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Background: The ability to recreate an optimal cellular microenvironment is critical to understand neuronal behavior and functionality in vitro. An organized neural extracellular matrix (nECM) promotes neural cell adhesion, proliferation and differentiation. Here, we expanded previous observations on the ability of nECM to support in vitro neuronal differentiation, with the following goals: (i) to recreate complex neuronal networks of embryonic rat hippocampal cells, and (ii) to achieve improved levels of dopaminergic differentiation of subventricular zone (SVZ) neural progenitor cells. Methods: Hippocampal cells from E18 rat embryos were seeded on PLL- and nECM-coated substrates. Neurosphere cultures were prepared from the SVZ of P4-P7 rat pups, and differentiation of neurospheres assayed on PLL- and nECM-coated substrates. Results: When seeded on nECM-coated substrates, both hippocampal cells and SVZ progenitor cells showed neural expression patterns that were similar to their poly-L-lysine-seeded counterparts. However, nECM-based cultures of both hippocampal neurons and SVZ progenitor cells could be maintained for longer times as compared to poly-L-lysine-based cultures. As a result, nECM-based cultures gave rise to a more branched neurite arborization of hippocampal neurons. Interestingly, the prolonged differentiation time of SVZ progenitor cells in nECM allowed us to obtain a purer population of dopaminergic neurons. Conclusions: We conclude that nECM-based coating is an efficient substrate to culture neural cells at different stages of differentiation. In addition, neural ECM-coated substrates increased neuronal survival and neuronal differentiation efficiency as compared to cationic polymers such as poly-L-lysine. [ABSTRACT FROM AUTHOR]

Neurotoxic effects of amyloid β peptides are mediated through deregulation of intracellular Ca2+ homeostasis and signaling, but relatively little is known about amyloid β modulation of Ca2+ homeostasis and its pathological influence on glia. Here, we found that amyloid β oligomers caused a cytoplasmic Ca2+ increase in cultured astrocytes, which was reduced by inhibitors of PLC and ER Ca2+ release. Furthermore, amyloid β peptides triggered increased expression of glial fibrillary acidic protein ( GFAP), as well as oxidative and ER stress, as indicated by eIF2α phosphorylation and overexpression of chaperone GRP78. These effects were decreased by ryanodine and 2 APB, inhibitors of ryanodine receptors and Ins P3 receptors, respectively, in both primary cultured astrocytes and organotypic cultures of hippocampus and entorhinal cortex. Importantly, intracerebroventricular injection of amyloid β oligomers triggered overexpression of GFAP and GRP78 in astrocytes of the hippocampal dentate gyrus. These data were validated in a triple-transgenic mouse model of Alzheimer's disease ( AD). Overexpression of GFAP and GRP78 in the hippocampal astrocytes correlated with the amyloid β oligomer load in 12-month-old mice, suggesting that this parameter drives astrocytic ER stress and astrogliosis in vivo. Together, these results provide evidence that amyloid β oligomers disrupt ER Ca2+ homeostasis, which induces ER stress that leads to astrogliosis; this mechanism may be relevant to AD pathophysiology. [ABSTRACT FROM AUTHOR]

Abstract: Amyloid beta (Aβ) oligomers accumulate in brain tissue of Alzheimer disease patients and are related to pathogenesis. The precise mechanisms by which Aβ oligomers cause neurotoxicity remain unresolved. In this study, we investigated the role of ionotropic glutamate receptors on the intracellular Ca2+ overload caused by Aβ. Using rat cortical neurons in culture and entorhinal–hippocampal organotypic slices, we found that Aβ oligomers significantly induced inward currents, intracellular Ca2+ increases and apoptotic cell death through a mechanism requiring NMDA and AMPA receptor activation. The massive entry of Ca2+ through NMDA and AMPA receptors induced by Aβ oligomers caused mitochondrial dysfunction as indicated by mitochondrial Ca2+ overload, oxidative stress and mitochondrial membrane depolarization. Importantly, chronic treatment with nanomolar concentration of Aβ oligomers also induced NMDA- and AMPA receptor-dependent cell death in entorhinal cortex and hippocampal slice cultures. Together, these results indicate that overactivation of NMDA and AMPA receptor, mitochondrial Ca2+ overload and mitochondrial damage underlie the neurotoxicity induced by Aβ oligomers. Hence, drugs that modulate these events can prevent from Aβ damage to neurons in Alzheimer''s disease. [Copyright &y& Elsevier]

