Systematic assessment of the contribution of structural variants to inherited retinal diseases.

Despite increasing success in determining genetic diagnosis for patients with inherited retinal diseases (IRDs), mutations in about 30% of the IRD cases remain unclear or unsettled after targeted gene panel or whole exome sequencing. In this study, we aimed to investigate the contributions of structural variants (SVs) to settling the molecular diagnosis of IRD with whole-genome sequencing (WGS). A cohort of 755 IRD patients whose pathogenic mutations remain undefined were subjected to WGS. Four SV calling algorithms including include MANTA, DELLY, LUMPY and CNVnator were used to detect SVs throughout the genome. All SVs identified by any one of these four algorithms were included for further analysis. AnnotSV was used to annotate these SVs. SVs that overlap with known IRD-associated genes were examined with sequencing coverage, junction reads and discordant read pairs. Polymerase Chain Reaction (PCR) followed by Sanger sequencing was used to further confirm the SVs and identify the breakpoints. Segregation of the candidate pathogenic alleles with the disease was performed when possible. A total of 16 candidate pathogenic SVs were identified in 16 families, including deletions and inversions, representing 2.1% of patients with previously unsolved IRDs. Autosomal dominant, autosomal recessive and X-linked inheritance of disease-causing SVs were observed in 12 different genes. Among these, SVs in CLN3, EYS and PRPF31 were found in multiple families. Our study suggests that the contribution of SVs detected by short-read WGS is about 0.25% of our IRD patient cohort and is significantly lower than that of single nucleotide changes and small insertions and deletions.

Fabrication of Fe/KB Composite as Sulfur Host for Li-S Battery.

Lithium sulfur battery is a novel kind of secondary battery which has high energy density, however its application is greatly affected by the shuttle effect of polysulfides generated in the redox reaction of cathode electrode. Metal active sites are supposed as effective catalysts which can absorb and accelerate the conversion efficiency of lithium polysulfides, thus the shuttle effect will be alleviated. In this work, we conducted a simple way to prepare a metal Fe doped ketjen black to serve as the sulfur host of lithium sulfur battery. Ketjen black has a large specific surface area and rich porous structure, while Fe nanodot is an excellent catalyst for lithium polysulfides. Because of these advantages, the Fe/KB host can effectively confine a large amount of active material and accelerate its, therefore the Fe/KB-S cathode electrode show an excellent electrochemical performance.

A Ni-MOF derived graphene oxide combined Ni3S2-Ni/C composite and its use in the separator coating for lithium sulfur batteries.

Lithium-sulfur batteries (LSBs) are widely regarded as reliable novel secondary batteries due to their low price and high capacity. Nevertheless, the notorious "shuttle effect" limits the commercialization of LSBs. In order to solve this problem, we fabricated a Ni3S2-Ni/C composite through carbonization, vulcanization and hydrothermal reactions by using a Ni-MOF precursor and applied it as a separator modification layer to enhance the electrochemical properties of LSBs. To further increase the conductivity of the material, a small amount of GO was added during the experiment. The prepared material was also used as separator modified coating material to optimize the electrochemical performance of LSBs. The as prepared Ni3S2-Ni/C(GO) composite shows good conductivity and has a superior porous structure and abundant active sites. Lithium polysulfides (LPs) can be physically confined and chemically adsorbed, what is more, the Ni and Ni3S2 active sites enable fast conversion of LPs which further optimizes the rate performance. From the cycle performance measurement, the initial discharge specific capacity of the Ni3S2-Ni/C(GO) modified separator battery is found to be 1263.4, 1181.5, 1090.6, and 840.3 mA h g-1 at 0.05, 0.1, 0.3 and 0.5C, respectively. After 400 charge/discharge cycles at 0.5C, the capacity remains at 483.6mA h g-1 with a capacity retention ratio of 57.56%.

The Role of Ceramide in Inherited Retinal Disease Pathology.

Ceramide (Cer) plays an essential role in photoreceptor cell death in the retina. On the one hand, Cer accumulation emerges as a common feature during retina neurodegeneration, leading to the death of photoreceptors. On the other hand, Cer deficiency has also recently been associated with retinal dysfunction and degeneration. Although more and more evidence supports the importance of maintaining Cer homeostasis in the retina, mechanistic explanations of the observed phenotypes, especially in the context of Cer deficiency, are still lacking. An enhanced understanding of Cer's role in the retina will help us explore the underlying molecular basis for clinical phenotypes of retinal dystrophies and provide us with potential therapeutic targets.

Ceramide synthase TLCD3B is a novel gene associated with human recessive retinal dystrophy.

