Diverse CMT2 neuropathies are linked to aberrant G3BP interactions in stress granules.

Complex diseases often involve the interplay between genetic and environmental factors. Charcot-Marie-Tooth type 2 neuropathies (CMT2) are a group of genetically heterogeneous disorders, in which similar peripheral neuropathology is inexplicably caused by various mutated genes. Their possible molecular links remain elusive. Here, we found that upon environmental stress, many CMT2-causing mutant proteins adopt similar properties by entering stress granules (SGs), where they aberrantly interact with G3BP and integrate into SG pathways. For example, glycyl-tRNA synthetase (GlyRS) is translocated from the cytoplasm into SGs upon stress, where the mutant GlyRS perturbs the G3BP-centric SG network by aberrantly binding to G3BP. This disrupts SG-mediated stress responses, leading to increased stress vulnerability in motoneurons. Disrupting this aberrant interaction rescues SG abnormalities and alleviates motor deficits in CMT2D mice. These findings reveal a stress-dependent molecular link across diverse CMT2 mutants and provide a conceptual framework for understanding genetic heterogeneity in light of environmental stress.

Celsr1 suppresses Wnt5a-mediated chemoattraction to prevent incorrect rostral migration of facial branchiomotor neurons.

In the developing hindbrain, facial branchiomotor (FBM) neurons migrate caudally from rhombomere 4 (r4) to r6 to establish the circuit that drives jaw movements. Although the mechanisms regulating initiation of FBM neuron migration are well defined, those regulating directionality are not. In mutants lacking the Wnt/planar cell polarity (PCP) component Celsr1, many FBM neurons inappropriately migrate rostrally into r3. We hypothesized that Celsr1 normally blocks inappropriate rostral migration of FBM neurons by suppressing chemoattraction towards Wnt5a in r3 and successfully tested this model. First, FBM neurons in Celsr1; Wnt5a double mutant embryos never migrated rostrally, indicating that inappropriate rostral migration in Celsr1 mutants results from Wnt5a-mediated chemoattraction, which is suppressed in wild-type embryos. Second, FBM neurons migrated rostrally toward Wnt5a-coated beads placed in r3 of wild-type hindbrain explants, suggesting that excess Wnt5a chemoattractant can overcome endogenous Celsr1-mediated suppression. Third, rostral migration of FBM neurons was greatly enhanced in Celsr1 mutants overexpressing Wnt5a in r3. These results reveal a novel role for a Wnt/PCP component in regulating neuronal migration through suppression of chemoattraction.

Wide bandgap semiconductor nanomembranes as a long-term biointerface for flexible, implanted neuromodulator.

Electrical neuron stimulation holds promise for treating chronic neurological disorders, including spinal cord injury, epilepsy, and Parkinson's disease. The implementation of ultrathin, flexible electrodes that can offer noninvasive attachment to soft neural tissues is a breakthrough for timely, continuous, programable, and spatial stimulations. With strict flexibility requirements in neural implanted stimulations, the use of conventional thick and bulky packages is no longer applicable, posing major technical issues such as short device lifetime and long-term stability. We introduce herein a concept of long-lived flexible neural electrodes using silicon carbide (SiC) nanomembranes as a faradic interface and thermal oxide thin films as an electrical barrier layer. The SiC nanomembranes were developed using a chemical vapor deposition (CVD) process at the wafer level, and thermal oxide was grown using a high-quality wet oxidation technique. The proposed material developments are highly scalable and compatible with MEMS technologies, facilitating the mass production of long-lived implanted bioelectrodes. Our experimental results showed excellent stability of the SiC/silicon dioxide (SiO2) bioelectronic system that can potentially last for several decades with well-maintained electronic properties in biofluid environments. We demonstrated the capability of the proposed material system for peripheral nerve stimulation in an animal model, showing muscle contraction responses comparable to those of a standard non-implanted nerve stimulation device. The design concept, scalable fabrication approach, and multimodal functionalities of SiC/SiO2 flexible electronics offer an exciting possibility for fundamental neuroscience studies, as well as for neural stimulation-based therapies.

Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy.

Charcot-Marie-Tooth disease (CMT) is a genetic peripheral neuropathy caused by mutations in many functionally diverse genes. The aminoacyl-tRNA synthetase (ARS) enzymes, which transfer amino acids to partner tRNAs for protein synthesis, represent the largest protein family genetically linked to CMT aetiology, suggesting pathomechanistic commonalities. Dominant intermediate CMT type C (DI-CMTC) is caused by YARS1 mutations driving a toxic gain-of-function in the encoded tyrosyl-tRNA synthetase (TyrRS), which is mediated by exposure of consensus neomorphic surfaces through conformational changes of the mutant protein. In this study, we first showed that human DI-CMTC-causing TyrRSE196K mis-interacts with the extracellular domain of the BDNF receptor TrkB, an aberrant association we have previously characterised for several mutant glycyl-tRNA synthetases linked to CMT type 2D (CMT2D). We then performed temporal neuromuscular assessments of YarsE196K mice modelling DI-CMT. We determined that YarsE196K homozygotes display a selective, age-dependent impairment in in vivo axonal transport of neurotrophin-containing signalling endosomes, phenocopying CMT2D mice. This impairment is replicated by injection of recombinant TyrRSE196K, but not TyrRSWT, into muscles of wild-type mice. Augmenting BDNF in DI-CMTC muscles, through injection of recombinant protein or muscle-specific gene therapy, resulted in complete axonal transport correction. Therefore, this work identifies a non-cell autonomous pathomechanism common to ARS-related neuropathies, and highlights the potential of boosting BDNF levels in muscles as a therapeutic strategy.

Upper motor neuron signs in primary lateral sclerosis and hereditary spastic paraplegia.

INTRODUCTION/AIMS: The frequency and distribution of upper motor neuron (UMN) signs in primary lateral sclerosis (PLS) are unknown. We aimed to study the spectrum of UMN signs in PLS and compare it with hereditary spastic paraplegia (HSP). METHODS: We retrospectively analyzed the frequency of different UMN signs, including hyperreflexia (limbs and jaw), limb and tongue spasticity, Babinski, and Hoffman signs, in PLS patients at first observation and compared this respect to onset region and symptom duration. We also compared PLS versus HSP patients. RESULTS: We included 34 PLS and 20 HSP patients, with a median symptom duration at first visit of 3.0 (interquartile range, IQR = 4.0) and 19.0 (IQR = 22.0) years, respectively. In PLS patients, hyperreflexia of upper (UL) (88.2%) and lower (LL) (91.2%) limbs, and LL spasticity (79.4%) were the most common findings. Spasticity of LL was significantly (p = .012) more frequent in LL-spinal onset subgroup, tongue spasticity in bulbar-onset subgroup (p = .021), and Hoffman sign in UL-spinal onset subgroup (p = .024). The PLS subgroup with shorter disease duration had a higher frequency of abnormal jaw jerk reflex (p = .037). Compared with HSP, PLS patients had a higher frequency of UL hyperreflexia (88.2% vs. 42.1%, p < .001) and UL spasticity (44.1% vs. 0.0%, p < .001). Asymmetric distribution of UMN signs was present in PLS and not in HSP. DISCUSSION: In PLS, UL UMN signs are nearly always present and UMN sign distribution appears to be associated with onset region. At first observation, bulbar involvement, asymmetrical distribution of UMN signs and UL spasticity may indicate PLS versus HSP.

Amyotrophic lateral sclerosis associated with Sjögren's syndrome: a case report.

