Cortical hyperexcitability in mouse models and patients with amyotrophic lateral sclerosis is linked to noradrenaline deficiency.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the death of upper (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord. Despite decades of research, ALS remains incurable, challenging to diagnose, and of extremely rapid progression. A unifying feature of sporadic and familial forms of ALS is cortical hyperexcitability, which precedes symptom onset, negatively correlates with survival, and is sufficient to trigger neurodegeneration in rodents. Using electrocorticography in the Sod1G86R and FusΔNLS/+ ALS mouse models and standard electroencephalography recordings in patients with sporadic ALS, we demonstrate a deficit in theta-gamma phase-amplitude coupling (PAC) in ALS. In mice, PAC deficits started before symptom onset, and in patients, PAC deficits correlated with the rate of disease progression. Using mass spectrometry analyses of CNS neuropeptides, we identified a presymptomatic reduction of noradrenaline (NA) in the motor cortex of ALS mouse models, further validated by in vivo two-photon imaging in behaving SOD1G93A and FusΔNLS/+ mice, that revealed pronounced reduction of locomotion-associated NA release. NA deficits were also detected in postmortem tissues from patients with ALS, along with transcriptomic alterations of noradrenergic signaling pathways. Pharmacological ablation of noradrenergic neurons with DSP-4 reduced theta-gamma PAC in wild-type mice and administration of a synthetic precursor of NA augmented theta-gamma PAC in ALS mice. Our findings suggest theta-gamma PAC as means to assess and monitor cortical dysfunction in ALS and warrant further investigation of the NA system as a potential therapeutic target.

Probing cerebellar circuit dysfunction in rodent models of spinocerebellar ataxia by means of in vivo two-photon calcium imaging.

Purkinje neuron degeneration characterizes spinocerebellar ataxia type 1, yet the comprehension of the impact on the broader cerebellar circuit remains incomplete. We here detail simultaneous in vivo two-photon calcium imaging of diverse neuronal populations in the cerebellar cortex of Sca1 mice while they are navigating a virtual environment. We outline surgical procedures and protocols to chronically record from identical neurons, and we detail data post-processing and analysis to delineate disease-related alterations in neuronal activity and sensorimotor-driven response properties. For complete details on the use and execution of this protocol, please refer to Pilotto et al.1.

Early molecular layer interneuron hyperactivity triggers Purkinje neuron degeneration in SCA1.

Toxic proteinaceous deposits and alterations in excitability and activity levels characterize vulnerable neuronal populations in neurodegenerative diseases. Using in vivo two-photon imaging in behaving spinocerebellar ataxia type 1 (Sca1) mice, wherein Purkinje neurons (PNs) degenerate, we identify an inhibitory circuit element (molecular layer interneurons [MLINs]) that becomes prematurely hyperexcitable, compromising sensorimotor signals in the cerebellum at early stages. Mutant MLINs express abnormally elevated parvalbumin, harbor high excitatory-to-inhibitory synaptic density, and display more numerous synaptic connections on PNs, indicating an excitation/inhibition imbalance. Chemogenetic inhibition of hyperexcitable MLINs normalizes parvalbumin expression and restores calcium signaling in Sca1 PNs. Chronic inhibition of mutant MLINs delayed PN degeneration, reduced pathology, and ameliorated motor deficits in Sca1 mice. Conserved proteomic signature of Sca1 MLINs, shared with human SCA1 interneurons, involved the higher expression of FRRS1L, implicated in AMPA receptor trafficking. We thus propose that circuit-level deficits upstream of PNs are one of the main disease triggers in SCA1.

Real-time High-Quality Computer-Generated Hologram Using Complex-Valued Convolutional Neural Network.