Abstract: A number of studies have already established the role of the subventricular zone in sustaining adult neurogenesis in different brain regions and under different pathological conditions, but nothing is reported about the role of this germinal area in preserving cell viability. In this work, we developed an organotypic culture model of the forebrain structures that comprise the neocortex, striatum, subventricular zone, and corpus callosum. With this model, we investigated the role of the subventricular zone in modulating cell viability in the cortex after oxygen/glucose deprivation. Here we have demonstrated that soluble heat-labile factors released by the subventricular zone in the media can lead to protection specifically in the cortical area. No protection was observed when medium, conditioned with factors released during the insult was administered to the hippocampal slices. Moreover, the use of different modifications of the slice cultures showed that the removal of the subventricular zone increased the cellular damage induced by oxygen/glucose deprivation. Furthermore, by using pharmacological experiments to investigate the possible mechanisms that regulate this subventricular function, we found evidence of purinergic involvement. We postulate that extracellular ATP signaling in the subventricular zone exacerbates cortical damage induced by hypoxia/hypoglycemia. For the first time, we demonstrate in vitro that the germinal subventricular zone can release factors that can be protective after exposure to a metabolic stressor. These released factors are not yet characterized but we identified in the extracellular ATP a factor that may interfere with the protective role of the subventricular zone during metabolic cortical damage. [Copyright &y& Elsevier]

Extracellular nucleotides exert a variety of biological actions through different subtypes of P2 receptors. Here we characterized in the human neuroblastoma SH-SY5Y cells the simultaneous presence of various P2 receptors, belonging to the P2X ionotropic and P2Y metabotropic families. Western blot analysis detected the P2X 1,2,4,5,6,7 and P2Y 1,2,4,6 , but not the P2X 3 and P2Y 12 receptors. We then investigated which biological effects were mediated by the P2Y 4 subtype and its physiological pyrimidine agonist UTP. We found that neuronal differentiation of the SH-SY5Y cells with dibutiryl-cAMP increased the expression of the P2Y 4 protein and that UTP itself was able to positively interfere with neuritogenesis. Moreover, transient transfection and activation of P2Y 4 also facilitated neuritogenesis in SH-SY5Y cells, as detected by morphological phase contrast analysis and confocal examination of neurofilament proteins NFL. This was concurrent with increased transcription of immediate–early genes linked to differentiation such as cdk-5 and NeuroD6 , and activity of AP-1 transcription family members such as c-fos, fos-B, and jun-D. Nevertheless, a prolonged activation of the P2Y 4 receptor by UTP also induced cell death, both in naive, differentiated, and P2Y 4 -transfected SH-SY5Y cells, as measured by direct count of intact nuclei and cytofluorimetric analysis of damaged DNA. Taken together, our data indicate that the high expression and activation of the P2Y 4 receptor participates in the neuronal differentiation and commitment to death of SH-SY5Y cells. [ABSTRACT FROM AUTHOR]

Electron transport in Luttinger liquids connected by tunnel barriers is reviewed. The non-analytic temperature behavior of the conductance of a single tunnel barrier is derived. An overview of charge and spin transport properties through a one-dimensional quantum dot formed by two impurities is given. The temperature and voltage dependences of conductance peaks reveal the non-Fermi liquid correlations. Several spin effects in the linear as well as non-linear transport are predicted. These include a parity effect in linear transport which is due to the Pauli exclusion principle, and negative differential conductances in non-linear transport. The latter are due to charge and spin selection rules and non-Fermi liquid correlations which lead to correlation-induced trapping of higher-spin states. The possibility for experimental verification of this novel effect is discussed. [Copyright &y& Elsevier]

Majorana bound states in topological superconductors have attracted intense research activity in view of applications in topological quantum computation. However, they are not the only example of topological bound states that can occur in such systems. Here, we study a model in which both Majorana and Tamm bound states compete. We show both numerically and analytically that, surprisingly, the Tamm state remains partially localized even when the spectrum becomes gapless. Despite this fact, we demonstrate that the Majorana polarization shows a clear transition between the two regimes. [ABSTRACT FROM AUTHOR]

Accumulation of the neuronal presynaptic protein alpha-synuclein within proteinaceous inclusions represents the key histophathological hallmark of a spectrum of neurodegenerative disorders, referred to by the umbrella term a-synucleinopathies. Even though alpha-synuclein is expressed predominantly in neurons, pathological aggregates of the protein are also found in the glial cells of the brain. In Parkinson's disease and dementia with Lewy bodies, alpha-synuclein accumulates mainly in neurons forming the Lewy bodies and Lewy neurites, whereas in multiple system atrophy, the protein aggregates mostly in the glial cytoplasmic inclusions within oligodendrocytes. In addition, astrogliosis and microgliosis are found in the synucleinopathy brains, whereas both astrocytes and microglia internalize alpha-synuclein and contribute to the spread of pathology. The mechanisms underlying the pathological accumulation of alpha-synuclein in glial cells that under physiological conditions express low to non-detectable levels of the protein are an area of intense research. Undoubtedly, the presence of aggregated alpha-synuclein can disrupt glial function in general and can contribute to neurodegeneration through numerous pathways. Herein, we summarize the current knowledge on the role of alpha-synuclein in both neurons and glia, highlighting the contribution of the neuron-glia connectome in the disease initiation and progression, which may represent potential therapeutic target for a-synucleinopathies. [ABSTRACT FROM AUTHOR]

