An algorithm based on immunotherapy discontinuation and liver biopsy spares corticosteroids in two thirds of cases of severe checkpoint inhibitor-induced liver injury.

BACKGROUND: There are few data on corticosteroids (CS)-sparing strategies for checkpoint inhibitor (ICI)-induced liver injury (ChILI). AIM: We aimed to assess the performance of a 2-step algorithm for severe ChILI, based on ICI temporary discontinuation (step-1) and, if lack of biochemical improvement, CS based on the degree of necroinflammation at biopsy (step-2). METHODS: Prospective study that included all subjects with grade 3/4 ChILI. Peripheral extended immunophenotyping was performed. Indication for CS: severe necroinflammation; mild or moderate necroinflammation with later biochemical worsening. RESULTS: From 111 subjects with increased transaminases (January 2020 to August 2023), 44 were diagnosed with grade 3 (N = 35) or grade 4 (N = 9) ChILI. Main reason for exclusion was alternative diagnosis. Lung cancer (13) and melanoma (12) were the most common malignancies. ICI: 23(52.3%) anti-PD1, 8(18.2%) anti-PD-L1, 3(6.8%) anti-CTLA-4, 10(22.7%) combined ICI. Liver injury pattern: hepatocellular (23,52.3%) mixed (12,27.3%) and cholestatic (9,20.5%). 14(32%) presented bilirubin >1.2 mg/dL. Overall, 30(68.2%) patients did not require CS: 22(50.0%) due to ICI discontinuation (step-1) and 8/22 (36.4%) based on the degree of necroinflammation (step-2). Biopsy mainly impacted on grade 3 ChILI, sparing CS in 8 out of 15 (53.3%) non-improvement patients after ICI discontinuation. CD8+ HLA-DR expression (p = 0.028), central memory (p = 0.046) were lower in CS-free managed subjects, but effector-memory cells (p = 0.002) were higher. Time to transaminases normalisation was shorter in those CS-free managed (overall: p < 0.001, grade 3: p < 0.001). Considering our results, a strategy based on ICI discontinuation and biopsy for grade 3 ChILI is proposed. CONCLUSIONS: An algorithm based on temporary immunotherapy discontinuation and biopsy allows CS avoidance in two thirds of cases of severe ChILI.

Exploratory analyses of treatment subgroup interaction by PD-L1 status and according to PD-L1 expression in the JAVELIN Bladder 100 trial.

PURPOSE: Post hoc analysis of the JAVELIN Bladder 100 trial of avelumab maintenance in locally advanced/metastatic urothelial carcinoma (la/mUC) to determine the interaction by programmed death ligand 1 (PD-L1) status for overall survival (OS), and additional analyses of survival per a different PD-L1 expression cutoff of ≥ 1% in tumor cells or immune cells (TC/IC). METHODS: JAVELIN Bladder 100 data were used for the analysis of the interaction by PD-L1 status (per cutoff used in the trial) for OS and, additionally, OS and progression-free survival (PFS) analyses per a different ≥ 1% TC/IC PD-L1 expression cutoff (Ventana SP263 assay). RESULTS: No significant interaction between treatment and PD-L1 status was observed for OS. Clinically meaningful and robust survival data were observed in favor of avelumab using the different ≥ 1% TC/IC PD-L1 expression cutoff. CONCLUSIONS: These results demonstrate the benefit of avelumab maintenance in la/mUC regardless of PD-L1 expression, consistent with approved labels.

Elucidating Mechanotransduction Processes During Magnetomechanical Neuromodulation Mediated by Magnetic Nanodiscs.

