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Although tyrosine kinase inhibitors (TKIs) determined an improvement of responses and overall survival (OS) in chronic phase chronic myeloid leukemia (CP-CML) patients, some patients still fail the achievement of important milestones.In this review, we focus on the need of appropriate molecular and mutational monitoring during TKI treatment with new laboratory tools and on new compounds developed to counteract the unmet clinical need in CP-CML.The appropriate identification of BCR::ABL1 dependent and independent mechanisms of resistance with Next Generation Sequencing (NGS) and digital droplet PCR (ddPCR) can allow to improve the therapeutic strategies and prevent the onset of a failure to treatment. New compounds have been recently approved or are still in investigational trials to improve the response in some critical forms of resistance and/or intolerance to available TKIs.

ALS is a rapidly progressive, fatal disorder caused by motor neuron degeneration, for which there is a great unmet therapeutic need. AMX0035, a combination of sodium phenylbutyrate (PB) and taurursodiol (TUDCA, TURSO), has shown promising results in early ALS clinical trials, but its mechanisms of action remain to be elucidated. Therefore, our goal was to obtain an unbiased landscape of the molecular effects of AMX0035 in ALS patient-derived cells.We investigated the transcriptomic and metabolomic profiles of primary skin fibroblasts from sporadic ALS patients and healthy controls (n = 12/group) treated with PB, TUDCA, or PB-TUDCA combination (Combo). Data were evaluated with multiple approaches including differential gene expression and metabolite abundance, Gene Ontology and metabolic pathway analysis, weighted gene co-expression correlation analysis (WGCNA), and combined multiomics integrated analysis.Combo changed many more genes and metabolites than either PB or TUDCA individually. Most changes were unique to Combo and affected the expression of genes involved in nucleocytoplasmic transport, unfolded protein response, mitochondrial function, RNA metabolism, and innate immunity. WGCNA showed significant correlations between ALS gene expression modules and clinical parameters that were abolished by Combo treatment.This study is the first to explore the molecular effects of Combo in ALS patient-derived cells. It shows that Combo has a greater and distinct impact compared with the individual compounds and provides clues to drug targets and mechanisms of action, which may underlie the benefits of this investigational drug combination.

JAK2 inhibitors have changed the therapeutic strategies for the management of primary and secondary myelofibrosis. Ruxolitinib, the first available agent, improved disease-related symptoms, spleen volume, and overall survival compared to conventional chemotherapy. It has been revealed that after 3 years of treatment, about 50% of patients discontinued ruxolitinib for resistance and/or intolerance and should be candidate to a second line of treatment.Second-generation tyrosine kinase inhibitors have been tested in this setting, but all these new drugs do not significantly impact on disease progression. Novel agents are in developments that target on different pathways, alone or in combination with JAK2 inhibitors.In this review, we summarize all the clinical efficacy and safety data of these drugs providing a vision of the possible future.

We present a numerical method to solve the Vlasov–Maxwell equations for spin-1/2 particles, in a semiclassical approximation where the orbital motion is treated classically while the spin variable is fully quantum. Unlike the spinless case, the phase-space distribution function is a $2\times 2$ matrix, which can also be represented, in the Pauli basis, as one scalar function $f_0$ and one three-component vector function $\boldsymbol f$ . The relationship between this ‘vectorial’ representation and the fully scalar representation on an extended phase space first proposed by Brodin et al. (Phys. Rev. Lett., vol. 101, 2008, p. 245002) is analysed in detail. By means of suitable approximations and symmetries, the vectorial spin-Vlasov–Maxwell model can be reduced to two-dimensions in the phase space, which is amenable to numerical solutions using a high-order grid-based Eulerian method. The vectorial model enjoys a Poisson structure that paves the way to accurate Hamiltonian split-time integrators. As an example, we study the stimulated Raman scattering of an electromagnetic wave interacting with an underdense plasma, and compare the results with those obtained earlier with the scalar spin-Vlasov–Maxwell model and a particle-in-cell code.

Supplementary Figure 1 from Positive Contribution of Pathogenic Mutations in the Mitochondrial Genome to the Promotion of Cancer by Prevention from Apoptosis

The role of mitochondrial dysfunction in cancer has been a subject of great interest and much ongoing investigation. Although most cancer cells harbor somatic mutations in mitochondrial DNA (mtDNA), the question of whether such mutations contribute to the promotion of carcinomas remains unsolved. Here we used trans-mitochondrial hybrids (cybrids) containing a common HeLa nucleus and mtDNA of interest to compare the role of mtDNA against the common nuclear background. We constructed cybrids with or without a homoplasmic pathogenic point mutation at nucleotide position 8,993 or 9,176 in the mtDNA ATP synthase subunit 6 gene (MTATP6) derived from patients with mitochondrial encephalomyopathy. When the cybrids were transplanted into nude mice, the MTATP6 mutations conferred an advantage in the early stage of tumor growth. The mutant cybrids also increased faster than wild type in culture. To complement the mtDNA mutations, we transfected a wild-type nuclear version of MTATP, whose codons were converted to the universal genetic codes containing a mitochondrial target sequence, into the nucleus of cybrids carrying mutant MTATP6. The restoration of MTATP slowed down the growth of tumor in transplantation. Conversely, expression of a mutant nuclear version of MTATP6 in the wild-type cybrids declined respiration and accelerated the tumor growth. These findings showed that the advantage in tumor growth depended upon the MTATP6 function but was not due to secondary nuclear mutations caused by the mutant mitochondria. Because apoptosis occurred less frequently in the mutant versus wild-type cybrids in cultures and tumors, the pathogenic mtDNA mutations seem to promote tumors by preventing apoptosis.