PURPOSE: Previous studies suggest that ceramide is a proapoptotic lipid as high levels of ceramides can lead to apoptosis of neuronal cells, including photoreceptors. However, no pathogenic variant in ceramide synthases has been identified in human patients and knockout of various ceramide synthases in mice has not led to photoreceptor degeneration. METHODS: Exome sequencing was used to identify candidate disease genes in patients with vision loss as confirmed by standard evaluation methods, including electroretinography (ERG) and optical coherence tomography. The vision loss phenotype in mice was evaluated by ERG and histological analyses. RESULTS: Here we have identified four patients with cone-rod dystrophy or maculopathy from three families carrying pathogenic variants in TLCD3B. Consistent with the phenotype observed in patients, the Tlcd3bKO/KO mice exhibited a significant reduction of the cone photoreceptor light responses, thinning of the outer nuclear layer, and loss of cone photoreceptors across the retina. CONCLUSION: Our results provide a link between loss-of-function variants in a ceramide synthase gene and human retinal dystrophy. Establishment of the Tlcd3b knockout murine model, an in vivo photoreceptor cell degeneration model due to loss of a ceramide synthase, will provide a unique opportunity in probing the role of ceramide in survival and function of photoreceptor cells.

Noncoding mutation in RPGRIP1 contributes to inherited retinal degenerations.

Purpose: Despite the extensive use of next-generation sequencing (NGS) technology to identify disease-causing genomic variations, a major gap in our understanding of Mendelian diseases is the unidentified molecular lesion in a significant portion of patients. For inherited retinal degenerations (IRDs), although currently close to 300 disease-associated genes have been identified, the mutations in approximately one-third of patients remain unknown. With mounting evidence that noncoding mutations might contribute significantly to disease burden, we aimed to systematically investigate the contributions of noncoding regions in the genome to IRDs. Methods: In this study, we focused on RPGRIP1, which has been linked to various IRD phenotypes, including Leber congenital amaurosis (LCA), retinitis pigmentosa (RP), and macular dystrophy (MD). As several noncoding mutant alleles have been reported in RPGRIP1, and we observed that the mutation carrier frequency of RPGRIP1 is higher in patient cohorts with unsolved IRDs, we hypothesized that mutations in the noncoding regions of RPGRIP1 might be a significant contributor to pathogenicity. To test this hypothesis, we performed whole-genome sequencing (WGS) for 25 patients with unassigned IRD who carry a single mutation in RPGRIP1. Results: Three noncoding variants in RPGRIP1, including a 2,890 bp deletion and two deep-intronic variants (c.2710+233G>A and c.1468-263G>C), were identified as putative second hits of RPGRIP1 in three patients with LCA. The mutant alleles were validated with direct sequencing or in vitro assays. Conclusions: The results highlight the significance of the contribution of noncoding pathogenic variants to unsolved IRD cases.

The long non-coding RNA HLNC1 potentiates hepatocellular carcinoma progression via interaction with USP49.

BACKGROUND: The hepatocellular carcinoma (HCC) represents a serious malignancy worldwide especially in China. Our transcriptome analysis identifies a novel long non-coding RNA (lncRNA) termed HLNC1. However, the function of HLNC1 in HCC remains to be determined. METHODS: Novel lncRNAs were screened using lncRNA profiling. Relative expression was quantified by qRT-PCR. In vitro experiments such as migration and viability assays were performed. In vivo implantation experiments were conducted to investigate tumorigenic functions. RNA-RNA interaction assay was performed to determine USP49 as HLNC1 binding partner. RESULTS: We found that HLNC1 was markedly upregulated in HCC samples and cell lines. HLNC1 could promote viability and migration of HCC cells. Meanwhile, we could also observe an oncogenic effect of HLNC1 in vivo. By RNA-RNA interaction assay, we unraveled USP49 transcript as the HLNC1 binding partner. HLNC1-USP49 interaction dramatically destabilized USP49. Heat-shock factor 1 (HSF1) was shown to directly induce HLNC1 expression. The therapeutic potential of targeting HLNC1 was investigated using antisense oligonucleotides (ASOs). The ASO construct which significantly depleted HLNC1 expression could strongly attenuate xenograft tumor growth. CONCLUSIONS: Our data suggested that HLNC1 may advance HCC progression and act as a potential target for intervention.

Effect of Nickel Coated Multi-Walled Carbon Nanotubes on Electrochemical Performance of Lithium-Sulfur Rechargeable Batteries.

