Novel insights into the role of hippocampal TLX in neurogenesis, neuroinflammation and behaviour in adolescence and adulthood

The orphan nuclear receptor TLX is a key regulator of embryonic and adult neurogenesis and is primarily expressed in the neurogenic niches of the brain. Adult hippocampal neurogenesis is characterized by the generation of new granule cells that become integrated into the circuitry and contribute to cognitive function. Impaired hippocampal neurogenesis has been reported in neurodegenerative and psychiatric conditions and efforts to develop therapeutic strategies that employ the hippocampal NSCs are ongoing. TLX is one of an array of intrinsic factors regulating NSC proliferation and differentiation, in combination with extrinsic regulators such as stress, exercise and neuroinflammation. Adolescence is a sensitive period of neurodevelopment, during which the environment can have profound effects. Little has been reported on TLX function during adolescence. TLX performs its role by transcriptional activation and repression of a number of genes in order to promote NPC proliferation and to maintain the neurogenic pool of NSCs in the DG. In its absence neurogenesis is dramatically decreased, positioning it as the master modulator of the neurogenic process. The aims of this thesis were to investigate the role of the immune cells of the brain, microglia, on hippocampal neurogenesis in the presence/absence of TLX, and to determine whether TLX plays a role in microglia-neuronal crosstalk; to investigate the role of TLX in hippocampal neurogenesis during adolescence, and the impact thereupon of exercise and stress; and to understand the role of TLX in behavioural and cognitive function during adolescence and adulthood, through evaluating two deletion models of TLX – a spontaneous deletion mouse model, and a rat model using lentiviral knockdown of TLX. We have shown that a lack of TLX is implicated in the deregulation of microglial phenotype, resulting in activated microglia and elevated levels of the pro-inflammatory cytokine IL-1β, and that consequently the survival and function of newborn cells in the hippocampus is impaired. Furthermore, we showed that when neuronal-microglial signalling is impaired in the absence of the chemokine receptor CX3CR1, the expression of TLX and some of its downstream targets is altered. We also have shown that TLX is necessary for the pro-neurogenic effects of exercise during adolescence, and that deletion of TLX modulates motor, cognitive and anxiety-related behaviours during adolescence and adulthood in both male and female mice. Lastly, we demonstrated that silencing of TLX expression in the dDG during adolescence resulted in impairments in hippocampal-independent behaviours, which either did not persist or were reversed during adulthood. In summary, we confirm the importance of TLX in the regulation of neurogenesis and neuronal-microglial cross-talk as well as the temporal importance and function of TLX during adolescent development. Disentangling the complex interactions between TLX, the immune system and other extrinsic regulators of hippocampal neurogenesis would thus provide valuable insights into the development of therapeutics for neurodegenerative disorders using stem-cell-stimulation based approaches

Are CDI Systems Multicolored, Facultative, Helping Greenbeards?

Competitive and cooperative interactions between organisms, including bacteria, can significantly impact the composition of a community and the fitness of its members, as well as the fitness of their hosts when communities are living on or within other organisms. Understanding the underlying mechanisms is critical to the development of strategies to control microbiological communities that impact animal and plant health and also for understanding the evolution of social behaviors, which has been challenging for evolutionary biologists. Contact-dependent growth inhibition (CDI) is a phenomenon defined by the delivery of a protein toxin to the cytoplasm of neighboring bacteria upon cell–cell contact, resulting in growth inhibition or death unless a specific immunity protein is present. CDI was first described based on observations of interbacterial killing and has been assumed to function primarily as a means of eliminating competitor cells. However, recent molecular evidence indicates that multiple levels of specificity restrict CDI toxin delivery and activity to the same bacterial strain, and that CDI system proteins can mediate cooperative behaviors among ‘self’ cells, a phenomenon called contact-dependent signaling (CDS). Here we review these recent findings and discuss potential biological and evolutionary implications of CDI system-mediated interbacterial competition and cooperation

Bacterial lysis liberates the neutrophil migration suppressor YbcL from the periplasm of uropathogenic Escherichia coli

