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An economical parabolized Navier–Stokes approximation for steady incompressible flow is combined with a compatible wind turbine model to simulate wind turbine flows, both upstream of the turbine and in downstream wake regions. The inviscid parabolizing approximation is based on a Helmholtz decomposition of the secondary velocity vector and physical order-of-magnitude estimates, rather than an axial pressure gradient approximation. The wind turbine is modeled by distributed source-term forces incorporating time-averaged aerodynamic forces generated by a blade-element momentum turbine model. A solution algorithm is given whose dependent variables are streamwise velocity, streamwise vorticity, and pressure, with secondary velocity determined by two-dimensional scalar and vector potentials. In addition to laminar and turbulent boundary-layer test cases, solutions for a streamwise vortex-convection test problem are assessed by mesh refinement and comparison with Navier–Stokes solutions using the same grid. Computed results for a single turbine and a three-turbine array are presented using the NREL offshore 5-MW baseline wind turbine. These are also compared with an unsteady Reynolds-averaged Navier–Stokes solution computed with full rotor resolution. On balance, the agreement in turbine wake predictions for these test cases is very encouraging given the substantial differences in physical modeling fidelity and computer resources required. [ABSTRACT FROM AUTHOR]

Development of Schwann cells is tightly regulated by concerted action of activating and inhibiting factors. Most of the regulatory feedback loops identified to date are transcriptional activators promoting induction of genes coding for integral myelin proteins and lipids. The mechanisms by which inhibitory factors are silenced during Schwann cell maturation are less well understood. We could recently show a pivotal function for the transcription factor zinc finger E-box binding homeobox 2 (Zeb2) during Schwann cell development and myelination as a transcriptional repressor of maturation inhibitors. Zeb2 belongs to a family of highly conserved 2-handed zincfinger proteins and represses gene transcription by binding to E-box sequences in the regulatory region of target genes. The protein is known to repress E-cadherin during epithelial to mesenchymal transition (EMT) in tumor malignancy and mediates its functions by interacting with multiple co-factors. During nervous system development, Zeb2 is expressed in neural crest cells, the precursors of Schwann cells, the myelinating glial cells of peripheral nerves. Schwann cells lacking Zeb2 fail to fully differentiate and are unable to sort and myelinate peripheral nerve axons. The maturation inhibitors Sox2, Ednrb and Hey2 emerge as targets for Zeb2-mediated transcriptional repression and show persistent aberrant expression in Zeb2-deficient Schwann cells. While dispensible for adult Schwann cells, re-activation of Zeb2 is essential after nerve injury to allow remyelination and functional recovery. In summary, Zeb2 emerges as an "inhibitor of inhibitors," a novel concept in Schwann cell development and nerve repair. [ABSTRACT FROM AUTHOR]

A method is proposed for determining the correlated and uncorrelated parts of phase noise spectra (PNS) of two continuous wave radio signals of different frequencies, ω1 and ω2. The PNS of the two signals and of mixed signals are measured. The PNS are modelled as having a correlated part that is the same for both signals, except for a multiplicative factor, and uncorrelated parts, that are different for the two signals. A property of the model that the PNS of some mixing products are linear combinations of the PNS of the signals at ω1, ω2, and ω1 − ω2 is experimentally verified. The difference of the PNS at ω1 + ω2 and ω1 − ω2 is proportional to the correlated part of the PNS and is a part of auxiliary functions that are used for finding the multiplicative factor and the correlated, partly correlated, and uncorrelated phase noise at different offset frequencies. A conventional spectrum analyser was used to characterise two signal generators, a phase‐coherent and a non‐phase‐coherent one. For the phase‐coherent generator the phase noise of two signals was found to be correlated for offset frequencies below 10 Hz, partly correlated for 10 Hz–1 kHz and uncorrelated above 1 kHz. [ABSTRACT FROM AUTHOR]

The blood barriers of the nervous system protect neural environments but can hinder therapeutic accessibility. The blood-brain barrier (BBB) is well characterized, consisting of endothelial cells with specialized tight junctions and low levels of transcytosis, properties conferred by contacting pericytes and astrocytes. In contrast, the blood-nerve barrier (BNB) of the peripheral nervous system is poorly defined. Here, we characterize the structure of the mammalian BNB, identify the processes that confer barrier function, and demonstrate how the barrier can be opened in response to injury. The homeostatic BNB is leakier than the BBB, which we show is due to higher levels of transcytosis. However, the barrier is reinforced by macrophages that specifically engulf leaked materials, identifying a role for resident macrophages as an important component of the BNB. Finally, we demonstrate the exploitation of these processes to effectively deliver RNA-targeting therapeutics to peripheral nerves, indicating new treatment approaches for nervous system pathologies. [Display omitted] • Definition of the vascular unit of the mammalian blood-nerve barrier • Macrophages enforce barrier function during homeostasis • Schwann cells open the barrier following injury by increasing transcytosis • Increased transcytosis improves the delivery of therapeutics to nerves Malong et al. characterize the conserved multicellular structures and processes that define the mammalian blood-nerve barrier (BNB). Macrophages enforce the BNB during homeostasis, whereas, following injury, Schwann cells transiently "open" the barrier by increasing transcytosis rates across blood vessels, permitting increased delivery of therapeutics to peripheral nerves. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 23 (FGF23) is an important phosphaturic hormone, yet few studies have focused on FGF23 in children with primary nephrotic syndrome (PNS) and children who progressed to end-stage renal disease (ESRD). This cross-sectional study investigated the significance of changes in FGF23 levels in childhood PNS and children who progressed to ESRD. Of the 41 children included in the study, 17 had PNS with proteinuria and normal renal function (PNS group), 4 had ESRD (ESRD group), and 20 were healthy (control group). Following corticosteroid treatment, patients with PNS and proteinuria entered the remission phase. Serum levels of FGF23, phosphate, parathyroid hormone (PTH), 25-hydroxyvitamin D (25-OH-D), and calcium were measured. It was found that FGF23 levels in the PNS and ESRD groups were higher than those in the control group, while serum 25-OH-D levels were lower. Serum PTH levels increased significantly in the ESRD group. In the control group, FGF23 levels were negatively correlated with serum PTH and positively correlated with serum 25-OH-D. FGF23 levels were positively correlated with serum calcium and corrected calcium levels in children with PNS during the remission phase. Increased FGF23 levels in children with PNS, particularly in children who progressed to ESRD. It was also confirmed that serum FGF23 levels begin to rise in children with PNS prior to Stage 1 chronic kidney disease. These findings indicated that increased FGF23 levels may be associated with the progression and severity of nephrosis in children, and that serum FGF23 levels were useful for early detection of abnormal mineral metabolism in children with PNS., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Liu et al.)