Minimal/measurable residual disease (MRD) monitoring is progressively changing the management of hematologic malignancies. The possibility of detecting the persistence/reappearance of disease in patients in apparent clinical remission offers a refined risk stratification and a treatment decision making tool. Several molecular techniques are employed to monitor MRD, from conventional real-time quantitative polymerase chain reaction (RQ-PCR) to next generation sequencing and digital droplet PCR (ddPCR), in different tissues or compartments through the detection of fusion genes, immunoglobulin and T-cell receptor gene rearrangements or disease-specific mutations. RQ-PCR is still the gold standard for MRD analysis despite some limitations. ddPCR, considered the third-generation PCR, yields a direct, absolute, and accurate detection and quantification of low-abundance nucleic acids. In the setting of MRD monitoring it carries the major advantage of not requiring a reference standard curve built with the diagnostic sample dilution and of allowing to reduce the number of samples below the quantitative range. At present, the broad use of ddPCR to monitor MRD in the clinical practice is limited by the lack of international guidelines. Its application within clinical trials is nonetheless progressively growing both in acute lymphoblastic leukemia as well as in chronic lymphocytic leukemia and non-Hodgkin lymphomas. The aim of this review is to summarize the accumulating data on the use of ddPCR for MRD monitoring in chronic lymphoid malignancies and to highlight how this new technique is likely to enter into the clinical practice.

This paper aims to test whether visual nudges help improving attention towards existing instructions to increase waste sorting accuracy. The study was conducted in a quasi-experimental setting over a period of 8 weeks in two buildings of a large UK university campus. Two treatments were tested against a control group: one considered the impact of visual nudges in the form of human eyes on recycling behaviour; the other one combined human eye with pre-existing sorting instructions. Results show that the combination of visual and information nudges decreased sorting errors by 7 percentage points. By contrast, visual nudges alone increased sorting error by 4.5 percentage points. These findings prove that, when combined, information and a visual nudge are cost-effective tools to improve sorting behaviour with strong efficacy, bringing new evidence to experiments based on neuroscientific theories. Behavioural Economics, Recycling, Neuroscience, Nudges

Cardiomyopathy is often fatal in Friedreich Ataxia (FA). However, the FA heart maintains adequate function until disease end stage, suggesting that it can initially adapt to the loss of frataxin (FXN). Conditional knockout mouse models with noFxnexpression show transcriptional and metabolic profiles of cardiomyopathy and mitochondrial integrated stress response (ISRmt). However, ISRmthas not been investigated in models with disease-relevant, partial decrease of FXN. We characterized the heart transcriptomes and metabolomes of three mouse models of partial FXN loss, YG8-800, KIKO-700, and FxnG127V. Few metabolites were significantly changed in YG8-800 mice and did not provide a signature of cardiomyopathy or ISRmt. Instead, several metabolites were altered in FxnG127Vand KIKO-700 hearts. Transcriptional changes were found in all models, but differentially expressed genes consistent with cardiomyopathy and ISRmtwere only identified in FxnG127Vhearts. However, these changes were surprisingly mild even at an advanced age (18-months), despite a severe decrease in FXN levels to 1% of WT. These findings indicate that the mouse heart has extremely low reliance on FXN, highlighting the difficulty in modeling genetically relevant FA cardiomyopathy.Summary statementThe mitochondrial integrated stress response in the heart of a Friedreich Ataxia mouse model is surprisingly mild, despite a severe decrease in frataxin levels below 1% of normal.

We consider the interaction dynamics of a classical oscillator and a quantum two-level system for different pure-dephasing Hamiltonians of the type $\widehat{H}(q,p)=H_C(q,p)\boldsymbol{1}+H_I(q,p)\widehat\sigma_z$. This type of systems represents a severe challenge for popular hybrid quantum-classical descriptions. For example, in the case of the common Ehrenfest model, the classical density evolution is shown to decouple entirely from the pure-dephasing quantum dynamics. We focus on a recently proposed hybrid wave equation that is based on Koopman's wavefunction description of classical mechanics. This model retains quantum-classical correlations whenever a coupling potential is present. Here, several benchmark problems are considered and the results are compared with those arising from fully quantum dynamics. A good agreement is found for a series of study cases involving harmonic oscillators with linear and quadratic coupling, as well as time-varying coupling parameters. In all these cases the classical evolution coincides exactly with the oscillator dynamics resulting from the fully quantum description. In the special case of time-independent coupling involving a classical oscillator with varying frequency, the quantum Bloch rotation exhibits peculiar features that escape from the hybrid description. In addition, nonlinear corrections to the harmonic Hamiltonian lead to an overall growth of decoherence at long times, which is absent in the fully quantum treatment., Comment: 24 pages, 10 figures. Contribution to the Special Collection "Koopman methods in classical and quantum-classical mechanics" in the Journal of Physics A

