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Abstract Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by progressive motoneuron degeneration, and effective clinical treatments are lacking. In this study, we evaluated whether intranasal delivery of mesenchymal stem cell–derived small extracellular vesicles (sEVs) is a strategy for ALS therapy using SOD1 G93A mice. In vivo tracing showed that intranasally-delivered sEVs entered the central nervous system and were extensively taken up by spinal neurons and some microglia. SOD1 G93A mice that intranasally received sEV administration showed significant improvements in motor performances and survival time. After sEV administration, pathological changes, including spinal motoneuron death and synaptic denervation, axon demyelination, neuromuscular junction degeneration and electrophysiological defects, and mitochondrial vacuolization were remarkably alleviated. sEV administration attenuated the elevation of proinflammatory cytokines and glial responses. Proteomics and transcriptomics analysis revealed upregulation of the complement and coagulation cascade and NF-ĸB signaling pathway in SOD1 G93A mouse spinal cords, which was significantly inhibited by sEV administration. The changes were further confirmed by detecting C1q and NF-ĸB expression using Western blots. In conclusion, intranasal administration of sEVs effectively delays the progression of ALS by inhibiting neuroinflammation and overactivation of the complement and coagulation cascades and NF-ĸB signaling pathway and is a potential option for ALS therapy. Graphical abstract

Abstract Climate and environmental changes threaten human mental health, but the impacts of specific environmental conditions on neuropsychiatric disorders remain largely unclear. Here, we show the impact of a humid heat environment on the brain and the gut microbiota using a conditioned housing male mouse model. We demonstrate that a humid heat environment can cause anxiety-like behaviour in male mice. Microbial 16 S rRNA sequencing analysis reveals that a humid heat environment caused gut microbiota dysbiosis (e.g., decreased abundance of Lactobacillus murinus), and metabolomics reveals an increase in serum levels of secondary bile acids (e.g., lithocholic acid). Moreover, increased neuroinflammation is indicated by the elevated expression of proinflammatory cytokines in the serum and cortex, activated PI3K/AKT/NF-κB signalling and a microglial response in the cortex. Strikingly, transplantation of the microbiota from mice reared in a humid heat environment readily recapitulates these abnormalities in germ-free mice, and these abnormalities are markedly reversed by Lactobacillus murinus administration. Human samples collected during the humid heat season also show a decrease in Lactobacillus murinus abundance and an increase in the serum lithocholic acid concentration. In conclusion, gut microbiota dysbiosis induced by a humid heat environment drives the progression of anxiety disorders by impairing bile acid metabolism and enhancing neuroinflammation, and probiotic administration is a potential therapeutic strategy for these disorders.

Abstract Background Deposition of amyloid β, which is produced by amyloidogenic cleavage of APP by β- and γ-secretase, is one of the primary hallmarks of AD pathology. APP can also be processed by α- and γ-secretase sequentially, to generate sAPPα, which has been shown to be neuroprotective by promoting neurite outgrowth and neuronal survival, etc. Methods The global expression profiles of miRNA in blood plasma samples taken from 11 AD patients as well as from 14 age and sex matched cognitively normal volunteers were analyzed using miRNA-seq. Then, overexpressed miR-140 and miR-122 both in vivo and in vitro, and knock-down of the endogenous expression of miR-140 and miR-122 in vitro. Used a combination of techniques, including molecular biology, immunohistochemistry, to detect the impact of miRNAs on AD pathology. Results In this study, we identified that two miRNAs, miR-140-3p and miR-122-5p, both targeting ADAM10, the main α-secretase in CNS, were upregulated in the blood plasma of AD patients. Overexpression of these two miRNAs in mouse brains induced cognitive decline in wild type C57BL/6J mice as well as exacerbated dyscognition in APP/PS1 mice. Although significant changes in APP and total Aβ were not detected, significantly downregulated ADAM10 and its non-amyloidogenic product, sAPPα, were observed in the mouse brains overexpressing miR-140/miR-122. Immunohistology analysis revealed increased neurite dystrophy that correlated with the reduced microglial chemotaxis in the hippocampi of these mice, independent of the other two ADAM10 substrates (neuronal CX3CL1 and microglial TREM2) that were involved in regulating the microglial immunoactivity. Further in vitro analysis demonstrated that both the reduced neuritic outgrowth of mouse embryonic neuronal cells overexpressing miR-140/miR-122 and the reduced Aβ phagocytosis in microglia cells co-cultured with HT22 cells overexpressing miR-140/miR-122 could be rescued by overexpressing the specific inhibitory sequence of miR-140/miR-122 TuD as well as by addition of sAPPα, rendering these miRNAs as potential therapeutic targets. Conclusions Our results suggested that neuroprotective sAPPα was a key player in the neuropathological progression induced by dysregulated expression of miR-140 and miR-122. Targeting these miRNAs might serve as a promising therapeutic strategy in AD treatment.

