Nanostructured gadolinium(III) micelles: Synthesis, characterization, cytotoxic activities, and MRI applications in vivo.

Gadolinium-based contrast agents (GBCAs) are used in around 40 % of MRI procedures. Despite initial perceptions of minimal risk, their long-term use has emphasized the need to reduce toxicity and develop more efficient GBCAs with extended blood retention. Advancements in nanomaterials have led to improved GBCAs, enhancing MRI diagnostics. This study synthesizes and characterizes nanostructured gadolinium(III) micelles as superior MRI contrast agents. The complexes, [Gd(L)2], where L is a ligand of the N-alkyl-N-methylglucamine surfactant series (L8, L10 or L12, L10), form nanostructured micelles in aqueous solution. Gd(L8)2 and Gd(L10)2 relaxivities remained stable across concentrations. Compared to Gd-DTPA, Gd(III) micelles showed enhanced T1-weighted MRI contrast. Gd(L12)2 micelles exhibited cytotoxicity against B16F10 melanoma cells (IC50 42.5 ± 2.2 µM) and L292L929 fibroblasts (IC50 52.0 ± 2.5 µM), with a selectivity index of 1.2. In vivo application in mice brain T2-weighted images suggests nanostructured Gd(III) micelles are promising MRI contrast agents for targeting healthy organs or tumors.

Transformations that preserve the uniqueness of the differential form for Lorenz-like systems.

Differential equations serve as models for many physical systems. But, are these equations unique? We prove here that when a 3D system of ordinary differential equations for a dynamical system is transformed to the jerk or differential form, the jerk form is preserved in relation to a given variable and, therefore, the transformed system shares the time series of that given variable with the original untransformed system. Multiple algebraically different systems of ordinary differential equations can share the same jerk form. They may also share the same time series of the transformed variable depending on the parameters of the jerk form. Here, we studied 17 algebraically different Lorenz-like systems that share the same functional jerk form. There are groups of these systems that share the jerk parameters and, therefore, also have the same time series of the transformed variable.

Network-motif delay differential analysis of brain activity during seizures.

Delay Differential Analysis (DDA) is a nonlinear method for analyzing time series based on principles from nonlinear dynamical systems. DDA is extended here to incorporate network aspects to improve the dynamical characterization of complex systems. To demonstrate its effectiveness, DDA with network capabilities was first applied to the well-known Rössler system under different parameter regimes and noise conditions. Network-motif DDA, based on cortical regions, was then applied to invasive intracranial electroencephalographic data from drug-resistant epilepsy patients undergoing presurgical monitoring. The directional network motifs between brain areas that emerge from this analysis change dramatically before, during, and after seizures. Neural systems provide a rich source of complex data, arising from varying internal states generated by network interactions.

Active probing to highlight approaching transitions to ictal states in coupled neural mass models.

The extraction of electrophysiological features that reliably forecast the occurrence of seizures is one of the most challenging goals in epilepsy research. Among possible approaches to tackle this problem is the use of active probing paradigms in which responses to stimuli are used to detect underlying system changes leading up to seizures. This work evaluates the theoretical and mechanistic underpinnings of this strategy using two coupled populations of the well-studied Wendling neural mass model. Different model settings are evaluated, shifting parameters (excitability, slow inhibition, or inter-population coupling gains) from normal towards ictal states while probing stimuli are applied every 2 seconds to the input of either one or both populations. The correlation between the extracted features and the ictogenic parameter shifting indicates if the impending transition to the ictal state may be identified in advance. Results show that not only can the response to the probing stimuli forecast seizures but this is true regardless of the altered ictogenic parameter. That is, similar feature changes are highlighted by probing stimuli responses in advance of the seizure including: increased response variance and lag-1 autocorrelation, decreased skewness, and increased mutual information between the outputs of both model subsets. These changes were mostly restricted to the stimulated population, showing a local effect of this perturbational approach. The transition latencies from normal activity to sustained discharges of spikes were not affected, suggesting that stimuli had no pro-ictal effects. However, stimuli were found to elicit interictal-like spikes just before the transition to the ictal state. Furthermore, the observed feature changes highlighted by probing the neuronal populations may reflect the phenomenon of critical slowing down, where increased recovery times from perturbations may signal the loss of a systems' resilience and are common hallmarks of an impending critical transition. These results provide more evidence that active probing approaches highlight information about underlying system changes involved in ictogenesis and may be able to play a role in assisting seizure forecasting methods which can be incorporated into early-warning systems that ultimately enable closing the loop for targeted seizure-controlling interventions.