Purpose: Noninvasive cell-type-specific manipulation of neural signaling is critical in basic neuroscience research and in developing therapies for neurological disorders. Magnetic nanotechnologies have emerged as non-invasive neuromodulation approaches with high spatiotemporal control. We recently developed a wireless force-induced neurostimulation platform utilizing micro-sized magnetic discs (MDs) and low-intensity alternating magnetic fields (AMFs). When targeted to the cell membrane, MDs AMFs-triggered mechanoactuation enhances specific cell membrane receptors resulting in cell depolarization. Although promising, it is critical to understand the role of mechanical forces in magnetomechanical neuromodulation and their transduction to molecular signals for its optimization and future translation. Methods: MDs are fabricated using top-down lithography techniques, functionalized with polymers and antibodies, and characterized for their physical properties. Primary cortical neurons co-cultured with MDs and transmembrane protein chemical inhibitors are subjected to 20 s pulses of weak AMFs (18 mT, 6 Hz). Calcium cell activity is recorded during AMFs stimulation. Results: Neuronal activity in primary rat cortical neurons is evoked by the AMFs-triggered actuation of targeted MDs. Ion channel chemical inhibition suggests that magnetomechanical neuromodulation results from MDs actuation on Piezo1 and TRPC1 mechanosensitive ion channels. The actuation mechanisms depend on MDs size, with cell membrane stretch and stress caused by the MDs torque being the most dominant. Conclusions: Magnetomechanical neuromodulation represents a tremendous potential since it fulfills the requirements of negligible heating (ΔT < 0.1 °C) and weak AMFs (< 100 Hz), which are limiting factors in the development of therapies and the design of clinical equipment. Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-023-00786-8.

Evolución y pronóstico de la insuficiencia tricuspídea moderada-grave tras tromboendarterectomía pulmonar o angioplastia de arterias pulmonares / Outcome of moderate-severe tricuspid regurgitation after pulmonary endarterectomy or balloon pulmonary angioplasty

Introducción y objetivos: No está definido el abordaje de la insuficiencia tricuspídea (IT) funcional moderada-grave en los pacientes con hipertensión pulmonar tromboembólica crónica tras la tromboendarterectomía pulmonar (TEA) o angioplastia con balón de las arterias pulmonares (ABAP). El objetivo de este estudio es analizar la evolución y los predictores de IT residual tras el procedimiento, así como su impacto pronóstico. Métodos: Estudio observacional unicéntrico. Se incluyó a 72 pacientes sometidos a TEA y 20 que completaron el programa de ABAP con diagnóstico de hipertensión pulmonar tromboembólica crónica y presentaban IT moderada-grave antes del procedimiento intervencionista. Resultados: La prevalencia de IT moderada-grave tras el procedimiento fue del 29%, sin diferencias entre los tratados con TEA o ABAP (el 30,6 frente al 25%; p=0,78). En el grupo con IT persistente se hallaron mayores presión arterial pulmonar media (40,2± 1,9 frente a 28,5±1,3mmHg; p<0,001), resistencia vascular pulmonar (472 [347-710] frente a 282 [196-408] dyn·s/cm5; p <0,001) y área de la aurícula derecha (23,0 [21-31] frente a 16,0 [14,0-20,0]; p <0,001) tras el procedimiento comparado con el de pacientes con IT ausente-ligera. La resistencia vascular pulmonar> 400dyn.s/cm5 y el área de la aurícula derecha> 22 cm2 tras el procedimiento se asociaron de manera independiente con la persistencia de la IT, pero no se identificaron predictores antes de la intervención. La IT moderada-grave residual y la presión pulmonar media> 30mmHg se asociaron con mayor mortalidad en 3 años de seguimiento. Conclusiones: La IT moderada-grave residual posterior a TEA o ABAP se asoció con la persistencia de una mayor poscarga y un persistente remodelado desfavorable de las cámaras cardiacas derechas tras el procedimiento. La IT moderada-grave y la hipertensión pulmonar residual se asociaron con un peor pronóstico a 3 años. (AU)