Disruption of sphingolipid homeostasis and signaling has been implicated in diabetes, cancer, cardiometabolic, and neurodegenerative disorders. Yet, mechanisms governing cellular sensing and regulation of sphingolipid homeostasis remain largely unknown. In yeast, serine palmitoyltransferase, catalyzing the first and rate-limiting step of sphingolipid de novo biosynthesis, is negatively regulated by Orm1 and 2. Lowering sphingolipids triggers Orms phosphorylation, upregulation of serine palmitoyltransferase activity and sphingolipid de novo biosynthesis. However, mammalian orthologs ORMDLs lack the N-terminus hosting the phosphosites. Thus, which sphingolipid(s) are sensed by the cells, and mechanisms of homeostasis remain largely unknown. Here, we identify sphingosine-1-phosphate (S1P) as key sphingolipid sensed by cells via S1PRs to maintain homeostasis. The increase in S1P-S1PR signaling stabilizes ORMDLs, restraining SPT activity. Mechanistically, the hydroxylation of ORMDLs at Pro137 allows a constitutive degradation of ORMDLs via ubiquitin-proteasome pathway, preserving SPT activity. Disrupting S1PR/ORMDL axis results in ceramide accrual, mitochondrial dysfunction, impaired signal transduction, all underlying endothelial dysfunction, early event in the onset of cardio- and cerebrovascular diseases. Our discovery may provide the molecular basis for therapeutic intervention restoring sphingolipid homeostasis.

Organic π-conjugated polymers are promising heterogeneous photocatalysts that involve photoredox or energy transfer processes. In such settings, the materials are usually applied in the form of dis...

ObjectiveAmyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease with limited therapeutic options. Diagnostic and surrogate endpoint biomarkers are needed for early disease detection, clinical trial design, and personalized medicine.MethodsWe tested the predictive power of a large set of primary skin fibroblast (n=443) from sporadic and familial ALS patients and healthy controls. We measured morphometric features of endoplasmic reticulum, mitochondria, and lysosomes by imaging with vital dyes. We also analysed immunofluorescence images of ALS-linked proteins, including TDP-43 and stress granule components. We studied fibroblasts under basal conditions and under metabolic (galactose medium), oxidative (arsenite), and heat stress conditions. We then employed machine learning (ML) techniques on the dataset to develop biomarkers.ResultsStress perturbations caused robust changes in the measured features, such as organellar morphology, stress granule formation, and TDP-43 mislocalization. ML approaches were able to predict the perturbation with near perfect performance (ROC-AUC > 0.99). However, when trying to predict disease state or disease groups (e.g., sporadic, or familial ALS), the performance of the ML algorithm was more modest (ROC-AUC Control vs ALS = 0.63). We also detected modest but significant scores when predicting clinical features, such as age of onset (ROC-AUC late vs early = 0.60).ConclusionsOur findings indicate that the ML morphometry we developed can accurately predict if human fibroblasts are under stress, but the differences between ALS and controls, while statistically significant, are small and pose a challenge for the development of biomarkers for clinical use by these approaches.

Retinal degeneration is one of the prevalent causes of blindness worldwide, for which no effective treatment has yet been identified. Inorganic photovoltaic devices have been investigated for visual restoration in advanced stage Retinitis pigmentosa (RP), although lack of implant flexibility and foreign-object reactions have limited their application. Organic photoactive retinal prostheses may overcome these limitations, being biomimetic and tissue friendly. Inspired by organic photovoltaic strategies involving graphene, a hybrid retinal prosthesis was recently engineered consisting of a dual poly-3-hexylthiophene (P3HT) and graphene layer onto a flexible substrate. Here, this hybrid prosthesis was subretinally implanted in vivo in 5-month-old Royal College of Surgeons (RCS) rats, a rodent model of RP. Implanted dystrophic rats restored visual performances at both subcortical and cortical levels in response to light stimuli, in the absence of marked inflammatory responses. Moreover, the analysis of the physical-mechanical properties after prolonged permanence in the eye showed excellent biocompatibility and robustness of the device. Overall, the results demonstrate that graphene-enhanced organic photovoltaic devices can be suitably employed for the rescue of retinal dystrophies and supports the translation of the organic strategy into the medical practice.TABLE OF CONTENTSInspired by organic photovoltaic, a hybrid retinal prosthesis consisting of poly-3-hexylthiophene (P3HT) and graphene on a flexible substrate was subretinally implanted in vivo in Royal College of Surgeons (RCS) rats, a model of Retinitis pigmentosa. Implanted dystrophic rats restored visual performances at both subcortical and cortical levels in response to light stimuli, in the absence of marked inflammatory responses.

