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Cell fate is largely determined by interactions that occur at the interface between cells and their surrounding microenvironment. For this reason, especially in the field of tissue‐engineering, there is a growing interest in developing techniques that allow evaluating cell–material interaction at the nanoscale, particularly focusing on cell adhesion processes. While for 2D culturing systems a consolidated series of tools already satisfy this need, in 3D environments, more closely recapitulating complex in vivo structures, there is still a lack of procedures furthering the comprehension of cell–material interactions. Here, the use of scanning electron microscopy coupled with a focused ion beam (SEM/FIB) for the characterization of cell interactions with 3D scaffolds obtained by different fabrication techniques is reported for the first time. The results clearly show the capability of the developed approach to preserve and finely resolve scaffold–cell interfaces highlighting details such as plasma membrane arrangement, extracellular matrix architecture and composition, and cellular structures playing a role in cell adhesion to the surface. It is anticipated that the developed approach will be relevant for the design of efficient cell‐instructive platforms in the study of cellular guidance strategies for tissue‐engineering applications as well as for in vitro 3D models. The application of ultrathin plasticization combined with FIB/SEM for cells cultured in 3D environments is shown. The developed approach, that allows investigating cell–cell and cell–material interaction, is described comparing different substrates. The established methodology allows for a deeper characterization of cell interactions with a wide range of architectures, therefore proving a powerful tool for a variety of applications. [ABSTRACT FROM AUTHOR]

• Hazelnut tree is highly susceptible to vapor pressure deficit. • Stomatal conductance early indicators of plant stress, easy to measure, efficient. • Stomatal conductance as an indicator of water stress compared with water potential. • North and west canopy aspects detected as best side to measure leaf conductance. • Methodological importance for the future design of experimental plans. Corylus avellana L. is a species highly susceptible to water stresses caused by vapor pressure deficit and high temperature. Under such conditions, transpiration is strongly constrained even with good soil water availability. This is due to ineffective drought resistance mechanisms and indicates the need to identify early indicators of plant stress that are easy to measure, effective and efficient. This research explored the possibility of using stomatal conductance and leaf water potentials as early indicators of stress. For this purpose, an experiment was set up in a commercial 5-year-old Corylus avellana L. var. 'McDonald' orchard located in Willamette valley. The experimental designed featured irrigated and rainfed trees, and potential stress indicators were monitored at different times of the day in canopy sections aligned to cardinal directions. Results show that hazelnut trees rapidly reduced leaf stomatal conductance when the vapor pressure deficit increased to 2 and 2.5 kPa during the diurnal cycle in both irrigated and rainfed trees, even with good water availability. This suggests leaf stomatal conductance can be an efficient and effective early indicator of stress. In addition, results suggest that stomatal conductance should be measured on leaves on the west and north aspects of the canopy, where they showed lowest and highest values respectively. Leaf and stem water potential values increased during the measurement period and show a strong correlation, but their mean values do not show statistically significant differences between treatments. In Willamette valley conditions, stomatal conductance provided earlier indication of stress than water potential. The results obtained are of methodological importance for the future design of experimental plans. [ABSTRACT FROM AUTHOR]

Recent studies reported increased plasma glial acidic fibrillary protein (GFAP) levels in amyotrophic lateral sclerosis (ALS) patients compared to controls. We expanded these findings in a larger cohort, including 156 ALS patients and 48 controls, and investigated the associations of plasma GFAP with clinical variables and other biofluid biomarkers. Plasma GFAP and Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers were assessed by the single molecule array and the Lumipulse platforms, respectively. In ALS patients, plasma GFAP was higher than in controls (p < 0.001) and associated with measures of cognitive decline. Twenty ALS patients (12.8%) showed a positive amyloid status (A+), of which nine also exhibited tau pathology (A+T+, namely ALS-AD). ALS-AD patients showed higher plasma GFAP than A− ALS participants (p < 0.001) and controls (p < 0.001), whereas the comparison between A− ALS and controls missed statistical significance (p = 0.07). Plasma GFAP distinguished ALS-AD subjects more accurately (area under the curve (AUC) 0.932 ± 0.027) than plasma p-tau181 (AUC 0.692 ± 0.058, p < 0.0001) and plasma neurofilament light chain protein (AUC, 0.548 ± 0.088, p < 0.0001). Cognitive measures differed between ALS-AD and other ALS patients. AD co-pathology deeply affects plasma GFAP values in ALS patients. Plasma GFAP is an accurate biomarker for identifying AD co-pathology in ALS, which can influence the cognitive phenotype. [ABSTRACT FROM AUTHOR]

Neuromorphic systems that display synaptic conditioning based on biochemical signaling activity have recently been introduced in the form of artificial synapses that are model devices to develop tissue‐interfaced platforms. In this regard, biohybrid synapses promise adaptive neuron‐integrated functions. However, these systems suffer from both molecular cross‐talk as biological neural circuits signal transmission typically involves more than one neuromodulator, and unstable electronics wirings as complex architectures are required to interface the tissues. Moreover, whilst novel spiking circuits can work as artificial neurons, they only recreate the biological electrical signaling pathway while electrochemical signal transduction is required for inter‐neuron communication. As such, artificial chemically‐mediated synapses are essential to perform memory/learning computing functions. Herein, an electrochemical neuromorphic organic device (ENODe) working as an artificial synapse that overcomes electrochemical and readout interferences while it emulates two neurotransmitters synaptic weight modulation and their recycling machinery at the synaptic cleft is shown. Neuronal short‐ and long‐term plasticity are replicated by transducing two separate neurotransmitter‐mediated chemical signals into reversible and nonreversible variations of PEDOT:PSS conductance. By exploiting the electrochromic properties of PEDOT:PSS, an alternative optical monitoring strategy is introduced which promises stable multidevice readout from complex bio‐hybrid interfaces. The platform emulates high‐order biological processes such as intrinsic forgetting, memory consolidation, and neurotransmitter co‐modulation. These brain‐inspired functionalities herald the development of tissue‐integrated neuromorphic systems that combine spiking (electrical neurons) and nonspiking (electrochemical synapses) elements, thus envisioning prosthetic bridges for neural engineering and regenerative medicine. [ABSTRACT FROM AUTHOR]