Conventional lithium-sulfur batteries suffer from severe capacity fade, which is induced by low electron conductivity and high dissolution of intermediated polysulfides. Recent studies have shown the metal (Pt, Au, Ni) as electrocatalyst of lithium polysulfides and improved the performance for lithium sulfur batteries. In this work, we present the nickel coated multi-walled carbon nanotubes (Ni-MWNTs) as additive materials for elemental sulfur positive electrodes for lithium-sulfur rechargeable batteries. Compared with MWNTs, the obtained Ni-MWNTs/sulfur composite cathode demonstrate a reversible specific capacity approaching 545 mAh after 200 cycles at a rate of 0.5C as well as improved cycling stability and excellent rate capacity. The improved electrochemical performance can be attributed to the fact the MWNTs shows a vital role on polysulfides adsorption and nickel has a catalytic effect on the redox reactions during charge­discharge process. Meanwhile, the Ni-MWNTs is a good electric conductor for sulfur cathode.

Mannan-Decorated Lipid Calcium Phosphate Nanoparticle Vaccine Increased the Antitumor Immune Response by Modulating the Tumor Microenvironment.

With the rapid development of tumor immunotherapy, nanoparticle vaccines have attracted much attention as potential therapeutic strategies. A systematic review and analysis must be carried out to investigate the effect of mannose modification on the immune response to nanoparticles in regulating the tumor microenvironment, as well as to explore its potential clinical application in tumor therapy. Despite the potential advantages of nanoparticle vaccines in immunotherapy, achieving an effective immune response in the tumor microenvironment remains a challenge. Tumor immune escape and the overexpression of immunosuppressive factors limit its clinical application. Therefore, our review explored how to intervene in the immunosuppressive mechanism in the tumor microenvironment through the use of mannan-decorated lipid calcium phosphate nanoparticle vaccines to improve the efficacy of immunotherapy in patients with tumors and to provide new ideas and strategies for the field of tumor therapy.

A Cellulose-Based Dual-Crosslinked Framework with Sensitive Shape and Color Changes in Acid/Alkaline Vapors.

Cellulose detectors, as green sensors, are some of the defensive mechanisms of plants which combat environmental stresses. However, extracted cellulose struggles to fulfil these functionalities due to its rigid physical/chemical properties. In this study, a novel cellulose dual-crosslinked framework (CDCF) is proposed. This comprises a denser temporary physical crosslinking bond (hydrogen bonding) and a looser covalent crosslinking bond (N,N-methylenebisacrylamide), which create deformable spaces between the two crosslinking sites. Abundant pH-sensitive carboxyl groups and ultralight, highly porous structures make CDCF response very sensitive in acid/alkaline vapor environments. Hence, a significant shrinkage of CDCF was observed following exposure to vapors. Moreover, a curcumin-incorporated CDCF exhibited dual shape and color changes when exposed to acid/alkaline vapors, demonstrating great potential for the multi-detection of acid/alkaline vapors.

Influence of Nd-MOF/CNF-derived Nd2O3-C/CNF composite on lithium-sulfur batteries.

The shuttle effect of soluble lithium polysulfide (LiPS) is a major obstacle to the practical application of lithium-sulfur (Li-S) batteries. In order to reduce the negative impact of the shuttle effect, Nd-MOF was combined with carbon nanofibers (CNFs) so that Nd-MOF was embedded in the CNFs and the Nd2O3-C/CNF composite was realized as a separation modification material. This embedded structure made the combination between Nd2O3-C and CNFs tighter, and it exhibited better synergistic effects to inhibit the shuttle effect of polysulfides while also enhancing the tensile strength of the separator and improving the safety performance of the battery. Based on these advantages, a lithium-sulfur coin cell with the Nd2O3-C/CNF-modified separator exhibited excellent electrochemical performance.

Enhancing the electrochemical properties of a lithium-sulfur battery using a modified separator with a phase-inversion layer.

The commercial application of lithium-sulfur (Li-S) batteries is limited by the inherent defects of poor conductivity of sulfur and the shuttling effect of polysulfides. To overcome these limitations, a modified layer comprising a porous network PVDF-PMMA skeleton and Ketjen black (KB) carbon nanoparticles was coated on the polyethylene (PE) separator using the phase inversion method. The PVDF-PMMA-KB (PPK) composite layer with a structure abundant in mesopores can effectively limit the shuttling effect of polysulfides via a physical barrier and adsorption. Moreover, the utilization of active substances substantially increased as the KB carbon nanoparticles could provide additional reaction sites for activating inactive polysulfides and depositing lithium sulfide. The electrochemical properties of the Li-S battery were considerably enhanced using the modified separator with a PPK layer, which was reflected in the higher rate capability and longer cycling life. The cell with a modified separator delivered a specific capacity of 723 mA h g-1 at 1 C, and the capacity retention reached 73.3% after 400 cycles with a low decay rate of 0.223% per cycle. This work provides a novel preparation method for a modified layer on the separator and promotes the large-scale application of Li-S batteries.

