Mathematical models of neuronal growth

The establishment of a functioning neuronal network is a crucial step in neural development. During this process, neurons extend neurites—axons and dendrites—to meet other neurons and interconnect. Therefore, these neurites need to migrate, grow, branch and find the correct path to their target by processing sensory cues from their environment. These processes rely on many coupled biophysical effects including elasticity, viscosity, growth, active forces, chemical signaling, adhesion and cellular transport. Mathematical models offer a direct way to test hypotheses and understand the underlying mechanisms responsible for neuron development. Here, we critically review the main models of neurite growth and morphogenesis from a mathematical viewpoint. We present different models for growth, guidance and morphogenesis, with a particular emphasis on mechanics and mechanisms, and on simple mathematical models that can be partially treated analytically.

Sagittal expansion of the maxilla in an adult. A clinical case

Relevance. Skeletal Class III malocclusion is one of the most difficult to correct. Genetics, environmental factors, and postembryonic development influence its etiology. Sagittal expansion of the upper jaw will ensure the correct position of the lower jaw, which in turn will improve the patient's aesthetic parameters and health. The study examines a treatment method using the Fixed anterior growth guidance appliance (FAGGA).Materials and methods. This clinical case presents a 21-year-old male with skeletal class III due to maxillary bone deficiency. The patient refused surgery to increase the size of the upper jaw and opted for orthodontic treatment. The latter was performed using a Fixed anterior growth guidance appliance (FAGGA), followed by a rapid palatal (maxillary) expansion (RME) and brackets. We removed the FAGGA after eight months. The profile and occlusion improved.Results. The change in the inclination and protrusion of the maxillary incisors improved the profile. We received 2mm of space behind the upper right canine and 1.5mm of space behind the left one and the SNA angle increased by 2 degrees. The treatment continues with RME and brackets.Conclusions. An increase in inclination and protrusion of the maxillary incisors and a slight skeletal change improved the aesthetic parameters of the facial area.

The Fine Art of Writing a Message: RNA Metabolism in the Shaping and Remodeling of the Nervous System

Neuronal morphogenesis, integration into circuits, and remodeling of synaptic connections occur in temporally and spatially defined steps. Accordingly, the expression of proteins and specific protein isoforms that contribute to these processes must be controlled quantitatively in time and space. A wide variety of post-transcriptional regulatory mechanisms, which act on pre-mRNA and mRNA molecules contribute to this control. They are thereby critically involved in physiological and pathophysiological nervous system development, function, and maintenance. Here, we review recent findings on how mRNA metabolism contributes to neuronal development, from neural stem cell maintenance to synapse specification, with a particular focus on axon growth, guidance, branching, and synapse formation. We emphasize the role of RNA-binding proteins, and highlight their emerging roles in the poorly understood molecular processes of RNA editing, alternative polyadenylation, and temporal control of splicing, while also discussing alternative splicing, RNA localization, and local translation. We illustrate with the example of the evolutionary conserved Musashi protein family how individual RNA-binding proteins are, on the one hand, acting in different processes of RNA metabolism, and, on the other hand, impacting multiple steps in neuronal development and circuit formation. Finally, we provide links to diseases that have been associated with the malfunction of RNA-binding proteins and disrupted post-transcriptional regulation.

Fibrin Glue and Conduit Form a Composite Structure in Digital Nerve Repair

Repair of severed nerves without auto- or allograft has included suture, suture with glue alone, suture with conduit and suture with glue augmentation to conduit, where use of conduit is considered for separation of the nerve ends from 5mm to 3cm. Repairs must not only serve acutely to provide apposition of nerve ends but must enable the healing of the nerve. Using biological conduit can place suture at the ends of the conduit while fibrin glue alone eliminates suture but with limited strength. The combination of conduit and glue offers the growth guidance of conduit with sufficient strength from the glue to maintain the nerve within the conduit. The role of glue in the repair integrity remains an open question, however. We sought to determine the factors in the strength of a glue-conduit-nerve construct and include consideration of standard suture repair. Fresh-frozen cadaveric digital nerves were repaired with suture alone, with glue alone or with suture and glue together and loaded to failure. Previously tested specimens with conduit, suture and glue were considered for comparison. The suture alone (2.02N) and suture with glue (2.24N) were not statistically different from each other but were statistically stronger than glue alone (0.15N). Compared to the earlier results of the strength of conduit with glue (0.65N), these results show that the glue and conduit act together. The increased area over which the glue adheres to the nerve and conduit creates a composite structure stronger than either alone.