In the last years, research has shown that zinc ions play an essential role in the physiology of brain function. Zinc acts as a potent neuromodulatory agent and signaling ions, regulating healthy brain development and the function of both neurons and glial cells. Therefore, the concentration of zinc within the brain and its cells is tightly controlled. Zinc transporters are key regulators of (extra-) cellular zinc levels, and deregulation of zinc homeostasis and zinc transporters has been associated with neurodegenerative and neuropsychiatric disorders. However, to date, the presence of specific family members and their subcellular localization within brain cells have not been investigated in detail. Here, we analyzed the expression of all zinc transporters (ZnTs) and Irt-like proteins (ZIPs) in the rat brain. We further used primary rat neurons and rat astrocyte cell lines to differentiate between the expression found in neurons or astrocytes or both. We identified ZIP4 expressed in astrocytes but significantly more so in neurons, a finding that has not been reported previously. In neurons, ZIP4 is localized to synapses and found in a complex with major postsynaptic scaffold proteins of excitatory synapses. Synaptic ZIP4 reacts to short-term fluctuations in local zinc levels. We conclude that ZIP4 may have a so-far undescribed functional role at excitatory postsynapses. [ABSTRACT FROM AUTHOR]

We present a systematic comparison of PAM-2 (NRZ), Duobinary-PAM-2, PAM-4, and Duobinary-PAM-4 (duo-quaternary) signaling in the context of short-reach photonic communications systems using a Mach–Zehnder modulator as transmitter. The effect on system performance with a relaxed and constrained system's opto-electronic bandwidth is analyzed for bit rates ranging from 20 to 116 Gb/s. In contrast to previous analyses, our approach employs the same experimental and simulation conditions for all modulation formats. Consequently, we were able to confidently determine the performance limits of each format for particular values of bit rate, system bandwidth, transmitter chirp, and fiber dispersion. We demonstrate that Duobinary-PAM-4 is a good signaling choice only for bandwidth-limited systems operating at relatively high speed. Otherwise, PAM-4 represents a more sensible choice. Moreover, our analysis put forward the existence of transition points: specific bit rate values where the BER versus bit rate curves for two different formats cross each other. They indicate the bit rate values where, for specific system conditions, switching from one modulation to another guarantees optimum performance. Their existence naturally led to the proposal of a format-selective transceiver, a component that, according to network conditions, operates with the most adequate modulation format. Since all analyzed modulations share similar implementation details, signaling switching is achieved by simply changing the sampling point and threshold count at the receiver, bringing flexibility to IM/DD-based optical networks. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that amyloid and tau protein are of vital importance in post-ischemic death of CA1 pyramidal neurons of the hippocampus. In this review, we summarize protein alterations associated with Alzheimer's disease and their gene expression (amyloid protein precursor and tau protein) after cerebral ischemia, as well as their roles in post-ischemic hippocampus neurodegeneration. In recent years, multiple studies aimed to elucidate the post-ischemic processes in the development of hippocampus neurodegeneration. Their findings have revealed the dysregulation of genes for amyloid protein precursor, β-secretase, presenilin 1 and 2, tau protein, autophagy, mitophagy, and apoptosis identical in nature to Alzheimer's disease. Herein, we present the latest data showing that amyloid and tau protein associated with Alzheimer's disease and their genes play a key role in post-ischemic neurodegeneration of the hippocampus with subsequent development of dementia. Therefore, understanding the underlying process for the development of post-ischemic CA1 area neurodegeneration in the hippocampus in conjunction with Alzheimer's disease-related proteins and genes will provide the most important therapeutic development goals to date. [ABSTRACT FROM AUTHOR]

When a parameter quench is performed in an isolated quantum system with a complete set of constants of motion, its out of equilibrium dynamics is considered to be well captured by the Generalized Gibbs Ensemble (GGE), characterized by a set { λ α } of coefficients related to the constants of motion. We determine the most elementary GGE deviation from the equilibrium distribution that leads to detectable effects. By quenching a suitable local attractive potential in a one-dimensional electron system, the resulting GGE differs from equilibrium by only one single λ α , corresponding to the emergence of an only partially occupied bound state lying below a fully occupied continuum of states. The effect is shown to induce optical gain, i.e., a negative peak in the absorption spectrum, indicating the stimulated emission of radiation, enabling one to identify GGE signatures in fermionic systems through optical measurements. We discuss the implementation in realistic setups. [ABSTRACT FROM AUTHOR]

The simplest possible structural transition that an electronic system can undergo is Wigner crystallization. The aim of this short review is to discuss the main aspects of three recent experimets on the one-dimensional Wigner molecule, starting from scratch. To achieve this task, the Luttinger liquid theory of weakly and strongly interacting fermions is briefly addressed, together with the basic properties of carbon nanotubes that are required. Then, the most relevant properties of Wigner molecules are addressed, and finally the experiments are described. The main physical points that are addressed are the suppression of the energy scales related to the spin and isospin sectors of the Hamiltonian, and the peculiar structure that the electron density acquires in the Wigner molecule regime. [ABSTRACT FROM AUTHOR]

