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Autoantibodies against the M2 subtype of muscarinic acetylcholine receptors with functional activities have been found in the sera of patients with dilated cardiomyopathy (DCM), and the second extracellular loop has been established as the predominant epitope. However, it has been shown that the third intracellular loop is recognized by Chagas disease patients with severe cardiac dysfunction. In this work, BALB/c mice were immunized with plasmids encoding these two epitopes, and a control group received the empty plasmid (pcDNA3 vector). Serum from these DNA-immunized animals had elevated and persistent titres of antibodies against respective antigens. Heart echocardiography indicated diminished left ventricular wall thickness and reduced ejection fraction for both epitope-immunized groups, and ergospirometry tests showed a significant decrease in the exercise time and oxygen consumption. Transfer of serum from these immunized mice into naïve recipients induced the same alterations in cardiac structure and function. Furthermore, electron microscopy analysis of donor-immunized animals revealed several ultrastructural alterations suggestive of autophagy and mitophagy, suggesting novel roles for these autoantibodies. Overall, greater functional and structural impairment was observed in the donor and recipient epitope groups, implicating the third intracellular loop epitope in the pathological effects for the first-time. Therefore, the corresponding peptides could be useful for autoimmune DCM diagnosis and targeted therapy.

Abstract Pannexin 1 (Panx1) forms ATP-permeable membrane channels that play a key role in purinergic signaling in the nervous system in both normal and pathological conditions. In the retina, particularly high levels of Panx1 are found in retinal ganglion cells (RGCs), but the normal physiological function in these cells remains unclear. In this study, we used patch clamp recordings in the intact inner retina to show that evoked currents characteristic of Panx1 channel activity were detected only in RGCs, particularly in the OFF-type cells. The analysis of pattern electroretinogram (PERG) recordings indicated that Panx1 contributes to the electrical output of the retina. Consistently, PERG amplitudes were significantly impaired in the eyes with targeted ablation of the Panx1 gene in RGCs. Under ocular hypertension and ischemic conditions, however, high Panx1 activity permeated cell membranes and facilitated the selective loss of RGCs or stably transfected Neuro2A cells. Our results show that high expression of the Panx1 channel in RGCs is essential for visual function in the inner retina but makes these cells highly sensitive to mechanical and ischemic stresses. These findings are relevant to the pathophysiology of retinal disorders induced by increased intraocular pressure, such as glaucoma.

Uveal melanoma (UM), the most common primary eye cancer, is strongly linked to mutations in the tumor suppressor BAP1. Here, the authors analyze 151 primary UM samples to find that BAP1 and other canonical genomic aberrations arise in an early punctuated burst followed by neutral tumor evolution.

This study analyses the connection between neighbourly relations and social cohesion. These concepts obviously overlap to a certain degree, but it is not clear how they are related. The crucial questions are if and how neighbourly relations can promote social cohesion. To answer this, a qualitative study based on interviews (n = 40) was conducted to examine neighbourly relations in two urban districts in Germany. Both districts are characterized by high levels of social segregation and cultural diversity but differ from each other in terms of the extent of resident turnover, the availability of local social service organizations, and their respective urban development profiles. The results show that there is a close connection between residents' perceptions of social cohesion and inclination for social participation in the neighbourhood. Local social service organizations and associations can play a critical role in facilitating the social encounters that create such perceptions. Basically, neighbourly relationships are influenced by the local conditions, especially by the extent of fluctuation but also by neighbourly behaviour, which promotes social cohesion at the neighbourhood level. [ABSTRACT FROM AUTHOR]

Abstract BEACH domain proteins are involved in membrane protein traffic and human diseases, but their molecular mechanisms are not understood. The BEACH protein LRBA has been implicated in immune response and cell proliferation, and human LRBA mutations cause severe immune deficiency. Here, we report a first functional and molecular phenotype outside the immune system of LRBA-knockout mice: compromised olfaction, manifesting in reduced electro-olfactogram response amplitude, impaired food-finding efficiency, and smaller olfactory bulbs. LRBA is prominently expressed in olfactory and vomeronasal chemosensory neurons of wild-type mice. Olfactory impairment in the LRBA-KO is explained by markedly reduced concentrations (20–40% of wild-type levels) of all three subunits αolf, β1 and γ13 of the olfactory heterotrimeric G-protein, Golf, in the sensory cilia of olfactory neurons. In contrast, cilia morphology and the concentrations of many other proteins of olfactory cilia are not or only slightly affected. LRBA is also highly expressed in photoreceptor cells, another cell type with a specialized sensory cilium and heterotrimeric G-protein-based signalling; however, visual function appeared unimpaired by the LRBA-KO. To our knowledge, this is the first observation that a BEACH protein is required for the efficient subcellular localization of a lipid-anchored protein, and of a ciliary protein.

Nitrous acid (HONO) fluxes were measured above an agricultural field site near Paris during different seasons. Above bare soil, different crops were measured using the aerodynamic gradient (AG) method. Two LOPAPs (LOng Path Absorption Photometer) were used to determine the HONO gradients between two heights. During daytime mainly positive HONO fluxes were observed, which showed strong correlation with the product of the NO2 concentration and the long wavelength UV light intensity, expressed by the photolysis frequency J(NO2). These results are consistent with HONO formation by photosensitized heterogeneous conversion of NO2 on soil surfaces as observed in recent laboratory studies. An additional influence of the soil temperature on the HONO flux can be explained by the temperature-dependent HONO adsorption on the soil surface. A parameterization of the HONO flux at this location with NO2 concentration, J(NO2), soil temperature and humidity fits reasonably well all flux observations at this location.