BACKGROUND: Motor neuron disease (MND) is a chronic and progressive neurodegenerative disorder with an unknown cause. The development of amyotrophic lateral sclerosis (ALS) is believed to be linked to an immune response. Monocytes/macrophages and T cells are key players in the disease's advancement. Monitoring levels of cytokines in the blood can help forecast patient outcomes, while immunotherapy shows promise in alleviating symptoms for certain individuals. CASE PRESENTATION: A 56-year-old male patient was admitted to the hospital due to progressive limb weakness persisting for eight months. The neurological examination revealed impairments in both upper and lower motor neurons, as well as sensory anomalies, without corresponding signs. Electrophysiological examination results indicated extensive neuronal damage and multiple peripheral nerve impairments, thereby the diagnosis was ALS. One month ago, the patient began experiencing symptoms of dry mouth and a bitter taste. Following tests for rheumatic immune-related antibodies and a lip gland biopsy, a diagnosis of Sjögren's syndrome (SS) was proposed. Despite treatment with medications such as hormones (methylprednisolone), immunosuppressants (hydroxychloroquine sulfate), and riluzole, the symptoms did not significantly improve, but also did not worsen. CONCLUSION: It is recommended to include screening for SS in the standard assessment of ALS. Furthermore, research should focus on understanding the immune mechanisms involved in ALS, providing new insights for the diagnosis and treatment of ALS in conjunction with SS.

Combined RNA interference and gene replacement therapy targeting MFN2 as proof of principle for the treatment of Charcot-Marie-Tooth type 2A.

Mitofusin-2 (MFN2) is an outer mitochondrial membrane protein essential for mitochondrial networking in most cells. Autosomal dominant mutations in the MFN2 gene cause Charcot-Marie-Tooth type 2A disease (CMT2A), a severe and disabling sensory-motor neuropathy that impacts the entire nervous system. Here, we propose a novel therapeutic strategy tailored to correcting the root genetic defect of CMT2A. Though mutant and wild-type MFN2 mRNA are inhibited by RNA interference (RNAi), the wild-type protein is restored by overexpressing cDNA encoding functional MFN2 modified to be resistant to RNAi. We tested this strategy in CMT2A patient-specific human induced pluripotent stem cell (iPSC)-differentiated motor neurons (MNs), demonstrating the correct silencing of endogenous MFN2 and replacement with an exogenous copy of the functional wild-type gene. This approach significantly rescues the CMT2A MN phenotype in vitro, stabilizing the altered axonal mitochondrial distribution and correcting abnormal mitophagic processes. The MFN2 molecular correction was also properly confirmed in vivo in the MitoCharc1 CMT2A transgenic mouse model after cerebrospinal fluid (CSF) delivery of the constructs into newborn mice using adeno-associated virus 9 (AAV9). Altogether, our data support the feasibility of a combined RNAi and gene therapy strategy for treating the broad spectrum of human diseases associated with MFN2 mutations.

A novel model of autologous tooth transplantation for the study of nerve recruitment.

BACKGROUND: Limited treatment options exist for damaged nerves and despite impressive advances in tissue engineering, scientists and clinicians have yet to fully replicate nerve development and recruitment. Innervation is a critical feature for normal organ function. While most organs are innervated prior to birth, a rare example of postnatal nerve recruitment occurs in the natural development of secondary teeth during adolescence. Many animals undergo postnatal shedding of deciduous teeth with development and eruption of secondary teeth, a process requiring recruitment of nerve and vasculature to each tooth pulp for viability. Here, the investigators created a novel model for the study of postnatal innervation by exploiting the natural phenomenon of tooth-driven nerve recruitment. METHODS: The investigators theorized that developing teeth possess a special capacity to induce innervation which could be harnessed in a clinical setting for nerve regeneration, and hyptothesized that a transplant model could be created to capture this phenomenon. In this descriptive study, a rat model of autologous tooth transplantation and de novo nerve recruitment was developed by surgically transferring whole developing molars to the autologous tibia. RESULTS: Downstream histological analysis performed 6 to 14 weeks after surgery demonstrated integration of molar into tibia in 81% of postoperative rats, with progressive pulpal expression of nerve marker ß-tubulin III suggestive of neuronal recruitment. CONCLUSIONS: These findings provide a novel model for the study of organ transplantation and support the theory that developing dental tissues may retain nerve-inductive properties postnatally.