Abstract: We analyze the shot noise of a spin-degenerate electronic level coupled to an harmonic oscillator in the presence of relaxation. We show that the electromechanical coupling can induce a suppression of the Fano factor below the value expected without phonons . Moreover, in the presence of finite relaxation, the Fano factor can be even reduced below . [Copyright &y& Elsevier]

Parkinson's disease (PD) affects millions of patients worldwide and is characterized by alpha-synuclein aggregation in dopamine neurons. Molecular tweezers have shown high potential as anti-aggregation agents targeting positively charged residues of proteins undergoing amyloidogenic processes. Here we report that the molecular tweezer CLR01 decreased aggregation and toxicity in induced pluripotent stem cell-derived dopaminergic cultures treated with PD brain protein extracts. In microfluidic devices CLR01 reduced alpha-synuclein aggregation in cell somas when axonal terminals were exposed to alpha-synuclein oligomers. We then tested CLR01 in vivo in a humanized alpha-synuclein overexpressing mouse model; mice treated at 12 months of age when motor defects are mild exhibited an improvement in motor defects and a decreased oligomeric alpha-synuclein burden. Finally, CLR01 reduced alpha-synuclein-associated pathology in mice injected with alpha-synuclein aggregates into the striatum or substantia nigra. Taken together, these results highlight CLR01 as a disease-modifying therapy for PD and support further clinical investigation. CLR01 is a molecular tweezer that inhibits protein aggregation. Here the authors show that CLR01 protects dopaminergic neurons in vitro and in vivo in human neurons and in mouse models showing potential as a disease-modifying therapy for Parkinson's disease. [ABSTRACT FROM AUTHOR]

The role of P2X7 receptors and pannexin-1 channels in ischemic damage remains controversial. Here, we analyzed their contribution to postanoxic depolarization after ischemia in cultured neurons and in brain slices. We observed that pharmacological blockade of P2X7 receptors or pannexin-1 channels delayed the onset of postanoxic currents and reduced their slope, and that simultaneous inhibition did not further enhance the effects of blocking either one. These results were confirmed in acute cortical slices from P2X7 and pannexin-1 knockout mice. Oxygen-glucose deprivation in cortical organotypic cultures caused neuronal death that was reduced with P2X7 and pannexin-1 blockers as well as in organotypic cultures derived from mice lacking P2X7 and pannexin 1. Subsequently, we used transient middle cerebral artery occlusion to monitor the neuroprotective effect of those drugs in vivo. We found that P2X7 and pannexin-1 antagonists, and their ablation in knockout mice, substantially attenuated the motor symptoms and reduced the infarct volume to ~50% of that in vehicle-treated or wild-type animals. These results show that P2X7 receptors and pannexin-1 channels are major mediators of postanoxic depolarization in neurons and of brain damage after ischemia, and that they operate in the same deleterious signaling cascade leading to neuronal and tissue demise. [ABSTRACT FROM AUTHOR]

Background: Retracted articles represent research withdrawn from the existing body of literature after publication. Research articles may be retracted for several reasons ranging from honest errors to intentional misconduct. They should not be used as reliable sources, and it is unclear why they are cited occasionally by other articles. This study hypothesized that several mechanisms may contribute to citing retracted literature and aimed to analyze the characteristics of articles citing retracted literature in anesthesiology and critical care.Methods: Using the Retraction Watch database, we retrieved retracted articles on anesthesiology and intensive care medicine up to August 16, 2021, and identified the papers citing these retracted articles. A survey designed to investigate the reasons for citing these articles was sent to the corresponding authors of the citing papers.Results: We identified 478 retracted articles, 220 (46%) of which were cited at least once. We contacted 1297 corresponding authors of the papers that cited these articles, 417 (30%) of whom responded to our survey and were included in the final analysis. The median number of authors in the analyzed articles was five, and the median elapsed time from retraction to citation was 3 yr. Most of the corresponding authors (372, 89%) were unaware of the retracted status of the cited article, mainly because of inadequate notification of the retraction status in journals and/or databases and the use of stored copies.Conclusions: The corresponding authors were generally unaware of the retraction of the cited article, usually because of inadequate identification of the retracted status in journals and/or web databases and the use of stored copies. Awareness of this phenomenon and rigorous control of the cited references before submitting a paper are of fundamental importance in research.Editor’s Perspective: [ABSTRACT FROM AUTHOR]

