Mechanisms of Swallowing, Speech and Voice Disorders in Parkinson's Disease: Literature Review with Our First Evidence for the Periperal Nervous System Involvement.

The majority of patients with Parkinson's disease (PD) develop swallowing, speech, and voice (SSV) disorders. Importantly, swallowing difficulty or dysphagia and related aspiration are life-threatening conditions for PD patients. Although PD treatments have significant therapeutic effects on limb motor function, their effects on SSV disorders are less impressive. A large gap in our knowledge is that the mechanisms of SSV disorders in PD are poorly understood. PD was long considered to be a central nervous system disorder caused by the death of dopaminergic neurons in the basal ganglia. Aggregates of phosphorylated α-synuclein (PAS) underlie PD pathology. SSV disorders were thought to be caused by the same dopaminergic problem as those causing impaired limb movement; however, there is little evidence to support this. The pharynx, larynx, and tongue play a critical role in performing upper airway (UA) motor tasks and their dysfunction results in disordered SSV. This review aims to provide an overview on the neuromuscular organization patterns, functions of the UA structures, clinical features of SSV disorders, and gaps in knowledge regarding the pathophysiology underlying SSV disorders in PD, and evidence supporting the hypothesis that SSV disorders in PD could be associated, at least in part, with PAS damage to the peripheral nervous system controlling the UA structures. Determining the presence and distribution of PAS lesions in the pharynx, larynx, and tongue will facilitate the identification of peripheral therapeutic targets and set a foundation for the development of new therapies to treat SSV disorders in PD.

Spinful Topological Phases in Acoustic Crystals with Projective PT Symmetry.

For the classification of topological phases of matter, an important consideration is whether a system is spinless or spinful, as these two classes have distinct symmetry algebra that gives rise to fundamentally different topological phases. However, only recently has it been realized theoretically that in the presence of gauge symmetry, the algebraic structure of symmetries can be projectively represented, which possibly enables the switch between spinless and spinful topological phases. Here, we report the experimental demonstration of this idea by realizing spinful topological phases in "spinless" acoustic crystals with projective space-time inversion symmetry. In particular, we realize a one-dimensional topologically gapped phase characterized by a 2Z winding number, which features double-degenerate bands in the entire Brillouin zone and two pairs of degenerate topological boundary modes. Our Letter thus overcomes a fundamental constraint on topological phases by spin classes.

Focal Application of Neurotrophic Factors Augments Outcomes of Nerve-Muscle-Endplate Grafting Technique for Limb Muscle Reinnervation.

BACKGROUND: We have developed a novel muscle reinnervation technique called "nerve-muscle-endplate grafting (NMEG) in the native motor zone (NMZ)." This study aimed to augment the outcomes of the NMEG-NMZ (NN) by focal application of exogenous neurotrophic factors (ENFs) for limb reinnervation. METHODS: Adult rats were used to conduct NN plus ENF (NN/ENF) and autologous nerve grafting (ANG, technique control). The nerve innervating the left tibialis anterior (TA) muscle was resected and the denervated TA was immediately treated with NN/ENF or ANG. For NN procedure, an NMEG pedicle was taken from the lateral gastrocnemius muscle and transferred to the NMZ of the denervated TA. For ANG, the nerve gap was bridged with sural nerve. Three months after treatment, the extent of functional and neuromuscular recovery was assessed by measuring static toe spread, maximal muscle force, wet muscle weight, regenerated axons, and innervated motor endplates (MEPs). RESULTS: NN/ENF resulted in 90% muscle force recovery of the treated TA, which is far superior to ANG (46%) and NN alone (79%) as reported elsewhere. Toe spread recovered up to 89 and 49% of the control for the NN/ENF and ANG groups, respectively. The average wet muscle weight was 87 and 52% of the control for muscles treated with NN/ENF and ANG, respectively. The mean number of the regenerated axons was 88% of the control for the muscles treated with NN/ENF, which was significantly larger than that for the ANG-repaired muscles (39%). The average percentage of the innervated MEPs in the NN/ENF-treated TA (89%) was higher compared with that in the ANG-repaired TA (48%). CONCLUSION: ENF enhances nerve regeneration and MEP reinnervation that further augment outcomes of NN. The NN technique could be an alternative option to treat denervated or paralyzed limb muscles caused by traumatic nerve injuries or lesions.

