Josephson current through a molecular transistor in a dissipative environment

We study the Josephson coupling between two superconductors through a single correlated molecular level, including Coulomb interaction on the level and coupling to a bosonic environment. All calculations are done to the lowest, i.e., the fourth, order in the tunneling coupling and we find a suppression of the supercurrent due to the combined effect of the Coulomb interaction and the coupling to environmental degrees of freedom. Both analytic and numerical results are presented.Comment: 11 pages, 6 figures, to appear in Phys. Rev. B; v3: several misprints corrected - in particular, sign inconsistencies throughout the paper should be fixe

MUNDUS project : MUltimodal neuroprosthesis for daily upper limb support

Background: MUNDUS is an assistive framework for recovering direct interaction capability of severely motor impaired people based on arm reaching and hand functions. It aims at achieving personalization, modularity and maximization of the user’s direct involvement in assistive systems. To this, MUNDUS exploits any residual control of the end-user and can be adapted to the level of severity or to the progression of the disease allowing the user to voluntarily interact with the environment. MUNDUS target pathologies are high-level spinal cord injury (SCI) and neurodegenerative and genetic neuromuscular diseases, such as amyotrophic lateral sclerosis, Friedreich ataxia, and multiple sclerosis (MS). The system can be alternatively driven by residual voluntary muscular activation, head/eye motion, and brain signals. MUNDUS modularly combines an antigravity lightweight and non-cumbersome exoskeleton, closed-loop controlled Neuromuscular Electrical Stimulation for arm and hand motion, and potentially a motorized hand orthosis, for grasping interactive objects. Methods: The definition of the requirements and of the interaction tasks were designed by a focus group with experts and a questionnaire with 36 potential end-users. Five end-users (3 SCI and 2 MS) tested the system in the configuration suitable to their specific level of impairment. They performed two exemplary tasks: reaching different points in the working volume and drinking. Three experts evaluated over a 3-level score (from 0, unsuccessful, to 2, completely functional) the execution of each assisted sub-action. Results: The functionality of all modules has been successfully demonstrated. User’s intention was detected with a 100% success. Averaging all subjects and tasks, the minimum evaluation score obtained was 1.13 ± 0.99 for the release of the handle during the drinking task, whilst all the other sub-actions achieved a mean value above 1.6. All users, but one, subjectively perceived the usefulness of the assistance and could easily control the system. Donning time ranged from 6 to 65 minutes, scaled on the configuration complexity. Conclusions: The MUNDUS platform provides functional assistance to daily life activities; the modules integration depends on the user’s need, the functionality of the system have been demonstrated for all the possible configurations, and preliminary assessment of usability and acceptance is promising

Mutations in orthologous PETALOSA TOE-type genes cause dominant double-flower phenotype in phylogenetically distant eudicots

The double-flower phenotype has been selected by humans for its attractiveness in various plant species and it is of great commercial value for the ornamental market. In this paper we investigated the genetic determinant of the dominant double-flower trait in carnation, petunia and Rosa rugosa, identifying mutant alleles of TARGET OF EAT (TOE)-type genes characterized by a disruption of the miR172 target sequence and of the C-terminal portion of the encoded protein. Despite the phylogenetic distance between these eudicots, which diverged in the early Cretaceous, the orthologous genes carrying such mutations all belong to a single TOE-type subgroup, herein referred to as PETALOSA (PET). Homology searches allowed us to identify PET sequences in various other species. To confirm the results on naturally occurring mutations, we used CrispR-Cas9 to induce lesions within the miR172 target site of Nicotiana tabacum PET genes, and this resulted in the development of supernumerary petaloid structures. This study describes pet alleles in economically important ornamentals and provides evidence about the possibility of identifying and engineering PET genes to obtain the desirable double-flower trait in different plants

Dissociated Representations of Deceptive Intentions and Kinematic Adaptations in the Observer’s Motor System

Previous studies showed that observing deceptive actions modulates the activity of the observer's motor system. However, it is unclear whether this modulation reflects the coding of deceptive intentions or the mapping of the kinematic adaptations required to attain deceptive actions. Here, we used single-pulse transcranial magnetic stimulation to measure cortico-spinal excitability (CSE) from hand and forearm muscles while participants predicted the weight of cubes lifted by actors who received truthful information on the object weight and provided 1) truthful (truthful actions) or 2) deceptive (deceptive actions) cues to the observers or 3) who received fooling information and were asked to provide truthful cues (deceived actions). This way, we independently manipulated actor's intentions and kinematic adaptations. We found that, as compared to truthful action observation, CSE increased during observation of deceptive actions, but decreased during observation of deceived actions. Importantly, while the CSE enhancement in response to deceptive intentions lacked muscle specificity, perceiving kinematic alterations in the deceived condition affected CSE only for the hand muscle involved in kinematic adaptations to unexpected object weight. This suggests that actor's intentions and movement kinematics may be coded by the observer's motor system at different hierarchical levels of action representation

A detailed characterization of the hyperpolarization-activated "funny" current (If) in human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes with pacemaker activity