Introduction and objectives: The management of persistent moderate-severe tricuspid regurgitation (TR) in patients with chronic thromboembolic pulmonary hypertension after treatment with pulmonary endarterectomy (PEA) or balloon pulmonary angioplasty (BPA) is not well defined. This study aimed to analyze the progression and predictors of significant persistent postintervention TR and its prognostic impact. Methods: This single-center observational study included 72 patients undergoing PEA and 20 who completed a BPA program with a previous diagnosis of chronic thromboembolic pulmonary hypertension and moderate-to-severe TR. Results: The postintervention prevalence of moderate-to-severe TR was 29%, with no difference between the PEA- or BPA-treated groups (30.6% vs 25% P=.78). Compared with patients with absent-mild postprocedure TR, those with persistent TR had higher mean pulmonary arterial pressure (40.2±1.9 vs 28.5±1.3mmHg P <.001), pulmonary vascular resistance (472 [347-710] vs 282 [196-408] dyn.s/cm5; P <.001), and right atrial area (23.0 [21-31] vs 16.0 [14.0-20.0] P <.001). The variables independently associated with persistent TR were pulmonary vascular resistance> 400 dyn.s/cm5 and postprocedure right atrial area> 22cm2. No preintervention predictors were identified. The variables associated with increased 3-year mortality were residual TR and mean pulmonary arterial pressure> 30mmHg. Conclusions: Residual moderate-to-severe TR following PEA-PBA was associated with persistently high afterload and unfavorable postintervention right chamber remodeling. Moderate-to-severe TR and residual pulmonary hypertension were associated with a worse 3-year prognosis. (AU)

Imagery in the entropic associative memory.

The Entropic Associative Memory is a novel declarative and distributed computational model of associative memory. The model is general, conceptually simple, and offers an alternative to models developed within the artificial neural networks paradigm. The memory uses a standard table as its medium, where the information is stored in an indeterminate form, and the entropy plays a functional and operation role. The memory register operation abstracts the input cue with the current memory content and is productive; memory recognition is performed through a logical test; and memory retrieval is constructive. The three operations can be performed in parallel using very few computing resources. In our previous work we explored the auto-associative properties of the memory and performed experiments to store, recognize and retrieve manuscript digits and letters with complete and incomplete cues, and also to recognize and learn phones, with satisfactory results. In such experiments a designated memory register was used to store all the objects of the same class, whereas in the present study we remove such restriction and use a single memory register to store all the objects in the domain. In this novel setting we explore the production of emerging objects and relations, such that cues are used not only to retrieve remembered objects, but also related and imaged objects, and to produce association chains. The present model supports the view that memory and classification are independent functions both conceptually and architecturally. The memory system can store images of the different modalities of perception and action, possibly multimodal, and offers a novel perspective on the imagery debate and computational models of declarative memory.

Outcome of moderate-severe tricuspid regurgitation after pulmonary endarterectomy or balloon pulmonary angioplasty.

INTRODUCTION AND OBJECTIVES: The management of persistent moderate-severe tricuspid regurgitation (TR) in patients with chronic thromboembolic pulmonary hypertension after treatment with pulmonary endarterectomy (PEA) or balloon pulmonary angioplasty (BPA) is not well defined. This study aimed to analyze the progression and predictors of significant persistent postintervention TR and its prognostic impact. METHODS: This single-center observational study included 72 patients undergoing PEA and 20 who completed a BPA program with a previous diagnosis of chronic thromboembolic pulmonary hypertension and moderate-to-severe TR. RESULTS: The postintervention prevalence of moderate-to-severe TR was 29%, with no difference between the PEA- or BPA-treated groups (30.6% vs 25% P=.78). Compared with patients with absent-mild postprocedure TR, those with persistent TR had higher mean pulmonary arterial pressure (40.2±1.9 vs 28.5±1.3mmHg P <.001), pulmonary vascular resistance (472 [347-710] vs 282 [196-408] dyn.s/cm5; P <.001), and right atrial area (23.0 [21-31] vs 16.0 [14.0-20.0] P <.001). The variables independently associated with persistent TR were pulmonary vascular resistance> 400 dyn.s/cm5 and postprocedure right atrial area> 22cm2. No preintervention predictors were identified. The variables associated with increased 3-year mortality were residual TR and mean pulmonary arterial pressure> 30mmHg. CONCLUSIONS: Residual moderate-to-severe TR following PEA-PBA was associated with persistently high afterload and unfavorable postintervention right chamber remodeling. Moderate-to-severe TR and residual pulmonary hypertension were associated with a worse 3-year prognosis.