Recent experimental advances enable the manipulation of quantum matter by exploiting the quantum nature of light. However, paradigmatic exactly solvable models, such as the Dicke, Rabi or Jaynes-Cummings models for quantum-optical systems, are scarce in the corresponding solid-state, quantum materials context. Focusing on the long-wavelength limit for the light, here, we provide such an exactly solvable model given by a tight-binding chain coupled to a single cavity mode via a quantized version of the Peierls substitution. We show that perturbative expansions in the light-matter coupling have to be taken with care and can easily lead to a false superradiant phase. Furthermore, we provide an analytical expression for the groundstate in the thermodynamic limit, in which the cavity photons are squeezed by the light-matter coupling. In addition, we derive analytical expressions for the electronic single-particle spectral function and optical conductivity. We unveil quantum Floquet engineering signatures in these dynamical response functions, such as analogs to dynamical localization and replica side bands, complementing paradigmatic classical Floquet engineering results. Strikingly, the Drude weight in the optical conductivity of the electrons is partially suppressed by the presence of a single cavity mode through an induced electron-electron interaction. For solid-state experiments, exactly solvable quantum light matter models, where the quantum nature of light is relevant, are scarce. Here, the authors introduce an exactly solvable model, where a one-dimensional tight-binding chain is coupled to a single cavity mode and derive analytic expressions for the ground state, where the photons are squeezed due to the light-matter coupling. [ABSTRACT FROM AUTHOR]

Abstract: Increased neurogenesis in response to brain injury is considered a mechanism of regeneration after neuronal loss. Using organotypic hippocampal cultures (OHC), we investigated the interplay between neuronal damage (propidium iodide uptake), microglia activation (OX-42 immunohistochemistry), cell proliferation (bromodeoxyuridine incorporation), and neurogenesis (double labeling of bromodeoxyuridine with doublecortin or β-III tubulin) after oxygen–glucose deprivation (OGD). We observed that microglia activation and upregulation of pro-inflammatory cytokines mRNA preceded neuronal loss and was followed by increased cell proliferation. Neurogenesis was inhibited 3 days after OGD in both neurogenic zones of the slice, the dentate gyrus and the posterior periventricle (pPV). After 6 days, neurogenesis was restored and significantly increased in the pPV. Indomethacin or minocycline reduced the OGD-induced damage, proliferation, and increase of microglia. Both agents did not interfere with OGD-induced pPV neurogenesis. Our study shows for the first time that neuroprotection against OGD-induced damage in OHC by anti-inflammatory treatment is associated with intact neurogenesis. [Copyright &y& Elsevier]

Introduction: Blood and cerebrospinal fluid represent emerging candidate fluids for biomarker identification in Parkinson's disease (PD).Methods: We studied 8 individuals carrying the E46K-SNCA mutation (3 PD dementia (PDD), 1 tremor-dominant PD, 2 young rigid-akinetic PD and 2 asymptomatic) and 8 age- and sex-matched healthy controls. We quantified the levels of total alpha-synuclein (a-syn), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), Tau and ubiquitin carboxy-terminal hydrolase L1 (UCHL1) with SiMoA (Quanterix) in cerebrospinal fluid (CSF) of mutation carriers and in serum of all participants. The correlation between the concentration of biofluid markers and clinical outcomes was evaluated.Results: Although based on a small number of cases, CSF a-syn was decreased in symptomatic E46K-SNCA carriers compared to the asymptomatic ones. Asymptomatic carriers exhibited similar serum biomarker levels as compared to matched controls, except for serum a-syn, which was higher in asymptomatic individuals. Carriers with PDD diagnosis displayed increased levels of serum NfL and GFAP compared to matched controls. These findings highly correlated with cognitive and motor status of E46K-SNCA carriers, but not with disease duration.Conclusions: Patients with familial forms of neurodegenerative disease exhibit variable penetrance of the phenotype and are exceptionally valuable for delineating biomarkers. Serum and CSF molecular biomarkers in E46K-SNCA mutation carriers show that a-syn might be suitable to track the conversion from asymptomatic to PD, whereas NfL and GFAP might serve to foresee the progression to PD dementia. These findings should be interpreted with caution and need to be replicated in other genetic synucleinopathy cohorts. [ABSTRACT FROM AUTHOR]

Providing a low-cost, reliable and end-to-end quality of service (QoS) guaranteed connectivity is going to be a major challenge in optical transport due to the immense growth in number of connected devices and traffic volume triggered by fifth-generation mobile networks (5G) and cloud networks. First, we discuss the architectures of the 5G transport network and the data center network, to capture the full value of connectivity. The paper offers an overview of the network requirements and how the integrated photonic platforms, along with the advanced modulation formats, play a key role to support the unprecedented requirements of 5G and massive cloud deployment. Second, we provide an overview of the recent work on the development of high-speed silicon photonic (SiPh) modulators to generate and transport PAM-4 signals. Third, recent advancements of the photodetectors, optical hybrids, and integrated coherent receivers on the silicon-on-insulator (SOI) platform are also described. The results suggest that, in the first access and aggregation segments of the network, integrated silicon-based modulators aided by PAM-4 modulation formats can support the stringent requirements of new generation transport networks in terms of speed, footprint and power consumption. [ABSTRACT FROM AUTHOR]