Holographic displays are ideal display technologies for virtual and augmented reality because all visual cues are provided. However, real-time high-quality holographic displays are difficult to achieve because the generation of high-quality computer-generated hologram (CGH) is inefficient in existing algorithms. Here, complex-valued convolutional neural network (CCNN) is proposed for phase-only CGH generation. The CCNN-CGH architecture is effective with a simple network structure based on the character design of complex amplitude. A holographic display prototype is set up for optical reconstruction. Experiments verify that state-of-the-art performance is achieved in terms of quality and generation speed in existing end-to-end neural holography methods using the ideal wave propagation model. The generation speed is three times faster than HoloNet and one-sixth faster than Holo-encoder, and the Peak Signal to Noise Ratio (PSNR) is increased by 3 dB and 9 dB, respectively. Real-time high-quality CGHs are generated in 1920×1072 and 3840×2160 resolutions for dynamic holographic displays.

Real-time dense-view imaging for three-dimensional light-field display based on image color calibration and self-supervised view synthesis.

Three-Dimensional (3D) light-field display has achieved promising improvement in recent years. However, since the dense-view images cannot be collected fast in real-world 3D scenes, the real-time 3D light-field display is still challenging to achieve in real scenes, especially at the high-resolution 3D display. Here, a real-time 3D light-field display method with dense-view is proposed based on image color correction and self-supervised optical flow estimation, and a high-quality and high frame rate of 3D light-field display can be realized simultaneously. A sparse camera array is firstly used to capture sparse-view images in the proposed method. To eliminate the color deviation of the sparse views, the imaging process of the camera is analyzed, and a practical multi-layer perception (MLP) network is proposed to perform color calibration. Given sparse views with consistent color, the optical flow can be estimated by a lightweight convolutional neural network (CNN) at high speed, which uses the input image pairs to learn the optical flow in a self-supervised manner. With inverse warp operation, dense-view images can be synthesized in the end. Quantitative and qualitative experiments are performed to evaluate the feasibility of the proposed method. Experimental results show that over 60 dense-view images at a resolution of 1024 × 512 can be generated with 11 input views at a frame rate over 20 fps, which is 4× faster than previous optical flow estimation methods PWC-Net and LiteFlowNet3. Finally, large viewing angles and high-quality 3D light-field display at 3840 × 2160 resolution can be achieved in real-time.

Self-supervised stereo depth estimation based on bi-directional pixel-movement learning.

Stereo depth estimation is an efficient method to perceive three-dimensional structures in real scenes. In this paper, we propose a novel self-supervised method, to the best of our knowledge, to extract depth information by learning bi-directional pixel movement with convolutional neural networks (CNNs). Given left and right views, we use CNNs to learn the task of middle-view synthesis for perceiving bi-directional pixel movement from left-right views to the middle view. The information of pixel movement will be stored in the features after CNNs are trained. Then we use several convolutional layers to extract the information of pixel movement for estimating a depth map of the given scene. Experiments show that our proposed method can significantly provide a high-quality depth map using only a color image as a supervisory signal.

Applications for natural deep eutectic solvents in Chinese herbal medicines.

Chinese herbal medicines (CHMs), with a wide range of bioactive components, are considered to be an important source for new drug discovery. However, the process to isolate and obtain those bioactive components to develop new drugs always consumes a large amount of organic solvents with high toxicity and non-biodegradability. Natural deep eutectic solvents (NADES), a new type of green and designable solvents composed of primary plant-based metabolites, have been used as eco-friendly substitutes for traditional organic solvents in various fields. Due to the advantages of easy preparation, low production cost, low toxicity, and eco-friendliness, NADES have been also applied as extraction solvents, media, and drug delivery agents in CHMs in recent years. Besides, the special properties of NADES have been contributed to elucidating the traditional processing (also named Paozhi in Chinese) theory of CHMs, especially processing with honey. In this paper, the development process, preparation, classification, and applications for NADES in CHMs have been reviewed. Prospects in the future applications and challenges have been discussed to better understand the possibilities of the new solvents in the drug development and other uses of CHMs.

Calcitonin Gene-Related Peptide Monoclonal Antibodies Versus Botulinum Neurotoxin a in the Preventive Treatment of Chronic Migraine: An Adjusted Indirect Treatment Comparison Meta-Analysis.

