Clinical and genetic analysis of 18 patients with KCNQ2 mutations from South China.

BACKGROUND: We aimed to delineate the genotype and phenotype of patients with KCNQ2 mutations from South China. METHODS: Clinical manifestations and characteristics of KCNQ2 mutations of patients from South China were analyzed. Previous patients with mutations detected in this study were reviewed. RESULTS: Eighteen epilepsy patients with KCNQ2 mutations, including seven self-limited neonatal epilepsy (SeLNE), two self-limited infantile epilepsy (SeLIE) and nine developmental and epileptic encephalopathy (DEE) were enrolled. The age of onset (p=0.006), mutation types (p=0.029), hypertonia (p=0.000), and seizure offset (p=0.029) were different in self-limited epilepsy (SeLE) and DEE. De novo mutations were mainly detected in DEE patients (p=0.026). The mutation position, EEG or the age of onset were not predictive for the seizure or ID/DD outcome in DEE, while the development of patients free of seizures was better than that of patients with seizures (p=0.008). Sodium channel blockers were the most effective anti-seizure medication, while the age of starting sodium channel blockers did not affect the seizure or development offset. We first discovered the seizure recurrence ratio in SeLNE/SeLIE was 23.1% in South China. Four novel mutations (c.790T>C, c.355_363delGAGAAGAG, c.296+2T>G, 20q13.33del) were discovered. Each of eight mutations (c.1918delC, c.1678C>T, c.683A>G, c.833T>C, c.868G>A, c.638G>A, c.997C>T, c.830C>T) only resulted in SeLE or DEE, while heterogeneity was also found. Six patients in this study have enriched the known phenotype caused by the mutations (c.365C>T, c.1A>G, c.683A>G, c.833T>C, c.830C>T, c.1678C>T). CONCLUSION: This research has expanded known phenotype and genotype of KCNQ2-related epilepsy, and the different clinical features of SeLE and DEE from South China.

Genotype-phenotype correlation and natural history analyses in a Chinese cohort with pelizaeus-merzbacher disease.

BACKGROUND: The natural history and genotype-phenotype correlation of Pelizaeus-Merzbacher disease (PMD) of Chinese patients has been rarely reported. METHOD: Patients who met the criteria for PMD were enrolled in our study. Genomic analysis was conducted by multiplex ligation probe amplification (MLPA) and Sanger or whole-exome sequencing (WES). Natural history differences and genotype-phenotype correlations were analyzed. RESULT: A total of 111 patients were enrolled in our follow-up study. The median follow-up interval was 53 m (1185). Among PMD patients, developmental delay was the most common sign, and nystagmus and hypotonia were the most common initial symptoms observed. A total of 78.4% of the patients were able to control their head, and 72.1% could speak words. However, few of the patients could stand (9.0%) or walk (4.5%) by themselves. Nystagmus improved in more than half of the patients, and hypotonia sometimes deteriorated to movement disorders. More PLP1 point mutations patients were categorized into severe group, while more patients with PLP1 duplications were categorized into mild group (p < 0.001). Compared to patients in mild groups, those in the severe group had earlier disease onset and had acquired fewer skills at a later age. CONCLUSION: PMD patients have early disease onset with nystagmus and hypotonia followed by decreased nystagmus and movement disorders, such as spasticit. Patients with PLP1 duplication were more likely to be categorized into the mild group, whereas patients with point mutations were more likely to be categorized into the severe group.

Ca2+ transfer via the ER-mitochondria tethering complex in neuronal cells contribute to cadmium-induced autophagy.

Mitochondrial-associated endoplasmic reticulum (ER) membranes (MAMs) play a key role in several physiological functions, including calcium ion (Ca2+) transfer and autophagy; however, the molecular mechanism controlling this interaction in cadmium (Cd)-induced neurotoxicity is unknown. This study shows that Cd induces alterations in MAMs and mitochondrial Ca2+ levels in PC12 cells and primary neurons. Ablation or silencing of mitofusin 2 (Mfn2) in PC12 cells or primary neurons blocks the colocalization of ER and mitochondria while reducing the efficiency of mitochondrial Ca2+ uptake. Moreover, Mfn2 defects reduce interactions or colocalization between GRP75 and VDAC1. Interestingly, the enhancement of autophagic protein levels, colocalization of LC3 and Lamp2, and GFP-LC3 puncta induced by Cd decreased in Mfn2-/- or Grp75-/- PC12 cells and Mfn2- or Grp75-silenced primary neurons. Notably, the specific Ca2+ uniporter inhibitor RuR blocked both mitochondrial Ca2+ uptake and autophagy induced by Cd. Finally, this study proves that the mechanism by which IP3R-Grp75-VDAC1 tethers in MAMs is associated with the regulation of autophagy by Mfn2 and involves their role in mediating mitochondrial Ca2+ uptake from ER stores. These results give new evidence into the organelle metabolic process by demonstrating that Ca2+ transport between ER-mitochondria is important in autophagosome formation in Cd-induced neurodegeneration.

