TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9.

Toll-like receptors (TLRs) have a crucial role in the recognition of pathogens and initiation of immune responses1-3. Here we show that a previously uncharacterized protein encoded by CXorf21-a gene that is associated with systemic lupus erythematosus4,5-interacts with the endolysosomal transporter SLC15A4, an essential but poorly understood component of the endolysosomal TLR machinery also linked to autoimmune disease4,6-9. Loss of this type-I-interferon-inducible protein, which we refer to as 'TLR adaptor interacting with SLC15A4 on the lysosome' (TASL), abrogated responses to endolysosomal TLR agonists in both primary and transformed human immune cells. Deletion of SLC15A4 or TASL specifically impaired the activation of the IRF pathway without affecting NF-κB and MAPK signalling, which indicates that ligand recognition and TLR engagement in the endolysosome occurred normally. Extensive mutagenesis of TASL demonstrated that its localization and function relies on the interaction with SLC15A4. TASL contains a conserved pLxIS motif (in which p denotes a hydrophilic residue and x denotes any residue) that mediates the recruitment and activation of IRF5. This finding shows that TASL is an innate immune adaptor for TLR7, TLR8 and TLR9 signalling, revealing a clear mechanistic analogy with the IRF3 adaptors STING, MAVS and TRIF10,11. The identification of TASL as the component that links endolysosomal TLRs to the IRF5 transcription factor via SLC15A4 provides a mechanistic explanation for the involvement of these proteins in systemic lupus erythematosus12-14.

Multiscale design of ZnO nanostructured photocatalysts.

A systematic investigation of the photocatalytic activity (PCA) of nanostructured ZnO films showed how this is directly affected by the films' morphology at different scales, from the macroscale morphology of films (e.g. thickness and surface area), to the microscale feature arrangement (e.g. aligned vs. randomly oriented structures or interpenetrated ones), to the nanoscale structure (e.g. crystal size and orientation). The interest in immobilizing photocatalysts in water treatment stems from concerns about the potential toxicity of their slurry form, which requires expensive downstream removal. Immobilisation, though, leads to a reduction in PCA, generally attributed to a lower surface area. By reducing the films' feature size to the nanoscale, an immobilized photocatalyst with high surface area can be achieved. At this scale, however, feature structuring and morphology become important as they determine the interaction between light and the photocatalytic material. In this work, nanostructured ZnO films with different morphology, arrangement and structure were produced by electrochemical anodization of zinc and were tested using the degradation of phenol in a batch reactor as a model system. Results show that the PCA for immobilized catalysts can be optimised by controlling microscale arrangement (light absorbance capacity) and nanoscale structure (crystal size and orientation) rather than macroscale morphology (surface area). These results provide a clear direction to maximising the photocatalytic activity of immobilised photocatalysts for the removal of organic pollutants from water.

Plant-derived extracellular vesicles: a synergetic combination of a drug delivery system and a source of natural bioactive compounds.

Exosomes are extracellular nanovesicles secreted by all cell types and have been studied to understand and treat many human diseases. Exosomes are involved in numerous physiological and pathological processes, intercellular communication, and the transfer of substances. Over the years, several studies have explored mammalian-derived exosomes for therapeutic and diagnostic uses. Only recently have plant-derived extracellular vesicles (EVs) attracted attention for their ability to overcome many defects associated with using mammalian-derived extracellular vesicles, such as safety and scale-up issues. The ease of large-scale production, low toxicity, low immunogenicity, efficient cellular uptake, high biocompatibility, and high stability of these nanovesicles make them attractive for drug delivery systems. In addition, their native contents of proteins, miRNAs and secondary metabolites could be exploited for pharmaceutical applications in combination with other drugs. The present review intends to provide adequate tools for studying and developing drug delivery systems based on plant-derived EVs. Therefore, indications concerning extraction methods, characterisation, and drug loading will be offered. Their biological composition and content will also be reported. Finally, the current applications of these systems as nanocarriers for pharmacologically active substances will be shown.

Low Frequency Brain Oscillations during the execution and imagination of simple hand movements for Brain-Computer Interface applications.

