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Genetic haemochromatosis (GH) is responsible for iron overload. Increased transferrin saturation (TSAT) has been associated with severe periodontitis, which is a chronic inflammatory disease affecting tissues surrounding the teeth and is related to dysbiosis of the subgingival microbiota. Because iron is essential for bacterial pathogens, alterations in iron homeostasis can drive dysbiosis. To unravel the relationships between serum iron biomarkers and the subgingival microbiota, we analysed samples from 66 GH patients. The co-occurrence analysis of the microbiota showed very different patterns according to TSAT. Healthy and periopathogenic bacterial clusters were found to compete in patients with normal TSAT (≤45%). However, significant correlations were found between TSAT and the proportions of Porphyromonas and Treponema , which are two genera that contain well-known periopathogenic species. In patients with high TSAT, the bacterial clusters exhibited no mutual exclusion. Increased iron bioavailability worsened periodontitis and promoted periopathogenic bacteria, such as Treponema . The radical changes in host-bacteria relationships and bacterial co-occurrence patterns according to the TSAT level also suggested a shift in the bacterial iron supply from transferrin to NTBI when TSAT exceeded 45%. Taken together, these results indicate that iron bioavailability in biological fluids is part of the equilibrium between the host and its microbiota.

Since December 2019, a global pandemic has been observed, caused by the emergence of a new coronavirus, SARS CoV-2. The latter is responsible for the respiratory disease, COVID-19. The infection is also characterized by renal, hepatic, and gastrointestinal dysfunctions suggesting the spread of the virus to other organs. A dysregulated immune response was also reported. To date, there is no measure to treat or prevent SARS CoV-2 infection. Additionally, as gut microbiota composition is altered in patients with COVID-19, alternative therapies using probiotics can be considered to fight SARS CoV-2 infection. This review aims at summarizing the current knowledge about next-generation probiotics (NGPs) and their benefits in viral respiratory tract infections and in COVID-19. We describe these bacteria, highlighted by studies using metagenomic approaches. In addition, these bacteria generate metabolites such as butyrate, desaminotyrosine, and secondary bile acid, suggested to prevent viral respiratory infections. Gut microbial metabolites transported via the circulation to the lungs could inhibit viral replication or improve the immune response against viruses. The use of probiotics and/or their metabolites may target either the virus itself and/or the immunologic process. However, this review showed that more studies are needed to determine the benefits of probiotics and metabolite products in COVID-19.

The authors show that the oncogene Bcl6 is necessary for proper cortical neurogenesis in vivo and from embryonic stem cells. BCL6 alters the composition of Notch-dependent transcriptional complexes at the Hes5 promoter, including the recruitment of Sirt1, to promote transition to a neurogenic fate despite active Notch signaling. During neurogenesis, neural stem/progenitor cells (NPCs) undergo an irreversible fate transition to become neurons. The Notch pathway is important for this process, and repression of Notch-dependent Hes genes is essential for triggering differentiation. However, Notch signaling often remains active throughout neuronal differentiation, implying a change in the transcriptional responsiveness to Notch during the neurogenic transition. We identified Bcl6 , an oncogene, as encoding a proneurogenic factor that is required for proper neurogenesis of the mouse cerebral cortex. BCL6 promoted the neurogenic conversion by switching the composition of Notch-dependent transcriptional complexes at the Hes5 promoter. BCL6 triggered exclusion of the co-activator Mastermind-like 1 and recruitment of the NAD + -dependent deacetylase Sirt1, which was required for BCL6-dependent neurogenesis. The resulting epigenetic silencing of Hes5 led to neuronal differentiation despite active Notch signaling. Our findings suggest a role for BCL6 in neurogenesis and uncover Notch-BCL6-Sirt1 interactions that may affect other aspects of physiology and disease.

