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Mutations in myelin regulatory factor (MYRF), a gene mapped to 11q12-q13.3, are responsible for autosomal dominant high hyperopia and seem to be associated with angle closure glaucoma, which is one of the leading causes of irreversible blindness worldwide. Whether there is a causal link from the MYRF mutations to the pathogenesis of primary angle-closure glaucoma (PACG) remains unclear at this time. Six truncation mutations, including five novel and one previously reported, in MYRF are identified in seven new probands with hyperopia, of whom all six adults have glaucoma, further confirming the association of MYRF mutations with PACG. Immunofluorescence microscopy demonstrates enriched expression of MYRF in the ciliary body and ganglion cell layer in humans and mice. Myrf

As a biomarker for liver disease, bilirubin has been utilized in prognostic scoring systems for cirrhosis. While laboratory-based methods are used to determine bilirubin levels in clinical settings, they do not readily lend themselves to applications outside of hospitals. Consequently, bilirubin monitoring for cirrhotic patients is often performed only intermittently; thus, episodes requiring clinical interventions could be missed. This work investigates the feasibility of measuring bilirubin concentration in whole porcine blood samples using dual-wavelength transmission measurement. A compact and low-cost dual-wavelength transmission measurement setup is developed and optimized to measure whole blood bilirubin concentrations. Using small volumes of whole porcine blood (72 µL), we measured the bilirubin concentration within a range corresponding to healthy individuals and cirrhotic patients (1.2-30 mg/dL). We demonstrate that bilirubin levels can be estimated with a positive correlation (R-square0.95) and an accuracy of ±1.7 mg/dL, with higher reliability in cirrhotic bilirubin concentrations (4 mg/dL) - critical for high-risk patients. The optical and electronic components utilized are economical and can be readily integrated into a miniature, low-cost, and user-friendly system. This could provide a pathway for point-of-care monitoring of blood bilirubin outside of medical facilities (e.g., patient's home).

We provide a perspective on monitoring the blood bilirubin concentration using simple methods, which are economical and can be adopted in point of care settings. These are a homecare test system, a miniature implant, and a neonatal wearable patch.

Background/aimsX-linked retinoschisis (XLRS), associated withRS1, is the most common type of X-linked retinopathy in children. This study aimed to identify clinical and genetic features of retinoschisis in 120 families withRS1variants in China.MethodsRS1variants were collected from our in-house exome data and were predicted by multiple-step bioinformatics analysis. Clinical data of 122 patients from 120 families with potential pathogenicRS1variants were analysed and summarised, respectively.ResultTotally, 79 hemizygous variants (53 missense, 25 truncation and 1 indel), were detected. All except one (78/79, 98.7%), including 22 novels, were classified as potential pathogenic and detected exclusively in 120 families with retinoschisis. Clinical data demonstrated an average age of presentation at 5 years (1 month–41 years). Macular changes were classified as macular schisis (87.5%), macular atrophy (10.7%), normal (0.9%) and unclassified (0.9%). Patients with macular atrophy had older age but similar visual acuity compared with macular schisis. Peripheral retinal changes included flat retinoschisis (52.4%), bullous retinoschisis (BRS) (10.7%) and normal-like (36.9%) patients. Spontaneous regression was observed in two patients with BRS on follow-up examination. Visual acuity in the peripheral retinoschisis group was worse than that without peripheral retinoschisis.ConclusionAlmost all rareRS1variants were potential pathogenic. All patients withRS1pathogenic variants showed detectable characteristics in the macula and/or peripheral retina. Our data onRS1variants and associated clinical phenotypes may be of value for clinical diagnosis and genetic test of retinoschisis.