Purpose: Calcitonin gene-related peptide monoclonal antibodies (CGRPmAbs) are new agents approved by the US Food and Drug Administration for preventive treatment of chronic migraine. Comparison between CGRPmAbs and previously approved Botulinum neurotoxin A (BoNT-A) will inform optimal preventive treatment of chronic migraine, but head-to-head trials are lacking. We therefore aimed to perform adjusted indirect comparison between CGRPmAbs and BoNT-A through a meta-analysis. Methods: OVID MEDLINE, EMBASE and the Cochrane central register of controlled trials, clinical registries, and government websites were searched from inception to September 2019. Randomized controlled trials comparing CGRPmAbs or BoNT-A with placebo in the preventive treatment of chronic migraine were included. The primary outcomes were headache days and migraine days measured at week 12. Data were synthesized by using a frequentist approach; and the treatments were ranked by P-score. Results: We included 10 trials (n = 4,678) after screening 1049 candidates. Six trials were with low risk of bias. Fremanezumab had an effect similar to BoNT-A in the reduction of headache days at week 12 (standard mean difference [SMD] 0.08, 95%CI -0.55 to -0.7). Galcanezumab reduced more migraine days than BoNT-A at week 12 (SMD, -0.94, 95%CI -1.24 to -0.63); fremanezumab showed similar findings (SMD, -0.55, 95%CI -0.85 to -0.24). Galcanezumab and fremanezumab had better effect in mitigating headache impact at week 12. CGRPmAbs and BoNT-A had similar adverse event rate. Conclusion: CGRPmAbs and BoNT-A had similar effect in the preventive treatment of chronic migraine. BoNT-A might be preferentially selected owing to its cost-effectiveness profiles. Further studies with direct comparison of the two treatments are warranted.

Analysis and removal of crosstalk in a time-multiplexed light-field display.

Time-multiplexed light-field displays (TMLFDs) can provide natural and realistic three-dimensional (3D) performance with a wide 120° viewing angle, which provides broad potential applications in 3D electronic sand table (EST) technology. However, current TMLFDs suffer from severe crosstalk, which can lead to image aliasing and the distortion of the depth information. In this paper, the mechanisms underlying the emergence of crosstalk in TMLFD systems are identified and analyzed. The results indicate that the specific structure of the slanted lenticular lens array (LLA) and the non-uniformity of the emergent light distribution in the lens elements are the two main factors responsible for the crosstalk. In order to produce clear depth perception and improve the image quality, a novel ladder-type LCD sub-pixel arrangement and a compound lens with three aspheric surfaces are proposed and introduced into a TMLFD to respectively reduce the two types of crosstalk. Crosstalk simulation experiments demonstrate the validity of the proposed methods. Structural similarity (SSIM) simulation experiments and light-field reconstruction experiments also indicate that aliasing is effectively reduced and the depth quality is significantly improved over the entire viewing range. In addition, a tabletop 3D EST based on the proposed TMLFD is presented. The proposed approaches to crosstalk reduction are also compatible with other lenticular lens-based 3D displays.

Virtual view synthesis for 3D light-field display based on scene tower blending.

Three-dimensional (3D) light-field display has achieved a great improvement. However, the collection of dense viewpoints in the real 3D scene is still a bottleneck. Virtual views can be generated by unsupervised networks, but the quality of different views is inconsistent because networks are separately trained on each posed view. Here, a virtual view synthesis method for the 3D light-field display based on scene tower blending is presented, which can synthesize high quality virtual views with correct occlusions by blending all tower results, and dense viewpoints on 3D light-field display can be provided with smooth motion parallax. Posed views are combinatorially input into diverse unsupervised CNNs to predict respective input-view towers, and towers of the same viewpoint are fused together. All posed-view towers are blended as a scene color tower and a scene selection tower, so that 3D scene distributions at different depth planes can be accurately estimated. Blended scene towers are soft-projected to synthesize virtual views with correct occlusions. A denoising network is used to improve the image quality of final synthetic views. Experimental results demonstrate the validity of the proposed method, which shows outstanding performances under various disparities. PSNR of the virtual views are about 30 dB and SSIM is above 0.91. We believe that our view synthesis method will be helpful for future applications of the 3D light-field display.