IP 3 receptor (IP 3 R)-mediated Ca 2+ transfer at the mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) drives mitochondrial Ca 2+ uptake and oxidative metabolism and is linked to different pathologies, including Parkinson's disease (PD). The dependence of Ca 2+ transfer efficiency on the ER-mitochondria distance remains unexplored. Employing molecular rulers that stabilize ER-mitochondrial distances at 5 nm resolution, and using genetically encoded Ca 2+ indicators targeting the ER lumen and the sub-mitochondrial compartments, we now show that a distance of ~20 nm is optimal for Ca 2+ transfer and mitochondrial oxidative metabolism due to enrichment of IP 3 R at MERCS. In human iPSC-derived astrocytes from PD patients, 20 nm MERCS were specifically reduced, which correlated with a reduction of mitochondrial Ca 2+ uptake. Stabilization of the ER-mitochondrial interaction at 20 nm, but not at 10 nm, fully rescued mitochondrial Ca 2+ uptake in PD astrocytes. Our work determines with precision the optimal distance for Ca 2+ flux between ER and mitochondria and suggests a new paradigm for fine control over mitochondrial function., (© 2024. The Author(s).)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

The simultaneous breaking of time-reversal and inversion symmetry, in connection to superconductivity, leads to transport properties with disrupting scientific and technological potential. Indeed, the anomalous Josephson effect and the superconducting-diode effect hold promises to enlarge the technological applications of superconductors and nanostructures in general. In this context, the system we theoretically analyze is a Josephson junction (JJ) with coupled reconstructed topological channels as a link; such channels are at the edges of a two-dimensional topological insulator (2DTI). We find a robust φ0 Josephson effect without requiring the presence of external magnetic fields. Our results, which rely on a fully analytical analysis, are substantiated by means of symmetry arguments: Our system breaks both time-reversal symmetry and inversion symmetry. Moreover, the anomalous current increases as a function of temperature. We interpret this surprising temperature dependence by means of simple qualitative arguments based on Fermi's golden rule.

Quantum thermal machines can perform useful tasks, such as delivering power, cooling, or heating. In this work, we consider hybrid thermal machines, that can execute more than one task simultaneously. We characterize and find optimal working conditions for a three-terminal quantum thermal machine, where the working medium is a quantum harmonic oscillator, coupled to three heat baths, with two of the couplings driven periodically in time. We show that it is possible to operate the thermal machine efficiently, in both pure and hybrid modes, and to switch between different operational modes simply by changing the driving frequency. Moreover, the proposed setup can also be used as a high-performance transistor, in terms of output-to-input signal and differential gain. Owing to its versatility and tunability, our model may be of interest for engineering thermodynamic tasks and for thermal management in quantum technologies., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Background: Since late 2019, a severe acute respiratory syndrome, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has spread with overwhelming speed causing over 214 million confirmed infections and more than 4.5 million deaths worldwide. In this framework, Italy had the second highest number of SARS-CoV-2 infections worldwide, and the largest number of deaths. A global effort of both the scientific community and governments has been undertaken to stem the pandemic. The aim of this paper is to perform a narrative review of the Italian contribution to the scientific literature regarding intensive care management of patients suffering from COVID-19, being one of the first western countries to face an outbreak of SARS-CoV-2 infection., Main Body: We performed a narrative review of the literature, dedicating particular attention and a dedicated paragraph to ventilatory support management, chest imaging findings, biomarkers, possible pharmacological interventions, bacterial superinfections, prognosis and non-clinical key aspects such as communication and interaction with relatives., Conclusions: Many colleagues, nurses and patients died leaving their families alone. To all of them, we send our thoughts and dedicate these pages., (© 2021. The Author(s).)

The principal hallmark of Parkinson's disease (PD) is the selective neurodegeneration of dopaminergic neurones. Mounting evidence suggests that astrocytes may contribute to dopaminergic neurodegeneration through decreased homoeostatic support and deficient neuroprotection. In this study, we generated induced pluripotent stem cells (iPSC)-derived astrocytes from PD patients with LRRK2 (G2019S) mutation and healthy donors of the similar age. In cell lines derived from PD patients, astrocytes were characterised by a significant decrease in S100B and GFAP-positive astrocytic profiles associated with marked decrease in astrocyte complexity. In addition, PD-derived astrocytes demonstrated aberrant mitochondrial morphology, decreased mitochondrial activity and ATP production along with an increase of glycolysis and increased production of reactive oxygen species. Taken together, our data indicate that astrocytic asthenia observed in patient-derived cultures with LRRK2 (G2019S) mutation may contribute to neuronal death through decreased homoeostatic support, elevated oxidative stress and failed neuroprotection.