Low Frequency Brain Oscillations (LFOs) are brief periods of oscillatory activity in delta and lower theta band that appear at motor cortical areas before and around movement onset. It has been shown that LFO power decreases in post-stroke patients and re-emerges with motor functional recovery. To date, LFOs have not yet been explored during the motor execution (ME) and imagination (MI) of simple hand movements, often used in BCI-supported motor rehabilitation protocols post-stroke. This study aims at analyzing the LFOs during the ME and MI of the finger extension task in a sample of 10 healthy subjects and 2 stroke patients in subacute phase. The results showed that LFO power peaks occur in the preparatory phase of both ME and MI tasks on the sensorimotor channels in healthy subjects and their alterations in stroke patients. Clinical Relevance- Results suggest that LFOs could be explored as biomarker of the motor function recovery in rehabilitative protocols based on the movement imagination.

Cortico-Muscular Coupling Allows to Discriminate Different Types of Hand Movements.

Cortico-muscular coupling (CMC) could be used as potential input of a novel hybrid Brain-Computer Interface (hBCI) for motor re-learning after stroke. Here, we aim of addressing the design of a hBCI able to classify different movement tasks taking into account the interplay between the cerebral and residual or recovered muscular activity involved in a given movement. Hence, we compared the performances of four classification methods based on CMC features to evaluate their ability in discriminating finger extension from grasping movements executed by 17 healthy subjects. We also explored how the variation in the dimensionality of the feature domain would influence the different classifier performances. Results showed that, regardless of the model, few CMC features (up to 10) allow for a successful classification of two different movements type. Moreover, support vector machine classifier with linear kernel showed the best trade-off between performances and system usability (few electrodes). Thus, these results suggest that a hBCI based on brain-muscular interplay holds the potential to enable more informed neural plasticity and functional motor recovery after stroke. Furthermore, this CMC-based BCI could also allow for a more "natural control" (l.e., that resembling physiological control) of prosthetic devices.

Distinctive physiological muscle synergy patterns define the Box and Block Task execution as revealed by electromyographic features.

Stroke survivors experience muscular pattern alterations of the upper limb that decrease their ability to perform daily-living activities. The Box and Block test (BBT) is widely used to assess the unilateral manual dexterity. Although BBT provides insights into functional performance, it returns limited information about the mechanisms contributing to the impaired movement. This study aims at exploring the BBT by means of muscle synergies analysis during the execution of BBT in a sample of 12 healthy participants with their dominant and non-dominant upper limb. Results revealed that: (i) the BBT can be described by 1 or 2 synergies; the number of synergies (ii) does not differ between dominant and non-dominant sides and (iii) varies considering each phase of the task; (iv) the transfer phase requires more synergies. Clinical Relevance- This preliminary study characterizes muscular synergies during the BBT task in order to establish normative patterns that could assist in understanding the neuromuscular demands and support future evaluations of stroke deficits.

Magnetic resonance imaging screening of cerebral thromboembolic events in children with acute lymphoblastic leukemia: a pilot study.

BACKGROUND: Thromboembolism is a complication of acute lymphoblastic leukemia therapy in children. The majority of thromboembolic events are cerebral thromboses and deep venous thromboses; many asymptomatic deep venous thromboses are detected in children with acute lymphoblastic leukemia by instrumental screening. The aim of this study was to assess the incidence of asymptomatic cerebral thromboembolic events in children with acute lymphoblastic leukemia (ALL) screened by magnetic resonance imaging and magnetic resonance venography. METHODS: 46 children with acute lymphoblastic leukemia, during the induction phase of the AIEOP ALL 2000 protocol, were stratified into 2 groups. In group "A" cerebral thromboembolic events were suspected following the appearance of suggestive signs and symptoms and confirmed by cerebral magnetic resonance imaging and magnetic resonance venography; in group "B" children underwent a screening by cerebral magnetic resonance imaging and magnetic resonance venography, at set times, in absence of symptoms. RESULTS: We observed one cerebral thromboembolic event in both groups; we found no differences between early detecting asymptomatic cerebral thromboembolic events among monitored and not monitored patients. CONCLUSIONS: Our study does not seem to suggest a screening for asymptomatic cerebral thromboembolic events in children with ALL during the induction phase.