Uropathogenic Escherichia coli (UPEC) modulates aspects of the innate immune response during urinary tract infection to facilitate bacterial invasion of the bladder epithelium, a requirement for the propagation of infection. For example, UPEC-encoded YbcL suppresses the traversal of bladder epithelia by neutrophils in both an in vitro model and an in vivo murine cystitis model. The suppressive activity of YbcL requires liberation from the bacterial periplasm, though the mechanism of release is undefined. Here we present findings on the site of action of YbcL and demonstrate a novel mode of secretion for a UPEC exoprotein. Suppression of neutrophil migration by purified YbcL(UTI), encoded by cystitis isolate UTI89, required the presence of a uroepithelial layer; YbcL(UTI) did not inhibit neutrophil chemotaxis directly. YbcL(UTI) was released to a greater extent during UPEC infection of uroepithelial cells than during that of neutrophils. Release of YbcL(UTI) was maximal when UPEC and bladder epithelial cells were in close proximity. Established modes of secretion, including outer membrane vesicles, the type II secretion system, and the type IV pilus, were dispensable for YbcL(UTI) release from UPEC. Instead, YbcL(UTI) was liberated during bacterial death, which was augmented upon exposure to bladder epithelial cells, as confirmed by detection of bacterial cytoplasmic proteins and DNA in the supernatant and enumeration of bacteria with compromised membranes. As YbcL(UTI) acts on the uroepithelium to attenuate neutrophil migration, this mode of release may represent a type of altruistic cooperation within a UPEC population during colonization of the urinary tract

When Heart Beats Differently in Depression: Review of Nonlinear Heart Rate Variability Measures

Background: Disturbed heart dynamics in depression seriously increases mortality risk. Heart rate variability (HRV) is a rich source of information for studying this dynamics. This paper is a meta-analytic review with methodological commentary of the application of nonlinear analysis of HRV and its possibility to address cardiovascular diseases in depression. Objective: This paper aimed to appeal for the introduction of cardiological screening to patients with depression, because it is still far from established practice. The other (main) objective of the paper was to show that nonlinear methods in HRV analysis give better results than standard ones. Methods: We systematically searched on the web for papers on nonlinear analyses of HRV in depression, in line with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 framework recommendations. We scrutinized the chosen publications and performed random-effects meta-analysis, using the esci module in jamovi software where standardized effect sizes (ESs) are corrected to yield the proof of the practical utility of their results. Results: In all, 26 publications on the connection of nonlinear HRV measures and depression meeting our inclusion criteria were selected, examining a total of 1537 patients diagnosed with depression and 1041 healthy controls (N=2578). The overall ES (unbiased) was 1.03 (95% CI 0.703-1.35; diamond ratio 3.60). We performed 3 more meta-analytic comparisons, demonstrating the overall effectiveness of 3 groups of nonlinear analysis: detrended fluctuation analysis (overall ES 0.364, 95% CI 0.237-0.491), entropy-based measures (overall ES 1.05, 95% CI 0.572-1.52), and all other nonlinear measures (overall ES 0.702, 95% CI 0.422-0.982). The effectiveness of the applied methods of electrocardiogram analysis was compared and discussed in the light of detection and prevention of depression-related cardiovascular risk. Conclusions: We compared the ESs of nonlinear and conventional time and spectral methods (found in the literature) and demonstrated that those of the former are larger, which recommends their use for the early screening of cardiovascular abnormalities in patients with depression to prevent possible deleterious events. ©Milena Čukić, Danka Savić, Julia Sidorova