ABSTRACTFive varieties of beans from Laibin, Guangxi, China, including mung beans, soybeans, black beans, red beans, and adzuki beans, were chosen as study subjects for multi-index determination and full assessment. Data on the fat, ash, crude fiber, trace element, thermogravimetric analysis and combustion heat of five different types of beans were gathered. The results showed that the order of combustion heat of the 5 kinds of beans was black beans>soybeans>mung beans>adzuki beans>red beans, the order of combustion stability was soybeans>mung beans>black beans>red beans>adzuki beans, the order of fat content was soybeans>red beans>adzuki beans>black beans>mung beans, the order of ash content was black beans>soybeans>adzuki beans>mung beans>red beans, the order of crude fiber content was red beans>soybeans>adzuki beans, and the order of multi-index stoichiometric analysis was soybeans>red beans>black beans>mung beans>adzuki beans. The quality of the food was assessed and classified using the stoichiometric approach, while the food nutrition was assessed from the perspectives of fat, ash, crude fiber, trace elements, thermogravimetric analysis and combustion heat. This work provides a solid scientific foundation for the assessment and investigation of the thermo gravimetric analysis of food combustion stability. This study’s multi-index comprehensive evaluation approach offers a novel concept for food nutrition.

As the core component of energy conversion for large wind turbines, the output performance of doubly-fed induction generators (DFIGs) plays a decisive role in the power quality of wind turbines. To realize the fast and accurate design optimization of DFIGs, this paper proposes a novel hybrid-driven surrogate-assisted optimization method. It firstly establishes an accurate subdomain model of DFIGs to analytically predict performance indexes. Furthermore, taking the inexpensive analytical dataset produced by the subdomain model as the source domain and the expensive finite element analysis dataset as the target domain, a high-precision surrogate model is trained in a transfer learning way and used for the subsequent multi-objective optimization process. Based on this model, taking the total harmonic distortion of electromotive force, cogging torque, and iron loss as objectives, and the slot and inner/outer diameters as parameters for optimizing the topology, achieve a rapid and accurate electromagnetic design for DFIGs. Finally, experiments are carried out on a 3MW DFIG to validate the effectiveness of the proposed method.

AimOur study utilized the Rasch analysis to examine the psychometric properties of the Autism Behavior Checklist (ABC) in children with autism spectrum disorder (ASD).MethodsA total of 3,319 children (44.77 ± 23.52 months) were included. The Rasch model (RM) was utilized to test the reliability and validity of the ABC. The GPCMlasso model was used to test the differential item functioning (DIF).ResultThe response pattern of this sample showed acceptable fitness to the RM. The analysis supported the unidimensionality assumption of the ABC. Disordered category functions and DIF were found in all items in the ABC. The participants responded to the ABC items differently depending not only on autistic traits but also on age groups, gender, and symptom classifications.ConclusionThe Rasch analysis produces reliable evidence to support that the ABC can precisely depict clinical ASD symptoms. Differences in population characteristics may cause unnecessary assessment bias and lead to overestimated or underestimated symptom severity. Hence, special consideration for population characteristics is needed in making an ASD diagnosis.

For patients with chronic spinal cord injury, the conventional treatment is rehabilitation and treatment of spinal cord injury complications such as urinary tract infection, pressure sores, osteoporosis, and deep vein thrombosis. Surgery is rarely performed on spinal cord injury in the chronic phase, and few treatments have been proven effective in chronic spinal cord injury patients. Development of effective therapies for chronic spinal cord injury patients is needed. We conducted a randomized controlled clinical trial in patients with chronic complete thoracic spinal cord injury to compare intensive rehabilitation (weight-bearing walking training) alone with surgical intervention plus intensive rehabilitation. This clinical trial was registered at ClinicalTrials.gov (NCT02663310). The goal of surgical intervention was spinal cord detethering, restoration of cerebrospinal fluid flow, and elimination of residual spinal cord compression. We found that surgical intervention plus weight-bearing walking training was associated with a higher incidence of American Spinal Injury Association Impairment Scale improvement, reduced spasticity, and more rapid bowel and bladder functional recovery than weight-bearing walking training alone. Overall, the surgical procedures and intensive rehabilitation were safe. American Spinal Injury Association Impairment Scale improvement was more common in T7–T11 injuries than in T2–T6 injuries. Surgery combined with rehabilitation appears to have a role in treatment of chronic spinal cord injury patients.