Effects of jaw clenching and mental stress on persistent inward currents estimated by two different methods.

Spinal motoneuron firing depends greatly on persistent inward currents (PICs), which in turn are facilitated by the neuromodulators serotonin and noradrenaline. The aim of this study was to determine whether jaw clenching (JC) and mental stress (MS), which may increase neuromodulator release, facilitate PICs in human motoneurons. The paired motor unit (MU) technique was used to estimate PIC contribution to motoneuron firing. Surface electromyograms were collected using a 32-channel matrix on gastrocnemius medialis (GM) during voluntary, ramp, plantar flexor contractions. MU discharges were identified, and delta frequency (ΔF), a measure of recruitment-derecruitment hysteresis, was calculated. Additionally, another technique was used (VibStim) that evokes involuntary contractions that persist after cessation of combined Achilles tendon vibration and triceps surae neuromuscular electrical stimulation. VibStim measures of plantar flexor torque and soleus activity may reflect PIC activation. ΔF was not significantly altered by JC (p = .679, n = 18, 9 females) or MS (p = .147, n = 14, 5 females). However, all VibStim variables quantifying involuntary torque and muscle activity during and after vibration cessation were significantly increased in JC (p < .011, n = 20, 10 females) and some, but not all, increased in MS (p = .017-.05, n = 19, 10 females). JC and MS significantly increased the magnitude of involuntary contractions (VibStim) but had no effect on GM ΔF during voluntary contractions. Effects of increased neuromodulator release on PIC contribution to motoneuron firing might differ between synergists or be context dependent. Based on these data, the background level of voluntary contraction and, hence, both neuromodulation and ionotropic inputs could influence neuromodulatory PIC enhancement.

Facial nerve vulnerability in spinal muscular atrophy and motor unit number index of the orbicularis oculi muscle.

INTRODUCTION/AIMS: Measures for assessing cranial nerve vulnerability in spinal muscular atrophy (SMA) have not yet been determined. Motor unit number index (MUNIX) studies have shown correlations with disease severity but have been used only in limb muscles. In the present study, we explore facial nerve response, MUNIX, and motor unit size index (MUSIX) of the orbicularis oculi muscle in a cohort of patients with SMA. METHODS: Facial nerve response (measured as compound muscle action potential, CMAP), MUNIX, and MUSIX of the orbicularis oculi muscle were cross-sectionally recorded in patients with SMA and compared to healthy control subjects (HCs). Active maximum mouth opening (aMMO) was also measured at baseline in our SMA cohort. RESULTS: Thirty-seven patients with SMA (21 SMA II; 16 SMA III) and 27 HCs were recruited. CMAP of the facial nerve and MUNIX of orbicularis oculi proved to be feasible and well tolerated techniques. CMAP amplitude and MUNIX scores were significantly lower in patients with SMA compared to HCs (p < .0001). Both MUNIX and CMAP amplitude were significantly higher in patients with SMA III compared to SMA II. No significant difference emerged comparing CMAP amplitude, MUNIX and MUSIX scores between those with different functional status or nusinersen treatment. DISCUSSION: Our results provide neurophysiological evidence of facial nerve and muscle involvement in patients with SMA. CMAP of the facial nerve and MUNIX of orbicularis oculi showed high accuracy in discriminating between the various subtypes of SMA and in quantifying the motor unit loss of the facial nerve.

Activation of Cerebellum, Basal Ganglia and Thalamus During Observation and Execution of Mouth, hand, and foot Actions.