The fruit fly Drosophila melanogaster has provided important insights into how sensory information is transduced by transient receptor potential (TRP) channels in the peripheral nervous system (PNS). However, TRP channels alone have not been able to completely model mechanosensitive transduction in mechanoreceptive chordotonal neurons (CNs). Here, we show that, in addition to TRP channels, the sole voltage-gated sodium channel (Na V ) in Drosophila , Para, is localized to the dendrites of CNs. Para is localized to the distal tip of the dendrites in all CNs, from embryos to adults, and is colocalized with the mechanosensitive TRP channels No mechanoreceptor potential C (NompC) and Inactive/Nanchung (Iav/Nan). Para localization also demarcates spike initiation zones (SIZs) in axons and the dendritic localization of Para is indicative of a likely dendritic SIZ in fly CNs. Para is not present in the dendrites of other peripheral sensory neurons. In both multipolar and bipolar neurons in the PNS, Para is present in a proximal region of the axon, comparable to the axonal initial segment (AIS) in vertebrates, 40-60 μm from the soma in multipolar neurons and 20-40 μm in bipolar neurons. Whole-cell reduction of para expression using RNAi in CNs of the adult Johnston's organ (JO) severely affects sound-evoked potentials (SEPs). However, the duality of Para localization in the CN dendrites and axons identifies a need to develop resources to study compartment-specific roles of proteins that will enable us to better understand Para's role in mechanosensitive transduction., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 Ravenscroft et al.)

Chemical neurotransmission occurs at specialized contacts where neurotransmitter release machinery apposes neurotransmitter receptors to underlie circuit function. A series of complex events underlies pre- and postsynaptic protein recruitment to neuronal connections. To better study synaptic development in individual neurons, we need cell-type-specific strategies to visualize endogenous synaptic proteins. Although presynaptic strategies exist, postsynaptic proteins remain less studied because of a paucity of cell-type-specific reagents. To study excitatory postsynapses with cell-type specificity, we engineered dlg1[4K] , a conditionally labeled marker of Drosophila excitatory postsynaptic densities. With binary expression systems, dlg1[4K] labels central and peripheral postsynapses in larvae and adults. Using dlg1[4K] , we find that distinct rules govern postsynaptic organization in adult neurons, multiple binary expression systems can concurrently label pre- and postsynapse in a cell-type-specific manner, and neuronal DLG1 can sometimes localize presynaptically. These results validate our strategy for conditional postsynaptic labeling and demonstrate principles of synaptic organization., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Tau is a microtubule-associated protein (MAP) that has multiple isoforms generated by alternative splicing of the MAPT gene at a range of 45-60 kDa [low-molecular-weight (LMW) tau] as well as a unique isoform termed Big tau containing an additional exon 4a encoding a large projecting domain of ∼250 aa to form a protein of 110 kDa. Big tau is expressed in adult PNS neurons such as DRG neurons and specific regions of CNS such as the cerebellum in a developmental transition from LMW tau to Big tau during the postnatal period. Despite a conserved size of the 4a exons across the vertebrate phylogeny, there is no sequence homology among different species outside the Mammalia class, which underscores the focus on structural preservation of Big tau. Despite the original discovery of Big tau in the early 1990s, there has been little progress elucidating its physiological properties and pathologic implications. We propose that Big tau may be able to improve axonal transport in projecting axons and speculate on the potential protective properties in preventing tau aggregation in pathologic conditions. This perspective highlights the importance and benefits of understanding of the role of Big tau in neuronal health and disease., Competing Interests: The author declares no competing financial interests., (Copyright © 2023 Fischer.)