Plcz1 Deficiency Decreased Fertility in Male Mice Which Is Associated with Sperm Quality Decline and Abnormal Cytoskeleton in Epididymis.

Phospholipase C zeta1 (Plcz1) was known to be a physiological factor in sperm that activates oocytes to complete meiosis by triggering Ca2+ oscillations after fertilisation. However, the role of male Plcz1 in spermatogenesis and early embryo development in progeny has been controversial. Plcz1 knockout (Plcz1-/-) mouse model (Plcz1m3 and Plcz1m5) was generated by using the CRISPR-Cas9 system. The fertility of Plcz1-/- mice was evaluated by analysing the number of offsprings, sperm quality, pathological changes in the testis and epididymis. RNA-seq and RT-PCR were performed to screen differentially expressed genes and signalling pathways related to fertility in Plcz1-/- mice. Further mechanism was explored by using Plcz1-/- cells. Plcz1 knockout led to hypofertility in male mice. In particular, a significant time delay in development and polyspermy was found in eggs fertilized by both Plcz1m3 and Plcz1m5 sperm. Interestingly, a decline in sperm quality combined with pathological changes in epididymis was found in Plcz1m3 mice but not in Plcz1m5 mice. Notably, abnormal cytoskeleton appears in epididymis of Plcz1m3 mice and Plcz1-/- cells. Cytoskeleton damage of epididymis is involved in fertility decline of males upon Plcz1 deficiency in this model.

[Soil organic and inorganic carbon pools as affected by straw return modes under a wheat-maize rotation system in the Guanzhong Plain, Northwest China]. / å ³ä¸­å¹³åŽŸéº¦çŽ‰è½®ä½œä½“ç³»ä½œç‰©ç§¸ç§†ä¸åŒè¿˜ç”°æ¨¡å¼ä¸‹åœŸå£¤æœ‰æœºç¢³å’Œæ— æœºç¢³åº“å˜åŒ–ç‰¹å¾.

To understand the effects of straw return modes on soil carbon pools, we investigated total soil organic carbon (SOC), labile organic carbon fractions, and inorganic carbon (SIC) in different straw return modes at a depth of 0-40 cm under a maize-wheat cropping system in the Guanzhong Plain, Shaanxi, based on an 11-year field experiment. There were five straw return modes, i.e., no return of straw of both wheat and maize (CK), the retention of high wheat stubble plus the return of chopped maize straw (WH-MC), the return of both chopped wheat and maize straw (WC-MC), the retention of high wheat stubble and no return of maize straw (WH-MN), and the return of chopped wheat straw and no return of maize straw (WC-MN). The proportions of SOC storage were significantly higher under the WH-MC and WC-MC treatments than that under the CK by 28.1% and 22.2%, respectively. The proportions of SIC storage were increased by 20.4% and 17.3%, respectively. Compared with the initial value, the increases of sequestered SOC and SIC ranged from -0.84 t·hm-2 to 6.55 t·hm-2, respectively, and from -0.26 t·hm-2 to 8.61 t·hm-2, respectively. The efficiency of sequestration of SOC was 7.5%. To maintain the basic SOC level, the minimum carbon input from straw was 4.65 t·hm-2·a-1. The contents of labile carbon fractions at the 0-20 cm layer increased significantly under the WH-MC and WC-MC treatments compared with those of the control. Results of principal component analysis showed that the changes in soil carbon pools were primarily affected by the amount of straw return. Additionally, the increases in SIC storage could be ascribed to the Ca2+ and Mg2+ ions derived from irrigation water and plant residues that could coprecipitate with the CO2 from SOC mineralization to form CaCO3. In conclusion, our results indicated that the straw return mode that utilized the retention of high wheat stubble and chopped maize straw was sufficient to maintain soil carbon storage and would be the optimal straw-returning strategy for the region.