Although the efficiency of organic polymer-based retinal devices has been proved, the interpretation of the working mechanisms that grant photostimulation at the polymer/neuron interface is still a matter of debate. To contribute solving this issue, we focus here on the characterization of the interface between poly(3-hexyltiophene) films and water by the combined use of electrochemistry and mathematical modeling. Simulations well reproduce the buildup of photovoltage (zero current condition) upon illumination of the working electrode made by a polymer film deposited onto an indium tin oxide (ITO) substrate. Due to the essential unipolar transport in the photoexcited film, diffusion leads to a space charge separation that is responsible for the initial photovoltage. Later, electron transfer reactions toward oxygen in the electrolyte extract negative charge from the polymer. In spite of the simple model studied, all of these considerations shed light on the possible coupling mechanisms between the polymeric device and the living cell, supporting the hypothesis of pseudocapacitive coupling.

The Doppler signature of a man walking in a forested area analysed at L‐band is presented here. The aim is twofold: to assess the best time‐frequency distribution to characterise the activity; to highlight the similarity of the simulated data to the measured ones to validate the simulation tool. Indeed, the Doppler‐Time (DT) signal variation represents the main characteristic of Artificial Neural Networks (ANNs) for classification. The more accurately the DT characterises the activity, the higher the machine’s accuracy in classifying it. Besides, in the training data frame, reliable simulated models may supply the amount of data needed by ANN applications. Thus, a short‐time Fourier transform (STFT), a reassigned spectrogram (RE‐Spect), and a pseudo‐Wigner–Ville distribution have been applied to the measured and simulated data. The measurements have been performed using a bistatic radar working at 1 GHz. Then, the measurement setup has been replicated in simulation, and 3‐D human bodies walking in free space have been computed using physical optics. The results show that the STFT is the most suitable time‐frequency method for recognising and classifying the walk. Moreover, the simulated data are in agreement with the measured data, regardless of the chosen Cohen’s technique.

ALS is a rapidly progressive, fatal disorder caused by motor neuron degeneration, for which there is a great unmet therapeutic need. AMX0035, a combination of sodium phenylbutyrate (PB) and taurursodiol (TUDCA, Turso), has shown promising results in early ALS clinical trials, but its mechanisms of action remain to be elucidated. To obtain an unbiased landscape of AMX0035 effects we investigated the transcriptomic and metabolomic profiles of primary skin fibroblasts from sporadic ALS patients and healthy controls treated with PB, TUDCA, or PB-TUDCA combination (Combo). Combo changed many more genes and metabolites than either PB or TUDCA individually. Most changes were unique to Combo and affected the expression of genes involved in ALS-relevant pathways, such as nucleocytoplasmic transport, unfolded protein response, mitochondrial function, RNA metabolism, and innate immunity. Weighted gene coexpression network analysis showed that significant correlations between ALS gene expression modules and clinical parameters were abolished by Combo. This study is the first to explore the molecular effects of Combo in ALS patient-derived cells. It shows that Combo has a greater and distinct impact compared to the individual compounds and provides clues to drug targets and mechanisms of actions, which may underlie the benefits of this investigational drug combination.

Mutations in the mitochondrial protein CHCHD2 cause autosomal-dominant PD characterized by the preferential loss of substantia nigra dopamine (DA) neurons. Therefore, understanding the function of CHCHD2 in neurons may provide vital insights into how mitochondrial dysfunction contributes to neurodegeneration in PD. To investigate the normal requirement and function of CHCHD2 in neurons, we first examined CHCHD2 levels, and showed that DA neurons have higher CHCHD2 levels than other neuron types, both in vivo and in co-culture. We then generated mice with either a targeted deletion of CHCHD2 in DA neurons, or a deletion in the brain or total body. All three models were viable, and loss of CHCHD2 in the brain did not cause degeneration of DA neurons. Mice lacking CHCHD2 in DA neurons did display sex-specific changes to locomotor activity, but we did not observe differences in assays of muscle strength, exercise endurance, or motor coordination. Furthermore, mitochondria derived from mice lacking CHCHD2 did not display abnormalities in OXPHOS function. Lastly, resilience to CHCHD2 deletion could not be explained by functional complementation by its paralog CHCHD10, as deletion of both CHCHD10 and CHCHD2 did not cause degeneration of DA neurons in the midbrain. These findings support the hypothesis that pathogenic CHCHD2 mutations cause PD through a toxic gain-of-function, rather than loss-of-function mechanism.