Automatic audiometry using auditory steady-state response and sequential test strategy applied to volunteers with normal hearing.

PURPOSE: In the present study, a new procedure to perform automatic audiometry using multifrequency Auditory Steady-State Response (ASSR) is proposed. METHODS: The automatic audiometry procedure consists of detecting the presence of multifrequency ASSR in real-time using the sequential test strategy and by adjusting the stimulus intensity independently. The ASSR audiometric thresholds of 18 adult volunteers with normal hearing were determined by automatically (four simultaneous frequencies per ear) at modulation frequencies in the 80 Hz range. The exam time and the difference between ASSR thresholds and pure-tone behavioural hearing thresholds were estimated as performance measures. RESULTS: The results showed that automatic audiometry can reduce the number of intensity levels used to obtain the ASSR threshold by up to 58% when compared to audiometry without using the techniques applied in automatic audiometry. In addition, the average of the difference between ASSR thresholds and Pure-Tone Behavioural Hearing thresholds was around 19 dB, which is similar to the results reported in similar studies. CONCLUSIONS: The audiometric procedure proposed in this study is fully automatic, i.e., does not require any human supervision throughout the exam, and is able to significantly reduce the conventional exam time.

Anaerobic Threshold in Stand-up Paddle: Comparison Between Direct and Alternative Methods.

ABSTRACT: Balikian, P, Gomes de Araujo, G, Prado, ES, Ryan Geraldes, AA, Marinho de Lima, AH, and Mendes, EV. Anaerobic threshold in stand-up paddle: comparison between direct and alternative methods. J Strength Cond Res 36(7): 1896-1900, 2022-The purpose of this study was to test the validity of alternative protocols, mean velocity during 30 minutes of continuous effort (V30min) and critical velocity (CV), to estimate the anaerobic threshold in stand-up paddle (SUP). Eight athletes performed: 3 maximal efforts at 400-, 500-, and 800-m distances to determine CV values, using the distance-time relationship; 3 efforts at 85, 90, and 100% of maximal 500-m effort to determine the velocity related to 3.5 mmol·L-1 of lactate, assumed as the onset of blood lactate accumulation (OBLA) and; a 30-minute continuous effort to determine the V30min. All evaluations were separated by 48 hours, with the athletes using their own boards and paddles in the water. No differences were observed between the OBLA (2.35 ± 0.13 m·s-1) and alternative methods (CV: 2.42 ± 0.20 m·s-1; p = 0.10 and V30min: 2.32 ± 0.13 m·s-1; p = 0.63). Although strong correlations were observed between the OBLA and alternative methods (CV: r = 0.84 and V30min: r = 0.94), the limits of agreement were higher in CV (±0.23 m·s-1) than V30min (±0.08 m·s-1). These results demonstrate that both the CV and V30min are valid to estimate the OBLA. In view of the specificity of SUP and the high levels of agreement, the use of the V30min is recommended to prescribe training intensities.

Gelation Kinetics-Structure Analysis of pH-triggered Low Molecular Weight Hydrogelators.

Properties such as shear modulus, gelation time, structure of supramolecular hydrogels are strongly dependent on self-assembly, gelation triggering mechanism and processes used to form the gel. In our work we extend reported rheology analysis methodologies to pH-triggered supramolecular gels to understand structural insight using a model system based on N-N' Dibenzoyl-L-Cystine pH-triggered hydrogelator and Glucono-δ-Lactone as the trigger. We observed that Avrami growth model when applied to time-sweep rheological data of gels formed at lower trigger concentrations provide estimates of fractal dimension which agree well compared with visualization of the microstructure as seen via Confocal Laser Scanning Microscopy, for a range of gelator concentrations.

Diffeomorphical equivalence vs topological equivalence among Sprott systems.

In 1994, Sprott [Phys. Rev. E 50, 647-650 (1994)] proposed a set of 19 different simple dynamical systems producing chaotic attractors. Among them, 14 systems have a single nonlinear term. To the best of our knowledge, their diffeomorphical equivalence and the topological equivalence of their chaotic attractors were never systematically investigated. This is the aim of this paper. We here propose to check their diffeomorphical equivalence through the jerk functions, which are obtained when the system is rewritten in terms of one of the variables and its first two derivatives (two systems are thus diffeomorphically equivalent when they have exactly the same jerk function, that is, the same functional form and the same coefficients). The chaotic attractors produced by these systems-for parameter values close to the ones initially proposed by Sprott-are characterized by a branched manifold. Systems B and C produce chaotic attractors, which are observed in the Lorenz system and are also briefly discussed. Those systems are classified according to their diffeomorphical and topological equivalence.

