60 kDa band appeared, which may represent a previously described bTRPV3 splice variant of equal length. Immunohistochemistry revealed staining from the ruminal stratum basale to stratum granulosum. Measurements with pH-sensitive microelectrodes showed that NH4+ acidifies Xenopus oocytes, with overexpression of bTRPV3 enhancing permeability to NH4+. Single-channel measurements revealed that Xenopus oocytes endogenously expressed small cation channels in addition to fourfold-larger channels only observed after expression of bTRPV3. Both endogenous and bTRPV3 channels conducted NH4+, Na+, and K+. We conclude that bTRPV3 is expressed by the ruminal epithelium on the protein level. In conjunction with data from previous studies, a role in the transport of Na+, Ca2+, and NH4+ emerges. Consequences for calcium homeostasis, ruminal pH, and nitrogen efficiency in cattle are discussed.Octopus cells in the ventral cochlear nucleus (VCN) have been difficult to study because of the very features that distinguish them from other VCN neurons. We performed in vivo recordings in cats on well-isolated units, some of which were intracellularly labeled and histologically reconstructed. We found that responses to low-frequency tones with frequencies less then 1 kHz reveal higher levels of neural synchrony and entrainment to the stimulus than the auditory nerve. In responses to higher frequency tones, the neural discharges occur mostly near the stimulus onset. These neurons also respond in a unique way to 100 % amplitude-modulated (AM) tones with discharges exhibiting a bandpass tuning. Responses to frequency-modulated sounds (FM) are unusual Octopus cells react more vigorously during the ascending than the descending parts of the FM stimulus. We examined responses of neurons in the ventral nucleus of the lateral lemniscus (VNLL) whose discharges to tones and AM sounds are similar to octopus cells. Repeated stimulation with short tone pips of VCN and VNLL onset neurons evokes trains of action potentials with gradual shifts toward later times in their first spike latency. This behavior parallels short-term post-synaptic depression observed by other authors in in vitro VCN recordings of octopus cells. VCN and VNLL onset units in cats respond to frozen noise stimuli with gaps as narrow as 1 ms with a robust discharge near the stimulus onset following the gap. This finding suggests that VCN and VNLL onset cells play a role in gap detection, which is of great importance to speech perception.Are humans a domesticated species? How is this issue related to debates on the roles of human agency in human evolution? This article discusses four views on human domestication (1) Darwin's view; (2) the view of those who link human domestication to anthropogenic niche construction and, more specifically, to sedentism; (3) the view of those who link human domestication to selection against aggression and the domestication syndrome; and (4) a novel view according to which human domestication can be conceived of in terms of a process of political selection. The article examines and compares these views to illustrate how discussions of human domestication can contribute to debates about how, and to what extent, human agency has affected human evolution.The Wnt/β-catenin pathway participates in many important physiological events such as cell proliferation and differentiation in the male reproductive system. We found that Kinesin-2 motor KIF3A is highly expressed during spermatogenesis in Eriocheir sinensis; it may potentially promote the intracellular transport of cargoes in this process. However, only a few studies have focused on the relationship between KIF3A and the Wnt/β-catenin pathway in the male reproductive system of decapod crustaceans. In this study, we cloned and characterized the CDS of β-catenin in E. sinensis for the first time. Fluorescence in situ hybridization and immunofluorescence results showed the colocalization of Es-KIF3A and Es-β-catenin at the mRNA and the protein level respectively. To further explore the regulatory function of Es-KIF3A to the Wnt/β-catenin pathway, the es-kif3a was knocked down by double-stranded RNA (dsRNA) in vivo and in primary cultured cells in testes of E. sinensis. Results showed that the expression of es-β-catenin and es-dvl were decreased in the es-kif3a knockdown group.