Observation of Dirac Hierarchy in Three-Dimensional Acoustic Topological Insulators.

Dirac cones (DCs) play a pivotal role in various unique phenomena ranging from massless electrons in graphene to robust surface states in topological insulators (TIs). Recent studies have theoretically revealed a full Dirac hierarchy comprising an eightfold bulk DC, a fourfold surface DC, and a twofold hinge DC, associated with a hierarchy of topological phases including first-order to third-order three-dimensional (3D) topological insulators, using the same 3D base lattice. Here, we report the first experimental observation of the Dirac hierarchy in 3D acoustic TIs. Using acoustic measurements, we unambiguously reveal that lifting of multifold DCs in each hierarchy can induce two-dimensional topological surface states with a fourfold DC in a first-order 3D TI, one-dimensional topological hinge states with a twofold DC in a second-order 3D TI, and zero-dimensional topological corner states in a third-order 3D TI. Our Letter not only expands the fundamental research scope of Dirac physics, but also opens up a new route for multidimensional robust wave manipulation.

Antimicrobial peptide AR-23 derivatives with high endosomal disrupting ability enhance poly(l-lysine)-mediated gene transfer.

BACKGROUND: pH-sensitive peptides are a relatively new strategy for conquering the poor endosomal release of cationic polymer-mediated transfection. Modification of antimicrobial peptides by exchanging positively-charged residues with negatively-charged glutamic acid residues (Glu) greatly improves its lytic activity at the endosomal pH, which could improve cationic polymer-mediated transfection. METHODS: In the present study, we investigated the effect of the number of Glu substituted for positively-charged residues on the endosomal escape activity of AR-23 and the ability of mutated AR-23 with respect to enhancing cationic polymer-mediated transfection. Three analogs were synthesized by replacing the positively-charged residues in the AR-23 sequence with Glu one-by-one. RESULTS: The pH-sensitive lysis ability of the peptides, the effect of peptides on the physicochemical characteristics, the intracellular trafficking, the transfection efficiency and the cytotoxicity of the polyplexes were determined. Increased lytic activity of peptides was observed with the increased number of Glu replacement in the AR-23 sequence at acidic pH. The number of Glu substituted for positively-charged residues of AR-23 dramatically affects its lysis ability at neutral pH. Triple-Glu substitution in the AR-23 sequence greatly improved poly(l-lysine)-mediated gene transfection efficiency at the same time as maintaining low cytotoxicity. CONCLUSIONS: The results indicate that replacement of positively-charged residues with sufficient Glu residues may be considered as a method for designing pH-sensitive peptides, which could be applied as potential enhancers for improving cationic polymer-mediated transfection.

ß2-adrenergic receptor control of endosomal PTH receptor signaling via Gßγ.

Cells express several G-protein-coupled receptors (GPCRs) at their surfaces, transmitting simultaneous extracellular hormonal and chemical signals into cells. A comprehensive understanding of mechanisms underlying the integrated signaling response induced by distinct GPCRs is thus required. Here we found that the ß2-adrenergic receptor, which induces a short cAMP response, prolongs nuclear cAMP and protein kinase A (PKA) activation by promoting endosomal cAMP production in parathyroid hormone (PTH) receptor signaling through the stimulatory action of G protein Gßγ subunits on adenylate cyclase type 2.

Short-term auricular electrical stimulation rapidly elevated cortical blood flow and promoted the expression of nicotinic acetylcholine receptor α4 in the 2 vessel occlusion rats model.