This article, aimed at transcultural education, examines the juncture of race and aesthetics. It argues that implicit in the hybrid identities produced by modern imperialism and colonialism is a more global figure of humanity. That figure remains suppressed by lingering race/ethnocentrism in contemporary art discourse. Postmodernist framing of art/culture as \"language\" has generally weakened the strong conceit of difference. But that progress is offset by failure to acknowledge how globally distributed and \"pre/non-modern\" that insight is, effectively making it exclusively \"Western.\" Furthermore, postmodern linguisticism's strong identification with verbal language maintains civilized/primitive dualisms, perpetuating the denigration of nonliterate cultures. Unfortunately, it also compromises the communicative efficacy of art/material culture. Consequently, linguisticism becomes a knot inhibiting the turn from racism to recognizing the relational origination of differences and their emergence from iconic similarity. Pivoting around iconic similarity uncovers the diverse non-Euro-Western genealogies of bricolage, collage, and cubism entangled and obscured by the resilient conceit of difference in différance. It redresses the asymmetry of attributing the deconstructive insight associated with bricolage/collage exclusively to postmodernist authorities. Nagarjuna's critique of self-generation, modernism's essential assumption, helps make the case for iconic similarity and for promoting it as a better basis for art-education theory and practice.

When mammalian spermatozoa are released in the female reproductive tract, they are incapable of fertilizing the oocyte. They need a prolonged exposure to the alkaline medium of the female genital tract before their flagellum gets hyperactivated and the acrosome reaction can take place, allowing the sperm to interact with the oocyte. Ionic fluxes across the sperm membrane are involved in two essential aspects of capacitation: the increase in intracellular pH and the membrane hyperpolarization. In particular, it has been shown that the SLO3 potassium channel and the sNHE sodium-proton exchanger, two sperm-specific transmembrane proteins, are necessary for the capacitation process to occur. As the SLO3 channel is activated by an increase in intracellular pH and sNHE is activated by hyperpolarization, they act together as a positive feedback system. Mathematical modeling provides a unique tool to capture the essence of a molecular mechanism and can be used to derive insight from the existing data. We have therefore developed a theoretical model formalizing the positive feedback loop between SLO3 and sHNE in mouse epididymal sperm to see if this non-linear interaction can provide the core mechanism explaining the existence of uncapacited and capacitated states. We show that the proposed model can fully explain the switch between the uncapacitated and capacited states and also predicts the existence of a bistable behaviour. Furthermore, our model indicates that SLO3 inhibition, above a certain threshold, can be effective to completely abolish capacitation.

Alzheimer’s disease is characterized by a marked dysregulation of intracellular Ca2+ homeostasis. In particular, toxic β-amyloids (Aβ) perturb the activities of numerous Ca2+ transporters or channels. Because of the tight coupling between Ca2+ dynamics and the membrane electrical activity, such perturbations are also expected to affect neuronal excitability. We used mathematical modeling to systematically investigate the effects of changing the activities of the various targets of Aβ peptides reported in the literature on calcium dynamics and neuronal excitability. We found that the evolution of Ca2+ concentration just below the plasma membrane is regulated by the exchanges with the extracellular medium, and is practically independent from the Ca2+ exchanges with the endoplasmic reticulum. Thus, disruptions of Ca2+ homeostasis interfering with signaling do not affect the electrical properties of the neurons at the single cell level. In contrast, the model predicts that by affecting the activities of L-type Ca2+ channels or Ca2+-activated K+ channels, Aβ peptides promote neuronal hyperexcitability. On the contrary, they induce hypo-excitability when acting on the plasma membrane Ca2+ ATPases. Finally, the presence of pores of amyloids in the plasma membrane can induce hypo- or hyperexcitability, depending on the conditions. These modeling conclusions should help with analyzing experimental observations in which Aβ peptides interfere at several levels with Ca2+ signaling and neuronal activity.

Understanding the electrical biophysical properties of the cell membrane can be difficult for neuroscience students as it relies solely on lectures of theoretical models without practical hands on experiments. To address this issue, we developed an open-source lipid bilayer amplifier, the OpenPicoAmp, which is appropriate for use in introductory courses in biophysics or neurosciences at the undergraduate level, dealing with the electrical properties of the cell membrane. The amplifier is designed using the common lithographic printed circuit board fabrication process and off-the-shelf electronic components. In addition, we propose a specific design for experimental chambers allowing the insertion of a commercially available polytetrafluoroethylene film. We provide a complete documentation allowing to build the amplifier and the experimental chamber. The students hand-out giving step-by step instructions to perform a recording is also included. Our experimental setup can be used in basic experiments in which students monitor the bilayer formation by capacitance measurement and record unitary currents produced by ionic channels like gramicidin A dimers. Used in combination with a low-cost data acquisition board this system provides a complete solution for hands-on lessons, therefore improving the effectiveness in teaching basic neurosciences or biophysics.