Humans and monkey studies showed that specific sectors of cerebellum and basal ganglia activate not only during execution but also during observation of hand actions. However, it is unknown whether, and how, these structures are engaged during the observation of actions performed by effectors different from the hand. To address this issue, in the present fMRI study, healthy human participants were required to execute or to observe grasping acts performed with different effectors, namely mouth, hand, and foot. As control, participants executed and observed simple movements performed with the same effectors. The results show that: (1) execution of goal-directed actions elicited somatotopically organized activations not only in the cerebral cortex but also in the cerebellum, basal ganglia, and thalamus; (2) action observation evoked cortical, cerebellar and subcortical activations, lacking a clear somatotopic organization; (3) in the territories displaying shared activations between execution and observation, a rough somatotopy could be revealed in both cortical, cerebellar and subcortical structures. The present study confirms previous findings that action observation, beyond the cerebral cortex, also activates specific sectors of cerebellum and subcortical structures and it shows, for the first time, that these latter are engaged not only during hand actions observation but also during the observation of mouth and foot actions. We suggest that each of the activated structures processes specific aspects of the observed action, such as performing internal simulation (cerebellum) or recruiting/inhibiting the overt execution of the observed action (basal ganglia and sensory-motor thalamus).

Dynein Dysfunction Prevents Maintenance of High Concentrations of Slow Axonal Transport Cargos at the Axon Terminal: A Computational Study.

Here, we report computational studies of bidirectional transport in an axon, specifically focusing on predictions when the retrograde motor becomes dysfunctional. We are motivated by reports that mutations in dynein-encoding genes can cause diseases associated with peripheral motor and sensory neurons, such as type 2O Charcot-Marie-Tooth disease. We use two different models to simulate bidirectional transport in an axon: an anterograde-retrograde model, which neglects passive transport by diffusion in the cytosol, and a full slow transport model, which includes passive transport by diffusion in the cytosol. As dynein is a retrograde motor, its dysfunction should not directly influence anterograde transport. However, our modeling results unexpectedly predict that slow axonal transport fails to transport cargos against their concentration gradient without dynein. The reason is the lack of a physical mechanism for the reverse information flow from the axon terminal, which is required so that the cargo concentration at the terminal could influence the cargo concentration distribution in the axon. Mathematically speaking, to achieve a prescribed concentration at the terminal, equations governing cargo transport must allow for the imposition of a boundary condition postulating the cargo concentration at the terminal. Perturbation analysis for the case when the retrograde motor velocity becomes close to zero predicts uniform cargo distributions along the axon. The obtained results explain why slow axonal transport must be bidirectional to allow for the maintenance of concentration gradients along the axon length. Our result is limited to small cargo diffusivity, which is a reasonable assumption for many slow axonal transport cargos (such as cytosolic and cytoskeletal proteins, neurofilaments, actin, and microtubules) which are transported as large multiprotein complexes or polymers.

How to Enhance the Success of Selective Neurectomy for Facial Synkinesis by Considering the Patient's Preferences: Lesson Learned from a Retrospective Analysis of 122 Cases.

BACKGROUND: Facial synkinesis can result in facial tightness, smile dysfunction, and eyelid aperture narrowing due to overactive and uncoordinated muscle activity. We hypothesized that the outcome of a selective neurectomy could rely on the patient's chief complaints. METHODS: We retrospectively reviewed 122 patients who underwent selective neurectomy at our hospital. Preoperatively, the patients were asked nine questionnaires to identify their two major chief complaints (treatment priorities). Postoperatively, facial tightness, limited mouth movement, and eyelid aperture narrowing were measured. RESULTS: The most common chief complaints in our series were facial tightness (n=38), eyelid narrowing (n=32), and limited mouth movement (n=28); the second most common chief complaints (second priority) were limited mouth movement (n=47), facial tightness (n=21), and eyelid narrowing (n=20). The mean score for facial tightness significantly improved from 4.3 to 1.1 in the first priority group. Among the 28 patients whose corners of the mouth constituted the top priority of surgical correction, the vertical inclination on the affected side significantly improved from 74.1 ± 7.6° to 55.5 ± 6.0°, and the horizontal angles were changed from 4.2 ± 2.7° to 2.0 ± 1.3° after selective neurectomy without statistically significant. Among the 32 patients for whom eyelid narrowing constituted the top priority, the mean eyelid narrowing score improved from 4.5 ± 1.1 to 1.5 ± 1.2. CONCLUSIONS: Selective neurectomy can provide a significantly satisfactory outcome regarding facial tightness and eyelid aperture narrowing. The vertical inclination of the mouth corner can be significantly improved, while the improvement of horizontal angles can be suboptimal. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Human gingival mesenchymal stem cells improve movement disorders and tyrosine hydroxylase neuronal damage in Parkinson disease rats.