Conductive 3D platforms have gained increasing attention in bioelectronics thanks to the improvement in the cell-chip coupling. PEDOT:PSS is nowadays widely employed in bioelectronic applications thanks to its electrical and mechanical properties. In this work, an innovative fabrication method for the realization of PEDOT:PSS-based conductive micropillars and 3D cage-like structures is presented, combining two-photon lithography and electrodeposition techniques. [ABSTRACT FROM AUTHOR]

Traditional bioelectronics, primarily comprised of nonliving synthetic materials, lack cellular behaviors such as adaptability and motility. This shortcoming results in mechanically invasive devices and nonnatural signal transduction across cells and tissues. Moreover, resolving heterocellular electrical communication in vivo is extremely limited due to the invasiveness of traditional interconnected electrical probes. In this paper, we present a cell-silicon hybrid that integrates native cellular behavior (e.g., gap junction formation and biosignal processing) with nongenetically enabled photosensitivity. This hybrid configuration allows interconnect-free cellular modulation with subcellular spatial resolution for bioelectric studies. Specifically, we hybridize cardiac myofibroblasts with silicon nanowires and use these engineered hybrids to synchronize the electrical activity of cardiomyocytes, studying heterocellular bioelectric coupling in vitro. Thereafter, we inject the engineered myofibroblasts into heart tissues and show their ability to seamlessly integrate into contractile tissues in vivo. Finally, we apply local photostimulation with high cell specificity to tackle a long-standing debate regarding the existence of myofibroblast-cardiomyocyte electrical coupling in vivo. [ABSTRACT FROM AUTHOR]

Three-dimensional nanostructures are becoming the standard tools for interfacing cells with biosensors and other devices. A morphology that develops in three dimensions leads to the engulfment of the nanostructures by the cell, reducing the cleft and largely improving the cell/material coupling and sealing. The recording of action potentials from electrogenic cells, as well as biomolecular sensing of generic biological samples, can benefit from 3D nano-objects due to the improved bio-interface. In this context, we present here a novel fabrication technique for producing 3D vertical nanostructures that can be tuned both in material composition and shape, being thus suitable for a large variety of applications, from SERS spectroscopy and microfluidics to intracellular recording. The technique is based on focus ion beam milling and gold electrodeposition. This combination allows to fabricate coaxial-like nanocylinders with a metallic core and an insulating shell. Moreover, the metallic core can be structured as a hollow donut to act as nano-channel, or as a bulky head to increase the contact surface. The nanostructure coupling with cells is evaluated by fluorescence imaging, SERS spectroscopy and FIB/SEM cross-section imaging of HL-1 cardiac cells cultured on the devices. [ABSTRACT FROM AUTHOR]

Chordoid meningioma is a rare variant of meningioma characterized by a more aggressive behavior. The present study documents the histological, radiological and clinical features of seven cases treated at the Policlinico Umberto I of Rome from 1999 to 2010. There were five males and two females. Most of the cases were located in the supratentorial space, especially the convexity. Surgical gross total resection was achieved in four cases. Of the remaining three cases, two relapsed and underwent further surgeries and adjuvant treatment. The MIB-1 index had a mean value of 7.5 (range 0.3–25.8). Tumors were composed of epithelioid cells or plump to spindle cells, forming cords, cribriforms or nests, in a mucoid matrix. All tumors showed diffuse positive immunoreactivity to vimentin and epithelial membrane antigen. Surgery is the first line of treatment for this kind of lesion. Gross total resection guaranteed a survival free from recurrences in our series. On the other hand, radiation therapy must be considered in patients submitted to a subtotal resection. [ABSTRACT FROM AUTHOR]

The article describes the case of a 66-year-old who presented with a history of confusion and disorientation, left upper limb weakness and left lateral homonymous hemianopsia. According to a spectroscopy study, the lesion was suggestive for a high-grade glioma. The patient discontinued taking dexamethasone and another magnetic resonance imaging (MRI) was conducted.