Properties of the funny current (If) have been studied in several animal and cellular models, but so far little is known concerning its properties in human pacemaker cells. This work provides a detailed characterization of If in human-induced pluripotent stem cell (iPSC)-derived pacemaker cardiomyocytes (pCMs), at different time points. Patch-clamp analysis showed that If density did not change during differentiation; however, after day 30, it activates at more negative potential and with slower time constants. These changes are accompanied by a slowing in beating rate. If displayed the voltage-dependent block by caesium and reversed (Erev) at-22mV, compatibly with the 3:1K+/Na+ permeability ratio. Lowering [Na+]o (30mM) shifted the Erev to-39mV without affecting conductance. Increasing [K+]o (30mM) shifted the Erev to-15mV with a fourfold increase in conductance. pCMs express mainly HCN4 and HCN1 together with the accessory subunits CAV3, KCR1, MiRP1, and SAP97 that contribute to the context-dependence of If. Autonomic agonists modulated the diastolic depolarization, and thus rate, of pCMs. The adrenergic agonist isoproterenol induced rate acceleration and a positive shift of If voltage-dependence (EC50 73.4nM). The muscarinic agonists had opposite effects (Carbachol EC50, 11,6nM). Carbachol effect was however small but it could be increased by pre-stimulation with isoproterenol, indicating low cAMP levels in pCMs. In conclusion, we demonstrated that pCMs display an If with the physiological properties expected by pacemaker cells and may thus represent a suitable model for studying human If-related sinus arrhythmias

Extravasated contrast volumetric assessment on computed tomography angiography in gastrointestinal bleeding: A useful predictor of positive angiographic findings

Background: Gastrointestinal bleeding (GIB) is a severe and potentially life-threatening condition, especially in cases of delayed treatment. Computed tomography angiography (CTA) plays a pivotal role in the early identification of upper and lower GIB and in the prompt treatment of the haemorrhage. Aim: To determine whether a volumetric estimation of the extravasated contrast at CTA in GIB may be a predictor of subsequent positive angiographic findings. Methods: In this retrospective single-centre study, 35 patients (22 men; median age 69 years; range 16-92 years) admitted to our institution for active GIB detected at CTA and further submitted to catheter angiography between January 2018 and February 2022 were enrolled. Twenty-three (65.7%) patients underwent endoscopy before CTA. Bleeding volumetry was evaluated in both arterial and venous phases via a semi-automated dedicated software. Bleeding rate was obtained from volume change between the two phases and standardised for unit time. Patients were divided into two groups, according to the angiographic signs and their concordance with CTA. Results: Upper bleeding accounted for 42.9% and lower GIB for 57.1%. Mean haemoglobin value at the admission was 7.7 g/dL. A concordance between positive CTA and direct angiographic bleeding signs was found in 19 (54.3%) cases. Despite no significant differences in terms of bleeding volume in the arterial phase (0.55 mL vs 0.33 mL, P = 0.35), a statistically significant volume increase in the venous phase was identified in the group of patients with positive angiography (2.06 mL vs 0.9 mL, P = 0.02). In the latter patient group, a significant increase in bleeding rate was also detected (2.18 mL/min vs 0.19 mL/min, P = 0.02). Conclusion: In GIB of any origin, extravasated contrast volumetric analysis at CTA could be a predictor of positive angiography and may help in avoiding further unnecessary procedures

Phase-contrast microtomography: are the tracers necessary for stem cell tracking in infarcted hearts?

Recent literature has identified innovative approaches of cellular therapy to generate new myocardium involving transcoronary and intramyocardial injection of cardiac progenitor cells (CPCs). One of the limiting factors in the overall interpretation of these preclinical results is the lack of reliable methods for 3D imaging and quantification of the injected cells and for the assessment of their fate within the myocardium. Here, for the first time to the authors' knowledge, we support by demonstrative experiments the hypothesis that phase-contrast microtomography (PhC-microCT) could offer an efficient 3D imaging approach to track the injected cells within the myocardium, without the need of any cell tracer. This deduction has been validated by several observations: i) a strong phase-contrast signal was observed in infarcted hearts injected with unlabeled cells; ii) the PhC-microCT 3D reconstructions of hearts injected with only vehicle saline solution and rhodamine particles, i.e. without CPCs, did not show any contrast; (iii) in the 3D PhC-microCT reconstructions of non infarcted hearts, injected with unlabeled CPCs, the contrast signal of the cells was present but differently distributed; and iv) the contrast signal of injected cells diminished over time apparently following the same timing of cell engraftment and differentiation, as confirmed in literature by histology and fluorescence analysis. The chance to avoid cell tracers is of paramount interest in determining the fate of transplanted stem cells because the quantification of the signal will not be any more dependent on injected dose, concentration of the tracer, cell proliferation and tracer uptake kinetics

