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In light of advancements in electronic skins (E-skins), their application in extreme environments poses significant challenges. Inspired by real human skin, we have developed a hierarchical structured electronic skin that utilizes flexible carbon fiber fabric as a framework. Copper nanoflakes and embedded sensors function as the neural layer, while Ethylene Vinyl Acetate acts as the dermal layer, and Polytetrafluoroethylene is employed as the epidermal layer. The reported E-skin demonstrates outstanding flexibility, excellent heat resistance, robust mechanical properties (fracture strength of 1600 MPa, Young's modulus approximately 3.8 GPa), exceptional bending/compression strain performance, excellent hydrophobicity (water contact angle of 120°), effective electromagnetic shielding performance (approximately 45 dB total shielding effectiveness for X-band), and electromagnetic wave absorption capability. Additionally, this E-skin possesses self-healing properties, capable of restoring to its original hydrophobic state within 30 s under a 9V voltage through the Joule heating effect, complemented by corresponding theoretical and mathematical modeling. This E-skin introduces a novel, environmentally friendly, and operationally simple strategy for enhancing the extreme environment resistance and durability of flexible devices.

For wearable smart textile sensors, stability, accuracy and multi-functionality are key objectives. Achieving the optimal application requires delicately balancing the crucial physical properties of strain sensors, presenting a key technological challenge. This study addresses these challenges by presenting several properties and potential applications of a triple hierarchic polymeric knitted fabric. The fabric incorporates an internal conductive network constructed with silver nanowires (AgNWs) and polydopamine (PDA) coating on its outer surface. This innovative textile successfully strikes a balance between strain sensing and electromagnetic interference shielding while concurrently exhibiting biocompatibility and antimicrobial properties. Significantly, acknowledging the susceptibility of measurements from polymer-based strain sensor materials to time drift, we introduce both a modeling approach and a novel calibration technique. This advancement facilitates the generation of stable cyclic sensing signals, even under substantial deformations of up to 80 % at a high stretching speed. Importantly, it provides a practical solution for addressing signal drift observed in flexible sensors when utilized in environments characterized by long-term and large deformations.

Radboud University, 16 mei 2023, Promotores : Bokhoven, J.H.L.M. van, Nadif Kasri, N. Co-promotor : Schubert, D., Contains fulltext : 292275.pdf (Publisher’s version ) (Closed access)

Contains fulltext : 296473.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext, Human induced pluripotent stem cell (hiPSC)-derived neuronal networks on multi-electrode arrays (MEAs) provide a unique phenotyping tool to study neurological disorders. However, it is difficult to infer cellular mechanisms underlying these phenotypes. Computational modeling can utilize the rich dataset generated by MEAs, and advance understanding of disease mechanisms. However, existing models lack biophysical detail, or validation and calibration to relevant experimental data. We developed a biophysical in silico model that accurately simulates healthy neuronal networks on MEAs. To demonstrate the potential of our model, we studied neuronal networks derived from a Dravet syndrome (DS) patient with a missense mutation in SCN1A, encoding sodium channel Na(V)1.1. Our in silico model revealed that sodium channel dysfunctions were insufficient to replicate the in vitro DS phenotype, and predicted decreased slow afterhyperpolarization and synaptic strengths. We verified these changes in DS patient-derived neurons, demonstrating the utility of our in silico model to predict disease mechanisms.

Contains fulltext : 295430.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 300240.pdf (Publisher’s version ) (Open Access), Dravet syndrome is a severe epileptic encephalopathy, characterized by (febrile) seizures, behavioural problems and developmental delay. Eighty per cent of patients with Dravet syndrome have a mutation in SCN1A, encoding Nav1.1. Milder clinical phenotypes, such as GEFS+ (generalized epilepsy with febrile seizures plus), can also arise from SCN1A mutations. Predicting the clinical phenotypic outcome based on the type of mutation remains challenging, even when the same mutation is inherited within one family. This clinical and genetic heterogeneity adds to the difficulties of predicting disease progression and tailoring the prescription of anti-seizure medication. Understanding the neuropathology of different SCN1A mutations may help to predict the expected clinical phenotypes and inform the selection of best-fit treatments. Initially, the loss of Na+-current in inhibitory neurons was recognized specifically to result in disinhibition and consequently seizure generation. However, the extent to which excitatory neurons contribute to the pathophysiology is currently debated and might depend on the patient clinical phenotype or the specific SCN1A mutation. To examine the genotype-phenotype correlations of SCN1A mutations in relation to excitatory neurons, we investigated a panel of patient-derived excitatory neuronal networks differentiated on multi-electrode arrays. We included patients with different clinical phenotypes, harbouring various SCN1A mutations, along with a family in which the same mutation led to febrile seizures, GEFS+ or Dravet syndrome. We hitherto describe a previously unidentified functional excitatory neuronal network phenotype in the context of epilepsy, which corresponds to seizurogenic network prediction patterns elicited by proconvulsive compounds. We found that excitatory neuronal networks were affected differently, depending on the type of SCN1A mutation, but did not segregate according to clinical severity. Specifically, loss-of-function mutat