Based on the mechanical characteristics of the core layer, which withstands the shear stress and deformation of a sandwich beam, a topology optimization framework based on the bi-directional evolutionary structural optimization method is proposed to optimize the core layer composed of a periodic base cell with extreme shear stiffness. The effects of the volume fraction, filter radius, and initial periodic base cell (PBC) aspect ratio on the micro-topology of the core and the dynamic response process, core compression, and energy absorption capacity of the sandwich beams under blast impact loading were analyzed by the finite element method. The results demonstrated that the over-pressure action stage was coupled with the core compression stage. Under the same loading and mass per unit area, the sandwich beam with a 20% volume fraction core layer had the best blast resistance. The filter radius has a slight effect on the shear stiffness and blast resistances of the sandwich beams, but increasing the filter radius could slightly improve the bending stiffness. Upon changing the initial PBC aspect ratio, there are three methods for PBC evolution: the first is to change the angle between the adjacent bars, the second is to further form holes in the bars, and the third is to combine the first two methods. However, not all three methods can improve the energy absorption capacity of the structure. Changing the aspect ratio of the PBC arbitrarily may lead to worse results. More detailed studies are necessary if further optimization is to be achieved.

Digital camera sensors use color filters on photodiodes to achieve color selectivity. As the color filters and photosensitive silicon layers are separate elements, these sensors suffer from optical cross-talk, which sets limits to the minimum pixel size. Here, we report hybrid silicon-aluminum nanostructures in the extreme limit of zero distance between color filters and sensors. This design could essentially achieve submicrometer pixel dimensions and minimize the optical cross-talk arising from tilt illuminations. The designed hybrid silicon-aluminum nanostructure has dual functionalities. Crucially, it supports a hybrid Mie-plasmon resonance of magnetic dipole to achieve color-selective light absorption, generating electron hole pairs. Simultaneously, the silicon-aluminum interface forms a Schottky barrier for charge separation and photodetection. This design potentially replaces the traditional dye-based filters for camera sensors at ultrahigh pixel densities with advanced functionalities in sensing polarization and directionality, and UV selectivity via interband plasmons of silicon.

The improvement of lipid metabolism by capsaicin (CAP) has been extensively studied, mostly with respect to the vanilloid type 1 (TRPV1) ion channel and intestinal flora. In this study, a model was established in germ-free mice by using resiniferatoxin (RTX) to ablate TRPV1 ion channels. Bile acid composition, blood parameters, and colonic transcriptome analyses revealed that CAP could improve dyslipidemia caused by high-fat diet even in the absence of TRPV1 ion channels and intestinal flora. CAP fed to germ mice decreased the concentrations of low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), fasting blood glucose and fasting insulin, increased the concentration of high-density lipoprotein (HDL-C), and decreased the levels of plasma endotoxin and pro-inflammatory factor interleukin 6 (IL-6). Furthermore, CAP could affect both classical and alternative pathways of cholesterol conversion by changing the composition of bile acids, reducing the concentrations of glycocholic acid (GCA), ursodeoxycholic acid (UDCA) and glycochenodeoxycholic acid (GCDCA). First, changing the composition of bile acids inhibited the expression of colon Fgf15. CAP promoted the expression of Cyp7a1 (Cytochrome p450, family 7, subfamily a, and polypeptide 1) in the liver, and thus reduced TC and TG levels. In addition, it could change the composition of bile acids and increase the expression of

The aim of this work is to investigate the mechanical behavior of architected materials mimicking a crystal microstructure. The initial collapse strength of the architected materials is predicted by limit analysis, and the post-collapse response is theoretically obtained, considering the elastic effect and large deformation. The unit cell of body-centered block (BCB)-architected materials is defined using two parameters: the angle $$\gamma_{0}$$ between the diagonal strut of the block and horizontal plane and the angle $$\varphi$$ between the diagonal and the hem of the horizontal plane. The results reveal that the initial collapse strength of the BCB under statically admissible fields is the same as that under the kinematically admissible field. The stress–strain curve of the BCB with smaller angle $$\gamma_{0}$$ possesses a plateau whose value is almost the same as the initial collapse strength. The BCB with larger angle $$\gamma_{0}$$ has a larger initial collapse strength; however, they exhibit a significant decline of post-collapse response during compression, which means that the transition of the deformation mechanism of BCB may occur in the angle range (35o, 40o). The stress–strain curve of the face-centered cubic (FCC)-architected materials generally features a sharp drop after a peak, without a plateau. A detailed finite simulation was carried out to verify the analytical model results.