BACKGROUND: Vascular dementia is the second dementing illness after Alzheimer's disease and caused by reduced blood flow to the brain, and affects cognitive abilities. Our previous study found that auricular electrical stimulation (ES) improved motor and learning impairment, and this phenomenon related with nicotinic acetylcholine receptor (nAChR) expressed cells. However, the underlying mechanism was not clear. In the present study, we investigated the effects of auricular ES on cortical blood flow (CBF) and acetylcholine (ACh) - nAChRs expressed cells. METHODS: Vascular dementia rat animal model was established by permanent occlusions of common carotid arteries with 6-0 nylon suture filament. At 21 day after surgery, motor impairment was confirmed by rotarod test. 15-Hz auricular ES were applied to the ears for 20 min and CBF was recorded at the mean time. The brains were immediately dissected for immunohistochemical stain and western blot analysis. RESULTS: Our results showed that 15-Hz auricular ES rapidly elevated CBF in the middle cerebral artery. The numbers of nAChR α4 immuno-positive cells and western blot levels were significally increased by 15-Hz auricular ES in the hippocampal CA2 output cortex. The numbers of choline acetyltransferase (ChAT) - a key enzyme for biosynthesis of ACh - immuno-positive cells and western blot levels had no significant differences. CONCLUSIONS: The present data suggested that the 15-Hz auricular ES for 20 min rapidly elevated cortical blood flow, promoted the expression of nAChR α4, and would be beneficial for the treatment of Alzheimer type and vascular type dementia.

Delayed Dural Arteriovenous Fistula at the Transverse-Sigmoid Sinus Secondary to Petroclival Meningioma Surgery Via Far Lateral Approach.

Intracranial dural arteriovenous fistulas (DAVFs) are typified by pathological anastomoses between meningeal arteries and dural venous sinuses or cortical veins. There are many causes contributing to the etiology of DAVFs. Among the variable causes, acquired DAVFs secondary to craniotomy had rarely been reported, especially for delayed DAVFs at the transverse-sigmoid sinus. Till now, there are only 12 published cases of delayed DAVFs at the transverse-sigmoid sinus secondary to craniotomy. Herein, the authors describe such an extraordinary rare case secondary to petroclival meningioma resection via far lateral approach, and to the best knowledge of us, this is the first well-documented case of delayed DAVF at the transverse-sigmoid sinus following far lateral craniotomy. Furthermore, cases of delayed DAVFs at the transverse-sigmoid sinus secondary to craniotomy were reviewed and investigated, and the clinical characteristics and treatment were also broadly discussed.

Nerve growth factor and basic fibroblast growth factor promote reinnervation by nerve-muscle-endplate grafting.

INTRODUCTION: This study was designed to test whether exogenous application of nerve growth factor (NGF) and basic fibroblast growth factor (FGF-2) to muscles reinnervated with nerve-muscle-endplate band grafting (NMEG) could promote specific outcomes. METHODS: The right sternomastoid muscle in adult rats was experimentally denervated and immediately reinnervated by implanting an NMEG pedicle from the ipsilateral sternohyoid muscle. A fibrin sealant containing NGF and FGF-2 was focally applied to the implantation site. Maximal tetanic force, muscle weight, regenerated axons, and motor endplates were analyzed 3 months after treatment. RESULTS: Mean tetanic force, wet muscle weight, and number of regenerated axons in the treated muscles were 91%, 92%, and 84% of the contralateral controls, respectively. The majority of endplates (86%) in the treated muscles were reinnervated by regenerated axons. DISCUSSION: Focal administration of NGF and FGF-2 promotes efficacy of the NMEG technique. Muscle Nerve 57: 449-459, 2018.

Immunohistochemical Detection of Motor Endplates in the Long-Term Denervated Muscle.

BACKGROUND: We have demonstrated that the native motor zone (NMZ) within a muscle is an ideal target for performing nerve-muscle-endplate band grafting (NMEG) to restore motor function of a denervated muscle. This study was designed to determine spatiotemporal alterations of the myofibers, motor endplates (MEPs), and axons in the NMZ of long-term denervated muscles for exploring if NMEG-NMZ technique would have the potential for delayed reinnervation. METHODS: Sternomastoid (SM) muscles of adult female Sprague-Dawley rats (n = 21) were experimentally denervated and denervation-induced changes in muscle weight, myofiber size, MEPs, and intramuscular nerve axons were evaluated histomorphometrically and immunohistochemically at the end of 3, 6, and 9 months after denervation. The values obtained from the ipsilateral normal side served as control. RESULTS: The denervated SM muscles exhibited a progressive reduction in muscle weight (38%, 31%, and 19% of the control) and fiber diameter (52%, 40%, and 28% of the control) for 3-, 6-, and 9-month denervation, respectively. The denervated MEPs were still detectable even 9 months after denervation. The mean number of the denervated MEPs was 79%, 65%, and 43% of the control in the 3-, 6-, and 9-month denervated SM, respectively. Degenerated axons in the denervated muscles became fragmented. CONCLUSIONS: Persistence of MEPs in the long-term denervated SM suggests that some surgeries targeting the MEPs such as NMEG-NMZ technique should be effective for delayed reinnervation. However, more work is needed to develop strategies for preservation of muscle mass and MEPs after denervation.