ALS (amyotrophic lateral sclerosis), the most common motor neuron disease, causes muscle denervation and rapidly fatal paralysis. While motor neurons are the most affected cells in ALS, studies on the pathophysiology of the disease have highlighted the importance of non-cell autonomous mechanisms, which implicate astrocytes and other glial cells. In ALS, subsets of reactive astrocytes lose their physiological functions and become toxic for motor neurons, thereby contributing to disease pathogenesis. Evidence of astrocyte contribution to disease pathogenesis are well established in cellular and animal models of familial ALS linked to mutant SOD1, where astrocytes promote motor neuron cell death. The mechanism underlying astrocytes reactivity in conditions of CNS injury have been shown to involve the MTOR pathway. However, the role of this conserved metabolic signaling pathway, and the potential therapeutic effects of its modulation, have not been investigated in ALS astrocytes. Here, we show elevated activation of the MTOR pathway in human-derived astrocytes harboring mutant SOD1, which results in inhibition of macroautophagy/autophagy, increased cell proliferation, and enhanced astrocyte reactivity. We demonstrate that MTOR pathway activation in mutant SOD1 astrocytes is due to post-transcriptional upregulation of the IGF1R (insulin like growth factor 1 receptor), an upstream positive modulator of the MTOR pathway. Importantly, inhibition of the IGF1R-MTOR pathway decreases cell proliferation and reactivity of mutant SOD1 astrocytes, and attenuates their toxicity to motor neurons. These results suggest that modulation of astrocytic IGF1R-MTOR pathway could be a viable therapeutic strategy in SOD1 ALS and potentially other neurological diseases.Abbreviations: ACM: astrocyte conditioned medium; AKT: AKT serine/threonine kinase; ALS: amyotrophic lateral sclerosis; BrdU: thymidine analog 5-bromo-2'-deoxyuridine; CNS: central nervous system; EIF4EBP1/4EBP1: eukaryotic translation initiation factor 4E binding protein 1; GFAP: glial fibrillary acidic protein; IGF1R: insulin like growth factor 1 receptor; INSR: insulin receptor; iPSA: iPSC-derived astrocytes; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta;MTOR: mechanistic target of rapamycin kinase; NES: nestin; PPK1: 3-phosphoinositide dependent protein kinase 1; PI: propidium iodide; PPP: picropodophyllotoxin; PTEN: phosphatase and tensin homolog; S100B/S100β: S100 calcium binding protein B; SLC1A3/ EAAT1: solute carrier family 1 member 3; SMI-32: antibody to nonphosphorylated NEFH; SOD1: superoxide dismutase 1; TUBB3: tubulin beta 3 class III; ULK1: unc-51 like autophagy activating kinase 1.

The gravitational force controls the evolution of the Universe on several scales. It is responsible for the formation of galaxies from the primordial matter distribution and the formation of planets from solar nebulae. Because the gravitational force is singular and has infinite range, making predictions based on fully three-dimensional models may be challenging. One-dimensional (1D) Newtonian gravity models were proposed as toy models for understanding the dynamics of gravitational systems. They can be integrated exactly and were used for computer simulations starting in the 1960s, providing the first demonstration of violent relaxation and the rapid development of long-lived quasi-stationary states (QSS). The present review provides the bases of the physics of 1D gravitational systems. It is divided into two main parts, the first concerning the approach to equilibrium and the second applications to cosmology. Each part is self-contained and can be read independently of the other. In the first part, we provide an introduction to the equilibrium thermodynamics of the one-dimensional gravitational sheet (OGS) system in the Vlasov limit. Both fixed and periodic boundary conditions are considered. The relaxation to equilibrium of the OGS is studied through numerical simulations which establish the role played by QSS and violent relaxation. We also survey existing work on the Lyapunov exponents of the OGS and on the chaotic dynamics of 1D systems with few particles, focusing on the 1D three-body problem. The second part summarizes work on dynamical structure formation in cosmology using 1D systems. By transforming to comoving coordinates, which follow the global expansion of the Universe, the 1D approach provides a useful laboratory for studying structure formation in various cosmological scenarios, from Einstein-de Sitter and ΛCDM to more recent, alternative cosmological models. A key result is the appearance of scale-free behavior with fractal dimension, which can be reliably studied in 1D for large systems over many epochs. Finally, an appendix gives some details on the numerical simulation methods used in these studies.

Tau (MAPT) drives neuronal dysfunction in Alzheimer disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize Tau interactomes modified by neuronal activity and mutations that cause frontotemporal dementia (FTD) in human induced pluripotent stem cell (iPSC)-derived neurons. We established interactions of Tau with presynaptic vesicle proteins during activity-dependent Tau secretion and mapped the Tau-binding sites to the cytosolic domains of integral synaptic vesicle proteins. We showed that FTD mutations impair bioenergetics and markedly diminished Tau's interaction with mitochondria proteins, which were downregulated inAD brains of multiple cohorts and correlated with disease severity. These multimodal and dynamic Tau interactomes with exquisite spatial resolution shed light on Tau's role in neuronal function and disease and highlight potential therapeutic targets to block Tau-mediated pathogenesis.

International audience; Transfer of angular momentum from helicity-controlled laser fields to a nonmagnetic electronic system can lead to the creation of magnetization. The underlying mechanism in metallic nanoparticles has been studied using different theoretical approaches. However, an understanding of the dynamics using an orbital-based quantum-mechanical method within the many-body theoretical framework is still due. To this end, the real-time formulation of time-dependent, density-functional theory is used to study induced orbital magnetism in metallic nanoparticles (clusters) excited by circularly polarized light. The nanoparticles are described by a spherical jellium model on a real-space grid. The polarized laser field gives rise to an angular momentum and, hence, a magnetic moment, which is maximum at the surface plasmon frequency of the nanoparticle, revealing that this is a resonant plasmonic effect. The primary contribution to the magnetic moment comes from surface currents generated by the plasmonic field, although some bulk contributions due to the quantum-mechanical nature of the system (Friedel oscillations) still persist. We compare several nanoparticles of K, Na, and Au having the same size and excited at their respective plasmon frequencies and show that the generated magnetic moment per energy pumped into the system is maximum for K and minimum for Au. A similar trend is observed for nanoparticles of the same chemical species but different sizes.