Background/AimsThis study aims to assess the contribution of biallelicCPAMD8variants in patients with different forms of glaucoma, especially primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG), based on a systematic analysis of exome sequencing (ES).MethodsPotentially pathogenicCPAMD8variants were selected from the ES data of 5307 subjects with various eye conditions through multiple bioinformatics analyses. Of the 5307 subjects, 1221 probands had different forms of primary glaucoma. The genotype–phenotype correlation was assessed by a systematic review of biallelicCPAMD8variants that including our data and data from the literature. The expression profile ofCPAMD8in human tissues was determined at the mRNA and protein levels.ResultsBiallelicCPAMD8variants, including one frameshift and six missense variants, were exclusively present and significantly enriched in patients with glaucoma (one with juvenile open-angle glaucoma (JOAG), two with POAG and two with PACG) compared with none of the 4086 probands with other eye conditions in this cohort (p=4.1E-07). The effect of variants in these patients is relatively mild compared with that reported in patients with anterior segment dysgenesis or primary congenital glaucoma.CPAMD8mRNA was highly expressed in the optic nerve, ciliary body, retina and iris, whereas the CPAMD8 protein was mainly detected in the nonpigmented epithelium of the iris and ciliary process, determined by immunohistochemistry.ConclusionsThe data from this study not only provide further evidence to support the association of biallelicCPAMD8variants with JOAG but also suggest that biallelicCPAMD8variants might be associated with POAG and PACG.

The purpose of this study was to elucidate the genetic basis of 2 distinct phenotypes associated with biallelic variants in RDH12.Patients with biallelic variants in RDH12 were recruited from our genetic eye clinic. Ocular phenotypes were evaluated. Genotype-phenotype correlations were further clarified using in-house and existing databases.In total, 22 biallelic RDH12 variants, including 5 novel variants, were identified in 29 patients from 27 families. Two distinct phenotypes were observed: early-onset and generalized retinal dystrophy with severe impairment of rods and cones in 24 patients (82.8%, 24/29), and late-onset cone-rod dystrophy (CORD) with central macular atrophy in 5 patients from 5 unrelated families (17.2%, 5/29), in which a hypomorphic allele (c.806CG/p.Ala269Gly) was shared by all 5 patients. During follow-up, patients with late-onset CORD were relatively stable and did not progress to the severe form, which was considered to be an independent manifestation of RDH12-associated retinopathy caused by specific genotypes.The hypomorphic allele is responsible for the unique late-onset CORD in 5 families with recessive RDH12-associated retinopathy, in contrast to the well-known severe and generalized retinopathy. Determining the therapeutic value of interventions may depend on understanding the molecular mechanisms underlying manifestation of this hypomorphic variant only in the central macular region, with relative preservation of the peripheral retina.

High myopia is one of the most common causes for blindness due to its associated complications. Genetic factor has been considered as the major cause for early-onset high myopia (eoHM), but exact genetic defects for most eoHM are yet to be identified. Through multi-step bioinformatics analysis of our in-house whole exome sequencing dataset from 6397 individuals, variants from 928 probands with eoHM were further compared with those from in-house controls as well as gnomAD database. The results showed that loss-of-function (LoF) variants in a novel gene HNRNPH1 were identified in two of 928 probands with eoHM but in none of 5469 probands with other eye conditions (p = 0.02). LoF variants in HNRNPH1 were extremely rare and intolerant, while two LoF variants in 928 eoHM were statistically higher than their frequency in gnomAD (p = 5.98 × 10