Purpose To characterize peripheral nerve stimulation (PNS) of an asymmetric head-only gradient coil that is compatible with a commercial high-channel-count receive-only array. Methods Two prototypes of an asymmetric head-only gradient coil set with a 42-cm inner diameter were constructed for brain imaging at 3T with maximum performance specifications of up to 85 mT/m and 708 T/m/s. Tests were performed in 24 volunteers to measure PNS thresholds with the transverse (x = left-right; y = anterior-posterior [A/P]) gradient coils of both prototypes. Fourteen of these 24 volunteers were also tested for the z-gradient PNS in the second prototype and were scanned with high-slew-rate echo planar imaging (EPI) immediately after the PNS tests. Results For both prototypes, the y-gradient PNS threshold was markedly higher than the x-gradient threshold. The z-gradient threshold was intermediate between those for the x- and y-coils. Of the 24 volunteers, only two experienced y-gradient PNS at 80 mT/m and 500 T/m/s. All volunteers underwent the EPI scan without PNS when the readout direction was set to A/P. Conclusion Measured PNS characteristics of asymmetric head-only gradient coil prototypes indicate that such coils, especially in the A/P direction, can be used for fast EPI readout in high-performance neuroimaging scans with substantially reduced PNS concerns compared with conventional whole body gradient coils. Magn Reson Med 76:1939-1950, 2016. © 2015 International Society for Magnetic Resonance in Medicine [ABSTRACT FROM AUTHOR]

Tujuan penelitian ini adalah untuk mengetahui pengaruh pembinaan terhadap produktivitas kerja melalui motivasi kerja pada organisasi pemerintahan daerah. Lokasi penelitian adalah pemerintah daerah Kabupaten Serdang Bedagai. Penelitian ini menggunakan teknik analisis Structural Equation Model (SEM), dengan responden sebanyak 139 orang yang penarikan sampelnya menggunakan Simple Random Sampling. Hasil analisis statistik menunjukkan bahwa pembinaan tidak berpengaruh signifikan terhadap produktivitas kerja, pembinaan berpengaruh signifikan terhadap motivasi kerja, motivasi kerja berpengaruh signifikan terhadap produktivitas kerja, dan pembinaan melalui motivasi kerja berpengaruh signifikan terhadap produktivitas kerja. The purpose of this study was to determine the effect of coaching on work productivity through motivation in organizational governance. What research is Serdang Bedagai local government. This study uses analytical techniques Structural Equation Model (SEM), with 139 respondents who recall sampled using Simple Random Sampling. The results of statistical analysis showed that no significant effect on guidance through, guidance through significant effect on work motivation, work motivation significant effect on workplace productivity, motivation and guidance through a significant effect on labor productivity.

Repair of the injured spinal cord is a major challenge in medicine. The limited intrinsic regenerative response mounted by adult central nervous system (CNS) neurons is further hampered by astrogliosis, myelin debris and scar tissue that characterize the damaged CNS. Improved axon regeneration and recovery can be elicited by targeting extrinsic factors as well as by boosting neuron-intrinsic growth regulators. Our knowledge of the molecular basis of intrinsic and extrinsic regulators of regeneration has expanded rapidly, resulting in promising new targets to promote repair. Intriguingly certain neuron-intrinsic growth regulators are emerging as promising targets to both stimulate growth and relieve extrinsic inhibition of regeneration. This crossroads between the intrinsic and extrinsic aspects of spinal cord injury is a promising target for effective therapies for this unmet need.

Objective: To investigate the effect of a-D3 on the prevention of osteoporosis in PNS patients during Pred hormone treatment. Methods: 70 patients with PNS were collected and randomly divided into the experiment group and the control group with 35 cases in each group. The patients in the control group were treated with prednisone, while the patients in the experiment group were treated with vitamin D3 (a -D3) besides the control group. Then the bone alkaline phosphatase (NBAP). tartrate resistant acid phosphatase (TRACP). 1.25- (OH) 2 D3. former thyroid hormone (iPTH) and bone density levels of the two groups were observed and compared. Results: Compared with before treatment, the levels of 1. 25 - (OH) 2 D3 and bone density in the two groups increased after treatment, and the differences were statistically significant (P<0.05); Compared with before treatment, the levels of NBAP. TRACP and iPTH in the two groups after treatment decreased, and the differences were statistically significant (P<0.05); Compared with control group after treatment, the levels of 1, 25-(OH)2 D3 and bone density of the experiment group were higher, and the differences were statistically significant (P<0.05) Compared with control group after treatment, the levels of NBAP. TRACP and iPTH in the experiment group were lower, and the differences were statistically significant (P<0.05). Conclusion: a -D3 can decrease the levels of NBAP. TRACP and iPTH of patients with PNS. and increase the levels of 1. 25- (OH)2 D3 and bone density levels, which would prevent the osteoporosis during Pred hormone treatment. [ABSTRACT FROM AUTHOR]