Spinal cord injury (SCI) leads to devastating physical consequences, such as severe sensorimotor dysfunction even lifetime disability, by damaging the corticospinal system. The conventional opinion that SCI is intractable due to the poor regeneration of neurons in the adult central nervous system (CNS) needs to be revisited as the CNS is capable of considerable plasticity, which underlie recovery from neural injury. Substantial spontaneous neuroplasticity has been demonstrated in the corticospinal motor circuitry following SCI. Some of these plastic changes appear to be beneficial while others are detrimental toward locomotor function recovery after SCI. The beneficial corticospinal plasticity in the spared corticospinal circuits can be harnessed therapeutically by multiple contemporary neuromodulatory approaches, especially the electrical stimulation-based modalities, in an activity-dependent manner to improve functional outcomes in post-SCI rehabilitation. Silent synapse generation and unsilencing contribute to profound neuroplasticity that is implicated in a variety of neurological disorders, thus they may be involved in the corticospinal motor circuit neuroplasticity following SCI. Exploring the underlying mechanisms of silent synapse-mediated neuroplasticity in the corticospinal motor circuitry that may be exploited by neuromodulation will inform a novel direction for optimizing therapeutic repair strategies and rehabilitative interventions in SCI patients.

[INLINE:1] Dendrites play irreplaceable roles in the nerve conduction pathway and are vulnerable to various insults. Peripheral axotomy of motor neurons results in the retraction of dendritic arbors, and the dendritic arbor can be re-expanded when reinnervation is allowed. RhoA is a target that regulates the cytoskeleton and promotes neuronal survival and axon regeneration. However, the role of RhoA in dendrite degeneration and regeneration is unknown. In this study, we explored the potential role of RhoA in dendrites. A line of motor neuronal RhoA conditional knockout mice was developed by crossbreeding HB9Cre+ mice with RhoAflox/flox mice. We established two models for assaying dendrite degeneration and regeneration, in which the brachial plexus was transection or crush injured, respectively. We found that at 28 days after brachial plexus transection, the density, complexity, and structural integrity of dendrites in the ventral horn of the spinal cord of RhoA conditional knockout mice were slightly decreased compared with that in Cre mice. Dendrites underwent degeneration at 7 and 14 days after brachial plexus transection and recovered at 28–56 days. The density, complexity, and structural integrity of dendrites in the ventral horn of the spinal cord of RhoA conditional knockout mice recovered compared with results in Cre mice. These findings suggest that RhoA knockout in motor neurons attenuates dendrite degeneration and promotes dendrite regeneration after peripheral nerve injury.

Abstract 5 kinds of genuine medicinal materials, including Diding (Latin name: Corydalis bungeana Turcz), Purslane (Latin name: Portulaca oleracea L.), straw sandal board (Latin name: Hoya carnosa (L.f.) R. Br), June snow (Latin name: Serissa japonica (Thunb.) Thunb.), pine vine rattan (Latin name: Lycopodiastrum casuarinoides (Spring) Holub. [Lycopodium casuarinoides Spring]), were selected as the research objects. The combustion heat, thermo gravimetric parameters, and fat content, calcium content, trace element content, ash content of 5 kinds of genuine medicinal materials were measured. The combustion heat, differential thermal gravimetric analysis, fat content, calcium content, trace elements content, and ash content of 5 kinds of genuine medicinal materials were used to build a systematic multi-index evaluation system by gray pattern recognition and grey correlation coefficient cluster analysis, which can make up for the gaps in this area and provide scientific basis and research significance for the study of genuine medicinal materials quality. The results showed that the order of combustion heat of 5 kinds of genuine medicinal materials, including Diding, Purslane, straw sandal board, June snow, pine vine rattan, was Diding > June snow > straw sandal board > Purslane > pine vine rattan, the order of fat content (%) of 5 kinds of genuine medicinal materials was straw sandal board > Diding > pine vine rattan > June snow > Purslane, the order of calcium content (%) was pine vine rattan > June snow > Purslane > straw sandal board > Diding, the order of ash content was June snow > Purslane > straw sandal board > pine vine rattan > Diding. From the analysis of thermogravimetric analysis results and thermogravimetric combustion stability, the order of combustion stability of 5 kinds of genuine medicinal materials was June snow > pine Vine rattan > straw sandal board > Diding > Portulaca oleracea. The order of the content of 12 trace elements in 5 kinds of genuine medicinal materials, in terms of trace element content, June snow contains the highest trace elements in all samples. According to combustion heat, combustibility (combustion stability of genuine medicinal materials), fat, calcium, ash, trace element content, the comprehensive evaluation results of multi-index analysis constructed by gray correlation degree, gray correlation coefficient factor analysis, and gray hierarchical cluster analysis showed that the comprehensive evaluation multi-index order of 5 genuine medicinal materials, including Diding, Purslane, straw sandal board, June snow and pine vine rattan, was June snow > straw sandal board > Diding > Purslane > pine vine rattan. Therefore, the comprehensive evaluation results of the quality of genuine medicinal materials selected in this study were June snow the best, followed by straw sandal board. This research has important theoretical and practical significance for the multi-index measurement and comprehensive evaluation of genuine medicinal materials, and can provide scientific basis and research significance for the research of multi-index quality control of genuine medicinal material.