Macrophage polarization is a dynamic and integral process in tissue inflammation and remodeling. In this study, we describe that lipoprotein-associated phospholipase A2 (Lp-PLA2) plays an important role in controlling inflammatory macrophage (M1) polarization in rodent experimental autoimmune encephalomyelitis (EAE) and in monocytes from multiple sclerosis (MS) patients. Specific inhibition of Lp-PLA2 led to an ameliorated EAE via markedly decreased inflammatory and demyelinating property of M1. The effects of Lp-PLA2 on M1 function were mediated by lysophosphatidylcholine, a bioactive product of oxidized lipids hydrolyzed by Lp-PLA2 through JAK2-independent activation of STAT5 and upregulation of IRF5. This process was directed by the G2A receptor, which was only found in differentiated M1 or monocytes from MS patients. M1 polarization could be inhibited by a G2A neutralizing Ab, which led to an inhibited disease in rat EAE. In addition, G2A-deficient rats showed an ameliorated EAE and an inhibited autoimmune response. This study has revealed a mechanism by which lipid metabolites control macrophage activation and function, modification of which could lead to a new therapeutic approach for MS and other inflammatory disorders.

The pathogenic variants in TSPAN12 could lead to familial exudative vitreoretinopathy (FEVR), which has high clinical variability. This study aims to assess the pathogenicity of TSPAN12 variants and their phenotypic spectrum based on exome sequencing from 7092 probands with different eye conditions. The variants in TSPAN12 were selected from exome sequencing data of samples from 7092 probands with different forms of eye conditions. Potentially pathogenic variants were evaluated through the annotation of types, locations, population frequencies, and in silico predictions of variants from in-house data, gnomAD, and published literature. The clinical features of patients with potentially pathogenic variants in TSPAN12 were assessed. A total of 45 variants in TSPAN12 with coding effects were detected based on the exome data from 7092 probands, among which 31 were classified as pathogenic variants including 15 novels. The 31 variants were identified in 34 probands with various initial diagnoses, including FEVR in 21 probands and diseases other than FEVR in the remaining 13 probands. Biallelic pathogenic variants were identified in one proband with initial diagnosis of high myopia. Truncating variants and the missense variants that are predicted as deleterious are likely pathogenic variants of TSPAN12. Approximately 61.8% of patients with pathogenic variants in this gene had an initial diagnosis of FEVR, and the remaining 38.2% of patients had various initial diagnoses. These findings expand the understanding about variant evaluation of TSPAN12 and phenotypic spectrum of TSPAN12-associated FEVR.

Autosomal dominant optic atrophy (ADOA) is an important cause of irreversible visual impairment in children and adolescents. About 60-90% of ADOA is caused by the pathogenic variants of OPA1 gene. By evaluating the pathogenicity of OPA1 variants and summarizing the relationship between the genotype and phenotype, this study aimed to provide a reference for clinical genetic test involving OPA1. Variants in OPA1 were selected from the exome sequencing results in 7092 cases of hereditary eye diseases and control groups from our in-house data. At the same time, the urine cells of some optic atrophy patients with OPA1 variants as well as their family members were collected and oxygen consumption rates (OCR) were measured in these cells to evaluate the pathogenicity of variants. As a result, 97 variants were detected, including 94 rare variants and 3 polymorphisms. And the 94 rare variants were classified into three groups: pathogenic (33), variants of uncertain significance (19), and likely benign (42). Our results indicated that the frameshift variants at the 3' terminus might be pathogenic, while the variants in exon 7 and intron 4 might be benign. The penetrance of the missense variants was higher than that of truncation variants. The OCR of cells with pathogenic OPA1 variants were significantly lower than those without pathogenic variants. In conclusion, some variants might be benign although predicted pathogenic in previous studies while some might have unknown pathogenesis. Measuring the OCR in urine cells could be used as a method to evaluate the pathogenicity of some OPA1 variants.

