Reconstruction-Induced φ0 Josephson Effect in Quantum Spin Hall Constrictions.

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.

Hybrid quantum thermal machines with dynamical couplings.

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.

Inappropriate Citation of Retracted Articles in Anesthesiology and Intensive Care Medicine Publications.

BACKGROUND: Retracted articles represent research withdrawn from the existing body of literature after publication.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.

Characterization of molecular biomarkers in cerebrospinal fluid and serum of E46K-SNCA mutation carriers.

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.

Signature of Generalized Gibbs Ensemble Deviation from Equilibrium: Negative Absorption Induced by a Local Quench.

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 {λα} 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 λα, 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.

Astrocytic atrophy as a pathological feature of Parkinson's disease with LRRK2 mutation.

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.

In vivo multimodal imaging of adenosine A1 receptors in neuroinflammation after experimental stroke.

Adenosine A1 receptors (A1ARs) are promising imaging biomarkers and targets for the treatment of stroke. Nevertheless, the role of A1ARs on ischemic damage and its subsequent neuroinflammatory response has been scarcely explored so far. Methods: In this study, the expression of A1ARs after transient middle cerebral artery occlusion (MCAO) was evaluated by positron emission tomography (PET) with [18F]CPFPX and immunohistochemistry (IHC). In addition, the role of A1ARs on stroke inflammation using pharmacological modulation was assessed with magnetic resonance imaging (MRI), PET imaging with [18F]DPA-714 (TSPO) and [18F]FLT (cellular proliferation), as well as IHC and neurofunctional studies. Results: In the ischemic territory, [18F]CPFPX signal and IHC showed the overexpression of A1ARs in microglia and infiltrated leukocytes after cerebral ischemia. Ischemic rats treated with the A1AR agonist ENBA showed a significant decrease in both [18F]DPA-714 and [18F]FLT signal intensities at day 7 after cerebral ischemia, a feature that was confirmed by IHC results. Besides, the activation of A1ARs promoted the reduction of the brain lesion, as measured with T2W-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 A1ARs expression after cerebral ischemia in rats and the application of [18F]FLT to evaluate glial proliferation in response to treatment. Conclusion: Notably, these data provide evidence for A1ARs 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.

Research on SARS-COV-2 pandemic: a narrative review focused on the Italian contribution.

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.

CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson's disease.

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.

In vivo PET Imaging of Gliogenesis After Cerebral Ischemia in Rats.

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 ([18F]FLT), magnetic resonance imaging (MRI) and fluorescence immunohistochemistry. MRI-T2W 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 [18F]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 [18F]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.

Topological classification of dynamical quantum phase transitions in the xy chain.

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.

50 Gb/s short-reach interconnects with DSP-free direct-detection enabled by CAPS codes.

We experimentally demonstrate 50 Gb/s transmission below an uncorrected bit error rate (BER) of 10-3 in the C band over a transmission reach that extends from 0 to 20 km using combined amplitude and phase shift (CAPS) codes. The CAPS signal, which is not required to be specifically dispersion compensated for each reach within the 20 km operating range, is amenable for simple direct detection using a single photodetector without any subsequent digital signal processing (DSP). Hence, the presented solution constitutes a potentially attractive low cost solution for mobile Xhaul applications employing single mode fiber interconnects with reaches extending to 20 km. Furthermore, the CAPS signaling is compared to other modulation schemes all delivering 50 Gb/s and is found to outperform on-off-keying (OOK), 4-level pulse amplitude modulation (PAM4) and dispersion precompensated OOK in terms of dispersion tolerance. At a lower reach of 10 km, the maximum bit rate that can be achieved using CAPS coding at a BER below 10-3 is found to increase to 67 Gb/s. In addition, using the same testbed, we experimentally tested the IQ duobinary modulation format, which is an alternative format that approximates the CAPS transmitted waveforms in order to omit the need for a power consuming digital-to-analog converter (DAC) to generate the transmitted waveforms at the expense of slightly worse dispersion tolerance. Though the IQ duobinary format can be in principle generated using a simple DAC-less analog transmitter, our proof-of-concept experiment used a DAC to emulate the analog transmitter by generating the corresponding transmitted waveforms due to unavailability of all required analog parts. The IQ duobinary format was found experimentally to enable 50 Gb/s over a reach of ~17 km; that is slightly less than a CAPS signal at the same bit rate. Finally, we verified the excellent performance of the CAPS signaling in an ASE-limited regime where the CAPS signal achieved very low OSNR penalty after 10 km relative to OOK in back-to-back.

Mangiferin and Morin Attenuate Oxidative Stress, Mitochondrial Dysfunction, and Neurocytotoxicity, Induced by Amyloid Beta Oligomers.