Contains fulltext : 299609.pdf (Publisher’s version ) (Open Access), Mechanisms that underlie homeostatic plasticity have been extensively investigated at single-cell levels in animal models, but are less well understood at the network level. Here, we used microelectrode arrays to characterize neuronal networks following induction of homeostatic plasticity in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons co-cultured with rat astrocytes. Chronic suppression of neuronal activity through tetrodotoxin (TTX) elicited a time-dependent network re-arrangement. Increased expression of AMPA receptors and the elongation of axon initial segments were associated with increased network excitability following TTX treatment. Transcriptomic profiling of TTX-treated neurons revealed up-regulated genes related to extracellular matrix organization, while down-regulated genes related to cell communication; also astrocytic gene expression was found altered. Overall, our study shows that hiPSC-derived neuronal networks provide a reliable in vitro platform to measure and characterize homeostatic plasticity at network and single-cell levels; this platform can be extended to investigate altered homeostatic plasticity in brain disorders.

Soil organic matter (SOM) is indispensable for soil health and, in the context of climate change, is considered a significant CO2 sink. Improving agricultural management to increase long-term soil organic carbon (SOC) stocks for mitigating climate change requires tools that estimate short and long-cycling SOM pools. In this study, we analyzed changes in fast-cycling particulate organic matter (POM) and slow-cycling mineral-associated organic matter (MAOM) induced by common management practices, i.e., fertilization and crop rotation in topsoils from 25 Central European long-term field experiments. When relating MAOM-C contents to recent MAOM-C saturation levels, estimated sequestration potentials were only met in coarse-textured soils under appropriate agricultural management or fine-textured soils under extreme organic fertilization. Soil texture, organic fertilization, and below-ground OC inputs through root exudates and root biomass were decisive for estimating MAOM-C, allowing for calibration of a mixed-effects model (Nakagawa’s: marginal R2m = 0.6, conditional R2c = 0.89). While the models containing soil texture and organic fertilization parameters can be validated and generalized (R2 = 0.43), the below-ground OC input predictor substantially decreases the generalizability of the validated models (R2 = 0.14). According to quantile regression models, we estimate the average difference in MAOM-C concentration between well-managed and control site (without organic fertilization) topsoils to 4.1 mg g−1 soil. In dependence on the soil bulk density, this amounts to 1.38 – 1.84 t ha−1 MAOM-C stocks or 5.06 – 10.1 t ha−1 CO2-equivalents. POM-C was difficult to predict (R2 = 0.28), presumably due to strong POM dynamics. The POM-C / MAOM-C ratio can inform on the effects of agricultural practices in before/after management change

Contains fulltext : 248864.pdf (Publisher’s version ) (Open Access), Macroautophagy (hereafter referred to as autophagy) is a finely tuned process of programmed degradation and recycling of proteins and cellular components, which is crucial in neuronal function and synaptic integrity. Mounting evidence implicates chromatin remodeling in fine-tuning autophagy pathways. However, this epigenetic regulation is poorly understood in neurons. Here, we investigate the role in autophagy of KANSL1, a member of the nonspecific lethal complex, which acetylates histone H4 on lysine 16 (H4K16ac) to facilitate transcriptional activation. Loss-of-function of KANSL1 is strongly associated with the neurodevelopmental disorder Koolen-de Vries Syndrome (KdVS). Starting from KANSL1-deficient human induced-pluripotent stem cells, both from KdVS patients and genome-edited lines, we identified SOD1 (superoxide dismutase 1), an antioxidant enzyme, to be significantly decreased, leading to a subsequent increase in oxidative stress and autophagosome accumulation. In KANSL1-deficient neurons, autophagosome accumulation at excitatory synapses resulted in reduced synaptic density, reduced GRIA/AMPA receptor-mediated transmission and impaired neuronal network activity. Furthermore, we found that increased oxidative stress-mediated autophagosome accumulation leads to increased MTOR activation and decreased lysosome function, further preventing the clearing of autophagosomes. Finally, by pharmacologically reducing oxidative stress, we could rescue the aberrant autophagosome formation as well as synaptic and neuronal network activity in KANSL1-deficient neurons. Our findings thus point toward an important relation between oxidative stress-induced autophagy and synapse function, and demonstrate the importance of H4K16ac-mediated changes in chromatin structure to balance reactive oxygen species- and MTOR-dependent autophagy.Abbreviations: APO: apocynin; ATG: autophagy related; BAF: bafilomycin A(1); BSO: buthionine sulfoximine; CV: coefficient of variation; DIV: days i