Novel Insight into the Potential Pathogenicity of Mitochondrial Dysfunction Resulting from PLP1 Duplication Mutations in Patients with Pelizaeus-Merzbacher Disease.

Among the hypomyelinating leukodystrophies, Pelizaeus-Merzbacher disease (PMD) is a representative disorder. The disease is caused by different types of PLP1 mutations, among which PLP1 duplication accounts for ∼70% of the mutations. Previous studies have shown that PLP1 duplications lead to PLP1 retention in the endoplasmic reticulum (ER); in parallel, recent studies have demonstrated that PLP1 duplication can also lead to mitochondrial dysfunction. As such, the respective roles and interactions of the ER and mitochondria in the pathogenesis of PLP1 duplication are not clear. In both PLP1 patients' and healthy fibroblasts, we measured mitochondrial respiration with a Seahorse XF Extracellular Analyzer and examined the interactions between the ER and mitochondria with super-resolution microscopy (spinning-disc pinhole-based structured illumination microscopy, SD-SIM). For the first time, we demonstrated that PLP1 duplication mutants had closer ER-mitochondrion interfaces mediated through structural and morphological changes in both the ER and mitochondria-associated membranes (MAMs). These changes in both the ER and mitochondria then led to mitochondrial dysfunction, as reported previously. This work highlights the roles of MAMs in bridging PLP1 expression in the ER and pathogenic dysfunction in mitochondria, providing novel insight into the pathogenicity of mitochondrial dysfunction resulting from PLP1 duplication. These findings suggest that interactions between the ER and mitochondria may underlie pathogenic mechanisms of hypomyelinating leukodystrophies diseases at the organelle level.

Chromosome-scale genome assembly of brown-spotted flathead Platycephalus sp.1 provides insights into demersal adaptation in flathead fish.

Flatheads are valuable commercial fish species endemic to the Indo-West Pacific. Due to their economic value and unique biological traits, such as metamorphosis and camouflage, they serve as ideal marine organisms for studies on demersal adaptation and evolution. The brown-spotted flathead (Platycephalus sp.1) is the most widely distributed in the northwestern Pacific. Despite the lack of a valid scientific name, it has been long recognized and exploited in the marine fisheries of China, Japan, and Korea. In the current study, we applied Illumina, PacBio, and Hi-C sequencing to assemble a chromosome-scale genome for this species. The assembled genome was 660.63 Mb long with a scaffold N50 of 28.65 Mb and 100% of the contigs were anchored onto 24 chromosomes. We predicted 22 743 protein-coding genes, 94.8% of which were functionally annotated. Comparative genomic analyses suggested that Platycephalus sp.1 diverged from its common ancestor with Gasterosteus aculeatus ~88.4 million years ago. The expanded gene families were significantly enriched in immune, biosynthetic, and metabolic pathways. Furthermore, three shared Gene Ontology terms and 377 common positively selected genes were identified between flathead and flatfish species, suggesting that these genes may contribute to demersal adaptation in flatheads. The assembled genomic data provide a valuable molecular resource for further research on the biological and adaptive evolution of flathead species.

Complete chloroplast genome sequence and phylogenetic analysis of Chimonobambusa sichuanensis (Bambusoideae).

Chimonobambusa sichuanensis is an ornamental shrubby bamboo endemic to southern China. In this study, the complete chloroplast genome (cpDNA) sequence of Chimonobambusa sichuanensis was first reported. The cpDNA is 139,594 bp in length, including a small single-copy (SSC) region of 12,820 bp and a large single-copy (LSC) region of 83,196 bp, which were separated by a pair of inverted repeat (IR) regions of 21,789 bp. The genome contains 140 genes, consisting of 93 protein-coding genes, seven ribosomal RNA (rRNA) genes, and 40 transfer RNA (tRNA) genes. The phylogenetic analysis showed that C. sichuanensis is highly clustered in the Phyllostachys clade, sister to C. tumidissinoda.

Synthesis of the Platinum Nanoribbons Regulated by Fluorine and Applications in Electrocatalysis.

