Abstract This study aimed to determine the mutational spectrum of familial Parkinson’s disease and sporadic early-onset Parkinson’s disease (sEOPD) in a mainland Chinese population and the clinical features of mutation carriers. We performed multiplex ligation-dependent probe amplification assays and whole-exome sequencing for 1676 unrelated patients with Parkinson’s disease in a mainland Chinese population, including 192 probands from families with autosomal-recessive Parkinson’s disease, 242 probands from families with autosomal-dominant Parkinson’s disease, and 1242 sEOPD patients (age at onset ≤ 50). According to standards and guidelines from the American College of Medical Genetics and Genomics, pathogenic/likely pathogenic variants in 23 known Parkinson’s disease-associated genes occurred more frequently in the autosomal-recessive Parkinson’s disease cohort (65 of 192, 33.85%) than in the autosomal-dominant Parkinson’s disease cohort (10 of 242, 4.13%) and the sEOPD cohort (57 of 1242, 4.59%), which leads to an overall molecular diagnostic yield of 7.88% (132 of 1676). We found that PRKN was the most frequently mutated gene (n = 83, 4.95%) and present the first evidence of an SNCA duplication and LRRK2 p.N1437D variant in mainland China. In addition, several novel pathogenic/likely pathogenic variants including LRRK2 (p.V1447M and p.Y1645S), ATP13A2 (p.R735X and p.A819D), FBXO7 (p.G67E), LRP10 (c.322dupC/p.G109Rfs*51) and TMEM230 (c.429delT/p.P144Qfs*2) were identified in our cohort. Furthermore, the age at onset of the 132 probands with genetic diagnoses (median, 31.5 years) was about 14.5 years earlier than that of patients without molecular diagnoses (i.e. non-carriers, median 46.0 years). Specifically, the age at onset of Parkinson’s disease patients with pathogenic/likely pathogenic variants in ATP13A2, PLA2G6, PRKN, or PINK1 was significantly lower than that of non-carriers, while the age at onset of carriers with other gene pathogenic/likely pathogenic variants was similar to that of non-carriers. The clinical spectrum of Parkinson’s disease-associated gene carriers in this mainland Chinese population was similar to that of other populations. We also detected 61 probands with GBA possibly pathogenic variants (3.64%) and 59 probands with GBA p.L444P (3.52%). These results shed insight into the genetic spectrum and clinical manifestations of Parkinson’s disease in mainland China and expand the existing repertoire of pathogenic or likely pathogenic variants involved in known Parkinson’s disease-associated genes. Our data highlight the importance of genetic testing in Parkinson’s disease patients with age at onset < 40 years, especially in those from families with a recessive inheritance pattern, who may benefit from early diagnosis and treatment.

Diffuse large B cell lymphoma (DLBCL) is one of the most common types of malignancy worldwide. The lack of clear symptoms and early detection make it difficult to diagnose at an early stage, leading to poor prognosis of the patients. Long non-coding RNAs (lncRNAs) have come into focus for their important regulatory roles in fundamental biological processes, particularly in cancer initiation, development and progression. The aim of the present study was to investigate the expression of lncRNA Hox transcript antisense intergenic RNA (HOTAIR) in a cohort of patients with DLBCL to assess its clinical value and biological function in DLBCL. The reverse transcription-polymerase chain reaction was used to detect HOTAIR expression levels and cells were transfected with small interfering RNA to compare cell proliferation, cell cycle progression and apoptosis. Western blotting was also conducted to detect possible signaling pathways. It was first found that the expression levels of HOTAIR were upregulated in DLBCL tumor tissues and cell lines, compared with normal tissues and cells. In addition, HOTAIR was significantly correlated with tumor size, clinical stage, B symptoms and International Prognostic Index scores; and higher expression levels of HOTAIR were correlated with improved prognosis. Univariate and multivariate analyses verified that HOTAIR was a key independent predictive factor for DLBCL prognosis. Furthermore, it was revealed that the knockdown of the expression of HOTAIR led to growth inhibition, cell cycle arrest and apoptosis in vitro, possibly through the phosphoinositide 3-kinase/AKT/nuclear factor-κB pathway. These results suggested that HOTAIR may be regarded as a novel indicator of poor prognosis, and may serve as a potential target for gene therapy in the treatment of DLBCL.