A decision support system based on artificial intelligence and systems biology for the simulation of pancreatic cancer patient status.

Oncology treatments require continuous individual adjustment based on the measurement of multiple clinical parameters. Prediction tools exploiting the patterns present in the clinical data could be used to assist decision making and ease the burden associated to the interpretation of all these parameters. The goal of this study was to predict the evolution of patients with pancreatic cancer at their next visit using information routinely recorded in health records, providing a decision-support system for clinicians. We selected hematological variables as the visit's clinical outcomes, under the assumption that they can be predictive of the evolution of the patient. Multivariate models based on regression trees were generated to predict next-visit values for each of the clinical outcomes selected, based on the longitudinal clinical data as well as on molecular data sets streaming from in silico simulations of individual patient status at each visit. The models predict, with a mean prediction score (balanced accuracy) of 0.79, the evolution trends of eosinophils, leukocytes, monocytes, and platelets. Time span between visits and neutropenia were among the most common factors contributing to the predicted evolution. The inclusion of molecular variables from the systems-biology in silico simulations provided a molecular background for the observed variations in the selected outcome variables, mostly in relation to the regulation of hematopoiesis. In spite of its limitations, this study serves as a proof of concept for the application of next-visit prediction tools in real-world settings, even when available data sets are small.

Epidemiological trends and trajectories of MAFLD-associated hepatocellular carcinoma 2002-2033: the ITA.LI.CA database.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) represents a new inclusive definition of the whole spectrum of liver diseases associated to metabolic disorders. The main objective of this study was to compare patients with MAFLD and non-MAFLD with hepatocellular carcinoma (HCC) included in a nationally representative cohort. METHODS: We analysed 6882 consecutive patients with HCC enrolled from 2002 to 2019 by 23 Italian Liver Cancer centres to compare epidemiological and future trends in three subgroups: pure, single aetiology MAFLD (S-MAFLD); mixed aetiology MAFLD (metabolic and others, M-MAFLD); and non-MAFLD HCC. RESULTS: MAFLD was diagnosed in the majority of patients with HCC (68.4%). The proportion of both total MAFLD and S-MAFLD HCC significantly increased over time (from 50.4% and 3.6% in 2002-2003, to 77.3% and 28.9% in 2018-2019, respectively, p<0.001). In Italy S-MAFLD HCC is expected to overcome M-MAFLD HCC in about 6 years. Patients with S-MAFLD HCC were older, more frequently men and less frequently cirrhotic with clinically relevant portal hypertension and a surveillance-related diagnosis. They had more frequently large tumours and extrahepatic metastases. After weighting, and compared with patients with non-MAFLD, S-MAFLD and M-MAFLD HCC showed a significantly lower overall (p=0.026, p=0.004) and HCC-related (p<0.001, for both) risk of death. Patients with S-MAFLD HCC showed a significantly higher risk of non-HCC-related death (p=0.006). CONCLUSIONS: The prevalence of MAFLD HCC in Italy is rapidly increasing to cover the majority of patients with HCC. Despite a less favourable cancer stage at diagnosis, patients with MAFLD HCC have a lower risk of HCC-related death, suggesting reduced cancer aggressiveness.

Axicabtagene ciloleucel compared to tisagenlecleucel for the treatment of aggressive B-cell lymphoma.

Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-targeted chimeric antigen receptor (CAR) T cells approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We performed a retrospective study to evaluate safety and efficacy of axi-cel and tisa-cel outside the setting of a clinical trial. Data from consecutive patients with R/R LBCL who underwent apheresis for axi-cel or tisa-cel were retrospectively collected from 12 Spanish centers. A total of 307 patients underwent apheresis for axi-cel (n=152) and tisa-cel (n=155) from November 2018 to August 2021, of which 261 (85%) received a CAR T infusion (88% and 82%, respectively). Median time from apheresis to infusion was 41 days for axi-cel and 52 days for tisa-cel (P=0.006). None of the baseline characteristics were significantly different between both cohorts. Both cytokine release syndrome and neurologic events (NE) were more frequent in the axi-cel group (88% vs. 73%, P=0.003, and 42% vs. 16%, P<0.001, respectively). Infections in the first 6 months post-infusion were also more common in patients treated with axi-cel (38% vs. 25%, P=0.033). Non-relapse mortality was not significantly different between the axi-cel and tisa-cel groups (7% and 4%, respectively, P=0.298). With a median follow-up of 9.2 months, median PFS and OS were 5.9 and 3 months, and 13.9 and 11.2 months for axi-cel and tisa-cel, respectively. The 12-month PFS and OS for axi-cel and tisa-cel were 41% and 33% (P=0.195), 51% and 47% (P=0.191), respectively. Factors associated with lower OS in the multivariate analysis were increased lactate dehydrogenase, ECOG ≥2 and progressive disease before lymphodepletion. Safety and efficacy results in our real-world experience were comparable with those reported in the pivotal trials. Patients treated with axi-cel experienced more toxicity but similar non-relapse mortality compared with those receiving tisa-cel. Efficacy was not significantly different between both products.

Weighted entropic associative memory and phonetic learning.

The Entropic Associative Memory (EAM) holds declarative but distributed representations of remembered objects. These are characterized as functions from features to discrete values in an abstract amodal space. Memory objects are registered or remembered through a declarative operation; memory recognition is defined as a logical test and cues of objects not contained in the memory are rejected directly without search; and memory retrieval is a constructive operation. In its original formulation, the content of basic memory units or cells was either on or off, hence all stored objects had the same weight or strength. In the present weighted version (W-EAM) we introduce a basic learning mechanism to the effect that the values of the cells used in the representation of an object are reinforced by the memory register operation. As memory cells are shared by different representations, the corresponding associations are reinforced too. The memory system supports a second form of learning: the distributed representation generalizes and renders a large set of potential or latent units that can used for recognizing novel inputs, which can in turn be used for improving the performance of both the deep neural networks used for modelling perception and action, and of the memory operations. This process can be performed recurrently in open-ended fashion and can be used in long term learning. An experiment in the phonetic domain using the Mexican Spanish DIMEx100 Corpus was carried out. This corpus was collected in a controlled noise-free environment, and was transcribed manually by human trained phoneticians, but consists of a relatively small number of utterances. DIMEx100 was used to produced the initial state of the perceptual and motor modules, and for testing the performance of the memory system at such state. Then the incremental learning cycle was modelled using the Spanish CIEMPIESS Corpus, consisting of a very large number of noisy untagged speech utterances collected from radio and TV. The results support the viability of the Weighted Entropic Associative Memory for modelling cognitive processes, such as phonetic representation and learning, for the construction of applications, such as speech recognition and synthesis, and as a computational model of natural memory.

UltraButton: A Minimalist Touchless Multimodal Haptic Button.

We present UltraButton a minimalist touchless button including haptic, audio and visual feedback costing only $200. While current mid-air haptic devices can be too bulky and expensive (around $2 k) to be integrated into simple mid-air interfaces such as point and select, we show how a clever arrangement of 83 ultrasound transducers and a new modulation algorithm can produce compelling mid-air haptic feedback and parametric audio at a minimal cost. To validate our prototype, we compared its haptic output to a commercially-available mid-air haptic device through force balance measurements and user perceived strength ratings and found no significant differences. With the addition of 20 RGB LEDs, a proximity sensor and other off-the-shelf electronics, we then propose a complete solution for a simple multimodal touchless button interface. We tested this interface in a second experiment that investigated user gestures and their dependence on system parameters such as the haptic and visual activation times and heights above the device. Finally, we discuss new interactions and applications scenarios for UltraButtons.