Untangling the physics of water transport in boron nitride nanotubes.

Carbon nanotubes (CNTs) have long been heralded as the material of choice for next-generation membranes. Some studies have suggested that boron nitride nanotubes (BNNTs) may offer higher transport of pure water than CNTs, while others conclude otherwise. In this work, we use a combination of simulations and experimental data to uncover the causes of this discrepancy and investigate the flow resistance through BNNT membranes in detail. By dividing the resistance of the nanotube membranes into their contributing components, we study the effects of pore end configuration, membrane length, and BNNT atom partial charges. Most molecular simulation studies of BNNT membranes use short membranes connected to high and low pressure reservoirs. Here we find that flow resistances in these short membranes are dominated by the resistance at the pore ends, which can obscure the understanding of water transport performance through the nanotubes and comparison between different nanotube materials. In contrast, it is the flow resistance inside the nanotubes that dominates microscale-thick laboratory membranes, and end resistances tend to be negligible. Judged by the nanotube flow resistance alone, we therefore find that CNTs are likely to consistently outperform BNNTs. Furthermore, we find a large role played by the choice of partial charges on the BN atoms in the flow resistance measurements in our molecular simulations. This paper highlights a way forward for comparing molecular simulations and experimental results.

A guide to plasma membrane solute carrier proteins.

This review aims to serve as an introduction to the solute carrier proteins (SLC) superfamily of transporter proteins and their roles in human cells. The SLC superfamily currently includes 458 transport proteins in 65 families that carry a wide variety of substances across cellular membranes. While members of this superfamily are found throughout cellular organelles, this review focuses on transporters expressed at the plasma membrane. At the cell surface, SLC proteins may be viewed as gatekeepers of the cellular milieu, dynamically responding to different metabolic states. With altered metabolism being one of the hallmarks of cancer, we also briefly review the roles that surface SLC proteins play in the development and progression of cancer through their influence on regulating metabolism and environmental conditions.

Metabolic syndrome in primary aldosteronism and essential hypertension: relationship to adiponectin gene variants.

BACKGROUND AND AIMS: Evidence shows that aldosterone excess is crucial for the development of cardiac and metabolic complications. Among the possible pathogenetic elements of the metabolic syndrome, adiponectin and its polymorphisms seem to confer a genetic risk for metabolic alterations and type 2 diabetes. Aims of the study were to investigate whether metabolic syndrome represents a common feature in patients with primary aldosteronism (PA) compared with essential hypertensives (EH) and to study the impact of two common adiponectin gene variants on the parameters of metabolic syndrome. METHODS AND RESULTS: Metabolic syndrome was defined according to ATPIII criteria. Eighty-nine patients with PA and 164 matched EH were studied. In all patients with PA and in 135 EH two single nucleotide polymorphisms of the adiponectin gene, T45G and G276T, were detected. Patients with PA displayed a higher prevalence of metabolic syndrome compared with EH (45% vs. 30%, p<0.05). In patients with PA, genotypes 45T/G+G/G were associated with significantly lower values of waist circumference, HOMA-IR and serum aldosterone. In both PA patients and EH, the 276T/T genotype was associated with significantly worse metabolic profile and a higher risk for the metabolic syndrome (OR=1.5 for PA and OR=1.3 for EH). CONCLUSIONS: Our data confirm a higher prevalence of metabolic syndrome among patients with PA compared with matched EH. Genetic analysis of T45G and G276T adiponectin gene polymorphisms showed that, while the genotypes 45G/G+G/T seemed to have a protective role on the metabolic complications, the genotype 276T/T defined PA and EH patients with a worse metabolic profile.

Thyroid function and thyroid autoimmunity in childhood acute lymphoblastic leukemia off-therapy patients treated only with chemotherapy.