Exciting Complexity: The Role of Motor Circuit Elements in ALS Pathophysiology.

Amyotrophic lateral sclerosis (ALS) is a fatal disease, characterized by the degeneration of both upper and lower motor neurons. Despite decades of research, we still to date lack a cure or disease modifying treatment, emphasizing the need for a much-improved insight into disease mechanisms and cell type vulnerability. Altered neuronal excitability is a common phenomenon reported in ALS patients, as well as in animal models of the disease, but the cellular and circuit processes involved, as well as the causal relevance of those observations to molecular alterations and final cell death, remain poorly understood. Here, we review evidence from clinical studies, cell type-specific electrophysiology, genetic manipulations and molecular characterizations in animal models and culture experiments, which argue for a causal involvement of complex alterations of structure, function and connectivity of different neuronal subtypes within the cortical and spinal cord motor circuitries. We also summarize the current knowledge regarding the detrimental role of astrocytes and reassess the frequently proposed hypothesis of glutamate-mediated excitotoxicity with respect to changes in neuronal excitability. Together, these findings suggest multifaceted cell type-, brain area- and disease stage- specific disturbances of the excitation/inhibition balance as a cardinal aspect of ALS pathophysiology.

The mammalian LINC complex component SUN1 regulates muscle regeneration by modulating drosha activity.

Here we show that a major muscle specific isoform of the murine LINC complex protein SUN1 is required for efficient muscle regeneration. The nucleoplasmic domain of the isoform specifically binds to and inhibits Drosha, a key component of the microprocessor complex required for miRNA synthesis. Comparison of the miRNA profiles between wildtype and SUN1 null myotubes identified a cluster of miRNAs encoded by a non-translated retrotransposon-like one antisense (Rtl1as) transcript that are decreased in the WT myoblasts due to SUN1 inhibition of Drosha. One of these miRNAs miR-127 inhibits the translation of the Rtl1 sense transcript, that encodes the retrotransposon-like one protein (RTL1), which is also required for muscle regeneration and is expressed in regenerating/dystrophic muscle. The LINC complex may therefore regulate gene expression during muscle regeneration by controlling miRNA processing. This provides new insights into the molecular pathology underlying muscular dystrophies and how the LINC complex may regulate mechanosignaling.

Acupuncture for poststroke spasticity: A protocol of a systematic review and meta-analysis.

INTRODUCTION: Spasticity is the most common complication after stroke, which is the main obstacle in the recovery of motor function. Spasticity seriously affects the quality of life and brings a heavy burden to families and society. Acupuncture is an effective method for stroke. However, whether acupuncture is effective for poststroke spasticity is still unknown. The purpose of this systematic review (SR) is to evaluate the effectiveness and safety of acupuncture for poststroke spasticity. METHODS AND ANALYSIS: We will search the following databases from inception to July 2019: China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), Wan Fang Data, the Chinese Science and Technology Periodical Database (VIP), PubMed, Embase, The Cochrane Library, and Web of Science. All relevant randomized controlled trials (RCTs) utilizing acupuncture for poststroke spasticity will be included. The primary outcome is the modified Ashworth scale. Secondary outcomes include composite spasticity scale, clinic spasticity index, electromyographic activity, Hoffmann reflex activity, or other spasticity-related outcomes. Study selection, data extraction, and quality assessment will be performed independently by 2 reviewers. Assessment of risk of bias and data synthesis will be conducted using Review Manager V5.3 software. ETHICS AND DISSEMINATION: The ethical approval is not required since SR is based on published studies. The results of this SR will be published in a peer-reviewed scientific journal according to the Preferred Reporting Item for Systematic Review and Meta-analysis (PRISMA) guidelines. PROSPERO REGISTRATION NUMBER: CRD42019129779.