Stress proteins in experimental nephrotoxicity: a ten year experience

Heat shock proteins and glucose­regulated proteins represent an extraordinary mechanism of defense induced in the kidney by chemicals or drugs and essential to survive. Here we resume our experience on the presence and regulation of stress proteins into acute and chronic nephrotoxic models in rodents and in vitro. In acute renal damage, induced in rats by a single injection of inorganic mercury, stress proteins enhanced in a dose-dependent manner to recover cytoskeleton and mitochondria and maintain nuclear activity. When we pre-treated mercury injected-rats with antioxidant melatonin or with bimoclomol, a stress proteins-coinducer, stress proteins expression was modulated together with tubular recovery. Similar data were obtained in ischemia-reperfusion in rats treated with stannous chloride, that provided cytoprotection stimulating heme oxygenase induction. During nephrotoxicity induced by administration of cyclosporine A at therapeutic dosage for 1-2 months, stress protein overexpression well correlated with oxidative and cell death, but decreased if we counteracted renal damage using antioxidants. In aluminium intoxication through drinking water for 3-6 months, we detected a time-dependent stress response in the rat kidney that was organ specific and different from the liver. In vitro studies on rat tubular proximal cells exposed to heavy metals demonstrated that stress protein expression was related to peculiar mechanisms of action of each metal. In conclusion, experimental studies on the renal chaperones can greatly contribute to understand their role, and agents able to modulate the stress response might be considered promising therapeutic tools to reduce nephrotoxicity

Artificial Intelligence in Lung Cancer Screening: The Future Is Now

Simple Summary Lung cancer is a widespread malignant tumour with a high mortality and morbidity rate and is frequently diagnosed in the middle and late stages when few therapies are available. Lung cancer screening allows an early-stage diagnosis and more effective therapies. Artificial intelligence (AI) plays a key role in lung cancer screening workflow for early diagnosis. Particularly, in low-dose computed tomography for screening programs, AI further reduces radiation dose maintaining an optimal image quality. AI also allows risk stratification and subsequent screening personalization. A computer-aided detection (CAD) system helps in lung nodule detection with a high sensibility, reducing imaging time interpretation. AI is additionally applied in nodule characterization (benign or malignant), using different approaches. This narrative review aims to provide an overall view of all possible AI applications in lung cancer screening.Abstract Lung cancer has one of the worst morbidity and fatality rates of any malignant tumour. Most lung cancers are discovered in the middle and late stages of the disease, when treatment choices are limited, and patients' survival rate is low. The aim of lung cancer screening is the identification of lung malignancies in the early stage of the disease, when more options for effective treatments are available, to improve the patients' outcomes. The desire to improve the efficacy and efficiency of clinical care continues to drive multiple innovations into practice for better patient management, and in this context, artificial intelligence (AI) plays a key role. AI may have a role in each process of the lung cancer screening workflow. First, in the acquisition of low-dose computed tomography for screening programs, AI-based reconstruction allows a further dose reduction, while still maintaining an optimal image quality. AI can help the personalization of screening programs through risk stratification based on the collection and analysis of a huge amount of imaging and clinical data. A computer-aided detection (CAD) system provides automatic detection of potential lung nodules with high sensitivity, working as a concurrent or second reader and reducing the time needed for image interpretation. Once a nodule has been detected, it should be characterized as benign or malignant. Two AI-based approaches are available to perform this task: the first one is represented by automatic segmentation with a consequent assessment of the lesion size, volume, and densitometric features; the second consists of segmentation first, followed by radiomic features extraction to characterize the whole abnormalities providing the so-called "virtual biopsy". This narrative review aims to provide an overview of all possible AI applications in lung cancer screening

Recombinant adeno associated viral (AAV) vector type 9 delivery of Ex1-Q138-mutant huntingtin in the rat striatum as a short-time model for in vivo studies in drug discovery

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by dyskinesia, cognitive impairment and emotional disturbances, presenting progressive neurodegeneration in the striatum and intracellular mutant Huntingtin (mHTT) aggregates in various areas of the brain. Recombinant Adeno Associated Viral (rAAV) vectors have been successfully used to transfer foreign genes to the brain of adult animals. In the present study we report a novel in vivo rat HD model obtained by stereotaxic injection of rAAV serotype2/9 containing Exon1-Q138 mHTT (Q138) and Exon1-Q17 wild type HTT (Q17; control), respectively in the right and in the left striatum, and expressed as C-terminal GFP fusions to facilitate detection of infected cells and aggregate production. Immunohistochemical analysis of brain slices from animals sacrificed twenty-one days after viral infection showed that Q138 injection resulted in robust formation of GFP-positive aggregates in the striatum, increased GFAP and microglial activation and neurodegeneration, with little evidence of any of these events in contralateral tissue infected with wild type (Q17) expressing construct. Differences in the relative metabolite concentrations (N-Acetyl Aspartate/Creatine and Myo-Inositol/Creatine) were observed by H1 MR Spectroscopy. By quantitative RT-PCR we also demonstrated that mHTT induced changes in the expression of genes previously shown to be altered in other rodent HD models. Importantly, administration of reference compounds previously shown to ameliorate the aggregation and neurodegeneration phenotypes in preclinical HD models was demonstrated to revert the mutant HTT-dependent effects in our model. In conclusion, the AAV2/9-Q138/Q17 exon 1 HTT stereotaxic injection represents a useful first-line in vivo preclinical model for studying the biology of mutant HTT exon 1 in the striatum and to provide early evidence of efficacy of therapeutic approaches