Friedreich's ataxia (FRDA) is a recessive neurodegenerative disorder commonly associated with hypertrophic cardiomyopathy. FRDA is due to expanded GAA repeats within the first intron of the gene encoding frataxin, a conserved mitochondrial protein involved in iron-sulphur cluster biosynthesis. This mutation leads to partial gene silencing and substantial reduction of the frataxin level. To overcome limitations of current cellular models of FRDA, we derived induced pluripotent stem cells (iPSCs) from two FRDA patients and successfully differentiated them into neurons and cardiomyocytes, two affected cell types in FRDA. All FRDA iPSC lines displayed expanded GAA alleles prone to high instability and decreased levels of frataxin, but no biochemical phenotype was observed. Interestingly, both FRDA iPSC-derived neurons and cardiomyocytes exhibited signs of impaired mitochondrial function, with decreased mitochondrial membrane potential and progressive mitochondrial degeneration, respectively. Our data show for the first time that FRDA iPSCs and their neuronal and cardiac derivatives represent promising models for the study of mitochondrial damage and GAA expansion instability in FRDA.

Neuronal signal integration as well as synaptic transmission and plasticity highly depend on the morphology of dendrites and their spines. Nogo-A is a membrane protein enriched in the adult central nervous system (CNS) myelin, where it restricts the capacity of axons to grow and regenerate after injury. Nogo-A is also expressed by certain neurons, in particular during development, but its physiological function in this cell type is less well understood. We addressed this question in the cerebellum, where Nogo-A is transitorily highly expressed in the Purkinje cells (PCs) during early postnatal development. We used general genetic ablation (KO) as well as selective overexpression of Nogo-A in PCs to analyze its effect on dendritogenesis and on the formation of their main input synapses from parallel (PFs) and climbing fibers (CFs). PC dendritic trees were larger and more complex in Nogo-A KO mice and smaller than in wild-type in Nogo-A overexpressing PCs. Nogo-A KO resulted in premature soma-to-dendrite translocation of CFs and an enlargement of the CF territory in the molecular layer during development. Although spine density was not influenced by Nogo-A, the size of postsynaptic densities of PF–PC synapses was negatively correlated with the Nogo-A expression level. Electrophysiological studies revealed that Nogo-A negatively regulates the strength of synaptic transmission at the PF–PC synapse. Thus, Nogo-A appears as a negative regulator of PC input synapses, which orchestrates cerebellar connectivity through regulation of synapse morphology and the size of the PC dendritic tree.

We propose an upgraded version of our previously designed open-source lipid bilayer amplifier. This improved amplifier is now suitable both for the use in introductory courses in biophysics and neurosciences at the undergraduate level and for scientific research. Similar to its predecessor, the OpenPicoAmp-100k is designed using the common lithographic printed circuit board fabrication process and off-the-shelf electronic components. It consists of the high-speed headstage, followed by voltage-gain amplifier with built-in 6-order Bessel filter. The amplifier has a bandwidth of 100 kHz in the presence of 100-pF input membrane capacitance and is capable of measuring ion channel current with amplitudes from sub-pA and up to ± 4 nA. At the full bandwidth and with a 1 GΩ transimpedance gain, the amplifier shows 12 pArms noise with an open input and 112 pArms noise in the presence of 100-pF input capacitance, while at the 5-kHz bandwidth (typical in single-channel experiments), noise amounts to 0.45 pArms and 2.11 pArms, respectively. Using an optocoupler circuit producing TTL-controlled current impulses and using 50% threshold analysis, we show that at full bandwidth, the amplifier has deadtimes of 3.5 μs and 5 μs at signal-to-noise ratios (SNR) of 9 and 1.7, respectively. Near 100% of true current impulses longer than 5 μs and 6.6 μs are detected at these two respective SNRs, while false event detection rate remains acceptably low. The wide bandwidth of the amplifier was confirmed in bilayer experiments with alamethicin, for which open ion channel current events shorter that 10 μs could be resolved.