Heterozygous variants in USP25 cause genetic generalized epilepsy.

USP25 encodes ubiquitin-specific proteases 25, a key member of deubiquitinating enzyme family and is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown etiology. Five heterozygous USP25 variants including two de novo and three co-segregated variants were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared to the East Asian population and all populations in the gnomAD database. The mean onset ages of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom except one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability. Usp25 was ubiquitously expressed in mouse brain with two peaks on embryonic days (E14‒E16) and postnatal day 21, respectively. Similarly, USP25 expressed in fetus/early childhood stage with a second peak at approximately 12‒20 years old in human brain, consistent with the seizure onset age at infancy and juvenile in the patients. To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knock-out mice, which showed increased seizure susceptibility compared to wild-type mice in pentylenetetrazol-induced seizure test. To explore the impact of USP25 variants, we employed multiple functional detections. In HEK293T cells, the severe phenotype associated variant (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed a stable truncated dimers with increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del increased neuronal excitability in mice brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating USP25 is potentially a predisposing gene for epilepsy. Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain.

NEXMIF variants are associated with epilepsy with or without intellectual disability.

OBJECTIVES: Variants in NEXMIF had been reported associated with intellectual disability (ID) without epilepsy or developmental epileptic encephalopathy (DEE). It is unkown whether NEXMIF variants are associated with epilepsy without ID. This study aims to explore the phenotypic spectrum of NEXMIF and the genotype-phenotype correlations. MATERIALS AND METHODS: Trio-based whole-exome sequencing was performed in patients with epilepsy. Previously reported NEXMIF variants were systematically reviewed to analyze the genotype-phenotype correlations. RESULTS: Six variants were identified in seven unrelated cases with epilepsy, including two de novo null variants and four hemizygous missense variants. The two de novo variants were absent in all populations of gnomAD and four hemizygous missense variants were absent in male controls of gnomAD. The two patients with de novo null variants exhibited severe developmental epileptic encephalopathy. While, the patients with hemizygous missense variants had mild focal epilepsy with favorable outcome. Analysis of previously reported cases revealed that males with missense variants presented significantly higher percentage of normal intellectual development and later onset age of seizure than those with null variants, indicating a genotype-phenotype correlation. CONCLUSION: This study suggested that NEXMIF variants were potentially associated with pure epilepsy with or without intellectual disability. The spectrum of epileptic phenotypes ranged from the mild epilepsy to severe developmental epileptic encephalopathy, where the epileptic phenotypes variability are potentially associated with patients' gender and variant type.

Si/Organic Integrated Narrowband Near-Infrared Photodetector.

Spectrally selective narrowband photodetection is critical for near-infrared (NIR) imaging applications, such as for communicationand night-vision utilities. It is a long-standing challenge for detectors based on silicon, to achieve narrowband photodetection without integrating any optical filters. Here, this work demonstrates a NIR nanograting Si/organic (PBDBT-DTBT:BTP-4F) heterojunction photodetector (PD), which for the first time obtains the full-width-at-half-maximum (FWHM) of only 26 nm and fast response of 74 µs at 895 nm. The response peak can be successfully tailored from 895 to 977 nm. The sharp and narrow response NIR peak is inherently attributed to the coherent overlapping between the NIR transmission spectrum of organic layer and diffraction enhanced absorption peak of patterned nanograting Si substrates. The finite difference time domain (FDTD) physics calculation confirms the resonant enhancement peaks, which is well consistent with the experiment results. Meanwhile, the relative characterization indicates that the introduction of the organic film can promote carrier transfer and charge collection, facilitating efficient photocurrent generation. This new device design strategy opens up a new window in developing low-cost sensitive NIR narrowband detection.

CELSR1 variants are associated with partial epilepsy of childhood.

CELSR1 gene, encoding cadherin EGF LAG seven-pass G-type receptor 1, is mainly expressed in neural stem cells during the embryonic period. It plays an important role in neurodevelopment. However, the relationship between CELSR1 and disease of the central nervous system has not been defined. In this study, we performed trios-based whole-exome sequencing in a cohort of 356 unrelated cases with partial epilepsy without acquired causes and identified CELSR1 variants in six unrelated cases. The variants included one de novo heterozygous nonsense variant, one de novo heterozygous missense variant, and four compound heterozygous missense variants that had one variant was located in the extracellular region and the other in the cytoplasm. The patients with biallelic variants presented severe epileptic phenotypes, whereas those with heterozygous variants were associated with a mild epileptic phenotype of benign epilepsy with centrotemporal spikes (BECTS). These variants had no or low allele frequency in the gnomAD database. The frequencies of the CELSR1 variants in this cohort were significantly higher than those in the control populations. The evidence from ClinGen Clinical-Validity Framework suggested a strong association between CELSR1 variants and epilepsy. These findings provide evidence that CELSR1 is potentially a candidate pathogenic gene of partial epilepsy of childhood.