Controlling the morphology of highly homogeneous nanoribbons is one of the main goals for synthesizing catalysts with excellent activity and durability. In this Communication, platinum (Pt) nanoribbons were synthesized by a one-pot method. We used ammonium fluoride (NH4F) as the regulator, under 8 atm of hydrogen (H2), to synthesize zigzag-shaped two-dimensional Pt nanoribbons. Benefiting from their unique morphology, the Pt nanoribbons display superior electrocatalytic activity and stability.

One-pot Synthesis of Pd/Azo-polymer as an Efficient Catalyst for 4-Nitrophenol Reduction and Suzuki-Miyaura Coupling Reaction.

The porous polymer matrix with good stability and confined microenvironment is considered as ideal support to stabilize isolated metal centers for catalysis. Herein, we report a "one-pot" method to prepare a kind of palladium complexed with azo porous organic polymer nanospheres (Pd-azo-POPs). The method combines the synthesis of azo-POPs with the reduction of the Pd ion, where azo serves as an anchoring group to limit the growth of Pd. The unique structure is conductive to the formation of a uniform active center and provides improved electron transfer. Pd-azo-POPs-80 exhibits a high catalytic activity and cycling stability both in 4-nitrophenol reduction and Suzuki-Miyaura coupling. The knor for the 4-nitrophenol reduction was 174.7 min-1 mM-1 and the conversion remains above 90% after 6 cycles. Meanwhile, the yield was still up to 94.5% after 5 cycles for the Suzuki-Miyaura coupling reaction of benzene derivatives with I/Br under mild conditions.

Ultrathin amorphous iron-doped cobalt-molybdenum hydroxide nanosheets for advanced oxygen evolution reactions.

Developing the highly efficient and low-cost electrocatalysts for the oxygen evolution reactions (OERs), as vital half reactions of water splitting, is crucial for renewable energy technology. The electrocatalysts based on multi-component and hierarchically structured non-noble metal hydr(oxy)oxide materials are of great prospects. Herein, we report an efficient strategy at low temperatures for synthesizing amorphous iron-doped cobalt-molybdenum ultrathin hydroxide (Fe-CoMo UH) nanosheets. Benefiting from the ultrathin amorphous structure and multi-metal coordination, Fe-CoMo UH nanosheets exhibit outstanding performance for OERs with a low overpotential of 245 mV at 10 mA cm-2, a small Tafel slope of 37 mV dec-1 and an excellent stability for 90 h. The mass activity of Fe-CoMo UH is higher than that of commercial Ir/C and most of the transition metal hydroxide catalysts. This work provides a feasible consideration for the construction of promising efficient non-noble metal catalysts.

Electronic modulation of nickel selenide by copper doping and in situ carbon coating towards high-rate and high-energy density lithium ion half/full batteries.

Over the past decades, metal selenides have drawn considerable attention due to their high theoretical specific capacity. However, huge volume changes and sluggish electrochemical transfer kinetics hinder their applications in energy storage and conversion. In this work, we demonstrate an efficient and ingenious synthesis strategy to regulate nickel selenide electrodes by the introduction of copper and in situ coating with carbon (Cu-NiSe2@C). When used as anodes for lithium-ion batteries, the as-synthesized Cu-NiSe2@C delivered a high capacity of 1630 mA h g-1 at 1.0 A g-1 after 200 cycles and excellent rate performance as well as long-term cycling stability with a high capacity of 489 mA h g-1 at 10 A g-1 after 20 000 cycles. When coupled with a commercial LiFePO4 cathode, the full cells showed a high capacity of 463 mA h g-1 at 0.2 A g-1. Their superior electrochemical performance can be attributed to the synergistic effect of the in situ carbon coating and copper doping, which can promote the electron/ion transfer kinetics, as well as alleviate the volume expansion during cycling. This work will open new opportunities for the development of high-performance anodes for lithium storage.

Cadmium induces mitophagy via AMP-activated protein kinases activation in a PINK1/Parkin-dependent manner in PC12 cells.

