Photoreceptor replacement by transplantation is proposed as a treatment for blindness. Transplantation of healthy photoreceptor precursor cells into diseased murine eyes leads to the presence of ...functional photoreceptors within host retinae that express an array of donor-specific proteins. The resulting improvement in visual function was understood to be due to donor cells integrating within host retinae. Here, however, we show that while integration occurs the majority of donor-reporter-labelled cells in the host arises as a result of material transfer between donor and host photoreceptors. Material transfer does not involve permanent donor-host nuclear or cell-cell fusion, or the uptake of free protein or nucleic acid from the extracellular environment. Instead, RNA and/or protein are exchanged between donor and host cells in vivo. These data require a re-evaluation of the mechanisms underlying rescue by photoreceptor transplantation and raise the possibility of material transfer as a strategy for the treatment of retinal disorders.
Abstract
Fast inhibitory GABAergic transmission plays a fundamental role in neural circuits. Current theories of cortical function assume that fast GABAergic inhibition acts via GABAA receptors on ...postsynaptic neurons, while presynaptic effects of GABA depend on GABAB receptor activation. Manipulations of GABAA receptor activity in vivo produced different effects on cortical function, which were generally ascribed to the mode of action of a drug, more than its site of action. Here we show that in rodent primary visual cortex, α4-containing GABAA receptors can be located on subsets of glutamatergic and GABAergic presynaptic terminals and decrease synaptic transmission. Our data provide a novel mechanistic insight into the effects of changes in cortical inhibition; the ability to modulate inputs onto cortical circuits locally, via presynaptic regulation of release by GABAA receptors.
Macrophages exhibit diverse phenotypes and functions; they are also a major cell type infiltrating chronically rejected allografts. The exact phenotypes and roles of macrophages in chronic graft loss ...remain poorly defined. In the present study, we used a mouse heart transplant model to examine macrophages in chronic allograft rejection. We found that treatment of C57BL/6 mice with CTLA4 immunoglobulin fusion protein (CTLA4‐Ig) prevented acute rejection of a Balb/c heart allograft but allowed chronic rejection to develop over time, characterized by prominent neointima formation in the graft. There was extensive macrophage infiltration in the chronically rejected allografts, and the graft‐infiltrating macrophages expressed markers associated with M2 cells but not M1 cells. In an in vitro system in which macrophages were polarized into either M1 or M2 cells, we screened phenotypic differences between M1 and M2 cells and identified purinergic receptor P2X7 (P2x7r), an adenosine triphosphate (ATP)–gated ion channel protein that was preferentially expressed by M2 cells. We further showed that blocking the P2x7r using oxidized ATP (oATP) inhibited M2 induction in a dose‐dependent fashion in vitro. Moreover, treatment of C57BL/6 recipients with the P2x7r antagonist oATP, in addition to CTLA4‐Ig treatment, inhibited graft‐infiltrating M2 cells, prevented transplant vasculopathy, and induced long‐term heart allografts survival. These findings highlight the importance of the P2x7r–M2 axis in chronic rejection and establish P2x7r as a potential therapeutic target in suppression of chronic rejection.
The authors demonstrate an association between chronic heart allograft rejection and preferential enrichment of M2 macrophages in grafts that express the purinergic receptor P2X7, and demonstrate a therapeutic potential for a P2X7 receptor antagonist. See the editorial from Baldwin and Morelli on page 2510.
We aimed to disclose the relationship between restless leg syndrome (RLS) and antiparkinsonian treatment, and its effect on quality of life (QoL) in patients with Parkinson's disease (PD).
Previous ...studies documented the prevalence of RLS among patients with PD to be higher than in the general population, but conclusions regarding the aetiology and impact were contradictory.
We examined 101 patients with idiopathic PD. All participants completed the five-dimension/five-level-EuroQoL questionnaire (EQ-5D-5L) and the International Restless-Legs-syndrome-study-group rating Scale (IRLS).
The prevalence of RLS was 22.77 %. There were no statistically significant differences in levodopa or dopamine agonists (DA) doses between RLS-positive and negative participants. However, the use of levodopa as the last night-time medication was connected with a higher risk of RLS (OR=2.049, p=0.041). There was significantly lower prevalence of RLS in patients after surgical treatment for PD (p=0.024). Participants with RLS were at a greater risk for sleep disturbances (OR=3.866, p=0.023) and excessive daytime sleepiness (OR=7.202, p<0.001). Greater RLS symptoms were associated with worse QoL (higher IRLS score predicted higher EQ5D5L score, p=0.023).