Objectives Anti-SOX1 antibodies are associated with small cell lung cancer (SCLC) and predict a paraneoplastic etiology in Lambert-Eaton myasthenic syndrome (LEMS). In 2010, a study described these antibodies in a small cohort of putative non-paraneoplastic, immune-mediated neuropathies. In this respect, we investigated the seroprevalence and specificity of anti-SOX1 antibodies in a large cohort of neurological disorders. Methods Overall, serum samples of 1493 consecutive patients were screened for anti-SOX1 reactivity by an ELISA: 471 with well-defined neurological disorders (multiple sclerosis, motor neuron disease, Guillain-Barré syndrome, and chronic inflammatory demyelinating polyneuropathy), 185 with polyneuropathy (PNP) of unknown origin, and 837 with neurological syndromes of suspicious paraneoplastic etiology. These were compared to eight positive controls with definite paraneoplastic neurological syndromes (PNS) and 92 healthy individuals. We also collected demographic and clinical data, including well-characterized onconeural antibodies in anti-SOX1–positive patients. Results Fifteen patients (1.0%) showed anti-SOX1 reactivity: two with multiple sclerosis, two with PNP of unknown origin, and 11 suspicious PNS cases. Remarkably, 9/15 anti-SOX1–positive patients had a PNP. However, antibody concentrations were significantly lower compared to positive controls, and none additionally harbored well-characterized onconeural antibodies. During a follow-up of at least four years, only five patients had cancer: one thyroid, one Hodgkin lymphoma, two breast, and one patient had multiple malignancies - prostate, penis, cecum, liver, and non–small cell lung cancer. However, none had SCLC, typically associated with SOX1 antibodies. Conclusions The seroprevalence of anti-SOX1 antibodies in patients with various neurological disorders is low. These patients predominantly have PNPs, which might represent a group of immune-mediated diseases. [ABSTRACT FROM AUTHOR]

Peripheral nerve myelination is a complex event resulting from spatially and temporally regulated reciprocal interactions between the neuron and myelin-forming Schwann cells. The dynamic process and the protein functional modules and networks that operate throughout the myelination process are poorly understood because of a lack of methodologies suitable for observing specific changes in the Schwann cell/neuron-unit. The identification of the precise roles for the proteins participating in the functional modules and networks that participate in the myelination process is hindered by the cellular and molecular complexity of the nervous tissue itself. We have developed an approach based on a myelinating dorsal root ganglion explant model that allows distinguishing clear, reproducible and predictable differences between the biochemical properties and the genomic and proteomic expression profiles of both cellular components of the Schwann cell/neuron unit at different stages of the myelination process. This model, derived from E13.5 C57 BL/6J mouse embryos, is sufficiently robust for use in identifying the protein functional networks and modules related to peripheral nerve myelin formation. The genomic expression profiles of the selected neuronal, Schwann cell and myelin-specific proteins in the cultures reflect in vivo profiles reported in the literature, and the structural and ultrastructural properties of the myelin, as well as the myelination schedule of the cultures, closely resemble those observed in peripheral nerves in situ. The RNA expression data set is available through NCBI gene expression omnibus accession GSE60345. [ABSTRACT FROM AUTHOR]

Drug discrimination studies for assessment of psychoactive properties of drugs in safety pharmacology and drug abuse and drug dependence potential evaluation have traditionally been focused on testing novel compounds against standard drugs for which drug abuse has been documented, e.g. opioids, CNS stimulants, cannabinoids etc. (e.g. Swedberg & Giarola, 2015), and results are interpreted such that the extent to which the test drug causes discriminative effects similar to those of the standard training drug, the test drug would be further characterized as a potential drug of abuse. Regulatory guidance for preclinical assessment of abuse liability by the European Medicines Agency (EMA, 2006), the U.S. Food and Drug Administration (FDA, 2010), the International Conference of Harmonization (ICH, 2009), and the Japanese Ministry of Health Education and Welfare (MHLW, 1994) detail that compounds with central nervous system (CNS) activity, whether by design or not, need abuse and dependence liability assessment. Therefore, drugs with peripheral targets and a potential to enter the CNS, as parent or metabolite, are also within scope (see Swedberg, 2013, for a recent review and strategy). Compounds with novel mechanisms of action present a special challenge due to unknown abuse potential, and should be carefully assessed against defined risk criteria. Apart from compounds sharing mechanisms of action with known drugs of abuse, compounds intended for indications currently treated with drugs with potential for abuse and or dependence are also within scope, regardless of mechanism of action. Examples of such compounds are analgesics, anxiolytics, cognition enhancers, appetite control drugs, sleep control drugs and drugs for psychiatric indications. Recent results (Swedberg et al., 2014; Swedberg & Raboisson, 2014; Swedberg, 2015) on the metabotropic glutamate receptor type 5 (mGluR5) antagonists demonstrate that compounds causing hallucinatory effects in humans did not exhibit clear discriminative effects when tested against classical drugs of abuse in drug discrimination studies, and were not self-administered by rats. However, these compounds did cause salient discriminative effects of their own in animals trained to discriminate them from no drug. Therefore, from a safety pharmacology perspective, novel compounds that do not cause discriminative effects similar to classical drugs of abuse, may still cause psychoactive effects in humans and carry the potential to maintain drug abuse, suggesting that proactive investigation of drug abuse potential is warranted (Swedberg, 2013). These and other findings will be discussed, and the application of drug discrimination procedures beyond the typical standard application of testing novel compounds against known and well characterized reference drugs will be addressed. [ABSTRACT FROM AUTHOR]

In order to reduce the dependence of pedestrian navigation on satellite navigation system and wireless communication, a new method is proposed to construct pedestrian navigation system (PNS) based on micro inertial technology. In this paper, the distributed system structure is arranged on human feet and trunk, and the key technologies, namely the system initial alignment, the error correction, the precise gait-phase detection, the effect and the inhibition of environmental magnetic field, have been studied. Besides, theories and applications of the key technologies are also discussed, and the performance of the PNS has been analyzed in the environment of electromagnetic interference. Experimental results show that the positioning error of the route with electromagnetic interference accounts for 2% of the travel distance. The key technologies proposed in the study can effectively improve the positioning accuracy of PNS, and independently achieve longer time personal navigation in the attenuate or even invalid global navigation satellite system (GNSS) and wireless communication signal environment. [ABSTRACT FROM AUTHOR]