Contains fulltext : 251390.pdf (Publisher’s version ) (Open Access), Depression is a highly prevalent, debilitating mental disorder. Chronic unpredictable mild stress (CUMS) is the most widely applied model to study this affliction in rodents. While studies incorporating CUMS prior to an intervention often require long-lasting stress effects that persist after exposure is ceased, the longevity of these effects is rarely studied. Additionally, it is unclear whether behavioural assessments can be performed before and after interventions without repeated testing effects. In rats, we investigated CUMS effects on components of depressive-like behaviour both acutely after stress cessation and after a recovery period, as well as effects of repeated testing. We observed acute disruptions of the circadian locomotor rhythm and a reduced sucrose preference immediately after CUMS exposure. While circadian locomotor rhythm effects persisted up until four weeks after stress cessation, independently of repeated testing, sucrose preference effects did not. Interestingly, CUMS animals tested once after a recovery period of four weeks showed reduced anxiety-like behaviour in the open field and elevated plus maze compared to their control group and repeatedly-tested CUMS animals. These findings suggest that distinct CUMS-induced components of depressive-like behaviour are affected differentially by recovery time and repeated testing; these aspects should be considered carefully in future study designs.

Contains fulltext : 251368.pdf (Publisher’s version ) (Open Access), Heterozygous loss-of-function (LoF) mutations in SETD1A, which encodes a subunit of histone H3 lysine 4 methyltransferase, cause a neurodevelopmental syndrome and increase the risk for schizophrenia. Using CRISPR-Cas9, we generate excitatory/inhibitory neuronal networks from human induced pluripotent stem cells with a SETD1A heterozygous LoF mutation (SETD1A(+/-)). Our data show that SETD1A haploinsufficiency results in morphologically increased dendritic complexity and functionally increased bursting activity. This network phenotype is primarily driven by SETD1A haploinsufficiency in glutamatergic neurons. In accordance with the functional changes, transcriptomic profiling reveals perturbations in gene sets associated with glutamatergic synaptic function. At the molecular level, we identify specific changes in the cyclic AMP (cAMP)/Protein Kinase A pathway pointing toward a hyperactive cAMP pathway in SETD1A(+/-) neurons. Finally, by pharmacologically targeting the cAMP pathway, we are able to rescue the network deficits in SETD1A(+/-) cultures. Our results demonstrate a link between SETD1A and the cAMP-dependent pathway in human neurons.

Contains fulltext : 244082.pdf (Publisher’s version ) (Open Access), Posttranslational modification of histones and related gene regulation are shown to be affected in an increasing number of neurological disorders. SETD1A is a chromatin remodeler that influences gene expression through the modulation of mono- di- and trimethylation marks on Histone-H3-Lysine-4 (H3K4me1/2/3). H3K4 methylation is predominantly described to result in transcriptional activation, with its mono- di- and trimethylated forms differentially enriched at promoters or enhancers. Recently, dominant mostly de novo variants in SETD1A have clinically been linked to developmental delay, intellectual disability (DD/ID), and schizophrenia (SCZ). Affected individuals often display both developmental and neuropsychiatric abnormalities. The primary diagnoses are mainly dependent on the age at which the individual is assessed. Investigations in mouse models of SETD1A dysfunction have been able to recapitulate key behavioral features associated with ID and SCZ. Furthermore, functional investigations suggest disrupted synaptic and neuronal network function in these mouse models. In this review, we provide an overview of pre-clinical studies on the role of SETD1A in neuronal development. A better understanding of the pathobiology underlying these disorders may provide novel opportunities for therapeutic intervention. As such, we will discuss possible strategies to move forward in elucidating the genotype-phenotype correlation in SETD1A associated disorders.

Contains fulltext : 230611.pdf (publisher's version ) (Open Access)

Radboud University, 27 september 2021, Promotores : Bokhoven, J.H.L.M. van, Nadif Kasri, N. Co-promotor : Schubert, D., Contains fulltext : 236413 .pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext, Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient-derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as loss-of-function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.