BACKGROUND AIMS: Gingival mesenchymal stem cells (GMSCs) demonstrate high proliferation, trilineage differentiation and immunomodulatory properties. Parkinson disease (PD) is the second most common type of neurodegenerative disease. This study aimed to explore the effect and mechanism of GMSC-based therapy in 6-hydroxydopamine-induced PD rats. METHODS: RNA sequencing and quantitative proteomics technology was used to validate the neuroprotective role of GMSCs therapeutic in 6-Hydroxydopamine -induced PD model in vitro and in vivo. Western blotting, immunofluorescence and real-time quantitative PCR verified the molecular mechanism of GMSCs treatment. RESULTS: Intravenous injection of GMSCs improved rotation and forelimb misalignment behavior, enhanced the anti-apoptotic B-cell lymphoma 2/B-cell lymphoma 2-associated X axis, protected tyrosine hydroxylase neurons, decreased the activation of astrocytes and reduced the astrocyte marker glial fibrillary acidic protein and microglia marker ionized calcium-binding adaptor molecule 1 in the substantia nigra and striatum of PD rats. The authors found that GMSCs upregulated nerve regeneration-related molecules and inhibited metabolic disorders and the activation of signal transducer and activator of transcription 3. GMSCs showed a strong ability to protect neurons and reduce mitochondrial membrane potential damage and reactive oxygen species accumulation. The safety of GMSC transplantation was confirmed by the lack of tumor formation following subcutaneous transplantation into nude mice for up to 8 weeks. CONCLUSIONS: The authors' research helps to explain the mechanism of GMSC-based therapeutic strategies and promote potential clinical application in Parkinson disease.

Evaluation of serum neuron specific enolase levels among patients with primary and secondary burning mouth syndrome.

INTRODUCTION: Burning mouth syndrome is a painful condition of the oral cavity with ambiguous pathogenesis and diagnosis. Neuron-specific enolase is increased in several conditions including peripheral neuropathy of diabetes, ophthalmopathies, spinal cord injuries and tumors. Evidence on association of burning mouth syndrome and neuron-specific enolase is limited. AIM: This study aims to evaluate neuron-specific enolase levels in primary and secondary burning mouth syndrome patients and compare the levels of neuron-specific enolase with associated conditions in secondary burning mouth syndrome. METHODS: One hundred and twenty-eight patients of more than 18 years of age with no gender predilection and having clinical symptoms of burning mouth syndrome and 135 healthy subjects were included. All the patients fulfilled Scala's criteria for the diagnosis of burning mouth syndrome, including "primary" (idiopathic) and "secondary" (resulting from identified precipitating factors) burning mouth syndrome patients. Blood samples were obtained from burning mouth syndrome patients. Serum neuron-specific enolase was evaluated using enzyme-linked immunosorbent assay. To compare means and standard deviations, among primary and secondary burning mouth syndrome, data was analysed with analysis of variance and multiple comparisons test. RESULTS: The mean age of the study participants for burning mouth syndrome and healthy subjects was 53.30 and 51.6 years, respectively. Amongst the secondary burning mouth syndrome group, 32 (25%) of the patients had menopause, 15 (11.7%) had diabetes, eight (6.2%) of the patients had nutritional deficiency, seven (5.4%) had combined diabetes, menopause, and depression, six (4.6%) had combined diabetes and depression, four (3.1%) were diagnosed with Sjögren's syndrome. A minor percentage of 2.3% (three) had gastroesophageal reflux disease, while the remaining three (2.3%) patients in the secondary burning mouth syndrome group were on anti-depressants. There was a statistically significant increase in the levels of neuron-specific enolase in primary burning mouth syndrome as compared to the secondary burning mouth syndrome and healthy groups. Among the subgroups of secondary burning mouth syndrome, diabetic individuals showed a significant increase in neuron-specific enolase level when compared with other conditions in the secondary burning mouth syndrome patients.Discussion and conclusion: The raised serum neuron-specific enolase levels in patients suffering from primary burning mouth syndrome highlight a possible neuropathic mechanism. It was also increased in the sub-group of secondary burning mouth syndrome patients having diabetes. Although it cannot be ascertained whether the deranged values in the diabetic group were due to burning mouth syndrome or due to diabetes, the raised quantity of neuron-specific enolase in the primary burning mouth syndrome group is a reliable diagnostic indicator. Future studies on the assessment of neuron-specific enolase levels as a diagnostic tool for onset and management of primary and secondary burning mouth syndrome are recommended.