Graphene conductive properties have been long exploited in the field of organic photovoltaics and optoelectronics by the scientific community worldwide. We engineered and characterized a hybrid biointerface in which graphene is coupled with photosensitive polymers, and tested its ability to elicit lighttriggered neural activity modulation in primary neurons and blind retina explants. We designed such a graphene-based device by modifying a photoactive P3HT-based retinal interface, previously reported to rescue light sensitivity in blind rodents, with a CVD graphene layer replacing the conductive PEDOT:PSS layer to enhance charge separation. The new graphene-based device was characterized for its electrochemical features and for the ability to photostimulate primary neurons and blind retina explants, while preserving biocompatibility. Light-triggered responses, recorded by patch-clamp in vitro or MEA ex vivo, show a stronger light-transduction efficiency when the neurons are interfaced with the graphene-based device with respect to the PEDOT:PSS-based one. The possibility to ameliorate flexible photo-stimulating devices via the insertion of graphene, paves the way for potential biomedical applications of graphenebased neuronal interfaces in the context of retinal implants., Comment: 10 pages, 5 figures

Mixed states in patients with a perinatal mood episode is seldom encountered. Lack of appropriate assessment tools could be partly responsible for this observation. The authors conducted a selective review of studies dealing with the reporting of mixed symptoms in women during the perinatal period with the intention to quantify the phenomenon. In many instances of reported postpartum depression, either a first onset or an onset in the context of bipolar disorder, mixed states were identifiable. However, the strict application of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, mixed features specifier to these episodes risks misdiagnosis.

The concept of Logical Entropy, SL = 1-Σni=1 pi2, where the pi are normalized probabilities, was introduced by David Ellerman in a series of recent papers. Although the mathematical formula itself is not new, Ellerman provided a sound probabilistic interpretation of SL as a measure of the distinctions of a partition on a given set. The same formula comes across as a useful definition of entropy in quantum mechanics, where it is linked to the notion of purity of a quantum state. The quadratic form of the logical entropy lends itself to a generalization of the probabilities that include negative values, an idea that goes back to Feynman and Wigner. Here, we analyze and reinterpret negative probabilities in the light of the concept of logical entropy. Several intriguing quantum-like properties of the logical entropy are derived and discussed in finite dimensional spaces. For infinite-dimensional spaces (continuum), we show that, under the sole hypothesis that the logical entropy and the total probability are preserved in time, one obtains an evolution equation for the probability density that is basically identical to the quantum evolution of the Wigner function in phase space, at least when one considers only the momentum variable. This result suggest that the logical entropy plays a profound role in establishing the peculiar rules of quantum physics.

The GTPase OPA1 and the AAA-protease OMA1 serve well-established roles in mitochondrial stress responses and mitochondria-initiated cell death. In addition to its role in mitochondrial membrane fusion, cristae structure, and bioenergetic function, OPA1 controls apoptosis by sequestering cytochrome c (cyt c) in mitochondrial cristae. Cleavage of functional long OPA1 (L-OPA1) isoforms by OMA1 inactivates mitochondrial fusion and primes apoptosis. OPA1 cleavage is regulated by the prohibitin (PHB) complex, a heteromeric, ring-shaped mitochondrial inner membrane scaffolding complex composed of PHB1 and PHB2. In neurons, PHB plays a protective role against various stresses, and PHB deletion destabilizes OPA1 causing neurodegeneration. While deletion of OMA1 prevents OPA1 destabilization and attenuates neurodegeneration in PHB2 KO mice, how PHB levels regulate OMA1 is still unknown. Here, we investigate the effects of modulating neuronal PHB levels on OMA1 stability and OPA1 cleavage. We demonstrate that PHB promotes OMA1 turnover, effectively decreasing the pool of OMA1. Further, we show that OMA1 binds to cardiolipin (CL), a major mitochondrial phospholipid. CL binding promotes OMA1 turnover, as we show that deleting the CL-binding domain of OMA1 decreases its turnover rate. Since PHB is known to stabilize CL, these data suggest that PHB modulates OMA1 through CL. Furthermore, we show that PHB decreases cyt c release induced by tBID and attenuates caspase 9 activation in response to hypoxic stress in neurons. Taken together, our results suggest that PHB-mediated CL stabilization regulates stress responses and cell death through OMA1 turnover and cyt c release.