Many microRNAs (miRs) have been demonstrated to play promoting or tumor suppressive roles in human cancers including breast cancer. However, the molecular mechanism of miR-133a underlying the malignant progression of breast cancer still remains obscure. In the present study we observed that the expression of miR-133a was significantly downregulated in breast cancer tissues and cell lines, when compared with adjacent non-tumor tissues and normal breast cell line, respectively. Reduced miR-133a levels were significantly associated with advanced clinical stage, lymph node metastasis, as well as shorter survival time of patients with breast cancer. Restoration of miR-133a expression led to significant decrease in the proliferation, migration, and invasion of SK-BR-3 and MDA-MB-231 cells in vitro, as well as in tumor xenograft growth in nude mice. Luciferase reporter gene assay data identified LASP1 as a target gene of miR-133a, and the expression of LASP1 was negatively regulated by miR-133a in breast cancer cells. LASP1 was significantly upregulated in breast cancer tissues and cell lines, and its upregulation was significantly associated with disease progression. siRNA-induced LASP1 downregulation caused a significant reduction in breast cancer cell proliferation, migration and invasion. Furthermore, overexpression of LASP1 impaired the suppressive effects of miR-133a upregulation on the proliferation, migration and invasion of SK-BR-3 and MDA-MB-231 cells. In summary, the present study demonstrates that miR-133a acts as a tumor suppressor in breast cancer partly at least via targeting LASP1, and thus suggests that the miR-133a/LASP1 axis may become a potential therapeutic target for breast cancer.

Algorithms for mobile robotic systems are generally implemented on purely digital computing platforms. Developing alternative computational platforms may lead to more energy-efficient and responsive mobile robotics. Here, we report a hybrid analog-digital computing platform enabled by memristors on a mobile inverted pendulum robot. Our mobile robotic system can tune the conductance states of memristors adaptively using a model-free optimization method to achieve optimal control performance. We implement sensor fusion and the motion control algorithms on our hybrid analog-digital computing platform and demonstrate more than one order of magnitude enhancement of speed and energy efficiency over traditional digital platforms.

Plasmon-enhanced fluorescence is demonstrated in the vicinity of metal surfaces due to strong local field enhancement. Meanwhile, fluorescence quenching is observed as the spacing between fluorophore molecules and the adjacent metal is reduced below a threshold of a few nanometers. Here, we introduce a technology, placing the fluorophore molecules in plasmonic hotspots between pairs of collapsible nanofingers with tunable gap sizes at sub-nanometer precision. Optimal gap sizes with maximum plasmon enhanced fluorescence are experimentally identified for different dielectric spacer materials. The ultrastrong local field enhancement enables simultaneous detection and characterization of sharp Raman fingerprints in the fluorescence spectra. This platform thus enables in situ monitoring of competing excitation enhancement and emission quenching processes. We systematically investigate the mechanisms behind fluorescence quenching. A quantum mechanical model is developed which explains the experimental data and will guide the future design of plasmon enhanced spectroscopy applications.