Effects of laminin-111 peptide coatings on rat neural stem/progenitor cell culture.

Neurons require adhesive scaffolds for their growth and differentiation. Laminins are a major cell adhesive component of basement membranes and have various biological activities in the peripheral and central nervous systems. Here, we evaluated the biological activities of 5 peptides derived from laminin-111 as a scaffold for mouse neuroblastoma Neuro2a cells and rat neural stem/progenitor cells (NPCs). The 5 peptides showed Neuro2a cell attachment activity similar to that of poly-d-lysine. However, when NPCs were cultured on the peptides, 2 syndecan-binding peptides, AG73 (RKRLQVQLSIRT, mouse laminin α1 chain 2719-2730) and C16 (KAFDITYVRLKF, laminin γ1 chain 139-150), demonstrated significantly higher cell attachment and neurite extension activities than other peptides including integrin-binding ones. Long-term cell culture experiments showed that both AG73 and C16 supported the growth of neurons and astrocytes that had differentiated from NPCs. Furthermore, C16 markedly promoted the expression of neuronal markers such as synaptosomal-associated protein-25 and syntaxin 1A. These results indicate that AG73 and C16 are useful for NPC cultures and that C16 can be applied to specialized research on synapses in differentiated neurons. These peptides have the potential for use as valuable biomaterials for NPC research.

A critical review on microbial degradation of petroleum-based plastics: quantitatively effects of chemical addition in cultivation media on biodegradation efficiency.

Petroleum-based plastics (PBP) with different properties have been developed to suit various needs of modern lives. Nevertheless, these well-developed properties also present the double-edged sword effect that significantly threatens the sustainability of the environment. This work focuses on the impact of microbial cultivating conditions (the elementary compositions and temperature) to provide insightful information for the process optimization of microbial degradation. The major elementary compositions in cultivation media and temperature from the literature were radically reviewed and assessed using the constructed supervised machine learning algorithm. Fifty-two literatures were collected as a training dataset to investigate the impact of major chemical elements and cultivation temperature upon PBP biodegradation. Among six singular parameters (NH4+, K+, PO43-, Mg2+, Ca2+, and temperature) and thirty corresponding binary parameters, four singular (NH4+, K+, PO43-, and Mg2+) and six binary parameters (NH4+/K+, NH4+/PO43-, NH4+/Ca2+, K+/PO43-, PO43-/Mg2+, Mg2+/Temp) were identified as statistically significant towards microbial degradation through analysis of variance (ANOVA). The binary effect (PO43-/Mg2+) is found to be the most statistically significant towards the microbial degradation of PBP. The concentration range, which locates at 0.1-0.6 g/L for Mg2+ and 0-2.8 g/L for PO43-, was identified to contribute to the maximum PBP biodegradation. Among all the investigated elements, Mg2+ is the only element that is statistically and significantly associated with the variations of cultivation temperature. The optimal preparation conditions within ± 20% uncertainties based upon the range of collected literature reports are recommended. Five representative cultivation elementary compositions (NH4+, K+, PO43-, Mg2+, and Ca2+) and temperature were reviewed from fifty two different literature reports to investigate their impacts on the microbial degradation of PBP using supervised machine learning algorithm. The optimal cultivation conditions based upon collected literature reports to achieve biodegradation over 80% were identified.