In recent years, there has been a growing interest in exploring the non-classical symptoms of multiple sclerosis (MS), with a particular focus on cognitive impairments associated with the disease's progression. These cognitive symptoms are now recognized as crucial elements in the assessment of disease activity. In this context, neurophysiology has emerged as a valuable and accessible tool for studying and addressing cognitive decline in individuals with MS. This scoping literature review investigates the role of neurophysiology in assessing and treating cognitive impairment in MS patients. The review focuses on Electroencephalography (EEG), Non-Invasive Brain Stimulation (NIBS), and magnetoencephalography (MEG) to assess cognitive decline in MS patients. Moreover, we discuss all the papers that tried to treat this cognitive impairment with NIBS techniques. While several neurophysiological markers show potential, standardization of protocols is essential for enhancing the reliability and consistency of these approaches. Further research is warranted to explore other NIBS techniques and deepen our understanding of the neurophysiological underpinnings of cognitive deficits in MS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Contact sites between the endoplasmic reticulum (ER) and plasma membrane (PM) play a crucial role in governing calcium regulation and lipid homeostasis. Despite their significance, the factors regulating their spatial distribution on the PM remain elusive. Inspired by observations in cardiomyocytes, where ER-PM contact sites concentrate on tubular PM invaginations known as transverse tubules, we hypothesize that PM curvature plays a role in ER-PM contact formation. Through precise control of PM invaginations, we show that PM curvatures locally induce the formation of ER-PM contacts in cardiomyocytes. Intriguingly, the junctophilin family of ER-PM tethering proteins, specifically expressed in excitable cells, is the key player in this process, whereas the ubiquitously expressed extended synaptotagmin-2 does not show a preference for PM curvature. At the mechanistic level, we find that the low-complexity region (LCR) and membrane occupation and recognition nexus (MORN) motifs of junctophilins can bind independently to the PM, but both the LCR and MORN motifs are required for targeting PM curvatures. By examining the junctophilin interactome, we identify a family of curvature-sensing proteins-Eps15 homology domain-containing proteins-that interact with the MORN&#95;LCR motifs and facilitate the preferential tethering of junctophilins to curved PM. These findings highlight the pivotal role of PM curvature in the formation of ER-PM contacts in cardiomyocytes and unveil a mechanism for the spatial regulation of ER-PM contacts through PM curvature modulation., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The development of organic artificial synapses that exhibit biomimicry features also may enable a more seamless integration of neuroelectronic devices in the nervous system, allowing artificial neuromodulation to be perceived as natural behavior by neuronal cells. Nevertheless, the capability to interact with both electroactive and non-electroactive neurotransmitters remains a challenge since state-of-the-art devices mainly rely on the oxidation of electroactive species. Here, the study proposes an organic artificial synapse engineered to enable interaction with non-electroactive species present in the central nervous system. By integrating a conductive polymeric film functionalized with platinum nanoparticles, the device can catalyze the oxidation of electroactive molecules (i.e., H 2 O 2 ) resulting from neurotransmitter-specific enzymatic reactions following an enzymatic functionalization, therefore exhibiting neuromorphic functions driven by non-electroactive neurotransmitters. The creation of devices that can interact with or monitor these neurotransmitters can be seen as a significant step toward innovative technologies to expand the understanding of the mechanisms underlying neurological disorders and the development of novel, more effective treatments for them., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

Significant challenges have emerged in the development of biomimetic electronic interfaces capable of dynamic interaction with living organisms and biological systems, including neurons, muscles, and sensory organs. Yet, there remains a need for interfaces that can function on demand, facilitating communication and biorecognition with living cells in bioelectronic systems. In this study, the design and engineering of a responsive and conductive material with cell-instructive properties, allowing for the modification of its topography through light irradiation, resulting in the formation of "pop-up structures", is presented. A deformable substrate, composed of a bilayer comprising a light-responsive, azobenzene-containing polymer, pDR1m, and a conductive polymer, PEDOT:PSS, is fabricated and characterized. Moreover, the successful formation of supported lipid bilayers (SLBs) and the maintenance of integrity while deforming the pDR1m/PEDOT:PSS films represent promising advancements for future applications in responsive bioelectronics and neuroelectronic interfaces., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) is an autoimmune disease characterized by suboptimal recovery from attacks and long-term disability. Experimental data suggest that AQP4 antibodies can disrupt neuroplasticity, a fundamental driver of brain recovery. A well-established method to assess brain LTP is through intermittent theta-burst stimulation (iTBS). This study aimed to explore neuroplasticity in AQP4-NMOSD patients by examining long-term potentiation (LTP) through iTBS. We conducted a proof-of-principle study including 8 patients with AQP4-NMOSD, 8 patients with multiple sclerosis (MS), and 8 healthy controls (HC) in which iTBS was administered to induce LTP-like effects. iTBS-induced LTP exhibited significant differences among the 3 groups (p: 0.006). Notably, AQP4-NMOSD patients demonstrated impaired plasticity compared to both HC (p = 0.01) and pwMS (p = 0.02). This pilot study provides the first in vivo evidence supporting impaired neuroplasticity in AQP4-NMOSD patients. Impaired cortical plasticity may hinder recovery following attacks suggesting a need for targeted rehabilitation strategies., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a discrete nosological entity characterized by punctate and curvilinear gadolinium enhancement "peppering" the pons and a strong response to steroids. MRI images typically show pontine and cerebellar punctate-enhancing lesions, which occasionally spread up to the juxtacortical areas and down to the spinal cord. Interestingly, the more distant the lesion is from the pons, the less intense they become. Herein, we describe an extremely rare case of CLIPPERS presenting with predominant spinal cord involvement; then, we searched in the literature the available cases with a similar presentation. Our case focuses attention on a rare MRI CLIPPERS presentation. Since CLIPPERS has a dramatic response to corticosteroid treatment, it is fundamental to promptly recognize its MRI pattern to start treatment as soon as possible., (© 2024. Fondazione Società Italiana di Neurologia.)

The development of biomaterials capable of regulating cellular processes and guiding cell fate decisions has broad implications in tissue engineering, regenerative medicine, and cell-based assays for drug development and disease modeling. Recent studies have shown that three-dimensional (3D) nanoscale physical cues such as nanotopography can modulate various cellular processes like adhesion and endocytosis by inducing nanoscale curvature on the plasma and nuclear membranes. Two-dimensional (2D) biochemical cues such as protein micropatterns can also regulate cell function and fate by controlling cellular geometries. Development of biomaterials with precise control over nanoscale physical and biochemical cues can significantly influence programming cell function and fate. In this study, we utilized a laser-assisted micropatterning technique to manipulate the 2D architectures of cells on 3D nanopillar platforms. We performed a comprehensive analysis of cellular and nuclear morphology and deformation on both nanopillar and flat substrates. Our findings demonstrate the precise engineering of single cell architectures through 2D micropatterning on nanopillar platforms. We show that the coupling between the nuclear and cell shape is disrupted on nanopillar surfaces compared to flat surfaces. Furthermore, our results suggest that cell elongation on nanopillars enhances nanopillar-induced endocytosis. We believe our platform serves as a versatile tool for further explorations into programming cell function and fate through combined physical cues that create nanoscale curvature on cell membranes and biochemical cues that control the geometry of the cell.