OBJECTIVE: Scanty data are available about the thyroid function in childhood acute lymphoblastic leukemia (ALL) off-therapy patients treated only with chemotherapy. We aimed to assess the prevalence of thyroid autoimmunity and thyroid dysfunction in such patients. DESIGN: Case-control cross-sectional study. METHODS: Eighty-four patients diagnosed with ALL and treated only with chemotherapy. Mean age at diagnosis 5.9+/-3.6 yr, at recruitment 12.1+/-4.3 yr. The treatment had been stopped 4.3+/-3.2 yr before recruitment. A control group of 60 subjects was recruited. Free T4, TSH, anti-thyroperoxidase, and anti-thyroglobulin antibodies were measured. RESULTS: Anti-thyroglobulin and anti-thyroperoxidase antibodies were negative in all patients. TSH was increased in 7 patients (8.3%) and 3 controls (5.0%). Free T4 was within the normal limits in all patients and controls.Mean TSH and free T4 levels did not statistically differ between controls and ALL offtherapy patients. TSH was negatively correlated with the age at the diagnosis (p=0.01) and the age at the end of therapy (p=0.008). Anti-thyroglobulin and/or anti-thyroperoxidase antibodies were detected in 3 controls (5%; vs study group: p=0.038), 1 of them with increased TSH. CONCLUSIONS: Some patients present hyperthyrotropinemia, without anti-thyroid antibodies, with a prevalence comparable to the control group. The thyroid gland seems more prone to be damaged by chemotherapy at a younger age. We think that a thyroid follow- up in ALL off-therapy patients may be advisable and should be differentiated on the basis of the age at the end of treatment, with more frequent tests for younger patients.

Targeted Degradation of SLC Transporters Reveals Amenability of Multi-Pass Transmembrane Proteins to Ligand-Induced Proteolysis.

With more than 450 members, the solute carrier (SLC) group of proteins represents the largest class of transporters encoded in the human genome. Their several-pass transmembrane domain structure and hydrophobicity contribute to the orphan status of many SLCs, devoid of known cargos or chemical inhibitors. We report that SLC proteins belonging to different families and subcellular compartments are amenable to induced degradation by heterobifunctional ligands. Engineering endogenous alleles via the degradation tag (dTAG) technology enabled chemical control of abundance of the transporter protein, SLC38A2. Moreover, we report the design of d9A-2, a chimeric compound engaging several members of the SLC9 family and leading to their degradation. d9A-2 impairs cellular pH homeostasis and promotes cell death in a range of cancer cell lines. These findings open the era of SLC-targeting chimeric degraders and demonstrate potential access of multi-pass transmembrane proteins of different subcellular localizations to the chemically exploitable degradation machinery.

Distribution of Mediastinal Lesions Across Multi-Institutional, International, Radiology Databases.

INTRODUCTION: Mediastinal lesions are uncommon; studies on their distribution are, in general, small and from a single institution. Furthermore, these studies are usually based on pathology or surgical databases and, therefore, miss many lesions that did not undergo biopsy or resection. Our aim was to identify the distribution of lesions in the mediastinum in a large international, multi-institutional cohort. METHODS: At each participating institution, a standardized retrospective radiology database search was performed for interpretations of computed tomography, positron emission tomography-computed tomography, and magnetic resonance imaging scans including any of the following terms: "mediastinal nodule," "mediastinal lesion," "mediastinal mass," or "mediastinal abnormality" (2011-2014). Standardized data were collected. Statistical analysis was performed. RESULTS: Among 3308 cases, thymomas (27.8%), benign mediastinal cysts (20.0%), and lymphomas (16.1%) were most common. The distribution of lesions varied among mediastinal compartments; thymomas (38.3%), benign cysts (16.8%), and neurogenic tumors (53.9%) were the most common lesions in the prevascular, visceral, and paravertebral mediastinum, respectively (p < 0.001). Mediastinal compartment was associated with age; patients with paravertebral lesions were the youngest (p < 0.0001). Mediastinal lesions differed by continent or country, with benign cysts being the most common mediastinal lesions in the People's Republic of China, thymomas in Europe, and lymphomas in North America and Israel (p < 0.001). Benign cysts, thymic carcinomas, and metastases were more often seen in larger hospitals, whereas lymphomas and thymic hyperplasia occurred more often in smaller hospitals (p < 0.01). CONCLUSIONS: Our study confirmed that the spectrum and frequency of mediastinal lesions depend on mediastinal compartment and age. This information provides helpful demographic data and is important when considering the differential diagnosis of a mediastinal lesion.