BackgroundCerebral microbleeds (CMBs) are an early sign of many neurological disorders and accompanied by local neuroinflammation and brain damage. As important regulators of immune response and neuroinflammation, the biological behavior and role of γδ T cells after CMBs remain largely unknown.MethodsWe made a spot injury of microvessel in the somatosensory cortex to mimic the model of CMBs by two-photon laser and in vivo tracked dynamical behaviors of γδ T cells induced by CMBs using TCR-δGFP transgenic mice. Biological features of γδ T cells in the peri-CMBs parenchyma were decoded by flow cytometry and Raman spectra. In wildtype and γδ T cell-deficient mice, neuroinflammation and neurite degeneration in the peri-CMBs cortex were studied by RNAseq, immunostaining and in vivo imaging respectively.ResultsAfter CMBs, γδ T cells in the dural vessels were tracked to cross the meningeal structure and invade the brain parenchyma in a few days, where the division process of γδ T cells were captured. Parenchymal γδ T cells were highly expressed by CXCR6 and CCR6, similar to meningeal γδ T cells, positive for IL-17A and Ki67 (more than 98%), and they contained abundant substances for energy metabolism and nucleic acid synthesis. In γδ T cell-deficient mice, cortical samples showed the upregulation of neuroinflammatory signaling pathways, enhanced glial response and M1 microglial polarization, and earlier neuronal degeneration in the peri-CMBs brain parenchyma compared with wildtype mice.ConclusionCMBs induce the accumulation and local proliferation of γδ T cells in the brain parenchyma, and γδ T cells exert anti-neuroinflammatory and neuroprotective effects at the early stage of CMBs.

Abstract Multi‐phase permanent‐magnet synchronous machines (MPMSMs) with high reliability due to sufficient fault‐tolerant capability have considerable potential for transportation electrification applications. Here, an efficient surrogate‐assisted design optimisation method is proposed based on analytical model transfer learning for torque characteristic optimisation of a five‐phase magnet‐shaping PMSM. By employing transfer learning of the source domain analytical model data and the target domain finite element analysis (FEA) data in surrogate model training, the proposed method can achieve both high accuracy and high efficiency from the merits of FEA‐ and analytical‐based optimisations, respectively. The studied machine with five‐phases and harmonic injected surface‐mounted PMs to enable harmonic injection for torque capability improvement is introduced and the analytical model is built based on the segmented PM and the complex conformal mapping methods. Besides, the optimal Latin hypercube design (LHD) and Taguchi methods are used to form the source and target domain datasets, respectively, so that data features can be efficiently captured over a wide range of optimisation variables. An optimal design is obtained by multi‐objective optimisation using the trained surrogate model, which is prototyped and measured to validate the proposed method.

Objective: To evaluate the biological function of cervical subtotal discectomy prosthesis (CSDP) implantation in a non-human primate model.Methods: A CSDP was tested for cytocompatibility and osseointegration capacity before implantation in non-human primates. Subsequently, the CSDP was improved based on three-dimensional CT measurements of the non-human primate cervical spine. Eight cynomolgus monkeys were selected for removal of the intervertebral disc and lower endplate of the C5/6 segment to complete the model construction for CSDP implantation. In 18-month follow-up, physiological indices, radiology, and kinematics were assessed to estimate the biological function of the CSDP in non-human primates, including biosafety, osseointegration, and biomechanics.Results: Co-cultured with the CSDP constituent titanium alloy (Ti6Al4V-AO), the mouse embryo osteoblast precursor cell MC3T3-E1 obtained extended adhesion, remarkable viability status, and cell proliferation. After implantation in the mouse femur for 28 days, the surface of Ti6Al4V-AO was covered by a large amount of new cancellous bone, which formed further connections with the femur cortical bone, and no toxicity was detected by blood physiology indices or histopathology. After completing implantation in primate models, no infection or osteolysis was observed, nor was any subsidence or displacement of the CSDP observed in CT scans in the 18-month follow-up. In particular, the interior of the cervical vertebra fixation structure was gradually filled with new trabecular bone, and the CSDP had achieved fixation and bony fusion in the vertebral body at 1 year post-operation. Meanwhile, no signs of inflammation, spinal cord compression, adjacent segment degeneration, or force line changes were observed in subsequent MRI observations. Moreover, there were no pathological changes of the joint trajectory, joint motion range, stride length, or the stance phase ratio revealed in the kinematics analysis at 3, 6, 12, or 18 months after CSDP implantation.Conclusion: We successfully designed a new cervical subtotal discectomy prosthesis and constructed an excellent non-human primate implantation model for the evaluation of subtotal disc replacement arthroplasty. Furthermore, we demonstrated that CSDP had outstanding safety, osseointegration capacity, and biomechanical stability in a non-human primate model, which might be a new choice in the treatment of cervical disc diseases and potentially change future outcomes of degenerative cervical diseases.