Neurohybrid systems have gained large attention for their potential as in vitro and in vivo platform to interrogate and modulate the activity of cells and tissue within nervous system. In this scenario organic neuromorphic devices have been engineered as bioelectronic platforms to resemble characteristic neuronal functions. However, aiming to a functional communication with neuronal cells, material synthesis, and surface engineering can yet be exploited for optimizing bio-recognition processes at the neuromorphic-neuronal hybrid interface. In this work, artificial neuronal-inspired lipid bilayers have been assembled on an electrochemical neuromorphic organic device (ENODe) to resemble post-synaptic structural and functional features of living synapses. Here, synaptic conditioning has been achieved by introducing two neurotransmitter-mediated biochemical signals, to induce an irreversible change in the device conductance thus achieving Pavlovian associative learning. This new class of in vitro devices can be further exploited for assembling hybrid neuronal networks and potentially for in vivo integration within living neuronal tissues., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Contact sites between the endoplasmic reticulum (ER) and the plasma membrane (PM) play a crucial role in governing calcium regulation and lipid homeostasis. Despite their significance, the factors regulating their spatial distribution on the PM remain elusive. Inspired by observations in cardiomyocytes, where ER-PM contact sites concentrate on tubular PM invaginations known as transverse tubules (T-tubules), we hypothesize that the PM curvature plays a role in ER-PM contact formation. Through precise control of PM invaginations, we show that PM curvatures locally induce the formation of ER-PM contacts in cardiomyocytes. Intriguingly, the junctophilin family of ER-PM tethering proteins, specifically expressed in excitable cells, is the key player in this process, while the ubiquitously expressed extended synaptotagmin 2 does not show a preference for PM curvature. At the mechanistic level, we find that the low complexity region (LCR) and the MORN motifs of junctophilins can independently bind to the PM, but both the LCR and MORN motifs are required for targeting PM curvatures. By examining the junctophilin interactome, we identify a family of curvature-sensing proteins, Eps15-homology domain containing proteins (EHDs), that interact with the MORN&#95;LCR motifs and facilitate junctophilins' preferential tethering to curved PM. These findings highlight the pivotal role of PM curvature in the formation of ER-PM contacts in cardiomyocytes and unveil a novel mechanism for the spatial regulation of ER-PM contacts through PM curvature modulation.

Organic neuromorphic platforms have recently received growing interest for the implementation and integration of artificial and hybrid neuronal networks. Here, achieving closed-loop and learning/training processes as in the human brain is still a major challenge especially exploiting time-dependent biosignalling such as neurotransmitter release. Here, we present an integrated organic platform capable of cooperating with standard silicon technologies, to achieve brain-inspired computing via adaptive synaptic potentiation and depression, in a closed-loop fashion. The microfabricated platform could be interfaced and control a robotic hand which ultimately was able to learn the grasping of differently sized objects, autonomously.

Signal communication mechanisms within the human body rely on the transmission and modulation of action potentials. Replicating the interdependent functions of receptors, neurons and synapses with organic artificial neurons and biohybrid synapses is an essential first step towards merging neuromorphic circuits and biological systems, crucial for computing at the biological interface. However, most organic neuromorphic systems are based on simple circuits which exhibit limited adaptability to both external and internal biological cues, and are restricted to emulate only specific the functions of an individual neuron/synapse. Here, we present a modular neuromorphic system which combines organic spiking neurons and biohybrid synapses to replicate a neural pathway. The spiking neuron mimics the sensory coding function of afferent neurons from light stimuli, while the neuromodulatory activity of interneurons is emulated by neurotransmitters-mediated biohybrid synapses. Combining these functions, we create a modular connection between multiple neurons to establish a pre-processing retinal pathway primitive., (© 2024. The Author(s).)

Realizing the full potential of organoids and assembloids to model neural development and disease will require improved methods for long-term, minimally invasive recording of electrical activity. Current technologies, such as patch clamp, penetrating microelectrodes, planar electrode arrays and substrate-attached flexible electrodes, do not allow chronic recording of organoids in suspension, which is necessary to preserve architecture. Inspired by kirigami art, we developed flexible electronics that transition from a two-dimensional to a three-dimensional basket-like configuration with either spiral or honeycomb patterns to accommodate the long-term culture of organoids in suspension. Here we show that this platform, named kirigami electronics (KiriE), integrates with and enables chronic recording of cortical organoids for up to 120 days while preserving their morphology, cytoarchitecture and cell composition. We demonstrate integration of KiriE with optogenetic and pharmacological manipulation and modeling phenotypes related to a genetic disease. Moreover, KiriE can capture corticostriatal connectivity in assembloids following optogenetic stimulation. Thus, KiriE will enable investigation of disease and activity patterns underlying nervous system assembly., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