Sclerosing mesenteritis due to Mycobacterium genavense infection: A case report.

RATIONALE: Since its first identification in the early 1990s, Mycobacterium genavense has been considered and opportunistic pathogen. It mainly causes gastrointestinal symptoms, but also disseminated infections in severely immunosuppressed patients. Sclerosing mesenteritis is a long-term complication with high morbidity and mortality. As it is a rare condition, there are no specific guidelines for its management. We report a challenging case of persistent M. genavense infection, and propose surgery as an alternative treatment strategy. PATIENT CONCERNS: A 38-year-old Caucasian man presented to the emergency room with fever, abdominal pain, and night sweats for 3 months. HIV screening revealed a previously unknown HIV-1 infection, with a CD4 cell count of 216 cell/µL and viral load of 361.000 copies/mL at diagnosis. A body CT-scan showed mild splenomegaly as well as mesenteric and retroperitoneal enlarged lymph nodes. Fine needle aspiration revealed the presence of acid-fast bacilli, but mycobacterial cultures were negative. In the second sample, 16S RNA sequencing yielded a diagnosis of M. genavense infection. Despite 2 years of corticosteroids and antimycobacterial treatment excluding rifampicin due to a severe cutaneous reaction, there was no clinical improvement and an increase in the mesenteric lymph node size was observed, with a sclerosing transformation of the mesentery. A surgical approach was proposed to release small bowel loops and to remove fibrin. A second surgery was required due to an acute peritonitis ought to yeyunal segmental isquemia and perforation. Finally, the patient evolved favorably, and antimycobacterial drugs were suspended without relapse. LESSONS: Despite a prolonged multidrug strategy, some patients develop persistent M. genavense infection. Once sclerosing mesenteritis is established, clinicians have few treatment options. Surgery should be considered in patients with sclerosing mesenteritis or bowel obstruction. The combination of medical and surgical treatment could be a potential cure for these patients.

Entropic associative memory for manuscript symbols.

Manuscript symbols can be stored, recognized and retrieved from an entropic digital memory that is associative and distributed but yet declarative; memory retrieval is a constructive operation, memory cues to objects not contained in the memory are rejected directly without search, and memory operations can be performed through parallel computations. Manuscript symbols, both letters and numerals, are represented in Associative Memory Registers that have an associated entropy. The memory recognition operation obeys an entropy trade-off between precision and recall, and the entropy level impacts on the quality of the objects recovered through the memory retrieval operation. The present proposal is contrasted in several dimensions with neural networks models of associative memory. We discuss the operational characteristics of the entropic associative memory for retrieving objects with both complete and incomplete information, such as severe occlusions. The experiments reported in this paper add evidence on the potential of this framework for developing practical applications and computational models of natural memory.

GECOP-MMC: phase IV randomized clinical trial to evaluate the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) with mytomicin-C after complete surgical cytoreduction in patients with colon cancer peritoneal metastases.