Inhibitor of DNA binding 2 (Id2) can promote axonal regeneration after injury of the central nervous system. However, whether Id2 can promote axonal regeneration and functional recovery after peripheral nerve injury is currently unknown. In this study, we established a mouse model of bilateral sciatic nerve crush injury. Two weeks before injury, AAV9-Id2-3×Flag-GFP was injected stereotaxically into the bilateral ventral horn of lumbar spinal cord. Our results showed that Id2 was successfully delivered into spinal cord motor neurons projecting to the sciatic nerve, and the number of regenerated motor axons in the sciatic nerve distal to the crush site was increased at 2 weeks after injury, arriving at the tibial nerve and reinnervating a few endplates in the gastrocnemius muscle. By 1 month after injury, extensive neuromuscular reinnervation occurred. In addition, the amplitude of compound muscle action potentials of the gastrocnemius muscle was markedly recovered, and their latency was shortened. These findings suggest that Id2 can accelerate axonal regeneration, promote neuromuscular reinnervation, and enhance functional improvement following sciatic nerve injury. Therefore, elevating the level of Id2 in adult neurons may present a promising strategy for peripheral nerve repair following injury. The study was approved by the Experimental Animal Ethics Committee of Jinan University (approval No. 20160302003) on March 2, 2016.

The necessity to align the rotor with the d-q magnetic axes is the main obstacle for the wide application of synchronous machine standstill parameter tests, especially for the high-power units. This paper presents an arbitrary rotor position parameter estimation method for standstill time-domain response (SSTRs) tests and applied on a 300 MVar, 20 kV large synchronous condenser, a DC step voltage signal is selected as the input signal. Firstly, a frequency-domain Dalton-Cameron transformation is demonstrated and used to simultaneously obtain both axes' operational inductances in an arbitrary rotor position, thus eliminating the need for the rotor prepositioning process. Then, a novel analytical parameter estimation method combined with an I/T transformation is proposed, all the parameters of both axes are determined without extra tests, the mutual leakage flux between the field winding and the d-axis damper winding is also taken in account. To validate the proposed method, this test is carried out and its parameter estimation results are compared against that of the three-phase sudden short-circuit test and the traditional SSTR test. Estimation results are given in the form of I-type and T-type circuits, the maximum relative error no more than 6% and 10%, respectively.

Summary: Atypical cadherin Celsr3 is critical for brain embryonic development, and its role in the postnatal cerebellum remains unknown. Using Celsr3-GFP mice, Celsr3 shows high expression in postnatal Purkinje cells (PCs). Mice with conditional knockout (cKO) of Celsr3 in postnatal PCs exhibit deficit in motor coordination and learning, atrophic PC dendrites, and decreased synapses. Whole-PC recording in cerebellar slices discloses a reduction frequency of mEPSC and defective postsynaptic plasticity (LTP and LTD) in Celsr3 cKO mutants. Wnt5a perfusion enhances LTP formation, which could be occluded by cAMP agonist and diminished by cAMP antagonist in control, but not in Celsr3 cKO or Fzd3 cKO cerebellar slices. Celsr3 cKO resulted in the failure of mGluR1 agonist-induced LTD and paired stimulation-induced PKCα overexpression in PC dendrites, and downregulation of mGluR1 expression compvared to controls. In conclusion, Celsr3 is required for PCs maturation and regulates postsynaptic LTP and LTD through Wnt5a/cAMP and mGluR1/PKCα signaling respectively.

Abstract Background POLR3-related leukodystrophy is an autosomal recessive neurodegenerative disorder characterized by onset time ranging from the neonatal period to late childhood, progressive motor decline that manifests as spasticity, ataxia, tremor, and cerebellar symptoms, as well as mild cognitive regression and hypodontia. POLR3-related leukodystrophy belongs to the family of RNA polymerase III-related leukodystrophy, which are caused by biallelic mutations in the POLR3A, POLR3B, POLRC1, or POLR3K genes. Case presentation In this study, we report a female child with POLR3-related leukodystrophy manifesting as cognitive decline, moderate dysarthria, motor decline, cerebellar syndrome, short stature, dysphagia, hypodontia, and mild delayed myelination by brain imaging. Interestingly, polytrichia and bronchodysplasia were first observed in a POLR3-related leukodystrophy patient. Medical exome sequencing with high coverage depth was employed to identify potential genetic variants in the patient. Novel compound heterozygous mutations of the POLR3A gene, c.1771-6C > G and c.2611del (p.M871Cfs*8), were detected. One of them is an uncommon splice site mutation, and this is the first report of this mutation in a Chinese family. The father was determined to be a heterozygous carrier of the c.2611del (p.M871Cfs*8) mutation and the mother a heterozygous carrier of the c.1771-6C > G mutation. Conclusion The patient’s newly emerged clinical features and mutations provide useful information for further exploration of genotype-phenotype correlations of POLR3-related leukodystrophy.