Adenosine A 1 receptors (A 1 ARs) are promising imaging biomarkers and targets for the treatment of stroke. Nevertheless, the role of A 1 ARs on ischemic damage and its subsequent neuroinflammatory response has been scarcely explored so far. Methods: In this study, the expression of A 1 ARs after transient middle cerebral artery occlusion (MCAO) was evaluated by positron emission tomography (PET) with [ 18 F]CPFPX and immunohistochemistry (IHC). In addition, the role of A 1 ARs on stroke inflammation using pharmacological modulation was assessed with magnetic resonance imaging (MRI), PET imaging with [ 18 F]DPA-714 (TSPO) and [ 18 F]FLT (cellular proliferation), as well as IHC and neurofunctional studies. Results: In the ischemic territory, [ 18 F]CPFPX signal and IHC showed the overexpression of A 1 ARs in microglia and infiltrated leukocytes after cerebral ischemia. Ischemic rats treated with the A 1 AR agonist ENBA showed a significant decrease in both [ 18 F]DPA-714 and [ 18 F]FLT signal intensities at day 7 after cerebral ischemia, a feature that was confirmed by IHC results. Besides, the activation of A 1 ARs promoted the reduction of the brain lesion, as measured with T 2 W-MRI, and the improvement of neurological outcome including motor, sensory and reflex responses. These results show for the first time the in vivo PET imaging of A 1 ARs expression after cerebral ischemia in rats and the application of [ 18 F]FLT to evaluate glial proliferation in response to treatment. Conclusion: Notably, these data provide evidence for A 1 ARs playing a key role in the control of both the activation of resident glia and the de novo proliferation of microglia and macrophages after experimental stroke in rats., Competing Interests: Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The author(s).)

In vivo positron emission tomography of neuroinflammation has mainly focused on the evaluation of glial cell activation using radiolabeled ligands. However, the non-invasive imaging of neuroinflammatory cell proliferation has been scarcely evaluated so far. In vivo and ex vivo assessment of gliogenesis after transient middle cerebral artery occlusion (MCAO) in rats was carried out using PET imaging with the marker of cell proliferation 3'-Deoxy-3'-[18F] fluorothymidine ([ 18 F]FLT), magnetic resonance imaging (MRI) and fluorescence immunohistochemistry. MRI-T 2 W studies showed the presence of the brain infarction at 24 h after MCAO affecting cerebral cortex and striatum. In vivo PET imaging showed a significant increase in [ 18 F]FLT uptake in the ischemic territory at day 7 followed by a progressive decline from day 14 to day 28 after ischemia onset. In addition, immunohistochemistry studies using Ki67, CD11b, and GFAP to evaluate proliferation of microglia and astrocytes confirmed the PET findings showing the increase of glial proliferation at day 7 after ischemia followed by decrease later on. Hence, these results show that [ 18 F]FLT provides accurate quantitative information on the time course of glial proliferation in experimental stroke. Finally, this novel brain imaging method might guide on the imaging evaluation of the role of gliogenesis after stroke., (Copyright © 2020 Ardaya, Joya, Padro, Plaza-García, Gómez-Vallejo, Sánchez, Garbizu, Cossío, Matute, Cavaliere, Llop and Martín.)

Understanding the properties of far-from-equilibrium quantum systems is becoming a major challenge of both fundamental and applied physics. For instance, the lack of thermalization in integrable and (many body) localized systems provides new insights in the understanding of the relaxation dynamics of quantum phases. On a more applicative side, the possibility of exploiting the properties of far-from-equilibrium states, for example in pump-probe experiments, opens unprecedented scenarios. The effort in providing a classification of far-from-equilibrium phases, in terms of local or topological order parameters, is hence intense. In this context, the concept of Dynamical Quantum Phase Transition (DQPT) has been introduced. A DQPT is (roughly) defined as a zero of the Loschmidt-Echo as a function of time and represents a natural non-equilibrium counterpart of a thermal phase transition. Here, we investigate the DQPTs occurring in the quantum xy chain subject to a quantum quench of finite duration. We show that the number of distinct DQPTs can vary as the duration of the quantum quench is varied. However, the parity of such number only depends on the pre-quench and post-quench Hamiltonians and is related to a topological invariant.