Born this way: Hippocampal neurogenesis across the lifespan

The capability of the mammalian brain to generate new neurons through the lifespan has gained much attention for the promise of new therapeutic possibilities especially for the aging brain. One of the brain regions that maintains a neurogenesis-permissive environment is the dentate gyrus of the hippocampus. Here, new neurons are generated from a pool of multipotent neural progenitor cells to become fully functional neurons that are integrated into the brain circuitry. A growing body of evidence points to the fact that neurogenesis in the adult hippocampus is necessary for certain memory processes, and in mood regulation, while alterations in hippocampal neurogenesis have been associated with a myriad of neurological and psychiatric disorders. More recently, evidence has come to light that new neurons may differ in their vulnerability to environmental and disease-related influences depending on the time during the life course at which they are exposed. Thus, it has been the topic of intense research in recent years. In this review, we will discuss the complex process and associated functional relevance of hippocampal neurogenesis during the embryonic/postnatal period and in adulthood. We consider the implications of hippocampal neurogenesis during the developmentally critical periods of adolescence and older age. We will further consider the literature surrounding hippocampal neurogenesis and its functional role during these critical periods with a view to providing insight into the potential of harnessing neurogenesis for health and therapeutic benefit

A role for the orphan nuclear receptor TLX in the interaction between neural precursor cells and microglia

Microglia are an essential component of the neurogenic niche in the adult hippocampus and are involved in the control of neural precursor cell (NPC) proliferation, differentiation and the survival and integration of newborn neurons in hippocampal circuitry. Microglial and neuronal cross-talk is mediated in part by the chemokine fractalkine/chemokine (C-X3-C motif) ligand 1 (CX3CL1) released from neurons, and its receptor CX3C chemokine receptor 1 (CX3CR1) which is expressed on microglia. A disruption in this pathway has been associated with impaired neurogenesis yet the specific molecular mechanisms by which this interaction occurs remain unclear. The orphan nuclear receptor TLX (Nr2e1; homologue of the Drosophila tailless gene) is a key regulator of hippocampal neurogenesis, and we have shown that in its absence microglia exhibit a pro-inflammatory activation phenotype. However, it is unclear whether a disturbance in CX3CL1/CX3CR1 communication mediates an impairment in TLX-related pathways which may have subsequent effects on neurogenesis. To this end, we assessed miRNA expression of up- and down-stream signalling molecules of TLX in the hippocampus of mice lacking CX3CR1. Our results demonstrate that a lack of CX3CR1 is associated with altered expression of TLX and its downstream targets in the hippocampus without significantly affecting upstream regulators of TLX. Thus, TLX may be a potential participant in neural stem cell (NSC)–microglial cross-talk and may be an important target in understanding inflammatory-associated impairments in neurogenesis

The impact of COVID-19 lock-downs for European (female) immunologists - our views as members of the EFIS gender and diversity task force

17 p.-1 fig.Peer reviewe

Assessment of structural and optical properties of self-assembled photonic structures

The great potential of self-assembled colloidal structures in several technological areas of modern photonics derives from the low cost and relative simplicity with which they are fabricated. The optical properties of this kind of medium are not only determined by the response of its isolated constituents but also by their spatial arrangement. When polystyrene spheres self-assemble in a periodic fashion, the spatially ordered variation of the dielectric function gives rise to photonic bands and thus the colloidal structure becomes a photonic crystal [1,2]. In this study, colloidal thin films were prepared by the spin-coating [3] and vertical deposition method [4]. By varying the spinning velocity, acceleration and duration of rotation, we obtained different number of colloidal crystal layers. Also, we have prepared opals (multilayer films) with the vertical deposition technique and compared the obtained structures with those obtained by the spin-coating method. In both cases, the thin films were fabricated by depositing colloidal dispersions of 300 nm polystyrene spheres onto microscope glass slide substrates. The morphology of samples was studied by atomic force microscopy, while their optical properties were investigated by spectroscopic ellipsometry and UV-VIS-IR spectrophotometry. An appropriate model has been developed for the determination of the optical properties of the colloidal films by ellipsometry. In order to validate the model applied, the parameters obtained have been compared with those determined by means of transmittance measurements. From transmittance measurements, in the case of monolayer films, diffraction peak in the visible range was observed. On the other side, in the case of opal has been verified the presence of a photonic band gap which should be attributed to Bragg diffraction [5].V International School and Conference on Photonics and COST actions: MP1204, BM1205 and MP1205 and the Second international workshop "Control of light and matter waves propagation and localization in photonic lattices" : PHOTONICA2015 : book of abstracts; August 24-28, 2015; Belgrad