The balance of excitatory and inhibitory neurons in the central nervous system is critical for maintaining brain function and sevoflurane, a general anesthetic and an GABA receptor modulator, may change the balance of excitatory and inhibitory neurons in the cortex during early brain development. Herein, we investigated whether prenatal sevoflurane exposure (PSE) disturbs cortical neuronal development and brain function. Pregnant rats at the gestational day 14.5 were subjected to sevoflurane exposure at 3.0% for 3 h and their offspring were studied thereafter. We found a significant increase of parvalbumin-positive neurons, vesicular GABA transporter (VGAT) and GAD67 expression, and GABA neurotransmitter, and a significant decrease of vesicular glutamate transporter 1 (VGLUT1) expression and glutamate in the medial prefrontal cortex (mPFC) of offspring. Pyramidal neurons showed atrophy with shorter dendrites, less branches and lower spine density visualized by Golgi stain and a decrease of excitability with the increased miniature inhibitory postsynaptic current (mIPSC) frequency and amplitude, the decreased miniature excitatory postsynaptic current (mEPSC) frequency and excitation/inhibition (E/I) ratio using whole-cell recording in offspring. There was a significant increase of inhibitory synapse in the mPFC detected by electron microscopy. Furthermore, PSE animals showed hypo-excitatory phenotype including depression-like behaviors and learning deficits. Thus, our studies provide novel evidence that PSE causes the persisted imbalance of excitatory and inhibitory neurons in the mPFC, and this is very likely the mechanisms of the sevoflurane-induced brain functional abnormalities.

As one major component of extracellular matrix (ECM) in the central nervous system, chondroitin sulfate proteoglycans (CSPGs) have long been known as inhibitors enriched in the glial scar that prevent axon regeneration after injury. Although many studies have shown that CSPGs inhibited neurite outgrowth in vitro using different types of neurons, the mechanism by which CSPGs inhibit axonal growth remains poorly understood. Using cerebellar granule neuron (CGN) culture, in this study, we evaluated the effects of different concentrations of both immobilized and soluble CSPGs on neuronal growth, including cell adhesion, spreading and neurite growth. Neurite length decreased while CSPGs concentration arised, meanwhile, a decrease in cell density accompanied by an increase in cell aggregates formation was observed. Soluble CSPGs also showed an inhibition on neurite outgrowth, but it required a higher concentration to induce cell aggregates formation than coated CSPGs. We also found that growth cone size was significantly reduced on CSPGs and neuronal cell spreading was restrained by CSPGs, attributing to an inhibition on lamellipodial extension. The effect of CSPGs on neuron adhesion was further evidenced by interference reflection microscopy (IRM) which directly demonstrated that both CGNs and cerebral cortical neurons were more loosely adherent to a CSPG substrate. These data demonstrate that CSPGs have an effect on cell adhesion and spreading in addition to neurite outgrowth.

In this paper, a gas detection system with an environmental compensation algorithm based on nondispersive infrared (NDIR) technology was designed. The prepared infrared pyroelectric detector was a dual-channel type based on the lithium tantalate (LiTaO3) wafer. The design of the optical gas chamber adopted a combination of two ellipsoids and a spherical top surface, which not only enhanced the coupling efficiency of the light propagation but also facilitated the miniaturization of the sensor module. In addition to this, a temperature and humidity compensation algorithm based on the least square method was proposed to make the measurement accuracy up to ±0.9% full scale (FS).

Abstract Cognitive impairments in bipolar patients deteriorate as the disorder progresses. Little is known about whether genetic risks impact cognitive recovery during the course from depression to remission. In this six-week open-label trial, we shed light on the impacts of six single nucleotide polymorphisms (SNPs) in the calcium voltage-gated channel subunit alpha1 C (CACNA1C) gene on cognitive recovery in 192 bipolar patients suffering a major depressive episode (MDE). The primary outcome measures were changes in a battery of neuropsychological tests following 6-week treatment. Carriers with rs10466907 GT genotype did not significantly improve their executive function total scores on the Wisconsin Card Sorting Test after six weeks of treatment compared to the TT genotypes (β = −0.944, 95% Confidence Interval (CI) = −1.482–−0.405). Moreover, during a MDE carriers with rs58619945 GG and GA genotypes performed significantly worse than those with AA genotype on the categories completed (p = 0.013 and p = 0.001), total errors (p = 0.039 and p = 0.009), and random errors (p = 0.055 and p = 0.014, respectively). Our data suggest that the tested CACNA1C SNPs may have impacts on cognitive recovery from depression.