Growth hormone deficiency and antipituitary antibodies in a patient with common variable immunodeficiency.

Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and T-lymphocytes dysfunction. Autoimmune diseases are frequent. A 10.7-yr-old female, diagnosed with CVID when 7 yr old, was referred because of short stature. She was pre-pubertal and short (height -2.86 SD score) with delayed bone age. Her intestinal absorption, routine biochemistry, heart, renal, liver, and thyroid functions were normal. Two stimulation tests for GH showed a maximum peak of 1.9 ng/ml (IGF-1: 154 ng/ml, 147-832). When the patient was 13 yr old (height -4.23 SD score, telarche and pubarche stage 2, bone age 6.25 yr), GH treatment was initiated. Despite poor compliance, the growth velocity showed improvement. Anti-thyrogobulin, anti-thyroperoxidase, anti-21-hydroxylase, and anti-tyrosine-phosphate antibodies were negative while anti- pituitary antibodies (APA) were positive. For the first time, the presence of APA (previously associated with GH deficiency in non-CVID subjects) is reported in a CVID patient. The possibility of an autoimmune involvement of the pituitary gland was previously debated for CVID patients, but had never been demonstrated. This case suggests that in CVID, the pituitary gland can be targeted by autoantibodies and thus a more comprehensive follow-up of these patients should be performed.

The Optimal Setting for Multilayer Modularity Optimization in Multilayer Brain Networks.

Community detection plays a key role in the study of brain networks, as mechanisms of modular integration and segregation are known to characterize the brain functioning. Moreover, brain networks are intrinsically multilayer: they can vary across time, frequency, subjects, conditions, and meaning, according to different definitions of connectivity. Several algorithms for the multilayer community detection were defined to identify communities in time-varying networks. The most used one is based on the optimization of a multilayer formulation of the modularity, in which two parameters linked to the spatial (γ) and temporal (ω) resolution of the uncovered communities can be set. While the effect of different γ-values has been largely explored, which ω-values are most suitable to different purposes and conditions is still an open issue. In this work, we test the algorithm performances under different values of ω by means of ad hoc implemented benchmark graphs that cover a wide range of conditions. Results provide a guide to the choice of the ω-values according to the network features. Finally, we show an application of the algorithm to real functional brain networks estimated from electro-encephalographic (EEG) signals collected at rest with closed and open eyes. The application to real data agrees with the results of the simulation study and confirms the conclusion drawn from it.

Adaptive learning in the detection of Movement Related Cortical Potentials improves usability of associative Brain-Computer Interfaces.

Brain-computer interfaces have increasingly found applications in motor function recovery in stroke patients. In this context, it has been demonstrated that associative-BCI protocols, implemented by means the movement related cortical potentials (MRCPs), induce significant cortical plasticity. To date, no methods have been proposed to deal with brain signal (i.e. MRCP feature) non-stationarity. This study introduces adaptive learning methods in MRCP detection and aims at comparing a no-adaptive approach based on the Locality Sensitive Discriminant Analysis (LSDA) with three LSDA-based adaptive approaches. As a proof of concept, EEG and force data were collected from six healthy subjects while performing isometric ankle dorsiflexion. Results revealed that adaptive algorithms increase the number of true detections and decrease the number of false positives per minute. Moreover, the markedly reduction of BCI system calibration time suggests that these methods have the potential to improve the usability of associative-BCI in post-stroke motor recovery.

Metastases to the breast: role of fine needle cytology samples. Our experience with nine cases in 2 years.