OBJECTIVES: Cadmium (Cd) induces mitophagy in neuronal cells, but the underlying mechanisms remain unknown. In this study, we aimed to investigate these mechanisms. MATERIALS AND METHODS: The effects of Cd on the mitophagy in rat pheochromocytoma PC12 cells were detected, and the role of PINK1/Parkin pathway in Cd-induced mitophagy was also analysed by using PINK1 siRNA. In order to explore the relationship between AMPK and PINK1/Parkin in Cd-induced mitophagy in PC12 cells, the CRISPR-Cas9 system was used to knock down AMPK expression. RESULTS: The results showed that Cd treatment triggered a significant increase in mitophagosome formation and the colocalization of mitochondria and lysosomes, which was further proved by the colocalization of LC3 puncta and its receptors NDP52 or P62 with mitochondria in PC12 cells. Moreover, an accumulation of PINK1 and Parkin was found in mitochondria. Additionally, upon PINK1 knock-down using PINK1 siRNA, Cd-induced mitophagy was efficiently suppressed. Interestingly, chemical or genetic reversal of AMPK activation: (a) significantly inhibited the activation of mitophagy and (b) promoted NLRP3 activation by inhibiting PINK/Parkin translocation. CONCLUSIONS: These results suggest that Cd induces mitophagy via the PINK/Parkin pathway following AMPK activation in PC12 cells. Targeting the balanced activity of AMPK/PINK1/Parkin-mediated mitophagy signalling may be a potential therapeutic approach to treat Cd-induced neurotoxicity.

Epilepsy in children with leukodystrophies.

BACKGROUND: Epilepsy might be one of the manifestations in children with leukodystrophies, but the incidence of epilepsy in different types of leukodystrophies is unclear yet. METHODS: A retrospective observational cohort study was performed on children diagnosed with leukodystrophies in Peking University First Hospital from January 2004 to June 2019, and the patients were followed for 5.5 years (0.4-14.2 years) after the first visit. RESULTS: A total of 333 patients were included. The overall incidence of epilepsy was 30.6% (102/333). Alexander disease had the highest incidence (77.3%, 51/66), followed by vanishing white matter disease (41.2%, 21/51), Canavan disease (33.3%, 1/3), megalencephalic leukoencephalopathy with subcortical cysts (32.1%, 9/28), X-linked adrenoleukodystrophy (23.1%, 3/13), Krabbe disease (18.8%, 3/16), metachromatic leukodystrophy (14.3%, 6/42), and Pelizaeus-Merzbacher disease (7.0%, 8/114). The incidence of epilepsy in leukodystrophies classified as astrocytopathies was higher than that in myelin disorders (55.9% vs. 11.2%, P < 0.001). Of the 102 patients with epilepsy, seizures were the chief complaint in 61.8% (63/102) and the initial symptom in 22.5% (23/102). The median age at seizure onset was 20.5 months (1 day-176 months). A total of 63.7% (65/102) of children were treated with antiepileptic drugs (AEDs), and the responder rate was 90.8% (59/65) at the last follow-up, including 71.2% (42/59) of children who were seizure free. CONCLUSIONS: Epilepsy was not uncommon in children with leukodystrophies. Children with Alexander disease had the highest incidence; whereas, children with Pelizaeus-Merzbacher disease had the lowest incidence. Children with leukodystrophies classified as astrocytopathies were more prone to have epilepsy than those classified as myelin disorders. Most children with leukodystrophies who presented with epilepsy showed a good response to antiepileptic drugs.

[Analysis of D4Z4 mutation in a child with facioscapulohumeral muscular dystrophy presented initially as mental retardation].

OBJECTIVE: To identify pathological mutation of D4Z4 in a child with facioscapulohumeral muscular dystrophy (FSHD) presented initially as mental retardation. METHODS: Wechsler Intelligence Scale for Children Revised in China (WISC-IV) was used to assess the patient's IQ. Other clinical data was also collected. With genomic DNA extracted from peripheral blood samples, the child and his parents were subjected to medical exome sequencing and copy number variation analysis by next generation sequencing (NGS). The D4Z4 repeats and their origin source were determined by molecular combing. RESULTS: By the WISC-IV test, the child was found to have a total IQ of 41, with a speech comprehension IQ of 45, and perceptual inference index IQ of 52. No pathological mutation was detected by NGS. By molecular combing method, the child was found to carry a D4Z4 spanning 5.2 kb with a copy number of 2. Analysis of his parents indicate that the mutation was de novo. CONCLUSION: The D4Z4 copy number variation may account for the FSHD and mental retardation in the child. The molecular combing method can be used to identify the number of repeat units and facilitate the diagnosis of FSHD.