The tumor suppressor protein adenomatous polyposis coli (APC) is multifunctional - it participates in the canonical Wnt/β-catenin signal transduction pathway as well as modulating cytoskeleton function. Although APC is expressed by Schwann cells, the role that it plays in these cells and in the myelination of the peripheral nervous system (PNS) is unknown. Therefore, we used the Cre-lox approach to generate a mouse model in which APC expression is specifically eliminated from Schwann cells. These mice display hindlimb weakness and impaired axonal conduction in sciatic nerves. Detailed morphological analyses revealed that APC loss delays radial axonal sorting and PNS myelination. Furthermore, APC loss delays Schwann cell differentiation in vivo, which correlates with persistent activation of the Wnt signaling pathway and results in perturbed extension of Schwann cell processes and disrupted lamellipodia formation. In addition, APC-deficient Schwann cells display a transient diminution of proliferative capacity. Our data indicate that APC is required by Schwann cells for their timely differentiation to mature, myelinating cells and plays a crucial role in radial axonal sorting and PNS myelination. [ABSTRACT FROM AUTHOR]

Neuroendocrine dysfunctions such as the hyperactivity of the vagus nerve and hypothalamus-pituitary-adrenal (HPA) axis greatly contribute to obesity and hyperinsulinemia; however, little is known about these dysfunctions in the pancreatic β-cells of obese individuals. We used a hypothalamic-obesity model obtained by neonatal treatment with monosodium L-glutamate (MSG) to induce obesity. To assess the role of the HPA axis and vagal tonus in the genesis of hypercorticosteronemia and hyperinsulinemia in an adult MSG-obese rat model, bilateral adrenalectomy (ADX) and subdiaphragmatic vagotomy (VAG) alone or combined surgeries (ADX-VAG) were performed. To study glucose-induced insulin secretion (GIIS) and the cholinergic insulinotropic process, pancreatic islets were incubated with different glucose concentrations with or without oxotremorine-M, a selective agonist of the M3 muscarinic acetylcholine receptor (M3AChR) subtype. Protein expression of M3AChR in pancreatic islets, corticosteronemia, and vagus nerve activity was also evaluated. Surgeries reduced 80% of the body weight gain. Fasting glucose and insulin were reduced both by ADX and ADX-VAG, whereas VAG was only associated with hyperglycemia. The serum insulin post-glucose stimulation was lower in all animals that underwent an operation. Vagal activity was decreased by 50% in ADX rats. In the highest glucose concentration, both surgeries reduced GIIS by 50%, whereas ADX-VAG decreased by 70%. Additionally, M3AChR activity was recovered by the individual surgeries. M3AChR protein expression was reduced by ADX. Both the adrenal gland and vagus nerve contribute to the hyperinsulinemia in the MSG model, although adrenal is more crucial as it appears to modulate parasympathetic activity and M3AChR expression in obesity. [ABSTRACT FROM AUTHOR]

Injuries to peripheral nerves cause loss of motor and sensory function, greatly affecting life quality. Successful repair of the lesioned nerve requires efficient cell debris removal, followed by axon regeneration and reinnervation of target organs. Such process is orchestrated by several cellular and molecular events in which glial and immune cells actively participate. It is known that tissue clearance is largely improved by macrophages, which activation is potentiated by cells and molecules of the acquired immune system, such as T helper lymphocytes and antibodies, respectively. In the present work, we evaluated the contribution of lymphocytes in the regenerative process of crushed sciatic nerves of immunocompetent (wild-type, WT) and T and B-deficient (RAG-KO) mice. In Knockout animals, we found increased amount of macrophages under basal conditions and during the initial phase of the regenerative process, that was evaluated at 2, 4, and 8 weeks after lesion (wal). That parallels with faster axonal regeneration evidenced by the quantification of neurofilament and a growth associated protein immunolabeling. The motor function, evaluated by the sciatic function index, was fully recovered in both mouse strains within 4 wal, either in a progressive fashion, as observed for RAG-KO mice, or presenting a subtle regression, as seen in WT mice between 2 and 3 wal. Interestingly, boosting the immune response by early adoptive transference of activated WT lymphocytes at 3 days after lesion improved motor recovery in WT and RAG-KO mice, which was not ameliorated when cells were transferred at 2 wal. When monitoring lymphocytes by in vivo imaging, in both mouse strains, cells migrated to the lesion site shortly after transference, remaining in the injured limb up to its complete motor recovery. Moreover, a first peak of hyperalgesia, determined by von-Frey test, was coincident with increased lymphocyte infiltration in the damaged paw. Overall, the present results suggest that a wave of immune cell infiltration takes place during subacute phase of axonal regeneration, resulting in transient set back of motor recovery following peripheral axonal injury. Moreover, modulation of the immune response can be an efficient approach to speed up nerve regeneration. [ABSTRACT FROM AUTHOR]