Integrated optical Mach-Zehnder interferometer-based defect detection using a laser-generated ultrasonic guided wave.

The laser-based transmitter used in this Letter is composed of an integrated optical Mach-Zehnder interferometer, which was first used in fault diagnosis. With the help of the effective signal processing method and laser-based integrated optical Mach-Zehnder (IOMZ) system, the location of the defect in an aluminum plate can be successfully determined. Moreover, a comparison study is conducted to investigate the effectiveness of both the conventional laser spot source and the IOMZ interferometer-based laser source. The results indicate that the IOMZ interferometer-based method can be very useful to the nondestructive testing research field. The potential for industrial applications is also significant, especially for the health monitoring and integrity inspection of metal plates.

A Signal Processing Approach with a Smooth Empirical Mode Decomposition to Reveal Hidden Trace of Corrosion in Highly Contaminated Guided Wave Signals for Concrete-Covered Pipes.

Ultrasonic guided waves have been extensively applied for non-destructive testing of plate-like structures particularly pipes in past two decades. In this regard, if a structure has a simple geometry, obtained guided waves' signals are easy to explain. However, any small degree of complexity in the geometry such as contacting with other materials may cause an extra amount of complication in the interpretation of guided wave signals. The problem deepens if defects have irregular shapes such as natural corrosion. Signal processing techniques that have been proposed for guided wave signals' analysis are generally good for simple signals obtained in a highly controlled experimental environment. In fact, guided wave signals in a real situation such as the existence of natural corrosion in wall-covered pipes are much more complicated. Considering pipes in residential buildings that pass through concrete walls, in this paper we introduced Smooth Empirical Mode Decomposition (SEMD) to efficiently separate overlapped guided waves. As empirical mode decomposition (EMD) which is a good candidate for analyzing non-stationary signals, suffers from some shortcomings, wavelet transform was adopted in the sifting stage of EMD to improve its outcome in SEMD. However, selection of mother wavelet that suits best for our purpose plays an important role. Since in guided wave inspection, the incident waves are well known and are usually tone-burst signals, we tailored a complex tone-burst signal to be used as our mother wavelet. In the sifting stage of EMD, wavelet de-noising was applied to eliminate unwanted frequency components from each IMF. SEMD greatly enhances the performance of EMD in guided wave analysis for highly contaminated signals. In our experiment on concrete covered pipes with natural corrosion, this method not only separates the concrete wall indication clearly in time domain signal, a natural corrosion with complex geometry that was hidden and located inside the concrete section was successfully exposed.

Outcomes of Muscle Reinnervation with Direct Nerve Implantation into the Native Motor Zone of the Target Muscle.

Background Our recent work has demonstrated that the native motor zone (NMZ) within a given skeletal muscle is the best site for muscle reinnervation. This study was designed to explore the outcomes of direct nerve implantation (DNI) into the NMZ of denervated sternomastoid (SM) muscle in a rat model. Methods The right SM muscle was experimentally denervated by transecting its innervating nerve. The proximal stump of the severed SM nerve was immediately implanted into a small muscle slit made in the NMZ of the muscle where denervated motor endplates were concentrated. The outcomes of DNI-NMZ reinnervation were evaluated 3 months after surgery. Specifically, the degree of functional recovery was examined with muscle force measurement. The extent of nerve regeneration and endplate reinnervation was assessed using histological and immunohistochemical methods. Results This study showed that the mean muscle force of the treated muscles was 64% of the contralateral control. Reinnervated SM muscles weighed 71% of the weight of the control muscles. Abundant regenerated axons were identified in the NMZ of the target muscle. The mean number and area of the regenerated axons in the treated muscles was computed to be 62% and 51% of the control muscles, respectively. On average, 66% of the denervated endplates in the treated muscles were reinnervated by regenerated axons. Conclusion Our results suggest that the NMZ within a muscle is an ideal site for endplate reinnervation and satisfactory functional recovery. Further studies are needed to promote the efficacy of DNI-NMZ technique for muscle reinnervation.