The complete chloroplast genome of Phyllostachys glauca (Bambusoideae), a dominant bamboo species in limestone mountains endemic to China.

Phyllostachys glauca is a dominant species in limestone mountains endemic to China. Here, we characterized its complete chloroplast genome. It is a circular DNA molecule of 139,689 bp in length, including a pair of 21,798 bp inverted repeats (IRs), a 12,872 bp small single-copy (SSC) region and an 83221 bp large single-copy (LSC) region. The total GC content of P. glauca chloroplast genome was 38.9%, and it encodes a total of 137 functional genes, including 89 protein-coding genes, 40 tRNA genes, and 8 rRNA genes. The phylogenetic analysis shows that P. glauca is highly clustered in the Phyllostachys clade (V), sister to the lineage of P. nigra var. henonis + P. sulphurea.

Delayed diagnosis of X-linked agammaglobulinaemia in a boy with recurrent meningitis.

BACKGROUND: X-linked agammaglobulinaemia (XLA) is a rare inherited primary immunodeficiency disease characterized by the B cell developmental defect, caused by mutations in the gene coding for Bruton's tyrosine kinase (BTK), which may cause serious recurrent infections. The diagnosis of XLA is sometimes challenging because a few number of patients have higher levels of serum immunoglobulins than expected. In this study, we reported an atypical case with recurrent meningitis, delayed diagnosis with XLA by genetic analysis at the second episode of meningitis at the age of 8 years. CASE REPORT: An 8-year-old Chinese boy presented with fever, dizziness and recurrent vomiting for 3 days. The cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) results were suggestive of bacterial meningoencephalitis, despite the negative gram staining and cultures of the CSF. The patient was treated with broad-spectrum antibiotics and responded well to the treatment. He had history of another episode of acute pneumococci meningitis 4 years before. The respective level of Immunoglobulin G (IgG), Immunoglobulin A (IgA) and Immunoglobulin M (IgM) was 4.85 g/L, 0.93 g/L and 0.1 g/L at 1st episode, whereas 1.9 g/L, 0.27 g/L and 0 g/L at second episode. The B lymphocytes were 0.21 and 0.06% of peripheral blood lymphocytes at first and second episode respectively. Sequencing of the BTK coding regions showed that the patient had a point mutation in the intron 14, hemizyous c.1349 + 5G > A, while his mother had a heterozygous mutation. It was a splice site mutation predicted to lead to exon skipping and cause a truncated BTK protein. CONCLUSION: Immunity function should be routinely checked in patients with severe intracranial bacterial infection. Absence of B cells even with normal level of serum immunoglobulin suggests the possibility of XLA, although this happens only in rare instances. Mutational analysis of BTK gene is crucial for accurate diagnosis to atypical patients with XLA.

Identification in Chinese patients with GLIALCAM mutations of megalencephalic leukoencephalopathy with subcortical cysts and brain pathological study on Glialcam knock-in mouse models.

BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare neurological degenerative disorder caused by the mutations of MLC1 or GLIALCAM with autosomal recessive or autosomal dominant inheritance and a different prognosis, characterized by macrocephaly, delayed motor and cognitive development, and bilateral abnormal signals in cerebral white matter (WM) with or without cysts on magnetic resonance imaging (MRI). This study aimed to reveal the clinical and genetic features of MLC patients with GLIALCAM mutations and to explore the brain pathological characteristics and prognosis of mouse models with different modes of inheritance. METHODS: Clinical information and peripheral venous blood were collected from six families. Genetic analysis was performed by Sanger sequencing of GLIALCAM. GlialcamArg92Trp/+ and GlialcamLys68Met/Thr132Asn mouse models were generated based on mutations from patients (c.274C>T(p.Arg92Trp) (c.203A>T(p.Lys68Met), and c.395C>A (p.Thr132Asn))). Brain pathologies of the mouse models at different time points were analyzed. RESULTS: Six patients were clinically diagnosed with MLC. Of the six patients, five (Pt1-Pt5) presented with a heterozygous mutation in GLIALCAM (c.274C>T(p.Arg92Trp) or c.275G>C(p.Arg92Pro)) and were diagnosed with MLC2B; the remaining patient (Pt6) with two compound heterozygous mutations in GLIALCAM (c.203A>T (p.Lys68Met) and c.395C>A (p.Thr132Asn)) was diagnosed with MLC2A. The mutation c.275C>G (p.Arg92Pro) has not been reported before. Clinical manifestations of the patient with MLC2A (Pt6) progressed with regression, whereas the course of the five MLC2B patients remained stable or improved. The GlialcamArg92Trp/+ and GlialcamLys68Met/ Thr132Asn mouse models showed vacuolization in the anterior commissural WM at 1 month of age and vacuolization in the cerebellar WM at 3 and 6 months, respectively. At 9 months, the vacuolization of the GlialcamLys68Met/ Thr132Asn mouse model was heavier than that of the GlialcamArg92Trp/+ mouse model. Decreased expression of Glialcam in GlialcamArg92Trp/+ and GlialcamLys68Met/ Thr132Asn mice may contribute to the vacuolization. CONCLUSIONS: Clinical and genetic characterization of patients with MLC and GLIALCAM mutations revealed a novel mutation, expanding the spectrum of GLIALCAM mutations. The first Glialcam mouse model with autosomal recessive inheritance and a new Glialcam mouse model with autosomal dominant inheritance were generated. The two mouse models with different modes of inheritance showed different degrees of brain pathological features, which were consistent with the patients' phenotype and further confirmed the pathogenicity of the corresponding mutations.

Targeted next generation sequencing in 112 Chinese patients with intellectual disability/developmental delay: novel mutations and candidate gene.

BACKGROUND: Intellectual disability/developmental delay is a complex condition with extraordinary heterogeneity. A large proportion of patients lacks a specific diagnosis. Next generation sequencing, enabling identification of genetic variations in multiple genes, has become an efficient strategy for genetic analysis in intellectual disability/developmental delay. METHODS: Clinical data of 112 Chinese families with unexplained intellectual disability/developmental delay was collected. Targeted next generation sequencing of 454 genes related to intellectual disability/developmental delay was performed for all 112 index patients. Patients with promising variants and their other family members underwent Sanger sequencing to validate the authenticity and segregation of the variants. RESULTS: Fourteen promising variants in genes EFNB1, MECP2, ATRX, NAA10, ANKRD11, DHCR7, LAMA1, NFIX, UBE3A, ARID1B and PTPRD were identified in 11 of 112 patients (11/112, 9.82%). Of 14 variants, eight arose de novo, and 13 are novel. Nine patients (9/112, 8.03%) got definite molecular diagnoses. It is the first time to report variants in EFNB1, NAA10, DHCR7, LAMA1 and NFIX in Chinese intellectual disability/developmental delay patients and first report about variants in NAA10 and LAMA1 in affected individuals of Asian ancestry. CONCLUSIONS: Targeted next generation sequencing of 454 genes is an effective test strategy for patients with unexplained intellectual disability/developmental delay. Genetic heterogenicity is significant in this Chinese cohort and de novo variants play an important role in the diagnosis. Findings of this study further delineate the corresponding phenotypes, expand the mutation spectrum and support the involvement of PTPRD in the disease.

Theoretical and Experimental Study of Reversible and Stable Wetting States of a Hierarchically Wrinkled Surface Tuned by Mechanical Strain.

The wetting behavior of hierarchically wrinkled surfaces has attracted great interest because of its broad application in flexible electronic, microfluidic chip, and biomedicine. However, theoretical studies concerning the relationship between the apparent contact angle and mechanical strain applied on the soft and flexible surface with a hierarchically wrinkled structure are still limited. We established a theoretical framework to describe and understand how prestrain and applied dynamic strain reversibly tune the wettability of the hierarchically wrinkled surface. More specifically, a direct relationship between the mechanical strain and contact angle was built through reversible tuning of the amplitude and the wavelength of the wrinkled structures caused by mechanical strain, which allowed for more precise adjustment of surface wettability. To verify the accuracy of the theoretical relationship between the contact angle and mechanical strain, a soft surface with a hierarchically wrinkled structure was prepared by combining wrinkled microstructures and strip ones. The results showed that the experimental contact angles were in agreement with the theoretical ones within a limited error range. This will be helpful for further investigation on the wettability of hierarchically wrinkled surfaces.