BACKGROUND: The French PRODIGE 7 trial, published on January 2021, has raised doubts about the specific survival benefit provided by HIPEC with oxaliplatin 460 mg/m2 (30 minutes) for the treatment of peritoneal metastases from colorectal cancer. However, several methodological flaws have been identified in PRODIGE 7, specially the HIPEC protocol or the choice of overall survival as the main endpoint, so its results have not been assumed as definitive, emphasizing the need for further research on HIPEC. It seems that the HIPEC protocol with high-dose mytomicin-C (35 mg/m2) is the preferred regime to evaluate in future clinical studies. METHODS: GECOP-MMC is a prospective, open-label, randomized, multicenter phase IV clinical trial that aims to evaluate the effectiveness of HIPEC with high-dose mytomicin-C in preventing the development of peritoneal recurrence in patients with limited peritoneal metastasis from colon cancer (not rectal), after complete surgical cytoreduction. This study will be performed in 31 Spanish HIPEC centres, starting in March 2022. Additional international recruiting centres are under consideration. Two hundred sixteen patients with PCI ≤ 20, in which complete cytoreduction (CCS 0) has been obtained, will be randomized intraoperatively to arm 1 (with HIPEC) or arm 2 (without HIPEC). We will stratified randomization by surgical PCI (1-10; 11-15; 16-20). Patients in both arms will be treated with personalized systemic chemotherapy. Primary endpoint is peritoneal recurrence-free survival at 3 years. An ancillary study will evaluate the correlation between surgical and pathological PCI, comparing their respective prognostic values. DISCUSSION: HIPEC with high-dose mytomicin-C, in patients with limited (PCI ≤ 20) and completely resected (CCS 0) peritoneal metastases, is assumed to reduce the expected risk of peritoneal recurrence from 50 to 30% at 3 years. TRIAL REGISTRATION: EudraCT number: 2019-004679-37; Clinicaltrials.gov: NCT05250648 (registration date 02/22/2022, ).

Magneto Twister: Magneto Deformation of the Water-Air Interface by a Superhydrophobic Magnetic Nanoparticle Layer.

Remote manipulation of superhydrophobic surfaces provides fascinating features in water interface-related applications. A superhydrophobic magnetic nanoparticle colloid layer is able to float on the water-air interface and form a stable water-solid-air interface due to its inherent water repulsion, buoyancy, and lateral capillarity properties. Moreover, it easily bends downward under an externally applied gradient magnetic field. Thanks to that, the layer creates a stable twister-like structure with a flipped conical shape, under controlled water levels, behaving as a soft and elastic material that proportionally deforms with the applied magnetic field and then goes back to its initial state in the absence of an external force. When the tip of the twister structure touches the bottom of the water container, it provides a stable magneto movable system, which has many applications in the microfluidic field. We introduce, as a proof-of-principle, three possible implementations of this structure in real scenarios, the cargo and transport of water droplets in aqueous media, the generation of magneto controllable plugs in open surface channels, and the removal of floating microplastics from the air-water interface.

Wireless Force-Inducing Neuronal Stimulation Mediated by High Magnetic Moment Microdiscs.

Noninvasive manipulation of cell signaling is critical in basic neuroscience research and in developing therapies for neurological disorders and psychiatric conditions. Here, the wireless force-induced stimulation of primary neuronal circuits through mechanotransduction mediated by magnetic microdiscs (MMDs) under applied low-intensity and low-frequency alternating magnetic fields (AMFs), is described. MMDs are fabricated by top-down lithography techniques that allow for cost-effective mass production of biocompatible MMDs with high saturation and zero magnetic magnetic moment at remanence. MMDs are utilized as transducers of AMFs into mechanical forces. When MMDs are exposed to primary rat neuronal circuits, their magneto-mechanical actuation triggers the response of specific mechanosensitive ion channels expressed on the cell membranes activating ≈50% of hippocampal and ≈90% of cortical neurons subjected to the treatment. Mechanotransduction is confirmed by the inhibition of mechanosensitive transmembrane channels with Gd3+ . Mechanotransduction mediated by MMDs cause no cytotoxic effect to neuronal cultures. This technology fulfills the requirements of cell-type specificity and weak magnetic fields, two limiting factors in the development of noninvasive neuromodulation therapies and clinical equipment design. Moreover, high efficiency and long-lasting stimulations are successfully achieved. This research represents a fundamental step forward for magneto-mechanical control of neural activity using disc-shaped micromaterials with tailored magnetic properties.

Antihyperglycemic activity of crude extract and isolation of phenolic compounds with antioxidant activity from Moringa oleifera Lam. leaves grown in Southern Brazil.