Faster automatic ASSR detection using sequential tests.

Objective: Objective Response Detection (ORD) can be used for auditory steady-state response (ASSR) detection. In conventional ORD methods, the statistical tests are applied at the end of data collection ('single-shot tests'). In sequential ORD methods, statistical tests are applied repeatedly, while data is being collected. However, repeated testing can increase False Positive (FP) rates. One solution is to infer that response is present only after the test remains significant for a predefined number of consecutive detections (NCD). Thus, this paper describes a new method for finding the required NCD that control the FP rate for ASSR detection.Design: NCD values are estimated using Monte Carlo simulations.Study sample: ASSR signals were recorded from 8 normal-hearing subjects.Results: The exam time was reduced by up to 38.9% compared to the single-shot test with loss of approximately 5% in detection rate. Alternatively, lower gains in time were achieved for a smaller (non-significant) loss in detection rate. The FP rates at the end of the test were kept at the nominal level expected (1%).Conclusion: The sequential test strategy with NCD as the stopping criterion can improve the speed of ASSR detection and prevent higher than expected FP rates.

Effects of ionizing radiation on woven bone: influence on the osteocyte lacunar network, collagen maturation, and microarchitecture.

OBJECTIVES: Evaluate the effects of ionizing radiation on microarchitecture, the osteocyte lacunar network, and collagen maturity in a bone repair site. MATERIALS AND METHODS: Bone defects were created on tibias of 20 New Zealand rabbits. After 2 weeks, the animals were randomly divided into (n = 10) NoIr (nonirradiated group) and Ir (irradiated group). In the Ir, the animals received single-dose irradiation of 30 Gy on the tibia and were euthanized after 2 weeks. Bone microarchitecture parameters were analyzed by using micro-CT, and the osteocyte lacunar network, bone matrix, and collagen maturation by histomorphometric analysis. The data were analyzed using unpaired Student's t test (α = 0.05). RESULTS: Trabecular thickness in Ir was lower than that in NoIr (P = 0.028). No difference was found for bone volume fraction and bone area. Lacunae filled with osteocytes were more numerous (P < 0.0001) in NoIr (2.6 ± 0.6) than in Ir (1.97 ± 0.53). Empty lacunae were more prevalent (P < 0.003) in Ir (0.14 ± 0.10) than in NoIr (0.1 ± 0.1). The mean osteocyte lacunae size was higher (P < 0.01) in Ir (15.4 ± 4.41) than in NoIr (12.7 ± 3.7). Picrosirius red analysis showed more (P < 0.05) mature collagen in NoIr (29.0 ± 5.3) than in Ir (23.4 ± 4.5). Immature collagen quantification revealed no difference between groups. CONCLUSIONS: Ionizing radiation compromised bone formation and an impairment in bone repair in irradiated woven bone was observed. CLINICAL RELEVANCE: Before radiotherapy, patients usually need surgical intervention, which may be better performed, if clinicians understand the repair process in irradiated bone, using novel approaches for treating these individuals.

Spatial Manipulation and Integration of Supramolecular Filaments on Hydrogel Substrates towards Advanced Soft Devices.

Supramolecular assemblies are promising building blocks for the fabrication of functional soft devices for high-tech applications. However, there is a lack of effective methods for large-scale manipulation and integration of nano-sized supramolecular structures on soft substrate. Now, functional soft devices composed of micellar filaments and hydrogels can be created through a versatile approach involving guided dewetting, transfer-printing, and laser-assisted patterning. Such an approach enables unprecedented control over the location and alignment of the micellar filaments on hydrogel substrates. As examples, freely suspended micellar fishnets immobilized on hydrogels are formed, showing the capability of trapping and releasing micro-objects and the piconewton force sensitivity. By incorporating responsive moieties into hydrogels, shape-morphing actuators with micelle-controlled rolling directionality are constructed.

Organocatalytic Control over a Fuel-Driven Transient-Esterification Network*.

Signal transduction in living systems is the conversion of information into a chemical change, and is the principal process by which cells communicate. In nature, these functions are encoded in non-equilibrium (bio)chemical reaction networks (CRNs) controlled by enzymes. However, man-made catalytically controlled networks are rare. We incorporated catalysis into an artificial fuel-driven out-of-equilibrium CRN, where the forward (ester formation) and backward (ester hydrolysis) reactions are controlled by varying the ratio of two organocatalysts: pyridine and imidazole. This catalytic regulation enables full control over ester yield and lifetime. This fuel-driven strategy was expanded to a responsive polymer system, where transient polymer conformation and aggregation are controlled through fuel and catalyst levels. Altogether, we show that organocatalysis can be used to control a man-made fuel-driven system and induce a change in a macromolecular superstructure, as in natural non-equilibrium systems.