Dense-view synthesis for three-dimensional light-field display based on unsupervised learning.

Three-dimensional (3D) light field display, as a potential future display method, has attracted considerable attention. However, there still exist certain issues to be addressed, especially the capture of dense views in real 3D scenes. Using sparse cameras associated with view synthesis algorithm has become a practical method. Supervised convolutional neural network (CNN) is used to synthesize virtual views. However, such a large amount of training target views is sometimes difficult to be obtained and the training position is relatively fixed. Novel views can also be synthesized by unsupervised network MPVN, but the method has strict requirements on capturing multiple uniform horizontal viewpoints, which is not suitable in practice. Here, a method of dense-view synthesis based on unsupervised learning is presented, which can synthesize arbitrary virtual views with multiple free-posed views captured in the real 3D scene based on unsupervised learning. Multiple posed views are reprojected to the target position and input into the neural network. The network outputs a color tower and a selection tower indicating the scene distribution along the depth direction. A single image is yielded by the weighted summation of two towers. The proposed network is end-to-end trained based on unsupervised learning by minimizing errors during reconstructions of posed views. A virtual view can be predicted in a high quality by reprojecting posed views to the desired position. Additionally, a sequence of dense virtual views can be generated for 3D light-field display by repeated predictions. Experimental results demonstrate the validity of our proposed network. PSNR of synthesized views are around 30dB and SSIM are over 0.90. Since multiple cameras are supported to be placed in free-posed positions, there are not strict physical requirements and the proposed method can be flexibly used for the real scene capture. We believe this approach will contribute to the wide applications of 3D light-field display in the future.

Synergistic effect of acupuncture and mirror therapy on post-stroke upper limb dysfunction: a study protocol for a randomized controlled trial.

BACKGROUND: Upper limb dysfunction is common after stroke, posing an important challenge for post-stroke rehabilitation. The clinical efficacy of acupuncture for the recovery of post-stroke upper limb function has been previously demonstrated. Mirror therapy (MT) has also been found to be effective. However, the effects of acupuncture and MT have not been systematically compared. This trial aims to elucidate the synergistic effects of acupuncture and MT on upper limb dysfunction after stroke. METHODS: A 2 × 2 factorial randomized controlled trial will be conducted at the rehabilitation hospitals affiliated with Fujian University of Traditional Chinese Medicine. A total of 136 eligible subjects will be randomly divided into acupuncture treatment (AT), MT, combined treatment, and control groups in a 1:1:1:1 ratio. All subjects will receive conventional treatment. The interventions will be performed 5 days per week for 4 weeks. AT, MT, and combined treatment will be performed for 30 min per day (combined treatment: AT 15 min + MT 15 min). The primary outcomes in this study will be the mean change in scores on both the FMA and WMFT from baseline to 4 weeks intervention and at 12 weeks follow-up between the two groups and within groups. The secondary outcomes are the mean change in the scores on the Visual Analogue Scale, Stroke Impact Scale, and modified Barthel index. Medical abstraction of adverse events will be assessed at each visit. DISCUSSION: The results of this trial will demonstrate the synergistic effect of acupuncture and MT on upper limb motor dysfunction after stroke. In addition, whether AT and MT, either combined or alone, are more effective than the conventional treatment in the management of post-stroke upper limb dysfunction will also be determined. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR-IOR-17011118 . Registered on April 11, 2017. Version number: 01.2016.09.1.

Hemangioma of the Rib: A Rare Case Report and Literature Review.

Hemangiomas of the rib are extremely rare benign neoplasm. Here we present a case in a 47-year-old female, detected by chest X-ray and underwent a surgical resection. Histologically, the tumor was composed of a homogeneous conglomerate, irregular, thin walled and dilated blood vessels containing red blood cells, supported by fibrous stroma and intermingled to regular bone trabeculae. The postoperative courses were uneventful, and there was no recurrence during 64 months follow-up.