Extraction and antioxidant activity of panax notoginseng saponins (PNS) were studied. PNS were extracted by enzymatic hydrolysis combined with ultrasonic treatment (EH & UT), and the antioxidant activity of the extracts was researched by pyrogallol autoxidation method and ferric ion reducing antioxidant power (FRAP). The results showed that the optimum parameters of ultrasonic treatment were 1:15 ratio of material to liquid, 70% of ethanol concentration, 35 min of ultrasonic time, and the optimum conditions of enzymatic hydrolysis were as follows: enzymatic hydrolysis time – 60 min, enzymatic hydrolysis temperature – 40°C, dosage of cellulase – 2.2%, pH value – 4.0, under which the extraction rate of PNS reached 1.795%. In addition, the extracts of PNS can remove superoxide anion free radicals, and can reduce ferric iron to divalent ions, which indicated that the extracts of PNS have a certain antioxidant activity. [ABSTRACT FROM AUTHOR]

Functional recovery of injured peripheral neurons often remains incomplete, but the clinical outcome can be improved by increasing the axonal growth rate. Adult transgenic GSK3αS/A/βS/A knock-in mice with sustained GSK3 activity show markedly accelerated sciatic nerve regeneration. Here, we unraveled the molecular mechanism underlying this phenomenon, which led to a novel pharmacological approach for the promotion of functional recovery after nerve injury. In vitro and in vivo analysis of GSK3 single knock-in mice revealed the unexpected contribution of GSK3α in addition to GSK3β, as both GSK3S/A knock-ins improved axon regeneration. Moreover, growth stimulation depended on overall GSK3 activity, correlating with increased phosphorylation of microtubule-associated protein IB and reduced microtubule detyrosination in axonal tips. Pharmacological inhibition of detyrosination by parthenolide or cnicin mimicked this axon growth promotion in wild-type animals, although it had no effect in GSK3αS/A/βS/A mice. These results support the conclusion that sustained GSK3 activity primarily targets microtubules in growing axons, maintaining them in a more dynamic state to facilitate growth. Accordingly, further manipulation of microtubule stability using either paditaxel or nocodazole compromised the effects of parthenolide. Strikingly, either local or systemic application of parthenolide in wild-type mice dose-dependently accelerated in vivo axon regeneration and functional recovery similar to GSK3αS/A/βS/A mice. Thus, reducing microtubule detyrosination in axonal tips may be a novel, clinically suitable strategy to treat nerve damage. [ABSTRACT FROM AUTHOR]

The X-linked form of Charcot–Marie–Tooth disease (CMTX) is caused by mutations in connexin32 (Cx32), a gap junction protein expressed by Schwann cells where it forms reflexive channels that allow the passage of ions and signaling molecules across the myelin sheath. Although most mutations result in loss of function, several studies have reported that some retain the ability to form homotypic intercellular channels. To gain insight into the molecular defect of three functional CMTX variants, S26L, Δ111–116 and R220stop, we have used several fluorescent tracers of different size and ionic charge to compare their permeation properties to those of wild-type Cx32. Although all mutations allowed the passage of the dye with the smallest molecular mass, they exhibited a clear reduction in the permeability of either one or all of the probes with respect to wild-type channels, as assessed by the percentage of injections showing dye coupling. These data reveal that a lower size cutoff distinguishes these functional CMTX variants from wild-type channels and suggest that this defect may be of pathophysiological relevance.

Recent developments in smartphone technology have increased user demand for indoors applications. The Global Navigation Satellite System (GNSS) and the Inertial Navigation System (INS) are the two advanced systems for navigation technology. However, it is still difficult for GNSS to provide an accurate and practical navigation solution, especially in environments with little or no signal availability. These failings should be easy to overcome; because of their portability and multiple embedded hardware sensors, smartphones seem well positioned to make pedestrian navigation easy and convenient in any environment. Pedestrian Dead Reckoning (PDR) is one of the most commonly used technologies used for pedestrian navigation, but it is not always accurate because its positioning errors tend to accumulate over time. Therefore, this research introduces a new tool to overcome this failing; a Bluetooth Low-Energy (BLE) beacon can maintain and improve the accuracy of PDR. Moreover, a BLE beacon can be initialized from any user position in an indoor environment. The random and unpredictable positions of pedestrians inevitably result in the degradation of navigation guidance systems’ data. To rectify this problem, we have implemented activity recognition technology to notify the proposed system so as to provide a more accurate heading estimate. This study proposes a Personal Navigation System (PNS) based on this technology; it can estimate navigation solutions in real time and combines the advantages of PDR and Bluetooth positioning technology. A series of experiments were conducted to evaluate the accuracy of the system and the efficacy of our proposed algorithms. Preliminary results show the average relative precision of PDR to be about 2.5%, when using a mobile hand-held device. The error of initial position from 2-D beacon positioning is less than two meters. The proposed system works well without post-processing, and the multi-sensor activity recognition system can determine the placement of the device when it is being carried or used by someone with close to 100% accuracy.

The homotrimeric P2X7 receptor (P2X7R) is expressed by virtually all cells of the innate and adaptive immune system and plays a crucial role in various pathophysiological processes such as autoimmune and neurodegenerative diseases, inflammation, neuropathic pain and cancer. Consequently, the P2X7R is considered a promising target for therapy and diagnosis. As the development of tracers comes hand-in-hand with the development of potent and selective receptor ligands, there is a rising number of PET tracers available in preclinical and clinical studies. This review analyzes the development of P2X7R positron emission tomography (PET) tracers and their potential in various PET imaging applications.

