Efficaciousness of low affinity compared to high affinity TSPO ligands in the inhibition of hypoxic mitochondrial cellular damage induced by cobalt chloride in human lung H1299 cells

The 18 kDa translocator protein (TSPO) plays an important role in apoptotic cell death, including apoptosis induced by the hypoxia mimicking agent cobalt chloride (CoCl2). In this study, the protective effects of a high (CB86; Ki = 1.6 nM) and a low (CB204; Ki = 117.7 nM) affinity TSPO ligands were investigated in H1299 lung cancer cell line exposed to CoCl2. The lung cell line H1299 was chosen in the present study since they express TSPO and able to undergo programmed cell death. The examined cell death markers included: ATP synthase reversal, reactive oxygen species (ROS) generation, mitochondrial membrane potential (D m) depolarization, cellular toxicity, and cellular viability. Pretreatment of the cells with the low affinity ligand CB204 at a concentration of 100 μM suppressed significantly (p < 0.05 for all) CoCl2-induced cellular cytotoxicity (100%), ATP synthase reversal (67%), ROS generation (82%), D m depolarization (100%), reduction in cellular density (97%), and also increased cell viability (85%). Furthermore, the low affinity TSPO ligand CB204, was harmless when given by itself at 100 μM. In contrast, the high affinity ligand (CB86) was significantly effective only in the prevention of CoCl2-induced ROS generation (39%, p < 0.001), and showed significant cytotoxic effects when given alone at 100 μM, as reflected in alterations in ADP/ATP ratio, oxidative stress, mitochondrial membrane potential depolarization and cell death. It appears that similar to previous studies on brain-derived cells, the relatively low affinity for the TSPO target enhances the potency of TSPO ligands in the protection from hypoxic cell death. Moreover, the high affinity TSPO ligand CB86, but not the low affinity ligand CB204, was lethal to the lung cells at high concentration (100 μM). The low affinity TSPO ligand CB204 may be a candidate for the treatment of pulmonary diseases related to hypoxia, such as pulmonary ischemia and chronic obstructive pulmonary disease COPD

Mouse cytomegalovirus-experienced ILC1s acquire a memory response dependent on the viral glycoprotein m12.

Innate lymphoid cells (ILCs) are tissue-resident sentinels that are essential for early host protection from pathogens at initial sites of infection. However, whether pathogen-derived antigens directly modulate the responses of tissue-resident ILCs has remained unclear. In the present study, it was found that liver-resident type 1 ILCs (ILC1s) expanded locally and persisted after the resolution of infection with mouse cytomegalovirus (MCMV). ILC1s acquired stable transcriptional, epigenetic and phenotypic changes a month after the resolution of MCMV infection, and showed an enhanced protective effector response to secondary challenge with MCMV consistent with a memory lymphocyte response. Memory ILC1 responses were dependent on the MCMV-encoded glycoprotein m12, and were independent of bystander activation by proinflammatory cytokines after heterologous infection. Thus, liver ILC1s acquire adaptive features in an MCMV-specific manner

Probiotics for Preterm Infants: a strain specific systematic review and network meta-analysis

Several randomised controlled trials (RCTs) on the use of probiotics to reduce morbidity and mortality in preterm infants have provided inconsistent results. Whilst meta-analyses that group all of the used strains together, suggest efficacy, it is not possible to determine the most effective strain which is more relevant to the clinician. We therefore used a network meta-analysis (NMA) approach in order to identify strains with greatest efficacy

Chromatin dynamics and gene expression response to heat exposure in field-conditioned versus laboratory-cultured Nematostella vectensis

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Weizman, E., Rinsky, M., Simon-Blecher, N., Lampert-Karako, S., Yaron, O., Tarrant, A. M., & Levy, O. Chromatin dynamics and gene expression response to heat exposure in field-conditioned versus laboratory-cultured Nematostella vectensis. International Journal of Molecular Sciences, 22(14), (2021): 7454, https://doi.org/10.3390/ijms22147454.Organisms’ survival is associated with the ability to respond to natural or anthropogenic environmental stressors. Frequently, these responses involve changes in gene regulation and expression, consequently altering physiology, development, or behavior. Here, we present modifications in response to heat exposure that mimics extreme summertime field conditions of lab-cultured and field-conditioned Nematostella vectensis. Using ATAC-seq and RNA-seq data, we found that field-conditioned animals had a more concentrated reaction to short-term thermal stress, expressed as enrichment of the DNA repair mechanism pathway. By contrast, lab animals had a more diffuse reaction that involved a larger number of differentially expressed genes and enriched pathways, including amino acid metabolism. Our results demonstrate that pre-conditioning affects the ability to respond efficiently to heat exposure in terms of both chromatin accessibility and gene expression and reinforces the importance of experimentally addressing ecological questions in the field

Baghdad’s thirdspace: Between liminality, anti-structures and territorial mappings

Wedged in-between the dense urban grain of Baghdad, blast walls of t-shaped concrete have littered the streets and neighbourhoods since 2003, after the US led invasion. The idiosyncrasy of these walls lies in their exaggerated spatial liminality. They appear, change location and disappear overnight, and on a daily basis, leaving Iraqis to navigate through labyrinths of in-between spaces. This article critically reveals the new social and power structures that have emerged in the context of the city in response to the condition resulting from this unique urban intervention. This uncanny spatial and social condition of permanent liminality will be analysed through Victor Turner’s critical theories of liminality and anti-structure coupled with Edward Soja’s theory of Thirdspace, interpreting, through a series of territorial mappings, a complex liminal condition in a contested and disrupted city

Selective serotonin reuptake inhibitors in the treatment of generalized anxiety disorder

Selective serotonin reuptake inhibitors have proven efficacy in the treatment of panic disorder, obsessive–compulsive disorder, post-traumatic stress disorder and social anxiety disorder. Accumulating data shows that selective serotonin reuptake inhibitor treatment can also be efficacious in patients with generalized anxiety disorder. This review summarizes the findings of randomized controlled trials of selective serotonin reuptake inhibitor treatment for generalized anxiety disorder, examines the strengths and weaknesses of other therapeutic approaches and considers potential new treatments for patients with this chronic and disabling anxiety disorder