Alpha-Synuclein Pathology in Sensory Nerve Terminals of the Upper Aerodigestive Tract of Parkinson's Disease Patients.

Dysphagia is common in Parkinson's disease (PD) and causes significant morbidity and mortality. PD dysphagia has usually been explained as dysfunction of central motor control, much like other motor symptoms that are characteristic of the disease. However, PD dysphagia does not correlate with severity of motor symptoms nor does it respond to motor therapies. It is known that PD patients have sensory deficits in the pharynx, and that impaired sensation may contribute to dysphagia. However, the underlying cause of the pharyngeal sensory deficits in PD is not known. We hypothesized that PD dysphagia with sensory deficits may be due to degeneration of the sensory nerve terminals in the upper aerodigestive tract (UAT). We have previously shown that Lewy-type synucleinopathy (LTS) is present in the main pharyngeal sensory nerves of PD patients, but not in controls. In this study, the sensory terminals in UAT mucosa were studied to discern the presence and distribution of LTS. Whole-mount specimens (tongue-pharynx-larynx-upper esophagus) were obtained from 10 deceased human subjects with clinically diagnosed and neuropathologically confirmed PD (five with dysphagia and five without) and four age-matched healthy controls. Samples were taken from six sites and immunostained for phosphorylated α-synuclein (PAS). The results showed the presence of PAS-immunoreactive (PAS-ir) axons in all the PD subjects and in none of the controls. Notably, PD patients with dysphagia had more PAS-ir axons in the regions that are critical for initiating the swallowing reflex. These findings suggest that Lewy pathology affects mucosal sensory axons in specific regions of the UAT and may be related to PD dysphagia.

Deforestation in Latin America in the 2000s predominantly occurred outside of typical mature forests.

The role of tropical forests in the global carbon budget remains controversial, as carbon emissions from deforestation are highly uncertain. This high uncertainty arises from the use of either fixed forest carbon stock density or maps generated from satellite-based optical reflectance with limited sensitivity to biomass to generate accurate estimates of emissions from deforestation. New space missions aiming to accurately map the carbon stock density rely on direct measurements of the spatial structures of forests using lidar and radar. We found that lost forests are special cases, and their spatial structures can be directly measured by combining archived data acquired before and after deforestation by space missions principally aimed at measuring topography. Thus, using biomass mapping, we obtained new estimates of carbon loss from deforestation ahead of forthcoming space missions. Here, using a high-resolution map of forest loss and the synergy of radar and lidar to estimate the aboveground biomass density of forests, we found that deforestation in the 2000s in Latin America, one of the severely deforested regions, mainly occurred in forests with a significantly lower carbon stock density than typical mature forests. Deforestation areas with carbon stock densities lower than 20.0, 50.0, and 100.0 Mg C/ha accounted for 42.1%, 62.0%, and 83.3% of the entire deforested area, respectively. The average carbon stock density of lost forests was only 49.13 Mg C/ha, which challenges the current knowledge on the carbon stock density of lost forests (with a default value 100 Mg C/ha according to the Intergovernmental Panel on Climate Change Tier 1 estimates, or approximately 112 Mg C/ha used in other studies). This is demonstrated over both the entire region and the footprints of the spaceborne lidar. Consequently, our estimate of carbon loss from deforestation in Latin America in the 2000s was 253.0 ± 21.5 Tg C/year, which was considerably less than existing remote-sensing-based estimates, namely 400-600 Tg C/year. This indicates that forests in Latin America were most likely not a net carbon source in the 2000s compared to established carbon sinks. In previous studies, considerable effort has been devoted to rectify the underestimation of carbon sinks; thus, the overestimation of carbon emissions should be given sufficient consideration in global carbon budgets. Our results also provide solid evidence for the necessity of renewing knowledge on the role of tropical forests in the global carbon budget in the future using observations from new space missions.

Brillouin Klein space and half-turn space in three-dimensional acoustic crystals.