Dual Diagnosis of Ellis-van Creveld Syndrome and Hearing Loss in a Consanguineous Family.

Multilocus analysis of rare or genetically heterogeneous diseases is a distinct advantage of next-generation sequencing (NGS) over conventional single-gene investigations. Recent studies have begun to uncover an under-recognized prevalence of dual molecular diagnoses in patients with a "blended" phenotype that is the result of 2 clinical diagnoses involving 2 separate genetic loci. This blended phenotype could be mistakenly interpreted as a novel clinical extension of a single-gene disorder. In this study, we ascertained a proband from a large consanguineous Iranian family who manifests postlingual, progressive, moderate hearing loss in addition to suspected Ellis-van Creveld syndrome phenotype. NGS with a customized skeletal dysplasia panel containing over 370 genes and subsequent bioinformatics analysis disclosed 2 homozygous mutations in EVC2 (c.2653C>T; p.Arg885*) and COL11A2 (c.966dup; p.Thr323Hisfs*19), respectively. This study highlights a dual molecular diagnosis in a patient with a blending of 2 distinct phenotypes and illustrates the advantage and importance of this staple technology to facilitate rapid and comprehensive genetic dissection of a heterogeneous phenotype. The differentiation between phenotypic expansion of a genetic disorder and a blended phenotype that is due to more than one distinct genetic aberration is essential in order to reduce the diagnostic odyssey endured by patients.

[Application of CT scan in diagnosis of pathological type and origin of metastatic ovarian tumors].

OBJECTIVE: To evaluate the application of CT scan in diagnosis of pathological types and origins of metastatic ovarian tumors. METHODS: Clinical data, histopathological results and CT images of 43 patients with pathologically-proved metastatic ovarian tumor were retrospectively analyzed. Diagnostic values of CT imaging for pathological type and origin of metastatic ovarian tumors were evaluated. RESULTS: The pathological types of metastatic ovarian tumor were related to the size of the lesion (P<0.01), while not related to the sites of lesion (unilateral or bilateral), the cystic-solid and mixed lesions with or without separation (all P>0.05). Metastatic ovarian tumors of colorectal origin were usually unilateral lesions, and showed cystic or cystic-solid masses, while those of gastric origin were usually bilateral lesions, and showed solid or solid-based masses. CONCLUSIONS: CT imaging may be of value in diagnosis of pathological types and origin of metastatic ovarian tumor.

Genetic Basis of Nonsyndromic and Syndromic Tooth Agenesis.

Human dentition development is a long and complex process which involves a series of reciprocal and sequential interactions between the embryonic stomodeal epithelium and the underlying neural crest-derived mesenchyme. Despite environment disturbances, tooth development is predominantly genetically controlled. To date, more than 200 genes have been identified in tooth development. These genes implied in various signaling pathways such as the bone morphogenetic protein, fibroblast growth factor, sonic hedgehog homolog, ectodysplasin A, wingless-type MMTV integration site family (Wnt), and transform growth factor pathways. Mutations in any of these strictly balanced signaling cascades may cause arrested odontogenesis and/or other dental defects. This article aims to review current knowledge about the genetic mechanisms responsible for selective nonsyndromic tooth agenesis in humans and to present a detailed summary of syndromes with hypodontia as regular features and their causative genes.

Review of the Genetic Basis of Jaw Malformations.

Genetic etiologies for congenital anomalies of the facial skeleton, namely, the maxilla and mandible, are important to understand and recognize. Malocclusions occur when there exist any significant deviation from what is considered a normal relationship between the upper jaw (maxilla) and the lower jaw (mandible). They may be the result of anomalies of the teeth alone, the bones alone, or both. A number of genes play a role in the facial skeletal development and are regulated by a host of additional regulatory molecules. As such, numerous craniofacial syndromes specifically affect the development of the jaws. The following review discusses several genetic anomalies that specifically affect the bones of the craniofacial skeleton and lead to malocclusion.