RLS is prevalent among PD patients and night-time dopaminergic over-excitation with levodopa plays an important role in its pathogenesis. Since the symptoms of RLS are associated with decreased QoL, early accurate diagnosis and appropriate adjustment of dopaminergic therapy can lead to immediate relief from RLS symptoms and to QoL improvement (Tab. 4, Fig. 1, Ref. 34).
In a Hamiltonian system with impacts (or "billiard with potential"), a point particle moves about the interior of a bounded domain according to a background potential and undergoes elastic collisions ...at the boundaries. When the background potential is identically zero, this is the hard-wall billiard model. Previous results on smooth billiard models (where the hard-wall boundary is replaced by a steep smooth billiard-like potential) have clarified how a smooth billiard may be rigorously approximated using a hard-wall billiard. These results are extended here to models with smooth background potential satisfying some natural conditions. This generalization is then applied to geometric models of collinear triatomic chemical reactions. (The models are far from integrable \(n\)-degree-of-freedom systems with \(n\geq2\).) The application demonstrates that the simpler analytical calculations for the hard-wall system may be used to obtain qualitative information with regard to the solution structure of the smooth system and to quantitatively assist in finding solutions of the soft impact system by continuation methods. In particular, stable periodic triatomic configurations are easily located for the smooth highly nonlinear two- and three-degree-of-freedom geometric models. PUBLICATION ABSTRACT
Deep brain stimulation is an effective and safe technique. Displacement of the electrode relative to the optimal stimulation site can lead to insufficient effect and sometimes to the need of ...operative electrode re-position.
This study was aimed to analyse targeting accuracy of deep brain stimulation electrode implantation to subthalamic nucleus (STN) and globus pallidus internus (Gpi). It detected possible causes of inaccuracy and prevalent shift to certain direction.
Targeting accuracy was analysed in 47 patients with Parkinson´s disease (PD) and 11 patients with dystonia with bilateral implantation of deep brain stimulation electrodes between years 2009 and 2016.
A shift of electrode to prevalent direction was observed on the left side to medial and posterior and on the right side to lateral direction. Greater shift was observed on the left side and in a higher angulation of trajectory laterally. Movement of the electrode, because of its traction in anchoring device, was identified as a possible factor for prevalent electrode shift. Calibration of stereotactic coordinates to correct prevalent shift was used.
Targeting inaccuracy is the result of accumulation of errors in individual steps of electrode implantation. Direction of the shift can be random or it can be toward a prevalent direction. A correction of prevalent error can prevent a suboptimal electrode placement (Tab. 3, Fig. 11, Ref. 29).
The oocytes of many invertebrate and non-mammalian vertebrate species are not only asymmetrical but also polar in the distribution of organelles, localized RNAs and proteins, and the oocyte polarity ...dictates the patterning of the future embryo. Polarily located within the oocytes of many species is the Balbiani body (Bb), which in
Xenopus is known to be associated with the germinal granules responsible for the determination of germ cell fate. In contrast, in mammals, it is widely believed that the patterning of the embryo does not occur before implantation, and that oocytes are non-polar and symmetrical. Although the oocytes of many mammals, including mice and humans, contain Bbs, it remains unknown how and if the presence of Bbs relates to mouse oocyte and egg polarity. Using three-dimensional reconstruction of mouse neonatal oocytes, we showed that mouse early oocytes are both asymmetrical and transiently polar. In addition, the specifics of polarity in mouse oocytes are highly reminiscent of those in
Xenopus early oocytes. Based on these findings, we conclude that the polarity of early oocytes imposed by the position of the centrioles at the cytoplasmic bridges is a fundamental and ancestral feature across the animal kingdom.
The symptoms of SARS-CoV-2 infection and COVID-19 provoked by this virus are poorly described in children. Here we analyse a case of orchiepididymitis associated with COVID-19 in a 14-year-old boy. ...We discuss the possibility of SARS-CoV-2-associated testicular inflammation. This report strengthens the necessity for more in-depth study of the clinical presentation of paediatric COVID-19 and the potential association with non-respiratory symptoms.
Over many decades, a great number of exceptions from the rule of equal segregation of the chromosomes during cell division have been found in different animal species. The most diversified is the ...process of chromosome re-arrangement that takes place during the specification of soma versus germ-line cell fate in the embryos from the whole spectrum of animal phyla. In nematodes, copepodes, insects, hagfish, and marsupials, the chromatin/chromosome elimination is a common path of normal cell differentiation and development. This also raises the question of the mechanisms and factors that promote elimination in pre-somatic cell lines and/or inhibit the elimination in the prospective germ cells. We will discuss the possible role of the germ plasm in this process.
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