Male Differentiation in the Marine Copepod Oithona nana Reveals the Development of a New Nervous Ganglion and Lin12-Notch-Repeat Protein-Associated Proteolysis

Copepods are among the most numerous animals, and they play an essential role in the marine trophic web and biogeochemical cycles. The genus Oithona is described as having the highest density of copepods. The Oithona male paradox describes the activity states of males, which are obliged to alternate between immobile and mobile phases for ambush feeding and mate searching, respectively, while the female is less mobile and feeds less. To characterize the molecular basis of this sexual dimorphism, we combined immunofluorescence, genomics, transcriptomics, and protein–protein interaction approaches and revealed the presence of a male-specific nervous ganglion. Transcriptomic analysis showed male-specific enrichment for nervous system development-related transcripts. Twenty-seven Lin12-Notch Repeat domain-containing protein coding genes (LDPGs) of the 75 LDPGs identified in the genome were specifically expressed in males. Furthermore, some LDPGs coded for proteins with predicted proteolytic activity, and proteases-associated transcripts showed a male-specific enrichment. Using yeast double–hybrid assays, we constructed a protein–protein interaction network involving two LDPs with proteases, extracellular matrix proteins, and neurogenesis-related proteins. We also hypothesized possible roles of the LDPGs in the development of the lateral ganglia through helping in extracellular matrix lysis, neurites growth guidance, and synapses genesis.

Maxillary sagittal expansion in an adult patient

Relevance. Skeletal Class III malocclusion is known to be one of the most difficult malocclusions to correct. Nonsurgical treatment of Class III in adults is a challenge; however, this patient refused surgery. A treatment method with Fixed Anterior Growth Guidance Appliance (FAGGA) was investigated in the study.Materials and methods. This case report presents a 37-year-old woman with skeletal Class III malocclusion for maxillary deficiency. As the patient didn’t agree to surgery, she was treated by Fixed Anterior Growth Guidance Appliance, followed by 3D SMILE® clear aligners. Fixed Anterior Growth Guidance Appliance was used initially. After 4 months, the appliance was removed and clear aligner treatment was initiated. Post-treatment radiographs showed improvement.Results. Intraorally, in the upper arch, a total of 4.00 mm of space were gained (about 2.00mm distal to each canine). The post-treatment cephalometric analysis showed a skeletal A-P Class I, the Upper incisor inclination to the optic plane was not significantly altered, ANS — antArc was improved by 1.5mm, the Effective Length of the Premaxilla increased by 2.6mm, U1 — ANS’ decreased by 1.7mm, Incisor mandibular plane angle (IMPA) autonomously improved by 11 degrees.Conclusions. Maxillary deficiency was corrected successfully with the Fixed Anterior Growth Guidance Appliance. The treatment is being continued by 3D SMILE® clear aligners. The goal was achieved despite the patient’s age and nonsurgical treatment.

Fundamentals of the Development of Connectivity in the Human Fetal Brain in Late Gestation: From 24 Weeks Gestational Age to Term

During the second half of gestation, the human cerebrum undergoes pivotal histogenetic events that underlie functional connectivity. These include the growth, guidance, selection of axonal pathways, and their first engagement in neuronal networks. Here, we characterize the spatiotemporal patterns of cerebral connectivity in extremely preterm (EPT), very preterm (VPT), preterm and term babies, focusing on magnetic resonance imaging (MRI) and histological data. In the EPT and VPT babies, thalamocortical axons enter into the cortical plate creating the electrical synapses. Additionally, the subplate zone gradually resolves in the preterm and term brain in conjunction with the growth of associative pathways leading to the activation of large-scale neural networks. We demonstrate that specific classes of axonal pathways within cerebral compartments are selectively vulnerable to temporally nested pathogenic factors. In particular, the radial distribution of axonal lesions, that is, radial vulnerability, is a robust predictor of clinical outcome. Furthermore, the subplate tangential nexus that we can visualize using MRI could be an additional marker as pivotal in the development of cortical connectivity. We suggest to direct future research toward the identification of sensitive markers of earlier lesions, the elucidation of genetic mechanisms underlying pathogenesis, and better long-term follow-up using structural and functional MRI.

ECM-Mimetic Nylon Nanofiber Scaffolds for Neurite Growth Guidance

Numerous nanostructured synthetic scaffolds mimicking the architecture of the natural extracellular matrix (ECM) have been described, but the polymeric nanofibers comprising the scaffold were substantially thicker than the natural collagen nanofibers of neural ECM. Here, we report neuron growth on electrospun scaffolds of nylon-4,6 fibers with an average diameter of 60 nm, which closely matches the diameter of collagen nanofibers of neural ECM, and compare their properties with the scaffolds of thicker 300 nm nanofibers. Previously unmodified nylon was not regarded as an independent nanostructured matrix for guided growth of neural cells; however, it is particularly useful for ultrathin nanofiber production. We demonstrate that, while both types of fibers stimulate directed growth of neuronal processes, ultrathin fibers are more efficient in promoting and accelerating neurite elongation. Both types of scaffolds also improved synaptogenesis and the formation of connections between hippocampal neurons; however, the mechanisms of interaction of neurites with the scaffolds were substantially different. While ultrathin fibers formed numerous weak immature β1-integrin-positive focal contacts localized over the entire cell surface, scaffolds of submicron fibers formed β1-integrin focal adhesions only on the cell soma. This indicates that the scaffold nanotopology can influence focal adhesion assembly involving various integrin subunits. The fabricated nanostructured scaffolds demonstrated high stability and resistance to biodegradation, as well as absence of toxic compound release after 1 month of incubation with live cells in vitro. Our results demonstrate the high potential of this novel type of nanofibers for clinical application as substrates facilitating regeneration of nervous tissue.