We propose to use a correlated noise bath to drive an optically trapped Brownian particle that mimics active biological matter. Thanks to the flexibility and precision of our setup, we are able to control the different parameters that drive the stochastic motion of the particle with unprecedented accuracy, thus reaching strongly correlated regimes that are not easily accessible with real active matter. In particular, by using the correlation time (i.e., the "color") of the noise as a control parameter, we can trigger transitions between two non-equilibrium steady states with no expended work, but only a calorific cost. Remarkably, the measured heat production is directly proportional to the spectral entropy of the correlated noise, in a fashion that is reminiscent of Landauer's principle. Our procedure can be viewed as a method for harvesting information from the active fluctuations., 5 pages, 4 figures, plus Appendix

Background: Majority of ALS cases are sporadic (sALS), as they lack defined genetic causes. Metabolic alterations shared between the nervous system and skin fibroblasts have emerged in ALS. Recently, we found that a subgroup of sALS fibroblasts (sALS1) is characterized by metabolic profiles (metabotype) distinct from other sALS cases (sALS2) and controls, suggesting that metabolic therapies could be effective in sALS. The metabolic modulators nicotinamide riboside and pterostilbene (EH301) are under clinical development for the treatment of ALS. Here, we studied the metabolome and transcriptome of sALS cells to understand the molecular bases of sALS metabotypes and the impact of EH301.Methods: Six fibroblast cell lines (3 male and 3 female subjects of similar ages) were used for each group (sALS1, sALS2, and controls). Metabolomics and transcriptomics were investigated at baseline and after EH301 treatment. Differential gene expression (DEGs) and metabolite abundance were assessed by a Wald Test and ANOVA, respectively, with FDR correction, and pathway analyses were performed. EH301 protection against metabolic stress was tested by thiol depletion. Weighted gene co-expression network analysis (WGCNA) was used to investigate the association of metabolic and clinical features and was also performed on the Answer ALS dataset from induced motor neurons (iMN). A machine learning model based on DEGs was tested as a sALS disease progression predictor. Results: We found that the sALS1 transcriptome is distinct from sALS2 and that EH301 modifies gene expression differently in sALS1, sALS2, and controls. Furthermore, EH301 had strong protective effects against metabolic stress, which is linked to anti-inflammatory and antioxidant pathways. WGCNA revealed that ALS functional rating scale and metabotypes are associated with gene modules enriched for cell cycle, immunity, autophagy, and metabolism terms, which are modified by EH301. Meta-analysis of publicly available transcriptomics data from iMNs confirmed functional associations of genes correlated with disease traits. A small subset of genes differentially expressed in sALS fibroblasts could be used in a machine learning model to predict disease progression.Conclusions: Multi-omics analyses of patient-derived fibroblasts highlighted differential metabolic and transcriptomic profiles in sALS metabotypes, which translate into differential responses to the investigational drug EH301.

Sphingolipids (SL) are both membrane building blocks and potent signaling molecules regulating a variety of cellular functions in both physiological and pathological conditions. Under normal physiology, sphingolipid levels are tightly regulated, whereas disruption of sphingolipid homeostasis and signaling has been implicated in diabetes, cancer, cardiovascular and autoimmune diseases. Yet, mechanisms governing cellular sensing of SL, and according regulation of their biosynthesis remain largely unknown.In yeast, serine palmitoyltransferase (SPT), catalyzing the first and rate limiting step of sphingolipid de novo biosynthesis, is negatively regulated by Orosomucoid 1 and 2 (Orm) proteins. Lowering sphingolipid levels triggers Orms phosphorylation, resulting in the removal of the inhibitory brake on SPT to enhance sphingolipid de novo biosynthesis. However, mammalian orthologs ORMDLs lack the N-terminus hosting the phosphosites. Thus, which sphingolipid(s) are sensed by the cells, and mechanisms of homeostasis remain largely unknown. This study is aimed at filling this knowledge gap.Here, we identify sphingosine-1-phosphate (S1P) as the key sphingolipid sensed by endothelial cells via S1PRs. The increase of S1P-S1PR signaling stabilizes ORMDLs, which downregulates SPT activity to maintain SL homeostasis. These findings reveal the S1PR/ORMDLs axis as the sensor-effector unit regulating SPT activity accordingly. Mechanistically, the hydroxylation of ORMDLs at Pro137 allows a constitutive degradation of ORMDLs via ubiquitin-proteasome pathway, therefore preserving SPT activity at steady state. The disruption of the S1PR/ORMDL axis results in ceramide accrual, mitochondrial dysfunction, and impaired signal transduction, all leading to endothelial dysfunction, which is an early event in the onset of cardio- and cerebrovascular diseases.The disruption of S1P-ORMDL-SPT signaling may be implicated in the pathogenesis of conditions such as diabetes, cancer, cardiometabolic disorders, and neurodegeneration, all characterized by deranged sphingolipid metabolism. Our discovery may provide the molecular basis for a therapeutic intervention to restore sphingolipid homeostasis.

Objectives During the lockdown that started in Italy on 10 March 2020 to address the COVID-19 pandemic, aggressive procedures were implemented to prevent SARS-CoV-2 transmission in SARS-CoV-2-negative patients with haematological malignancies. These efforts progressively reduced Klebsiella pneumonia carbapenemase-producing K. pneumoniae (KPC-KP) spread among these patients. Here we evaluated the potential effects of measures against COVID-19 that reduced KPC-KP transmission. Patients and methods We analysed KPC-KP spread among 123 patients with haematological malignancies, hospitalized between March and August 2020, who were managed using measures against COVID-19. Their outcomes were compared with those of 80 patients hospitalized during the preceding 4 months (November 2019–February 2020). Results During March–August 2020, 15.5% of hospitalized patients were KPC-KP positive, compared with 52.5% in November 2019–February 2020 (P Conclusions Aggressive strategies to prevent SARS-CoV-2 transmission were applied to all hospitalized patients, characterized by high levels of KPC-KP endemicity and nosocomial transmission. Such measures prevented SARS-CoV-2 infection acquisition and KPC-KP horizontal transmission. Reduced KPC-KP spread, fewer associated clinical complications and decreased ceftazidime/avibactam consumption represented unexpected ‘collateral benefits’ of strategies to prevent COVID-19.