tACS (transcranial alternating current stimulation) is a technique for modulating brain activity through electrical current. Its effects depend on cortical entrainment, which is most effective when transcranial alternating current stimulation matches the brain's natural rhythm. High-frequency oscillations produced by external stimuli are useful for studying the somatosensory pathway. Our study aims to explore transcranial alternating current stimulation's impact on the somatosensory system when synchronized with individual high-frequency oscillation frequencies. We conducted a randomized, sham-controlled study with 14 healthy participants. The study had three phases: Individualized transcranial alternating current stimulation (matching the individual's high-frequency oscillation rhythm), Standard transcranial alternating current stimulation (600 Hz), and sham stimulation. We measured early and late HFO components after median nerve electrical stimulation at three time points: before (T0), immediately after (T1), and 10 min after transcranial alternating current stimulation (T2). Compared to Sham and Standard stimulation Individualized transcranial alternating current stimulation significantly enhanced high-frequency oscillations, especially the early component, immediately after stimulation and for at least 15 min. No other effects were observed for other high-frequency oscillation measures. In summary, our study provides initial evidence that transcranial alternating current stimulation synchronized with an individual's high-frequency oscillation frequency can precisely and time-specifically modulate thalamocortical activity. These insights may pave the way for innovative, personalized neuromodulation methods for the somatosensory system., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Recent advancements in nano- and microfabrication techniques have led to the development of highly biomimetic patterned substrates able to guide neuronal sprouting, routing, elongation, and branching. Such substrates, recapitulating shapes and geometries found in the native brain, may pave the way toward the development of cell instructive paradigms able to guide morphogenesis at the neuron-material interface. In this scenario, high-resolution electron microscopy approaches, owing to their ability of discerning the details of neural morphogenesis at a nanoscale resolution, may play a crucial role in unravelling the fine ultrastructure of neurons interfacing with biomimetic structured substrates., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Exploiting the light-matter interplay to realize advanced light responsive multimodal platforms is an emerging strategy to engineer bioinspired systems such as optoelectronic synaptic devices. However, existing neuroinspired optoelectronic devices rely on complex processing of hybrid materials which often do not exhibit the required features for biological interfacing such as biocompatibility and low Young's modulus. Recently, organic photoelectrochemical transistors (OPECTs) have paved the way towards multimodal devices that can better couple to biological systems benefiting from the characteristics of conjugated polymers. Neurohybrid OPECTs can be designed to optimally interface neuronal systems while resembling typical plasticity-driven processes to create more sophisticated integrated architectures between neuron and neuromorphic ends. Here, an innovative photo-switchable PEDOT:PSS was synthesized and successfully integrated into an OPECT. The OPECT device uses an azobenzene-based organic neuro-hybrid building block to mimic the retina's structure exhibiting the capability to emulate visual pathways. Moreover, dually operating the device with opto- and electrical functions, a light-dependent conditioning and extinction processes were achieved faithful mimicking synaptic neural functions such as short- and long-term plasticity., (© 2023. Springer Nature Limited.)

Over the past decades, among all the non-invasive brain stimulation (NIBS) techniques, those aiming for neuromodulatory protocols have gained special attention. The traditional neurophysiological outcome to estimate the neuromodulatory effect is the motor evoked potential (MEP), the impact of NIBS techniques is commonly estimated as the change in MEP amplitude. This approach has several limitations: first, the use of MEP limits the evaluation of stimulation to the motor cortex excluding all the other brain areas. Second, MEP is an indirect measure of brain activity and is influenced by several factors. To overcome these limitations several studies have used new outcomes to measure brain changes after neuromodulation techniques with the concurrent use of transcranial magnetic stimulation (TMS) and electroencephalogram (EEG). In the present review, we examine studies that use TMS-EEG before and after a single session of neuromodulatory TMS. Then, we focused our literature research on the description of the different metrics derived from TMS-EEG to measure the effect of neuromodulation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cruciani, Mancuso, Sveva, Maccarrone, Todisco, Motolese, Santoro, Pilato, Spampinato, Rocchi, Di Lazzaro and Capone.)

Recreating human tissues and organs in the petri dish to establish models as tools in biomedical sciences has gained momentum. These models can provide insight into mechanisms of human physiology, disease onset, and progression, and improve drug target validation, as well as the development of new medical therapeutics. Transformative materials play an important role in this evolution, as they can be programmed to direct cell behavior and fate by controlling the activity of bioactive molecules and material properties. Using nature as an inspiration, scientists are creating materials that incorporate specific biological processes observed during human organogenesis and tissue regeneration. This article presents the reader with state-of-the-art developments in the field of in vitro tissue engineering and the challenges related to the design, production, and translation of these transformative materials. Advances regarding (stem) cell sources, expansion, and differentiation, and how novel responsive materials, automated and large-scale fabrication processes, culture conditions, in situ monitoring systems, and computer simulations are required to create functional human tissue models that are relevant and efficient for drug discovery, are described. This paper illustrates how these different technologies need to converge to generate in vitro life-like human tissue models that provide a platform to answer health-based scientific questions., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

Neural interfaces are evolving at a rapid pace owing to advances in material science and fabrication, reduced cost of scalable complementary metal oxide semiconductor (CMOS) technologies, and highly interdisciplinary teams of researchers and engineers that span a large range from basic to applied and clinical sciences. This study outlines currently established technologies, defined as instruments and biological study systems that are routinely used in neuroscientific research. After identifying the shortcomings of current technologies, such as a lack of biocompatibility, topological optimization, low bandwidth, and lack of transparency, it maps out promising directions along which progress should be made to achieve the next generation of symbiotic and intelligent neural interfaces. Lastly, it proposes novel applications that can be achieved by these developments, ranging from the understanding and reproduction of synaptic learning to live-long multimodal measurements to monitor and treat various neuronal disorders., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