The antihyperglicemic activity of crude extract from Moringa oleifera leaves and isolation of phenolic compounds with antioxidant activity using bioguided assay were employed by the first time in leaves cultivated in Brazil. The hydroalcoholic extract (HE) was produced by using ethanol:water (80:20 v/v) and purified by solid-liquid procedure using solvents in ascending order of polarity. The ethyl acetate fraction (Fr-EtOAc) presented high antioxidant potential and it was purified using chromatographic techniques rendering isolated compounds that were identified from the spectral data. The HE extract (500 mg kg-1) was adimistrated in diabetic rats induced by streptozotocin and chemical markers and lipid peroxidation in liver and kidney were evaluated. The Fr-EtOAc showed high antioxidant potential by FRAP reduction method (1678 µmol Fe2+ g-1), DPPH and ABTS scavenging methods (526.7 and 671.5 µmol TEAC g-1 respectively) and ORAC assay (3560.6 µmol TEAC g-1). Therefore, the Fr-EtOAc was purified and yielded three bioactive subfractions (S-12, S-13 abd S-15) that were rechromatoghaphed in HPLC-SemiPrep. After that, two main bioactive glycosylated flavonoids (isoquercitrin and astragalin) and phenolic acid (3-O-caffeoylquinic acid) were obtained. Additionally, the HE extract provided protection against oxidative damage in liver and kidney of diabetic rats ameliorating endogenous antioxidant defenses by increase catalase (CAT), glutathione S-transferase (GST) and non-protein thiol groups (NPSH) levels as well as decreased the lipid peroxidation in these tissues. Our results indicate that three phenolic compounds with high antioxidant activity were isolated and, the chemical composition of HE crude extract, rich in flavonoids glycosylated could be intimately related to antihyperglycemic action. So, it is possible to suggest that these compounds may be used as chemical biomarkers for this plant in Brazil, ensuring quality and supporting the use of aerial parts in tradicional medicine.

An entropic associative memory.

Natural memories are associative, declarative and distributed, and memory retrieval is a constructive operation. In addition, cues of objects that are not contained in the memory are rejected directly. Symbolic computing memories resemble natural memories in their declarative character, and information can be stored and recovered explicitly; however, they are reproductive rather than constructive, and lack the associative and distributed properties. Sub-symbolic memories developed within the connectionist or artificial neural networks paradigm are associative and distributed, but lack the declarative property, the capability of rejecting objects that are not included in the memory, and memory retrieval is also reproductive. In this paper we present a memory model that sustains the five properties of natural memories. We use Relational-Indeterminate Computing to model associative memory registers that hold distributed representations of individual objects. This mode of computing has an intrinsic computing entropy which measures the indeterminacy of representations. This parameter determines the operational characteristics of the memory. Associative registers are embedded in an architecture that maps concrete images expressed in modality specific buffers into abstract representations and vice versa. The framework has been used to model a visual memory holding the representations of hand-written digits. The system has been tested with a set of memory recognition and retrieval experiments with complete and severely occluded images. The results show that there is a range of entropy values, not too low and not too high, in which associative memory registers have a satisfactory performance. The experiments were implemented in a simulation using a standard computer with a GPU, but a parallel architecture may be built where the memory operations would take a very reduced number of computing steps.

Feeling of Safety and Comfort towards a Socially Assistive Unmanned Aerial Vehicle That Monitors People in a Virtual Home.

Unmanned aerial vehicles (UAVs) represent a new model of social robots for home care of dependent persons. In this regard, this article introduces a study on people's feeling of safety and comfort while watching the monitoring trajectory of a quadrotor dedicated to determining their condition. Three main parameters are evaluated: the relative monitoring altitude, the monitoring velocity and the shape of the monitoring path around the person (ellipsoidal or circular). For this purpose, a new trajectory generator based on a state machine, which is successfully implemented and simulated in MATLAB/Simulink®, is described. The study is carried out with 37 participants using a virtual reality (VR) platform based on two modules, UAV simulator and VR Visualiser, both communicating through the MQTT protocol. The participants' preferences have been a high relative monitoring altitude, a high monitoring velocity and a circular path. These choices are a starting point for the design of trustworthy socially assistive UAVs flying in real homes.