Introduction: To assess the efficacy of whole-body computed tomography (WB-CT) as imaging procedure to exclude cancer in patients with neurological symptoms and signs at clinical onset., Methods: A retrospective observational study was designed to identify consecutive WB-CT requested by the Neurology Unit with a suspicion of an underlying tumor potentially linked to a paraneoplastic neurological syndrome (PNS) between January 2019 and February 2022. The following data were collected: diagnosis at admission and at discharge, the presence of onconeural antibodies, the scans dose length product (DLP), the estimated effective dose (ED), the total estimated time requested; the PNS-Care-Score was retrospectively calculated only in subjects with available antibodies., Results: The total number of patients included was 158. In 13/158 (positive group) a malignant or locally aggressive neoplasm was found while in 145/158 no malignant lesions were found on the WB-CT. Among the positive group, in 7/13 onconeural antibodies were diagnosed, resulting negative in all cases and the most frequent tumor was lung cancer (30.8%). PNS-Care-Score was of 6-7 in 2/7 (probable PNS) and in no case the PNS-Care-Score was ≥8 (definite PNS). The mean DLP for all the scans was 2798 ± 952 mGy cm (average estimated ED of 42 ± 14 mSv). The total estimated time requested for all scans was 11,060 min., Conclusion: If a PNS is suspected, we encourage the prescription of unenhanced chest CT and/or abdomen/testis/female pelvis ultrasound and/or mammography based on clinical picture. The WB-CT using a single portal phase would be appropriate as a second-line technique while magnetic resonance imaging might be indicated for the exclusion of nervous system diseases., Implications for Practice: Our suggestion results in saving in terms of radiation exposure, financial resources and time., Competing Interests: Conflict of interest statement None., (Copyright © 2022 The College of Radiographers. Published by Elsevier Ltd. All rights reserved.)

Autoimmune disorders are increasingly recognized causes of several neurological disorders leading to significant clinical disability. This article reviews recent developments in our understanding on the pathophysiology, clinical presentations, and diagnoses of selected immune-mediated neurological disorders. It also provides a brief summary of current theories on autoimmunity and the role that certain environmental factors play in the development of immune-mediated neurological disorders. Recently recognized biomarkers might play a pathogenetic role or simply serve as a diagnostic tool. [ABSTRACT FROM AUTHOR]

Proper migration of cells through the dense and complex extracellular matrix (ECM) requires constant restructuring of the ECM to allow cells to move forward in a smooth manner. This restructuring can occur through the action of extracellular enzymes. Among these extracellular enzymes is the ADAMTS ( A D isintegrin A nd M etalloprotease with T hrombo S pondin repeats) family of secreted extracellular proteases. Drosophila stl encodes an ADAMTS protease expressed in and around the peripheral nervous system (PNS) during embryogenesis. The absence of stl displayed one specific neuron, the v'ch1 sensory neuron, migrating to its target sooner than in wild type. During normal development, the v'ch1 sensory neuron migrates dorsally at the same time it is extending an axon ventrally toward the CNS. Surprisingly, in the absence of stl , the v'ch1 neuron migrated further dorsally as compared to the wild type at stage 15, but did not migrate past its correct target at stage 16, suggesting a novel role for this extracellular protease in inhibiting migration of this neuron past a certain point. [ABSTRACT FROM AUTHOR]

Repair of the injured spinal cord is a major challenge in medicine. The limited intrinsic regenerative response mounted by adult central nervous system (CNS) neurons is further hampered by astrogliosis, myelin debris and scar tissue that characterize the damaged CNS. Improved axon regeneration and recovery can be elicited by targeting extrinsic factors as well as by boosting neuron-intrinsic growth regulators. Our knowledge of the molecular basis of intrinsic and extrinsic regulators of regeneration has expanded rapidly, resulting in promising new targets to promote repair. Intriguingly certain neuron-intrinsic growth regulators are emerging as promising targets to both stimulate growth and relieve extrinsic inhibition of regeneration. This crossroads between the intrinsic and extrinsic aspects of spinal cord injury is a promising target for effective therapies for this unmet need. [ABSTRACT FROM AUTHOR]

Objectives Paraneoplastic neurological syndromes (PNSs) are rare disorders in association with cancer and sub-divided into “classical” and “non-classical” syndromes according to a 2004 consensus paper proposed by a panel of PNS experts. “Classical” PNSs are regarded to account for the vast majority of cases. However, systematic reports on clinical PNS manifestations are rare. Therefore, we analyzed the spectrum of PNS in our clinic. Methods We retrospectively investigated medical records from consecutive patients diagnosed with definite PNS and serological evidence of well-characterized onconeural antibodies (anti-Hu, Yo, Ri, CV2/CRMP5, Ma1, Ma2, and amphiphysin) analyzed between 1991 and 2014 in our clinic. Results Of the 50 patients identified with onconeural antibody-positive PNS, 28 patients (56.0%) had “classical” PNS, and 22 (44.0%) “non-classical” PNS. Subacute cerebellar degeneration was the most frequent “classical” syndrome, brainstem encephalitis and subacute sensorimotor neuronopathy the most frequent “non-classical” syndromes. Anti-Hu antibodies were most frequent in both groups. 86.1% of patients developed neurological symptoms before the cancer was known. No differences between “classical” and “non-classical” syndromes were detected with respect to age, tumor entities and median time to diagnosis. However, whereas most patients with “classical” syndromes were females, there was no gender predominance in patients with “non-classical” PNS and the latter had significantly more frequent peripheral neurological syndromes. Conclusions The so-called “non-classical” PNSs in association with well-characterized onconeural antibodies were more common in our patient population than expected. Therefore, in neurological disorders of unclear etiology with a subacute onset and atypical presentation further diagnostic work-up including investigation of onconeural antibodies is necessary. [ABSTRACT FROM AUTHOR]