Ischemic stroke is characterized by a complex cascade of events starting from vessel occlusion. The term "penumbra" denotes the area of severely hypo-perfused brain tissue surrounding the ischemic core that can be potentially recovered if blood flow is reestablished. From the neurophysiological perspective, there are local alterations-reflecting the loss of function of the core and the penumbra-and widespread changes in neural networks functioning, since structural and functional connectivity is disrupted. These dynamic changes are closely related to blood flow in the affected area. However, the pathological process of stroke does not end after the acute phase, but it determines a long-term cascade of events, including changes of cortical excitability, that are quite precocious and might precede clinical evolution. Neurophysiological tools-such as Transcranial Magnetic Stimulation (TMS) or Electroencephalography (EEG)-have enough time resolution to efficiently reflect the pathological changes occurring after stroke. Even if they do not have a role in acute stroke management, EEG and TMS might be helpful for monitoring ischemia evolution-also in the sub-acute and chronic stages. The present review aims to describe the changes occurring in the infarcted area after stroke from the neurophysiological perspective, starting from the acute to the chronic phase., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AM declared a past co-authorship with the author FP to the handling editor., (Copyright © 2023 Motolese, Lanzone, Todisco, Rossi, Santoro, Cruciani, Capone, Di Lazzaro and Pilato.)

The correct wiring of a neural network requires neuron to integrate an incredible repertoire of cues found in their extracellular environment. The astonishing efficiency of this process plays a pivotal role in the correct wiring of the brain during development and axon regeneration. Biologically inspired micro- and nanostructured substrates have been shown to regulate axonal outgrowth. In parallel, several studies investigated graphene's potential as a conductive neural interface, able to enhance cell adhesion, neurite sprouting and outgrowth. Here, we engineered a 3D single- to few-layer fuzzy graphene morphology (3DFG), 3DFG on a collapsed Si nanowire (SiNW) mesh template (NT-3DFGc), and 3DFG on a noncollapsed SiNW mesh template (NT-3DFGnc) as neural-instructive materials. The micrometric protruding features of the NWs templates dictated neuronal growth cone establishment, as well as influencing axon elongation and branching. Furthermore, neurons-to-graphene coupling was investigated with comprehensive view of integrin-mediated contact adhesion points and plasma membrane curvature processes.

One of the main challenges in neuroelectronics is the implementation of electronic platforms able to secure a tight coupling with neuronal cells and achieve an optimal signal to noise ratio during stimulation/recording of electrophysiological activity. In this context, supported lipid bilayers (SLBs), recapitulating the structure and the dynamicity of the biological plasma membrane, offer a promising biomimetic approach to trick cells to recognize a device as part of their native environment, tightening the cell-chip coupling. Among possible functionalization strategies used to improve cell adhesion on SLBs, the modification of the bilayer surface charge has been exploited to enhance the electrostatic interaction between the artificial membrane and its biological counterpart. In this work, several SLBs with different lipidic composition were synthesized and interfaced with primary neurons. Starting from a neuron-inspired biomembrane, the negative charges were increased through the addition of 1,2-dipalmitoyl- sn-glycero -3-phosphoethanolamine- N -(succinyl) (succinyl-PE), a lipid exposing phosphate (PO 4 - ) groups; furthermore, the reactivity of the succinyl carboxylate group enabled the subsequent addition of negatively charged sulfonate (SO 3 - ) groups. The synthesized SLBs were then tested as platforms for neuronal adhesion and network formation. Despite the expected repulsive electrostatic interactions, our work suggests that negatively charged SLBs may influence neurite elongation and branching, highlighting the potential of surface charge to tune neuronal processes at the neuron-SLB interface., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

The 2020's decade will likely witness an unprecedented development and deployment of neurotechnologies for human rehabilitation, personalized use, and cognitive or other enhancement. New materials and algorithms are already enabling active brain monitoring and are allowing the development of biohybrid and neuromorphic systems that can adapt to the brain. Novel brain-computer interfaces (BCIs) have been proposed to tackle a variety of enhancement and therapeutic challenges, from improving decision-making to modulating mood disorders. While these BCIs have generally been developed in an open-loop modality to optimize their internal neural decoders, this decade will increasingly witness their validation in closed-loop systems that are able to continuously adapt to the user's mental states. Therefore, a proactive ethical approach is needed to ensure that these new technological developments go hand in hand with the development of a sound ethical framework. In this perspective article, we summarize recent developments in neural interfaces, ranging from neurohybrid synapses to closed-loop BCIs, and thereby identify the most promising macro-trends in BCI research, such as simulating vs. interfacing the brain, brain recording vs. brain stimulation, and hardware vs. software technology. Particular attention is devoted to central nervous system interfaces, especially those with application in healthcare and human enhancement. Finally, we critically assess the possible futures of neural interfacing and analyze the short- and long-term implications of such neurotechnologies., Competing Interests: Author DV is an employee of Neurable Inc. Author MI has served as an ethics advisor to the Council of Europe, the OECD, and Kernel. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Valeriani, Santoro and Ienca.)