Synucleinopathies are a group of diseases characterized by the presence of intracellular protein aggregates containing α-synuclein (α-syn). While α-syn aggregates have been shown to induce multimodal cellular dysfunctions, uptake and transport mechanisms remain unclear. Using high-content imaging on cortical neurons and astrocytes, we here define the kinetics of neuronal and astrocytic abnormalities induced by human-derived α-syn aggregates grounding the use of such system to identify and test putative therapeutic compounds. We then aimed at characterizing uptake and transport mechanisms using primary cultures of cortical neurons and astrocytes either in single well or in microfluidic chambers allowing connection between cells and cell-types. We report that astrocytes take up α-syn-aggregates far more efficiently than neurons through an endocytic event. We also highlight that active α-syn transport occurs between cells and any cell-types. Of special interest regarding the disease, we also show that uptake and spreading of α-syn from astrocytes to neurons can lead to neuronal death. Altogether, we here show that patients-derived α-synuclein aggregates, which are taken up by neurons and astrocytes, induce a differential endogenous response in the two cell types including a peculiar astrocytic toxic gain-of-function that leads to neuronal death., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purinergic signalling in neurons and glia is relevant to acute and chronic neurological diseases. In particular, emerging evidence indicates that adenosine can play a neuromodulatory role in balancing GABA and glutamate neurotransmission and thus, have a tremendous therapeutic potential for the treatment of epilepsy. On the other hand, signalling via P2 purinergic receptors contributes to post-ischemic injury to grey and white matter as well as endogenous neurogenesis in response to tissue damage. Likewise, P2 receptors mediate demyelinating damage in animal models of multiple sclerosis, and recent evidences suggest that P2X receptor function is altered in this disorder. In all instances, complex interactions between neurons and glia via purine signals are relevant to disease and its prevention or attenuation. Here, we review current knowledge on how purinergic signalling is involved in the pathophysiology of CNS diseases, with an emphasis in epilepsy, ischemia and multiple sclerosis. Understanding in depth the primary and secondary mechanisms relevant to the control of excitation and/or damage by purines will undoubtedly lead to the development of novel therapies based on the use of drugs acting at the purinergic system., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Functional and reliable in vitro models of Parkinson's disease (PD) are valuable for studying mechanisms of dopaminergic degeneration before proceeding to animal testing. At present, all in vitro models involve substitute cell types and thus their direct relevance to PD is questionable. Here, we describe an organotypic culture model which conserves the 3D architecture of the nigro-striatal pathway, together with the subventricular zone and cerebral cortex, and recapitulates a specific pattern of dopaminergic degeneration which is the principal hallmark of PD. The organotypic culture is kept in vitro for up to 12 days and dopaminergic degeneration is induced by the simple cutting of dopaminergic fibers. This organotypic model represents a rapid and useful method (30 min/pup for preparation and up to 12 days of cultivation) to investigate in vitro the mechanisms underlying neuronal death and protection, as well as neurogenesis and repair after nigro-striatal neurodegeneration., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Amyloid beta (Abeta) oligomers accumulate in brain tissue of Alzheimer disease patients and are related to pathogenesis. The precise mechanisms by which Abeta oligomers cause neurotoxicity remain unresolved. In this study, we investigated the role of ionotropic glutamate receptors on the intracellular Ca2+ overload caused by Abeta. Using rat cortical neurons in culture and entorhinal-hippocampal organotypic slices, we found that Abeta oligomers significantly induced inward currents, intracellular Ca2+ increases and apoptotic cell death through a mechanism requiring NMDA and AMPA receptor activation. The massive entry of Ca2+ through NMDA and AMPA receptors induced by Abeta oligomers caused mitochondrial dysfunction as indicated by mitochondrial Ca2+ overload, oxidative stress and mitochondrial membrane depolarization. Importantly, chronic treatment with nanomolar concentration of Abeta oligomers also induced NMDA- and AMPA receptor-dependent cell death in entorhinal cortex and hippocampal slice cultures. Together, these results indicate that overactivation of NMDA and AMPA receptor, mitochondrial Ca2+ overload and mitochondrial damage underlie the neurotoxicity induced by Abeta oligomers. Hence, drugs that modulate these events can prevent from Abeta damage to neurons in Alzheimer's disease., (2009 Elsevier Ltd. All rights reserved.)

ATP is a potent signaling molecule abundantly present in the CNS. It elicits a wide array of physiological effects and is regarded as the phylogenetically most ancient epigenetic factor playing crucial biological roles in several different tissues. These can range from neurotransmission, smooth muscle contraction, chemosensory signaling, secretion and vasodilatation, to more complex phenomena such as immune responses, pain, male reproduction, fertilization and embryonic development. ATP is released into the extracellular space either exocytotically or from damaged and dying cells. It is often co-released with other neurotransmitters and it can interact with growth factors at both receptor- and/or signal transduction-level. Once in the extracellular environment, ATP binds to specific receptors termed P2. Based on pharmacological profiles, on selectivity of coupling to second-messenger pathways and on molecular cloning, two main subclasses with multiple subtypes have been distinguished. They are P2X, i.e. fast cation-selective receptor channels (Na+, K+, Ca2+), possessing low affinity for ATP and responsible for fast excitatory neurotransmission, and P2Y, i.e. slow G protein-coupled metabotropic receptors, possessing higher affinity for the ligand. In the nervous system, they are broadly expressed in both neurons and glial cells and can mediate dual effects: short-term such as neurotransmission, and long-term such as trophic actions. Since massive extracellular release of ATP often occurs after metabolic stress, brain ischemia and trauma, purinergic mechanisms are also correlated to and involved in the etiopathology of many neurodegenerative conditions. Furthermore, extracellular ATP per se is toxic for primary neuronal dissociated and organotypic CNS cultures from cortex, striatum and cerebellum and P2 receptors can mediate and aggravate hypoxic signaling in many CNS neurons. Conversely, several P2 receptor antagonists abolish the cell death fate of primary neuronal cultures exposed to excessive glutamate, serum/potassium deprivation, hypoglycemia and chemical hypoxia. In parallel with these detrimental effects, also trophic functions have been extensively described for extracellular purines (both for neuronal and non-neuronal cells), but these might either aggravate or ameliorate the normal cellular conditions. In summary, extracellular ATP plays a very complex role not only in the repair, remodeling and survival occurring in the nervous system, but even in cell death and this can occur either after normal developmental conditions, after injury, or acute and chronic diseases.