The Pox neuro ( Poxn ) gene of Drosophila plays a crucial role in the development of poly-innervated external sensory (p-es) organs. However, how Poxn exerts this role has remained elusive. In this study, we have analyzed the cell lineages of all larval p-es organs, namely of the kölbchen, papilla 6, and hair 3. Surprisingly, these lineages are distinct from any previously reported cell lineages of sensory organs. Unlike the well-established lineage of mono-innervated external sensory (m-es) organs and a previously proposed model of the p-es lineage, we demonstrate that all wild-type p-es lineages exhibit the following features: the secondary precursor, pIIa, gives rise to all three support cells—socket, shaft, and sheath, whereas the other secondary precursor, pIIb, is neuronal and gives rise to all neurons. We further show that in one of the p-es lineages, that of papilla 6, one cell undergoes apoptosis. By contrast in Poxn null mutants, all p-es lineages have a reduced number of cells and their pattern of cell divisions is changed to that of an m-es organ, with the exception of a lineage in a minority of mutant kölbchen that retains a second bipolar neuron. Indeed, the role of Poxn in p-es lineages is consistent with the specification of the developmental potential of secondary precursors and the regulation of cell division but not apoptosis. [ABSTRACT FROM AUTHOR]

This study analyses whether science–policy interactions linked to the management of hazardous chemicals in the European marine environment have developed in accordance with general theories on public involvement in policymaking in general and post-normal science (PNS) in particular. Special attention is given to a comparison between key EU policy frameworks, namely the “polluter-oriented” registration, evaluation, authorisation and restriction of chemicals (REACH) and the “environment-oriented” Marine Strategy Framework Directive (MSFD), based on in-depth analysis of key policy-related documents and interviews with scientists and policy actors. The results outline that in spite of a substantial amount of rhetoric in EU sources about recommending wide and ambitious public involvement, current participation and deliberation practices are rather undeveloped in the studied EU policy frameworks. Furthermore, it can be concluded that the introduction of more radical approaches to knowledge co-production and participation (like PNS) would require epistemological, institutional and constitutional changes that are not feasible in the foreseeable future, at least not in respect to chemicals management. This study generates empirical data with regard to the management of chemicals in the European marine environment, specifically data on participation, the role of science, and uncertainty treatment at the science–policy interface. These data provide empirical information that can be used by environmental managers involved in the development of EU marine policy. At the same time, the results can be used theoretically to reflect on and problematise the current state of wider public participation in EU environmental policies and PNS development in particular cases. [ABSTRACT FROM AUTHOR]

Following recent discoveries, diagnostic criteria for paraneoplastic neurological syndromes (PNS) have been recently updated. However, how the criteria impact PNS diagnosis is still unclear. We retrospectively applied the previously existing 2004 criteria (2004-c) and the updated 2021 diagnostic criteria (2021-c) to 74 patients with suspect PNS. The 2021 criteria were highly sensitive (88%) and specific (80%). There was good concordance between the definite PNS group (2004-c) and the definite plus probable PNS group (2021-c). The inter-rater reliability for the 2021-c was excellent. The application of the 2021 criteria improves the diagnosis of patients with PNS., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Gene therapy offers great promise in addressing neuropathologies associated with the central and peripheral nervous systems (CNS and PNS). However, genetic access remains difficult, reflecting the critical need for the development of effective and non-invasive gene delivery vectors across species. To that end, we evolved adeno-associated virus serotype 9 (AAV9) capsid in mice and validated two capsids, AAV-MaCPNS1 and AAV-MaCPNS2, across rodent species (mice and rats) and non-human primate (NHP) species (marmosets and rhesus macaques). Intravenous administration of either AAV efficiently transduced the PNS in rodents and both the PNS and CNS in NHPs. Furthermore, we used AAV-MaCPNS1 in mice to systemically deliver the following: (1) the neuronal sensor jGCaMP8s to record calcium signal dynamics in nodose ganglia and (2) the neuronal actuator DREADD to dorsal root ganglia to mediate pain. This conclusively demonstrates the translatability of these two systemic AAVs across four species and their functional utility through proof-of-concept studies in mice. [Display omitted] • Directed evolution in rodents identified AAV vectors targeting the PNS • Systemically administered MaCPNS1 and MaCPNS2 efficiently target the PNS in rodents • Systemic MaCPNS1 is used for functional readout and non-invasive modulation of the PNS • Systemic MaCPNS1 and MaCPNS2 transduce both the PNS and CNS in macaque and marmoset Chen et al. evolved a family of AAV capsid variants, including MaCPNS1 and MaCPNS2, that efficiently transduced the PNS in rodents following systemic administration, enabling functional readout and non-invasive modulation of PNS. Both vectors could also enable efficient gene delivery to both PNS and CNS in macaque and marmoset. [ABSTRACT FROM AUTHOR]