BACKGROUND: The increased survival due to the introduction of effective antineoplastic regimens has caused a modification of the natural history of numerous malignancies. Follow-up of neoplastic patients often includes the evaluation of masses in various body sites by fine needle cytology (FNC) in order to rule out cancer recurrence. Besides primary neoplasms, the breast can host a number of metastases: these rarely do have a typical presentation, so FNC is requested for their cytomorphological assessment. PATIENTS AND METHODS: This report describes nine consecutive cases in which a cytopathological diagnosis of metastasis to the breast was carried out on FNC samples. RESULTS: Primary sites were identified on cytomorphological and immunocytochemical bases and were represented by the ovary (three cases), melanoma (two cases), endocervix (one case), endometrium (one case), lung (one case) and prostate (one case). CONCLUSION: The cytopathological diagnosis of metastatic neoplasms to the breast is not always straightforward, especially in the absence of a clinical history of cancer. The usage of improved cytopathological criteria combined with immunocytochemistry may be of great diagnostic help in the identification of breast metastases.

Tracking the time-varying cortical connectivity patterns by adaptive multivariate estimators.

The directed transfer function (DTF) and the partial directed coherence (PDC) are frequency-domain estimators that are able to describe interactions between cortical areas in terms of the concept of Granger causality. However, the classical estimation of these methods is based on the multivariate autoregressive modelling (MVAR) of time series, which requires the stationarity of the signals. In this way, transient pathways of information transfer remains hidden. The objective of this study is to test a time-varying multivariate method for the estimation of rapidly changing connectivity relationships between cortical areas of the human brain, based on DTF/PDC and on the use of adaptive MVAR modelling (AMVAR) and to apply it to a set of real high resolution EEG data. This approach will allow the observation of rapidly changing influences between the cortical areas during the execution of a task. The simulation results indicated that time-varying DTF and PDC are able to estimate correctly the imposed connectivity patterns under reasonable operative conditions of signal-to-noise ratio (SNR) ad number of trials. An SNR of five and a number of trials of at least 20 provide a good accuracy in the estimation. After testing the method by the simulation study, we provide an application to the cortical estimations obtained from high resolution EEG data recorded from a group of healthy subject during a combined foot-lips movement and present the time-varying connectivity patterns resulting from the application of both DTF and PDC. Two different cortical networks were detected with the proposed methods, one constant across the task and the other evolving during the preparation of the joint movement.

EEG source estimation accuracy in presence of simulated cortical lesions.

Methods to reconstruct the neuroelectrical activity in the brain source space can be used to improve the spatial resolution of scalp-recorded EEG and to estimate the locations of electrical sources in the brain. This procedure can improve the investigation of the functional organization of the human brain, exploiting the high temporal resolution of EEG to follow the temporal dynamics of information processing. As for today, the uncertainties about the effects of inhomogeneities due to brain lesions preclude the adoption of EEG functional mapping on patients with lesioned brain. The aim of this work is to quantify the accuracy of a distributed source localization method in recovering extended sources of activated cortex when cortical lesions of different dimensions are introduced in simulated data. For this purpose, EEG source-distributed activity estimated from real data was modified including silent lesion areas. Then, for each simulated lesion, forward and inverse calculations were carried out to localize the produced scalp activity and the reconstructed cortical activity. Finally, the error induced in the reconstruction by the presence of the lesion was computed and analyzed in relation to the number of electrodes and to the size of the simulated lesion. Results returned values of global error in the whole cortex and of error in the non-lesioned area which are strongly dependent on the number of recorded scalp sensors, as they increase when a lower spatial sampling is performed on the scalp (64 versus 32 EEG channels). For increasing spatial sampling frequencies, the accuracy of the source reconstruction improves and even the presence of small lesions induces significantly higher error levels with respect to the lesion-free condition.

Brain connectivity networks at the basis of human attention components: An EEG study.

The Attention Network Task (ANT) was developed to disentangle the three components of attention identified in the Posner's theoretical model (alerting, orienting and executive control) and to measure the corresponding behavioral efficiency. Several fMRI studies have already provided evidences on the anatomical separability and interdependency of these three networks, and EEG studies have also unveiled the associated brain rhythms. What is still missing is a characterization of the brain circuits subtending the attentional components in terms of directed relationships between the brain areas and their frequency content. Here, we want to exploit the high temporal resolution of the EEG, improving its spatial resolution by means of advanced source localization methods, and to integrate the resulting information by a directed connectivity analysis. The results showed in the present study demonstrate the possibility to associate a specific directed brain circuit to each attention component and to identify synthetic indices able to selectively describe their neurophysiological, spatial and spectral properties.