Purpose: Corneal irregularities can lead to high order aberrations (HOAs) and may influence the outcomes in terms of intraocular lens (IOL) selection and visual acuity assessment. The aim of this study was to evaluate the visual acuity and satisfaction after IC-8 implants in patients characterized by corneal irregularities and HOAs who could not undergo refractive surgery due to the poor residual thickness of the cornea or other conditions such as astigmatism secondary to previous radial keratotomy., Methods: This descriptive, retrospective cohort study was conducted on nine eyes in six patients affected by corneal irregularities and HOAs who had undergone IC-8 IOL implantation. The primary endpoint was the best-corrected visual acuity (BCVA), the subjective visual function, and the visual field., Results: Nine eyes of six patients (three bilateral implantation) were enrolled. For each patient, BCVA, vision, and lifestyle quality were evaluated. In all patients, we noticed an improvement in all parameters without visual field defects., Conclusion: Our work encourages the use of the IC8 lens to improve visual acuity in patients with irregular corneas and HOAs who cannot be treated with customized refractive surgery. Patients experience a subjective improvement of their quality of vision and also more self-confidence in their daily life. IC-8 lenses do not interfere with the visualization of retinal fundus and there is no impairment of the visual field detected by patients., Competing Interests: There are no conflicts of interest., (Copyright © 2022 Franco et al.)

Reactive oxygen species (ROS) are active molecules involved in several biological functions. When the production of ROS is not counterbalanced by the action of protective antioxidant mechanisms present in living organisms, a condition of oxidative stress can arise with consequent damage to biological structures. The brain is one of the main ROS-generating organs in the human body, with the consequence that most of the neurological disorders are associated with an overproduction of ROS. Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease associated with mutations in the sacsin gene ( SACS ). At cellular level, ARSACS is characterized by mitochondrial impairments, a reduction in bioenergetic processes, and by both an over-production of and an over-sensitivity to ROS. Several antioxidant molecules have been proposed as a potential treatment for ARSACS, such as idebenone and resveratrol. Polydopamine nanoparticles (PDNPs) gained significant attention in recent years owing to their peculiar physical/chemical properties, and especially because of their antioxidant activity. PDNPs have shown a great ROS scavenging capacity that, combined with their completely organic nature that grants them the ability to be degraded and excreted by living organisms, make them a promising candidate in the treatment of oxidative stress-related disorders. In this work, we assessed the effect of PDNPs on human fibroblasts derived from ARSACS patients in terms of antioxidant properties and protein expression. PDNP interaction with fibroblasts was analyzed in terms of biocompatibility, internalization and uptake pathway, reduction of ROS levels, prevention of ROS-induced apoptosis/necrosis, and protective action upon ROS-induced mitochondrial dysfunctions. Moreover, a complete proteomic analysis was performed. Altogether, our data showed that PDNPs can partially counteract ROS-induced damages in ARSACS patient-derived fibroblasts, making them a potential therapeutic candidate to treat - or at least to ameliorate - the condition of oxidative stress associated with ARSACS.

Background: Pathological brain processes may induce adaptive cortical reorganization, however, the mechanisms underlying neuroplasticity that occurs in the presence of lesions in eloquent areas are not fully explained. The aim of this study was to evaluate functional compensatory cortical activations in patients with frontal brain gliomas during a phonemic fluency task and to explore correlations with cognitive performance, white matter tracts microstructural alterations, and tumor histopathological and molecular characterization., Methods: Fifteen patients with frontal glioma were preoperatively investigated with an MRI study on a 3T scanner and a subgroup underwent an extensive neuropsychological assessment. The hemispheric laterality index (LI) was calculated through phonemic fluency task functional MRI (fMRI) activations in the frontal, parietal, and temporal lobe parcellations. Diffusion-weighted images were acquired for all patients and for a group of 24 matched healthy volunteers. Arcuate Fasciculus (AF) and Frontal Aslant Tract (FAT) tractography was performed using constrained spherical deconvolution diffusivity modeling and probabilistic fiber tracking. All patients were operated on with a resective aim and underwent adjuvant therapies, depending on the final diagnosis., Results: All patients during the phonemic fluency task fMRI showed left hemispheric dominance in temporal and parietal regions. Regarding frontal regions (i.e., frontal operculum) we found right hemispheric dominance that increases when considering only those patients with tumors located on the left side. These latter activations positively correlate with verbal and visuo-spatial short-term memory, and executive functions. No correlations were found between the left frontal operculum and cognitive performance. Furthermore, patients with IDH-1 mutation and without TERT mutation, showed higher rightward frontal operculum fMRI activations and better cognitive performance in tests measuring general cognitive abilities, semantic fluency, verbal short-term memory, and executive functions. As for white matter tracts, we found left and right AF and FAT microstructural alterations in patients with, respectively, left-sided and right-side glioma compared to controls., Conclusions: Compensatory cortical activation of the corresponding region in the non-dominant hemisphere and its association with better cognitive performance and more favorable histopathological and molecular tumor characteristics shed light on the neuroplasticity mechanisms that occur in the presence of a tumor, helping to predict the rate of post-operative deficit, with the final goal of improving patients'quality of life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mitolo, Zoli, Testa, Morandi, Rochat, Zaccagna, Martinoni, Santoro, Asioli, Badaloni, Conti, Sturiale, Lodi, Mazzatenta and Tonon.)

Objective: The aim of the present study is to evaluate a neurocognitive outcome in patients affected by late-onset idiopathic aqueductal stenosis (LIAS) who underwent endoscopic third ventriculostomy (ETV)., Materials and Methods: A prospective study was conducted between January 2015 and December 2017 in a series of 10 consecutive adult patients referred to the Neurosurgery Department of IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy. All the adult patients admitted with absence of CSF flow through the aqueduct in phase-contrast (PC)-MRI sequences or a turbulence void signal in T2-weighted images in midsagittal thin-slice MR sequences underwent a specific neuroradiological, neurological, and neurocognitive assessment pre- and postoperatively., Results: All patients affected by gait and sphincter disturbances improved after ETV. Attentive and executive functions as well as visuo-spatial memory and verbal executive functions improved in several patients. Similarly, the affective and behavioral scales improved in almost 50% of the patients. No major complications have been recorded, and no patients required a second surgery for shunt placement., Conclusion: Endoscopic third ventriculostomy represents a safe and effective surgical procedure for the treatment of LIAS. In addition to neurological improvement, we demonstrated also postoperative neurocognitive improvement mainly in attentive and executive functions, visuo-spatial memory, verbal executive functions, and behavioral and affective domains., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Martinoni, Miccoli, Riccioli, Santoro, Bertolini, Zenesini, Mazzatenta, Conti, Cavallo and Palandri.)