SHANK3 mutations, including de novo deletions, have been associated with autism spectrum disorders (ASD). However, the effects of SHANK3 loss of function on neurodevelopment remain poorly understood. Here we generated human induced pluripotent stem cells (iPSC) in vitro, followed by neuro-differentiation and lentivirus-mediated shRNA expression to evaluate how SHANK3 knockdown affects the in vitro neurodevelopmental process at multiple time points (up to 4 weeks). We found that SHANK3 knockdown impaired both early stage of neuronal development and mature neuronal function, as demonstrated by a reduction in neuronal soma size, growth cone area, neurite length and branch numbers. Notably, electrophysiology analyses showed defects in excitatory and inhibitory synaptic transmission. Furthermore, transcriptome analyses revealed that multiple biological pathways related to neuron projection, motility and regulation of neurogenesis were disrupted in cells with SHANK3 knockdown. In conclusion, utilizing a human iPSC-based neural induction model, this study presented combined morphological, electrophysiological and transcription evidence that support that SHANK3 as an intrinsic, cell autonomous factor that controls cellular function development in human neurons.

Our previous studies showed that mutant mice with congenital absence of the corticospinal tract (CST) undergo spontaneous remodeling of motor networks to partially compensate for absent CST function. Here, we asked whether voluntary wheel running could further improve locomotor plasticity in CST-deficient mice. Adult mutant mice were randomly allocated to a “runners” group with free access to a wheel, or a “non-runners” group with no access to a wheel. In comparison with non-runners, there was a significant motor improvement including fine movement, grip strength, decreased footslip errors in runners after 8-week training, which was supported by the elevated amplitude of electromyography recording and increased neuromuscular junctions in the biceps. In runners, terminal ramifications of monoaminergic and rubrospinal descending axons were significantly increased in spinal segments after 12 weeks of exercise compared to non-runners. 5-ethynyl-2′-deoxyuridine (EDU) labeling showed that proliferating cells, 90% of which were Olig2-positive oligodendrocyte progenitors, were 4.8-fold more abundant in runners than in non-runners. In 8-week runners, RNAseq analysis of spinal samples identified 404 genes up-regulated and 398 genes down-regulated, and 69 differently expressed genes involved in signal transduction, among which the NF-κB, PI3K-Akt and cyclic AMP (cAMP) signaling were three top pathways. Twelve-week training induced a significant elevation of postsynaptic density protein 95 (PSD95), synaptophysin 38 and myelin basic protein (MBP), but not of brain derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and insulin like growth factor-1 (IGF-1). Thus, locomotor training activates multiple signaling pathways, contributes to neural plasticity and functional improvement, and might palliate locomotor deficits in patients.

This study presents an analytical modelling method of the ultra-high voltage direct current (UHVDC) receiving system including converter station, AC power grid, novel synchronous condenser, and wind turbine. A detailed model of UHVDC receiving converter station, considering the novel synchronous condenser system, is proposed. A simplified model of wind farm is established to consider the influence of renewable generation plant near to converter station. Based on the proposed model, the characteristics of novel synchronous condenser is studied in different dynamic condition of power grid, like AC voltage drop and DC bipolar blocking. A numerical simulation model by Simulink^® is applied to validate the presented analytical model.

Short-read sequencing has inherent limitations in the characterisation of long repeat elements. Shi and Guo et al.combine single-molecule real-time sequencing and IrysChip to construct a Chinese reference genome that fills many gaps in the reference genome, and identify novel spliced genes.

After complete transection of the thoracic spinal segment, neonatal rats exhibit spontaneous locomotor recovery of hindlimbs, but this recovery is not found in adult rats after similar injury. The potential mechanism related to the difference in recovery of neonatal and adult rats remains unknown. In this study, 342 animals were analyzed. The vascular endothelial growth factor (VEGF) level in spinal segments below injury sites was significantly higher in postnatal day 1 rats (P1) compared with 28-day-old adult rats (P28) following a complete T9 transection. VEGF administration in P28 rats with T9 transection significantly improved the functional recovery; by contrast, treatment with VEGF receptor inhibitors in P1 rats with T9 transection slowed down the spontaneous functional recovery. Results showed more neurons reduced in the lumbar spinal cord and worse local neural network reorganization below injury sites in P28 rats than those in P1 rats. Transynaptic tracing with pseudorabies virus and double immunofluorescence analysis indicated that VEGF treatment in P28 rats alleviated the reduced number of neurons and improved their network reorganization. VEGF inhibition in neonates resulted in high neuronal death rate and deteriorated network reorganization. In in vivo studies, T9 transection induced less increase in the number of microglia in the spinal cord in P1 animals than P28 animals. VEGF treatment reduced the increase in microglial cells in P28 animals. VEGF administration in cultured spinal motoneurons prevented lipopolysaccharide (LPS)-induced neuronal death and facilitated neurite growth. Western blots of the samples of lumbar spinal cord after spinal transection and cultured spinal motoneurons showed a lower level of Erk1/2 phosphorylation after the injury or LPS induction compared with that in the control. The phosphorylation level increased after VEGF treatment. In conclusion, VEGF is a critical mediator involved in functional recovery after spinal transection and can be considered a potential target for clinical therapy.