Interfacial Microcompartmentalization by Kinetic Control of Selective Interfacial Accumulation.

Reported here is a 2D, interfacial microcompartmentalization strategy governed by 3D phase separation. In aqueous polyethylene glycol (PEG) solutions doped with biotinylated polymers, the polymers spontaneously accumulate in the interfacial layer between the oil-surfactant-water interface and the adjacent polymer phase. In aqueous two-phase systems, these polymers first accumulated in the interfacial layer separating two polymer solutions and then selectively migrated to the oil-PEG interfacial layer. By using polymers with varying photopolymerizable groups and crosslinking rates, kinetic control and capture of spatial organisation in a variety of compartmentalized macroscopic structures, without the need of creating barrier layers, was achieved. This selective interfacial accumulation provides an extension of 3D phase separation towards synthetic compartmentalization, and is also relevant for understanding intracellular organisation.

Biomimetic Strain-Stiffening Self-Assembled Hydrogels.

Supramolecular structures with strain-stiffening properties are ubiquitous in nature but remain rare in the lab. Herein, we report on strain-stiffening supramolecular hydrogels that are entirely produced through the self-assembly of synthetic molecular gelators. The involved gelators self-assemble into semi-flexible fibers, which thereby crosslink into hydrogels. Interestingly, these hydrogels are capable of stiffening in response to applied stress, resembling biological intermediate filaments system. Furthermore, strain-stiffening hydrogel networks embedded with liposomes are constructed through orthogonal self-assembly of gelators and phospholipids, mimicking biological tissues in both architecture and mechanical properties. This work furthers the development of biomimetic soft materials with mechanical responsiveness and presents potentially enticing applications in diverse fields, such as tissue engineering, artificial life, and strain sensors.

Responsive biomimetic networks from polyisocyanopeptide hydrogels.

Mechanical responsiveness is essential to all biological systems down to the level of tissues and cells. The intra- and extracellular mechanics of such systems are governed by a series of proteins, such as microtubules, actin, intermediate filaments and collagen. As a general design motif, these proteins self-assemble into helical structures and superstructures that differ in diameter and persistence length to cover the full mechanical spectrum. Gels of cytoskeletal proteins display particular mechanical responses (stress stiffening) that until now have been absent in synthetic polymeric and low-molar-mass gels. Here we present synthetic gels that mimic in nearly all aspects gels prepared from intermediate filaments. They are prepared from polyisocyanopeptides grafted with oligo(ethylene glycol) side chains. These responsive polymers possess a stiff and helical architecture, and show a tunable thermal transition where the chains bundle together to generate transparent gels at extremely low concentrations. Using characterization techniques operating at different length scales (for example, macroscopic rheology, atomic force microscopy and molecular force spectroscopy) combined with an appropriate theoretical network model, we establish the hierarchical relationship between the bulk mechanical properties and the single-molecule parameters. Our results show that to develop artificial cytoskeletal or extracellular matrix mimics, the essential design parameters are not only the molecular stiffness, but also the extent of bundling. In contrast to the peptidic materials, our polyisocyanide polymers are readily modified, giving a starting point for functional biomimetic hydrogels with potentially a wide variety of applications, in particular in the biomedical field.

Self-Orienting Hydrogel Micro-Buckets as Novel Cell Carriers.

Hydrogel microparticles are important in materials engineering, but their applications remain limited owing to the difficulties associated with their manipulation. Herein, we report the self-orientation of crescent-shaped hydrogel microparticles and elucidate its mechanism. Additionally, the microparticles were used, for the first time, as micro-buckets to carry living cells. In aqueous solution, the microparticles spontaneously rotated to a preferred orientation with the cavity facing up. We developed a geometric model that explains the self-orienting behavior of crescent-shaped particles by minimizing the potential energy of this specific morphology. Finally, we selectively modified the particles' cavities with RGD peptide and exploited their preferred orientation to load them with living cells. Cells could adhere, proliferate, and be transported and released in vitro. These micro-buckets hold a great potential for applications in smart materials, cell therapy, and biological engineering.

Early Formation Pathways of Surfactant Micelle Directed Ultrasmall Silica Ring and Cage Structures.