The Bloch band theory and Brillouin zone (BZ) that characterize wave-like behaviors in periodic mediums are two cornerstones of contemporary physics, ranging from condensed matter to topological physics. Recent theoretical breakthrough revealed that, under the projective symmetry algebra enforced by artificial gauge fields, the usual two-dimensional (2D) BZ (orientable Brillouin two-torus) can be fundamentally modified to a non-orientable Brillouin Klein bottle with radically distinct manifold topology. However, the physical consequence of artificial gauge fields on the more general three-dimensional (3D) BZ (orientable Brillouin three-torus) was so far missing. Here, we theoretically discovered and experimentally observed that the fundamental domain and topology of the usual 3D BZ can be reduced to a non-orientable Brillouin Klein space or an orientable Brillouin half-turn space in a 3D acoustic crystal with artificial gauge fields. We experimentally identify peculiar 3D momentum-space non-symmorphic screw rotation and glide reflection symmetries in the measured band structures. Moreover, we experimentally demonstrate a novel stacked weak Klein bottle insulator featuring a nonzero Z2 topological invariant and self-collimated topological surface states at two opposite surfaces related by a nonlocal twist, radically distinct from all previous 3D topological insulators. Our discovery not only fundamentally modifies the fundamental domain and topology of 3D BZ, but also opens the door towards a wealth of previously overlooked momentum-space multidimensional manifold topologies and novel gauge-symmetry-enriched topological physics and robust acoustic wave manipulations beyond the existing paradigms.

Reinnervation of Paralyzed Limb Muscle by Nerve-Muscle-Endplate Grafting Technique.

BACKGROUND: We have developed a novel reinnervation technique called nerve-muscle-endplate grafting in the native motor zone (NMEG-NMZ). However, it remains unknown whether the NMEG-NMZ is effective for limb reinnervation. OBJECTIVE: To evaluate the efficacy of the NMEG-NMZ in limb muscle reinnervation. METHODS: Forty-five adult rats were divided into 3 groups: NMEG, end-to-end anastomosis (EEA, technique control), and denervation control (DC). The left tibialis anterior muscle was denervated by resecting its nerve. For NMEG-NMZ, the denervated tibialis anterior was reinnervated by transferring a NMEG pedicle from the lateral gastrocnemius muscle. Three months after surgery, static toe spread analysis was performed for all rats and muscle force was measured for the rats treated with NMEG and EEA. Muscle weight, myofiber morphology, regenerated axons, and reinnervated motor endplates in the treated muscles were also quantified and compared with those in the DC group. RESULTS: NMEG-NMZ technique resulted in better muscle force recovery (79% of the control) compared with EEA (51% of the control, P = .048). Toe spread analysis in NMEG-NMZ reinnervated muscles showed static sciatic index = -16.8, whereas -41.4 in EEA, P < .0001). The average weight of the NMEG-NMZ reinnervated muscles (86%) was greater than those of the EEA treated (71%) and DC (26%) muscles (all P < .0001). The mean count of the regenerated axons in the muscles with NMEG-NMZ was 76% of the control, which was larger than that in the muscles with EEA (46%), P < .0001. CONCLUSION: NMEG-NMZ technique has unique advantages and is superior to EEA for muscle reinnervation and functional recovery.

Topological antichiral surface states in a magnetic Weyl photonic crystal.

Chiral edge states that propagate oppositely at two parallel strip edges are a hallmark feature of Chern insulators which were first proposed in the celebrated two-dimensional (2D) Haldane model. Subsequently, counterintuitive antichiral edge states that propagate in the same direction at two parallel strip edges were discovered in a 2D modified Haldane model. Recently, chiral surface states, the 2D extension of one-dimensional (1D) chiral edge states, have also been observed in a photonic analogue of a 3D Haldane model. However, despite many recent advances in antichiral edge states and chiral surface states, antichiral surface states, the 2D extension of 1D antichiral edge states, have never been realized in any physical system. Here, we report the experimental observation of antichiral surface states by constructing a 3D modified Haldane model in a magnetic Weyl photonic crystal with two pairs of frequency-shifted Weyl points (WPs). The 3D magnetic Weyl photonic crystal consists of gyromagnetic cylinders with opposite magnetization in different triangular sublattices of a 3D honeycomb lattice. Using microwave field-mapping measurements, unique properties of antichiral surface states have been observed directly, including the antichiral robust propagation, tilted surface dispersion, a single open Fermi arc connecting two projected WPs and a single Fermi loop winding around the surface Brillouin zone (BZ). These results extend the scope of antichiral topological states and enrich the family of magnetic Weyl semimetals.