Commonly used anesthetic agents, e.g. ketamine, may be neurotoxic to the developing brain but there has been little attention to the neurobehavioral consequences for offspring when used for maternal anesthesia. We hypothesize that treatment of pregnant rats with ketamine during the second trimester would affect brain development of the offspring. Pregnant rats on gestational day 14, about equal to midtrimester pregnancy in humans, received a sedative dose of ketamine intravenously for 2 h. Brain hippocampal morphology of their pups at postnatal days 0 (P0) and P30 was examined by Nissl-staining and the characteristics of dendrites were determined using the Golgi-Cox staining, while cell proliferation in subventricular zone (SVZ) and dentate gyrus (DG) was labeled with bromodeoxyuridine (BrdU). Their neurobehavioral functions were tested at P25–30 after which the NR1 and NR2 subunits of N-methyl-d-aspartate (NMDA) receptor, brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD-95) in the hippocampus were analyzed by western blot. When pregnant rats were exposed to ketamine, there was neuronal loss, pyramidal neuronal abnormality and reduced cell proliferation in the hippocampus of offspring. These morphological abnormalities were associated with depression- and anxiety-like behaviors, and impaired memory up to young adult age. The treatment further caused NR2A receptor subunit up-regulation and NR2B receptor subunit, BDNF and PSD-95 down-regulation. These data suggest that maternal anesthesia with ketamine during the fetal brain development period can cause fetal brain damage and subsequent neurobehavioral abnormality, which is likely associated with the imbalanced expression of NMDA receptor subunits.

This paper presents a novel method for calculating the transient parameters of a saturated salient-pole synchronous machine (SPSM) with damper cage using finite element analysis. All detailed leakage inductances in a modified d-q model are discussed and separately extracted. In addition; the frozen permeability method is used in a 2-D finite element analysis to consider saturation and skin effects for determining the inductances. The terminal reactance parameters are obtained from all elements of the d- and q-axis equivalent circuits in all the chosen time constants during the transient process. The variation of leakage inductances of the SPSM in transient processes is also investigated and discussed. To determine transient time constant parameters; the Prony algorithm is applied in the presented method. A program developed to automatically solve the simulation and computation with the proposed method is described. This method is applied to a prototype and validated by experimental results. Some discussion about the relationship between rotor geometric design and the transient parameters of SPSMs is provided. The variation of leakage magnetic field of SPSMs in transient processes is also investigated. This method can be applied in transient parameter estimation and optimization of SPSMs in the design stage.

Brachial plexus injury (BPI) and experimental spinal root avulsion result in loss of motor function in the affected segments. After root avulsion, significant motoneuron function is restored by re-implantation of the avulsed root. How much this functional recovery depends on corticospinal inputs is not known. Here, we studied that question using Celsr3|Emx1 mice, in which the corticospinal tract (CST) is genetically absent. In adult mice, we tore off right C5-C7 motor and sensory roots and re-implanted the right C6 roots. Behavioral studies showed impaired recovery of elbow flexion in Celsr3|Emx1 mice compared to controls. Five months after surgery, a reduced number of small axons, and higher G-ratio of inner to outer diameter of myelin sheaths were observed in mutant versus control mice. At early stages post-surgery, mutant mice displayed lower expression of GAP-43 in spinal cord and of myelin basic protein (MBP) in peripheral nerves than control animals. After five months, mutant animals had atrophy of the right biceps brachii, with less newly formed neuromuscular junctions (NMJs) and reduced peak-to-peak amplitudes in electromyogram (EMG), than controls. However, quite unexpectedly, a higher motoneuron survival rate was found in mutant than in control mice. Thus, following root avulsion/re-implantation, the absence of the CST is probably an important reason to hamper axonal regeneration and remyelination, as well as target re-innervation and formation of new NMJ, resulting in lower functional recovery, while fostering motoneuron survival. These results indicate that manipulation of corticospinal transmission may help improve functional recovery following BPI.