Synaptic plasticity is a fundamental process for neuronal communication and is involved in neurodegeneration. This process has been recently exploited to inspire the design of next-generation bioelectronic platforms. Neuromorphic devices have emerged as ideal candidates in mimicking brain functionalities, thanks to their ionic-to-electronic signal transduction, biocompatibility, and their ability to display short- and long-term memory as biological synapses. However, these devices still fail in bridging the gap between electronics and biological systems due to the lack of biomimetic features. Here, a biomembrane-based organic electrochemical transistor (OECT) is implemented and the supported-lipid-bilayer-mediated short-term depression of the device is investigated. After morphological and electrical characterization of the lipid bilayer, its ionic barrier behavior is exploited to enhance the neuromorphic operation of the OECT. Such biomimetic neuromorphic devices pave the way toward the implementation of synapses-resembling in vitro platforms to investigate and characterize neurodegenerative processes involving synaptic plasticity loss., (© 2022 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

The plasma membrane (PM) is often described as a wall, a physical barrier separating the cell cytoplasm from the extracellular matrix (ECM). Yet, this wall is a highly dynamic structure that can stretch, bend, and bud, allowing cells to respond and adapt to their surrounding environment. Inspired by shapes and geometries found in the biological world and exploiting the intrinsic properties of conductive polymers (CPs), several biomimetic strategies based on substrate dimensionality have been tailored in order to optimize the cell-chip coupling. Furthermore, device biofunctionalization through the use of ECM proteins or lipid bilayers have proven successful approaches to further maximize interfacial interactions. As the bio-electronic field aims at narrowing the gap between the electronic and the biological world, the possibility of effectively disguising conductive materials to "trick" cells to recognize artificial devices as part of their biological environment is a promising approach on the road to the seamless platform integration with cells.

Intracellular delivery of advanced therapeutics, including biologicals and supramolecular agents, is complex because of the natural biological barriers that have evolved to protect the cell. Efficient delivery of therapeutic nucleic acids, proteins, peptides and nanoparticles is crucial for clinical adoption of emerging technologies that can benefit disease treatment through gene and cell therapy. Nanoneedles are arrays of vertical high-aspect-ratio nanostructures that can precisely manipulate complex processes at the cell interface, enabling effective intracellular delivery. This emerging technology has already enabled the development of efficient and non-destructive routes for direct access to intracellular environments and delivery of cell-impermeant payloads. However, successful implementation of this technology requires knowledge of several scientific fields, making it complex to access and adopt by researchers who are not directly involved in developing nanoneedle platforms. This presents an obstacle to the widespread adoption of nanoneedle technologies for drug delivery. This tutorial aims to equip researchers with the knowledge required to develop a nanoinjection workflow. It discusses the selection of nanoneedle devices, approaches for cargo loading and strategies for interfacing to biological systems and summarises an array of bioassays that can be used to evaluate the efficacy of intracellular delivery., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Lysosomal storage disorders characterized by altered metabolism of heparan sulfate, including Mucopolysaccharidosis (MPS) III and MPS-II, exhibit lysosomal dysfunctions leading to neurodegeneration and dementia in children. In lysosomal storage disorders, dementia is preceded by severe and therapy-resistant autistic-like symptoms of unknown cause. Using mouse and cellular models of MPS-IIIA, we discovered that autistic-like behaviours are due to increased proliferation of mesencephalic dopamine neurons originating during embryogenesis, which is not due to lysosomal dysfunction, but to altered HS function. Hyperdopaminergia and autistic-like behaviours are corrected by the dopamine D1-like receptor antagonist SCH-23390, providing a potential alternative strategy to the D2-like antagonist haloperidol that has only minimal therapeutic effects in MPS-IIIA. These findings identify embryonic dopaminergic neurodevelopmental defects due to altered function of HS leading to autistic-like behaviours in MPS-II and MPS-IIIA and support evidence showing that altered HS-related gene function is causative of autism.

Surface topography profoundly influences cell adhesion, differentiation, and stem cell fate control. Numerous studies using a variety of materials demonstrate that nanoscale topographies change the intracellular organization of actin cytoskeleton and therefore a broad range of cellular dynamics in live cells. However, the underlying molecular mechanism is not well understood, leaving why actin cytoskeleton responds to topographical features unexplained and therefore preventing researchers from predicting optimal topographic features for desired cell behavior. Here we demonstrate that topography-induced membrane curvature plays a crucial role in modulating intracellular actin organization. By inducing precisely controlled membrane curvatures using engineered vertical nanostructures as topographies, we find that actin fibers form at the sites of nanostructures in a curvature-dependent manner with an upper limit for the diameter of curvature at ∼400 nm. Nanotopography-induced actin fibers are branched actin nucleated by the Arp2/3 complex and are mediated by a curvature-sensing protein FBP17. Our study reveals that the formation of nanotopography-induced actin fibers drastically reduces the amount of stress fibers and mature focal adhesions to result in the reorganization of actin cytoskeleton in the entire cell. These findings establish the membrane curvature as a key linkage between surface topography and topography-induced cell signaling and behavior., Competing Interests: The authors declare no competing interest.