inherent drawbacks of transmissive displays. First, all light from a transmissive display is provided by an active light source that consumes energy continuously when the display works. Besides, the display can be quite dim under direct sunlight. Compared to transmissive display, reflective display is illuminated by ambient light. Therefore, it does not consume energy for backlight and is readable under bright sunlight. Then, we invented a "perfect" display by stacking a full-color reflective display on top of a transmissive display ( Figure S1, Supporting Information). This hybrid display can operate in either transmissive or reflective mode. It has not only low power consumption by staying at low-power reflective mode most of the time, but also superior display quality in both low-light and bright sunlight environments. While there are mature transmissive display technologies, reflective display technologies that satisfy hybrid display requirements are still unavailable. One fundamental issue is that the parallel architecture is currently adopted in full-color reflective display technologies [1] (Figure S2, Supporting Information). Even in the ideal case, the optical efficiency of a parallel architecture is limited to a poor value of 33% owing to the filling ratio of each subpixels. Additionally, none of the proposed color reflective displays could be switched into a transparent state, [2] which is critical in a hybrid display.Fortunately, the breakthroughs of nanophotonics [3] and nanofabrication technologies [4] in past decades have vigorously promoted the development of optical metasurfaces, which provide an opportunity to get a "perfect" hybrid display. With the help of precisely designed metasurfaces, incident light can be effectively manipulated. [5] Compared to metallic metasurfaces, all-dielectric metasurfaces have higher optical efficiency and broader bandwidth. [6] However, the difficulty in finding highindex and low-loss dielectrics in near-IR or visible wavelength range limited the application of all-dielectric metasurfaces to longer wavelengths. To solve this problem, we recently pioneered hybrid all-dielectric metasurfaces for efficient ultrabroadband reflector and spectrum splitting. [7] In parallel, we also tailored nanoimprint lithography (NIL) to fabricate largearea metasurfaces in near-IR or visible ranges. [8] Based on these, we proposed a novel application of all-dielectric metasurface High energy consumption and lack of readability under bright sunlight of conventional transmissive display technology greatly limit the user experience of mobile and wearable devices. To solve this issue, a hybrid display by overlaying a full-color reflective display on top of a transmissive display is invented.The key component of this technology is a full-color reflective display based on tandem switchable all-dielectric metasurfaces. The switchable all-dielectric metasurfaces in large size (average area ≈5 cm 2 ) are invented and fabricated by low-cost and high-throughput nanoimprint lithography. Each ...

Background and purpose The purpose was to provide an overview of genotype and phenotype distribution in a cohort of patients with Charcot–Marie–Tooth disease (CMT) and related disorders from central south China. Methods In all, 435 patients were enrolled and detailed clinical data were collected. Multiplex ligation‐dependent probe amplification for PMP22 duplication/deletion and CMT multi‐gene panel sequencing were performed. Whole exome sequencing was further applied in the remaining patients who failed to achieve molecular diagnosis. Results Among the 435 patients, 216 had CMT1, 14 had hereditary neuropathy with pressure palsies (HNPP), 178 had CMT2, 24 had distal hereditary motor neuropathy (dHMN) and three had hereditary sensory and autonomic neuropathy (HSAN). The overall molecular diagnosis rate was 70%: 75.7% in CMT1, 100% in HNPP, 64.6% in CMT2, 41.7% in dHMN and 33.3% in HSAN. The most common four genotypes accounted for 68.9% of molecular diagnosed patients. Relatively frequent causes were missense changes in PMP22 (4.6%) and SH3TC2 (2.3%) in CMT1; and GDAP1 (5.1%), IGHMBP2 (4.5%) and MORC2 (3.9%) in CMT2. Twenty of 160 detected pathogenic variants and the associated phenotypes have not been previously reported. Broad phenotype spectra were observed in six genes, amongst which the pathogenic variants in BAG3 and SPTLC1 were detected in two sporadic patients presenting with the CMT2 phenotype. Conclusions Our results provided a unique genotypic and phenotypic landscape of patients with CMT and related disorders from central south China, including a relatively high proportion of CMT2 and lower occurrence of PMP22 duplication. The broad phenotype spectra in certain genes have advanced our understanding of CMT.

Artificial neuronal devices that functionally resemble biological neurons are important toward realizing advanced brain emulation and for building bioinspired electronic systems. In this Communication, the stochastic behaviors of a neuronal oscillator based on the charge-density-wave (CDW) phase transition of a 1T-TaS2 thin film are reported, and the capability of this neuronal oscillator to generate spike trains with statistical features closely matching those of biological neurons is demonstrated. The stochastic behaviors of the neuronal device result from the melt-quench-induced reconfiguration of CDW domains during each oscillation cycle. Owing to the stochasticity, numerous key features of the Hodgkin-Huxley description of neurons can be realized in this compact two-terminal neuronal oscillator. A statistical analysis of the spike train generated by the artificial neuron indicates that it resembles the neurons in the superior olivary complex of a mammalian nervous system, in terms of its interspike interval distribution, the time-correlation of spiking behavior, and its response to acoustic stimuli.