Vegetation Dynamics in Response to Climate Change and Human Activities in a Typical Alpine Region in the Tibetan Plateau.

Understanding past and future vegetation dynamics is important for assessing the effectiveness of ecological engineering, designing policies for adaptive ecological management, and improving the ecological environment. Here, inter-annual changes in vegetation dynamics during 2000-2020, contributions of climate change (CC) and human activities (HA) to vegetation dynamics, and sustainability of vegetation dynamics in the future were determined in Gannan Prefecture (a typical alpine region in the Tibetan Plateau), China. MODIS-based normalized difference vegetation index (NDVI), air temperature, precipitation, and land cover data were used, and trend analysis, multiple regression residuals analysis, and Hurst exponent analysis were employed. NDVI increased at a rate of 2.4 × 10-3∙a-1 during the growing season, and vegetation improved in most parts of the study area and some sporadically degraded areas also existed. The increasing rate was the highest in the Grain to Green Project (GTGP) areas. The vegetation in the southern and northern regions was mainly affected by CC and HA, respectively, with CC and HA contributions to vegetation change being 52.32% and 47.68%, respectively. The GTGP area (59.89%) was most evidently affected by HA. Moreover, a Hurst exponent analysis indicated that, in the future, the vegetation in Gannan Prefecture would continuously improve. The study can assist in formulating ecological protection and restoration projects and ensuring sustainable development.

Recessive LAMA5 Variants Associated With Partial Epilepsy and Spasms in Infancy.

Objective: The LAMA5 gene encodes the laminin subunit α5, the most abundant laminin α subunit in the human brain. It forms heterotrimers with the subunit ß1/ß2 and γ1/γ3 and regulates neurodevelopmental processes. Genes encoding subunits of the laminin heterotrimers containing subunit α5 have been reported to be associated with human diseases. Among LAMAs encoding the laminin α subunit, LAMA1-4 have also been reported to be associated with human disease. In this study, we investigated the association between LAMA5 and epilepsy. Methods: Trios-based whole-exome sequencing was performed in a cohort of 118 infants suffering from focal seizures with or without spasms. Protein modeling was used to assess the damaging effects of variations. The LAMAs expression was analyzed with data from the GTEX and VarCards databases. Results: Six pairs of compound heterozygous missense variants in LAMA5 were identified in six unrelated patients. All affected individuals suffered from focal seizures with mild developmental delay, and three patients presented also spasms. These variants had no or low allele frequencies in controls and presented statistically higher frequency in the case cohort than in controls. The recessive burden analysis showed that recessive LAMA5 variants identified in this cohort were significantly more than the expected number in the East Asian population. Protein modeling showed that at least one variant in each pair of biallelic variants affected hydrogen bonds with surrounding amino acids. Among the biallelic variants in cases with only focal seizures, two variants of each pair were located in different structural domains or domains/links, whereas in the cases with spasms, the biallelic variants were constituted by two variants in the identical functional domains or both with hydrogen bond changes. Conclusion: Recessive LAMA5 variants were potentially associated with infant epilepsy. The establishment of the association between LAMA5 and epilepsy will facilitate the genetic diagnosis and management in patients with infant epilepsy.

A novel ring-beam piezoelectric actuator for small-size and high-precision manipulator.

A new type of ring (joint)-beam (arm) element based on piezoelectric actuator is designed in this paper. By using piezoelectric ceramics, the vibration modes of two parallel beams are excited and coupled to form in-plane waves on the ring. As the piezoelectric actuator has the dual effect of acting as the power source and the main body structure of the arm joint, compared with the rotating joint using DC motor as the power source, the actuator does not need additional space to install the motor, which makes joint mechanism have the advantages of simple structure and small volume. Furthermore, the micro-displacement control of joints can be achieved by the characteristics of fast response and power self-locking based on the friction driving principle. A two-degree-of-freedom three-arm prototype of the joint mechanism is designed to obtain the parameters of the piezoelectric actuator and carry out related experiments. The prototype of the mechanism is 72 g in weight and 105 mm in length, and the maximum rotation angle of each joint is 210 deg. The experimental results indicate that, when driving frequency is 58.6 kHz and the driving voltage is 300 Vpp, the angular speed of the prototype reaches 45.9 deg/s, the resolution is 0.015 deg and the startup and shutdown response time are 35 ms and 21 ms, respectively. Due to its simple and compact structure, the manipulator have strong growth potential for meeting the requirements of wet hyperbaric environment. The characteristics of fast response time and high resolution enable good mobility and high precision.