Amyloid beta- (Aß-) mediated ROS overproduction disrupts intraneuronal redox balance and exacerbates mitochondrial dysfunction which leads to neuronal injury. Polyphenols have been investigated as therapeutic agents that promote neuroprotective effects in experimental models of brain injury and neurodegenerative diseases. The aim of this study was to identify the neuroprotective effects of morin and mangiferin against Aß oligomers in cultured cortical neurons and organotypic slices as well as their mechanisms of action. Cell death caused by Aß oligomers in neuronal cultures was decreased in the presence of micromolar concentrations of mangiferin or morin, which in turn attenuated oxidative stress. The neuroprotective effects of antioxidants against Aß were associated with the reduction of Aß-induced calcium load to mitochondria; mitochondrial membrane depolarization; and release of cytochrome c from mitochondria, a key trigger of apoptosis. Additionally, we observed that both polyphenols activated the endogenous enzymatic antioxidant system and restored oxidized protein levels. Finally, Aß induced an impairment of energy homeostasis due to a decreased respiratory capacity that was mitigated by morin and mangiferin. Overall, the beneficial effects of polyphenols in preventing mitochondrial dysfunction and neuronal injury in AD cell models suggest that morin and mangiferin hold promise for the treatment of this neurological disorder.

In vitro α-synuclein neurotoxicity and spreading among neurons and astrocytes using Lewy body extracts from Parkinson disease brains.

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.

Adenosine A1 receptor inhibits postnatal neurogenesis and sustains astrogliogenesis from the subventricular zone.

We previously demonstrated that activation of ATP P2X receptors during oxygen and glucose deprivation inhibits neuroblast migration and in vitro neurogenesis from the subventricular zone (SVZ). Here, we have studied the effects of adenosine, the natural end-product of ATP hydrolysis, in modulating neurogenesis and gliogenesis from the SVZ. We provide immunochemical, molecular and pharmacological evidence that adenosine via A1 receptors reduces neuronal differentiation of neurosphere cultures generated from postnatal SVZ. Furthermore, activation of A1 receptors induces downregulation of genes related to neurogenesis as demonstrated by gene expression analysis. Specifically, we found that A1 receptors trigger a signaling cascade that, through the release of IL10, turns on the Bmp2/SMAD pathway. Furthermore, activating A1 receptors in SVZ-neural progenitor cells inhibits neurogenesis and stimulates astrogliogenesis as assayed in vitro in neurosphere cultures and in vivo in the olfactory bulb. Together, these data indicate that adenosine acting at A1 receptors negatively regulates adult neurogenesis while promoting astrogliogenesis, and that this feature may be relevant to pathological conditions whereby purines are profusely released. GLIA 2016;64:1465-1478.

Organotypic Cultures as a Model to Study Adult Neurogenesis in CNS Disorders.

Neural regeneration resides in certain specific regions of adult CNS. Adult neurogenesis occurs throughout life, especially from the subgranular zone of hippocampus and the subventricular zone, and can be modulated in physiological and pathological conditions. Numerous techniques and animal models have been developed to demonstrate and observe neural regeneration but, in order to study the molecular and cellular mechanisms and to characterize multiple types of cell populations involved in the activation of neurogenesis and gliogenesis, investigators have to turn to in vitro models. Organotypic cultures best recapitulate the 3D organization of the CNS and can be explored taking advantage of many techniques. Here, we review the use of organotypic cultures as a reliable and well defined method to study the mechanisms of neurogenesis under normal and pathological conditions. As an example, we will focus on the possibilities these cultures offer to study the pathophysiology of diseases like Alzheimer disease, Parkinson's disease, and cerebral ischemia.

Purinergic signaling: a common pathway for neural and mesenchymal stem cell maintenance and differentiation.

Extracellular ATP, related nucleotides and adenosine are among the earliest signaling molecules, operating in virtually all tissues and cells. Through their specific receptors, namely purinergic P1 for nucleosides and P2 for nucleotides, they are involved in a wide array of physiological effects ranging from neurotransmission and muscle contraction to endocrine secretion, vasodilation, immune response, and fertility. The purinergic system also participates in the proliferation and differentiation of stem cells from different niches. In particular, both mesenchymal stem cells (MSCs) and neural stem cells are endowed with several purinergic receptors and ecto-nucleotide metabolizing enzymes, and release extracellular purines that mediate autocrine and paracrine growth/proliferation, pro- or anti-apoptotic processes, differentiation-promoting effects and immunomodulatory actions. Here, we discuss the often opposing roles played by ATP and adenosine in adult neurogenesis in both physiological and pathological conditions, as well as in adipogenic and osteogenic MSC differentiation. We also focus on how purinergic ligands produced and released by transplanted stem cells can be regarded as ideal candidates to mediate the crosstalk with resident stem cell niches, promoting cell growth and survival, regulating inflammation and, therefore, contributing to local tissue homeostasis and repair.

Blockade of P2X7 receptors or pannexin-1 channels similarly attenuates postischemic damage.

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.