By combining a surfactant, an organic pore expander, a silane, and poly(ethylene glycol) (PEG), we have observed the formation of a previously unknown set of ultrasmall silica structures in aqueous solutions. At appropriate concentrations of reagents, ∼2 nm primary silica clusters arrange around surfactant micelles to form ultrasmall silica rings, which can further evolve into cage-like structures. With increasing concentration, these rings line up into segmented worm-like one-dimensional (1D) structures, an effect that can be dramatically enhanced by PEG addition. PEG adsorbed 1D striped cylinders further arrange into higher order assemblies in the form of two-dimensional (2D) sheets or three-dimensional (3D) helical structures. Results provide insights into synergies between deformable noncovalent organic molecule assemblies and covalent inorganic network formation as well as early transformation pathways from spherical soft materials into 1D, 2D, and 3D silica solution structures, hallmarks of mesoporous silica materials formation. The ultrasmall silica ring and cage structures may prove useful in nanomedicine and other nanotechnology based applications.

Inhibiting constitutive neurogenesis compromises long-term social recognition memory.

Although the functional role for newborn neurons in neural circuits is still matter of investigation, there is no doubt that neurogenesis modulates learning and memory in rodents. In general, boosting neurogenesis before learning, using genetic-target tools or drugs, improves hippocampus-dependent memories. However, inhibiting neurogenesis may yield contradictory results depending on the type of memory evaluated. Here we tested the hypothesis that inhibiting constitutive neurogenesis would compromise social recognition memory (SRM). Male Swiss mice were submitted to three distinct procedures to inhibit neurogenesis: (1) intra-cerebral infusion of Cystosine-ß-D-Arabinofuranoside (AraC); (2) intra-peritoneal injection of temozolomide (TMZ) and (3) cranial gamma irradiation. All three methods decreased cell proliferation and neurogenesis in the dentate gyrus of the dorsal (dDG) and ventral hippocampus (vDG), and the olfactory bulb (OB). However, the percentage inhibition diverged between methods and brain regions. Ara-C, TMZ and gamma irradiation impaired SRM, though only gamma irradiation did not cause side effects on weight gain, locomotor activity and anxiety. Finally, we examined the contribution of cell proliferation in vDG, dDG and OB to SRM. The percent of inhibition in the dDG correlates with SRM, independently of the method utilized. This correlation was observed for granular cell layer of OB and vDG, only when the inhibition was induced by gamma irradiation. Animal's performance was restrained by the inhibition of dDG cell proliferation, suggesting that cell proliferation in the dDG has a greater contribution to SRM. Altogether, our results demonstrate that SRM, similarly to other hippocampus-dependent memories, has its formation impaired by reducing constitutive neurogenesis.

Deep brain stimulation probing performance is enhanced by pairing stimulus with epileptic seizure.

The unpredictability of spontaneous and recurrent seizures significantly impairs the quality of life of patients with epilepsy. Probing neural network excitability with deep brain electrical stimulation (DBS) has shown promising results predicting pathological shifts in brain states. This work presents a proof-of-principal that active electroencephalographic (EEG) probing, as a seizure predictive tool, is enhanced by pairing DBS and the electrographic seizure itself. The ictogenic model used consisted of inducing seizures by continuous intravenous infusion of pentylenetetrazol (PTZ - 2.5 mg/ml/min) while a probing DBS was delivered to the thalamus (TH) or amygdaloid complex to detect changes prior to seizure onset. Cortical electrophysiological recordings were performed before, during, and after PTZ infusion. Thalamic DBS probing, but not amygdaloid, was able to predict seizure onset without any observable proconvulsant effects. However, previously pairing amygdaloid DBS and epileptic polyspike discharges (day-1) elicited distinct preictal cortically recorded evoked response (CRER) (day-2) when compared with control groups that received the same amount of electrical pulses at different moments of the ictogenic progress at day-1. In conclusion, our results have demonstrated that the pairing strategy potentiated the detection of an altered brain state prior to the seizure onset. The EEG probing enhancement method opens many possibilities for both diagnosis and treatment of epilepsy.

Chemical physics of electroactive materials - the oft-overlooked faces of electrochemistry.

Electroactive materials and their applications are enjoying renewed attention, in no small part motivated by the advent of nanoscale tools for their preparation and study. While the fundamentals of charge and mass transport in electrolytes on this scale are by and large well understood, their interplay can have subtle manifestations in the more complex situations typical of, for example, integrated microfluidics-based applications. In particular, the role of faradaic processes is often overlooked or, at best, purposefully suppressed via experimental design. In this introductory article we discuss, using simple illustrations from our laboratories, some of the manifestations of electrochemistry in electroactive materials.