In this article, we present a fast and accurate numerical method for the computation of scattered electromagnetic field from targets of different sizes and complex shapes. The approach is based on the sampling representation of the complex reflection coefficient of the target where both amplitude and phase information are considered, rather than the usual radar cross section (RCS) where the phase information is missed. The scattering features of the target are organized in a 5-D complex matrix H calculated numerically. The electromagnetic tool (CST) computes this H matrix evaluating the scattered field in a finite number of selected directions. This number is chosen in order to obtain a good reconstruction of overall scattering feature. As assumed for the scattered field, matrix H is also calculated for the same discrete set of directions of the incident wave. Two numerical examples are provided to demonstrate the correctness and the efficiency of the proposed method.

The spatial and temporal diversity provided by Sentinel-1 SAR images is used to detect archaeological structures. The temporal mean over a year suppresses speckle without reducing spatial resolution. The combined use of the ascending and descending orbits makes it possible to highlight man-made features.

The Doppler frequency signature and the cadence frequency of a couple of people moving simultaneously into the forest are presented in this paper. A brisk walk and a run have been analyzed in L-band. The results are based on measured data that have been collected by a bistatic radar working in continuous wave (CW). The purpose of the analysis is to assess the reliability of the short-time Fourier transform (STFT) and of the cadence frequency diagram to distinguish two physical activities performed simultaneously in a forested area and recorded at 1 GHz. Obstructing trees and small movements of the undergrowth largely impacted the spectrogram, making it difficult to interpret. Instead, the cadence frequency looks reliable for detecting the two activities and distinguishing them from the surrounding vegetation.

Background: Early-stage follicular lymphoma (FL) is usually managed with involved field radiotherapy (IFRT), allowing a complete and long lasting eradication of the disease only in 40-50% of patients (pts). The aim of this multicenter phase II prospective study was to evaluate the role of MRD in identifying pts unlikely to be cured by IFRT, for whom an immunotherapy consolidation could improve outcome. Methods: 110 pts with stage I/II FL were enrolled and treated with 24 Gy IFRT. Peripheral blood (PB) and bone marrow (BM) samples were centralized to the FIL (Fondazione Italiani Linfomi) MRD Network of EuroMRD-certified laboratories. In BCL2/IGH+ pts at baseline by both nested PCR (NEST) and RQ-PCR (RQ) in BM a/o PB, MRD was analyzed after IFRT and every 6 months over a 3-year period. Pts with MRD+ by both NEST and RQ in BM a/o PB after IFRT or who became MRD+ during the follow-up were treated with 8 weekly doses of the anti-CD20 MoAb ofatumumab (OFA). The primary objective of the study was to define the efficacy of immunotherapy in obtaining a negative MRD. Results: Of the 106 evaluable pts, 50 were males. Median age was 55 y (29-83). The FLIPI score was 0 in 59% of pts, 1 in 35%, 2 in 6%. 68% of pts had inguinal site involvement. At baseline, 30% of pts had a BCL2/IGH rearrangement (30 MBR, 1 MBR and mcr, 1 mcr) in BM a/ o PB;the concordance between compartments was 90%. All but one pt achieved a clinical response after IFRT;one additional pt died soon after IFRT of unrelated causes. MRD evaluation after IFRT revealed the persistence of BCL2/IGH+ cells in PB a/o BM in 60% of pts. MRD + pts, either after IFRT (n = 18) or in case of conversion to MRD+ during the follow-up (n = 6), received OFA, obtaining a conversion to MRD-in 22/24 pts (91.7%-CI 73.0-99.0), significantly superior to the expected 50% (Fig). After a median F-U of 38 m, 17 pts who achieved a MRD-with OFA are still negative;5 converted to MRD+ (2 received OFA retreatment, achieving a second MRD-;2 pts were not re-treated due to Sars-Cov2 pandemic;1 relapsed). A clinical relapse or progression was observed in 23 pts: 18 (24.6%) among the 73 “no marker” pts and 5 (15.6%) among the 32 BCL2/IGH+ at baseline (p = 0.3), with no significant difference in PFS (p = 0.25). Two early relapses were observed among the 12 pts who became MRD-after IFRT and 3 among the 24 treated at least once with OFA (1 MRD+, 1 MRD-, 1 converted from MRD-to MRD+). Only 1 Pt relapsed while MRD-after OFA. Conclusions: MRD data indicate that RT alone is often insufficient to eradicate the disease, inducing a MRD-only in 40% of pts, notably long-lasting only in half of them. The primary objective of this study-MRD conversion after immunotherapy-was largely achieved. The strategy of an immunotherapy consolidation after IFRT in MRD+ pts allowed increasing molecular responses. However, this strategy is applicable only to 30% of enrolled pts. A clinical advantage of the MRD driven treatment strategy is suggested although not significan.