This study aims to characterize disease-causing variants in the myocilin gene (MYOC), which is associated with autosomal dominant primary open-angle glaucoma (adPOAG).Case-control study.MYOC variants were collected from in-house exome sequencing data of 7092 individuals. Genotype-phenotype analysis and bioinformatics evaluation were used to distinguish potential pathogenic variants for POAG from others. MYOC mutations in published works of literature were also systemically analyzed.In total, 53 variants in MYOC were detected in the 7092 subjects, including 45 rare variants (MAF 0.01) and 8 polymorphisms (MAF ≥ 0.01), or 48 missense variants and 5 truncation variants. There was no difference in the frequency of the 8 polymorphisms between subjects with and without POAG (P 0.05). The total number of rare MYOC variants was significantly higher in POAG than that in in-house controls (P = 3.31E-14). The pathogenic/likely pathogenic variants (p.P254T, p.S341P, p.G367R, p.P370L, p.D378G, p.C433Y, and p.L486F) were exclusively present in 8 POAG but absent in in-house controls (P = 2.79E-10). Rare truncation MYOC variants were not enriched in POAG as compared with those in in-house controls (P = 0.28). Further analysis of previously reported MYOC variants suggested that pathogenic/likely pathogenic variants were enriched in the conserved olfactomedin domain. Truncation MYOC variants were scattered in the coding region, where only p.Q368∗ had relatively strong evidence to be causative for adPOAG, whereas most others are questionable.Most MYOC variants contributing to adPOAG could be characterized as rare missense variants located in OLF-domain and predicted to be damaging through multiple tools. The effect of other variants, especially for truncation variants (except for p.Q368∗) need further clarification.

Variants in FDXR reportedly cause autosomal recessive auditory neuropathy and optic atrophy, expanding to retinal dystrophy. This study aimed to further clarify associated phenotypes. FDXR variants were selected from our in-house whole-exome sequencing dataset of 6397 families with different eye conditions. The clinical data of the identified patients were summarized. Biallelic pathogenic or likely pathogenic FDXR variants were identified in 11 unrelated patients, including 14 missense variants of which 10 were novel. Fundus observation showed complete optic disc pallor, silver wiring or severe attenuation of retinal vessels, and varying degrees of generalized retinal degeneration. Before the detection of FDXR variants, four patients were clinically diagnosed as congenital amaurosis due to the presence of nystagmus a few months after birth, while seven were diagnosed as early-onset severe retinal dystrophy due to the presence of nyctalopia and/or poor vision in early childhood. Biallelic FDXR variants are a frequent cause of congenital or early-onset severe retinal dystrophy, especially for patients with severe optic atrophy and retinal dystrophy in early childhood.

Heterozygous truncating variants of TOPORS have been reported to cause autosomal dominant retinitis pigmentosa (adRP). The purpose of this study was to investigate whether all heterozygous truncating variants, including copy number variants (CNVs), are pathogenic.TOPORS truncating variants were collected and reviewed through an in-house dataset and existing databases. Individuals with truncating variants underwent ophthalmological evaluation.Six truncating variants were detected in seven families. Three N-terminus truncating variants were detected in three families without RP, and the other three were identified in four unrelated families with typical RP. Based on the in-house dataset and published literature, 17 truncating variants were identified in 47 families with RP. All RP-associated truncating alleles, except one, were distributed in the last exon of TOPORS and clustered in amino acid residues 807 to 867 (46/47, 97.9%). Conversely, in the gnomAD database, only one truncating allele (1/27, 3.7%) was in this region, and the others were outside (26/27, 96.3%), suggesting that the pathogenic truncating variants were significantly clustered in residues 807 to 867 (χ2 = 65.6, P = 1.1 × 10-17). Additionally, three CNVs involving the N-terminus of TOPORS were recorded in control populations but were absent in affected patients.This study suggests that all pathogenic truncating variants of TOPORS were clustered in residues 807 to 867, whereas the truncating variants outside this region and the CNVs involving the N-terminus were not associated with RP. A dominant-negative effect, rather than haploinsufficiency, is speculated to be the underlying pathogenesis. These findings provide valuable information for interpreting variation in TOPORS and other genes in similar situations, especially for CNVs.

To elucidate genetic background of early-onset high myopia (eoHM) and characteristics ofVariants in 14 genes reported to contribute to eoHM, includingPathogenic and likely pathogenic variants in three of 14 genes were identified in 52 of 928 families with eoHM, including 29 inThis study reveals