Mastication in Patients with Spinal Muscular Atrophy Types 2 and 3 is Characterized by Abnormal Efficiency, Reduced Endurance, and Fatigue.

Mastication problems can have a negative impact on the intake of food and quality of life. This cross-sectional study characterizes mastication problems using clinical and instrumental assessments in patients with spinal muscular atrophy (SMA) types 2 and 3 with self-reported bulbar problems. We included 27 patients (aged 13-67 years), 18 with SMA type 2 and 9 patients with SMA type 3 (of whom three were still ambulant) and applied a questionnaire, clinical mastication tests (TOMASS and 6-min mastication test), and muscle ultrasound of the mastication muscles. Non-ambulant patients demonstrated inefficient mastication as reflected by median z scores for masticatory cycles (z = 1.8), number of swallows (z = 4.3) and time needed to finish the cracker (z = 3.4), and limited endurance of continuous mastication as demonstrated by the median z scores of the 6-min mastication test (z = - 1.5). Patients reported increased fatigue directly after the 6-min mastication test as well as 5 min after completing the test (p < 0.001; p = 0.003). Reduced maximal mouth opening was associated with mastication problems (p < 0.001). Muscle ultrasound of the mastication muscles showed an abnormal muscle structure in 90% of both ambulant and non-ambulant patients. This study aims to understand the nature and underlying mechanisms of mastication problems in patients with SMA types 2 and 3 with reported bulbar problems.

How Temperature Influences Sleep.

Sleep is a fundamental, evolutionarily conserved, plastic behavior that is regulated by circadian and homeostatic mechanisms as well as genetic factors and environmental factors, such as light, humidity, and temperature. Among environmental cues, temperature plays an important role in the regulation of sleep. This review presents an overview of thermoreception in animals and the neural circuits that link this process to sleep. Understanding the influence of temperature on sleep can provide insight into basic physiologic processes that are required for survival and guide strategies to manage sleep disorders.

Retrograde Axonal Transport of Liposomes from Peripheral Tissue to Spinal Cord and DRGs by Optimized Phospholipid and CTB Modification.

Despite recent advancements in therapeutic options for disorders of the central nervous system (CNS), the lack of an efficient drug-delivery system (DDS) hampers their clinical application. We hypothesized that liposomes could be optimized for retrograde transport in axons as a DDS from peripheral tissues to the spinal cord and dorsal root ganglia (DRGs). Three types of liposomes consisting of DSPC, DSPC/POPC, or POPC in combination with cholesterol (Chol) and polyethylene glycol (PEG) lipid were administered to sciatic nerves or the tibialis anterior muscle of mature rats. Liposomes in cell bodies were detected with infrared fluorescence of DiD conjugated to liposomes. Three days later, all nerve-administered liposomes were retrogradely transported to the spinal cord and DRGs, whereas only muscle-administered liposomes consisting of DSPC reached the spinal cord and DRGs. Modification with Cholera toxin B subunit improved the transport efficiency of liposomes to the spinal cord and DRGs from 4.5% to 17.3% and from 3.9% to 14.3% via nerve administration, and from 2.6% to 4.8% and from 2.3% to 4.1% via muscle administration, respectively. Modification with octa-arginine (R8) improved the transport efficiency via nerve administration but abolished the transport capability via muscle administration. These findings provide the initial data for the development of a novel DDS targeting the spinal cord and DRGs via peripheral administration.