Lipid Nanoparticle (LNP) Delivery Carrier-Assisted Targeted Controlled Release mRNA Vaccines in Tumor Immunity.

In recent years, lipid nanoparticles (LNPs) have attracted extensive attention in tumor immunotherapy. Targeting immune cells in cancer therapy has become a strategy of great research interest. mRNA vaccines are a potential choice for tumor immunotherapy, due to their ability to directly encode antigen proteins and stimulate a strong immune response. However, the mode of delivery and lack of stability of mRNA are key issues limiting its application. LNPs are an excellent mRNA delivery carrier, and their structural stability and biocompatibility make them an effective means for delivering mRNA to specific targets. This study summarizes the research progress in LNP delivery carrier-assisted targeted controlled release mRNA vaccines in tumor immunity. The role of LNPs in improving mRNA stability, immunogenicity, and targeting is discussed. This review aims to systematically summarize the latest research progress in LNP delivery carrier-assisted targeted controlled release mRNA vaccines in tumor immunity to provide new ideas and strategies for tumor immunotherapy, as well as to provide more effective treatment plans for patients.

Preoperative prediction of hepatocellular carcinoma microvascular invasion based on magnetic resonance imaging feature extraction artificial neural network.

BACKGROUND: Hepatocellular carcinoma (HCC) recurrence is highly correlated with increased mortality. Microvascular invasion (MVI) is indicative of aggressive tumor biology in HCC. AIM: To construct an artificial neural network (ANN) capable of accurately predicting MVI presence in HCC using magnetic resonance imaging. METHODS: This study included 255 patients with HCC with tumors < 3 cm. Radiologists annotated the tumors on the T1-weighted plain MR images. Subsequently, a three-layer ANN was constructed using image features as inputs to predict MVI status in patients with HCC. Postoperative pathological examination is considered the gold standard for determining MVI. Receiver operating characteristic analysis was used to evaluate the effectiveness of the algorithm. RESULTS: Using the bagging strategy to vote for 50 classifier classification results, a prediction model yielded an area under the curve (AUC) of 0.79. Moreover, correlation analysis revealed that alpha-fetoprotein values and tumor volume were not significantly correlated with the occurrence of MVI, whereas tumor sphericity was significantly correlated with MVI (P < 0.01). CONCLUSION: Analysis of variable correlations regarding MVI in tumors with diameters < 3 cm should prioritize tumor sphericity. The ANN model demonstrated strong predictive MVI for patients with HCC (AUC = 0.79).

CircUBE3B High Expression Participates in Sevoflurane-Induced Human Hippocampal Neuron Injury via Targeting miR-326 and Regulating MYD88 Expression.

The clinical application of Sevoflurane (Sevo) brings about non-negligible neuron injury, leading to postoperative cognitive dysfunction (POCD). However, related pathogenesis is complex and not fully established. We aimed to disclose the role of circRNA UBE3B (circUBE3B) in neuron injury induced by Sevo. Cell viability and apoptosis were determined by CCK-8 and flow cytometry experiments. Inflammation production was monitored by ELISA. The expression of circUBE3B, miR-326, and myeloid differentiation factor 88 (MYD88) mRNA was assessed by quantitative real-time PCR (qPCR). Apoptosis-associated markers and MYD88 protein were quantified by western blot. The putative binding site between miR-326 and circUBE3B or MYD88 was verified by a dual-luciferase reporter experiment, and their binding was validated by a pull-down assay. Sevo treatment weakened cell viability and promoted cell apoptosis and inflammatory response. CircUBE3B expression was elevated in Sevo-treated neurons. Sevo-induced neuron injury was alleviated by circUBE3B downregulation but aggravated by circUBE3B overexpression. MiR-326 was targeted by circUBE3B, and miR-326 inhibition recovered neuron injury that was repressed by circUBE3B absence in Sevo-treated neurons. MiR-326 interacted with MYD88. MiR-326 enrichment attenuated Sevo-induced neuron injury, while these effects were reversed by MYD88 overexpression. CircUBE3B dysregulation was involved in Sevo-induced human hippocampal neuron injury via targeting the miR-326/MYD88 network.

Ceramide compensation by ceramide synthases preserves retinal function and structure in a retinal dystrophy mouse model.

Increasing evidence has supported the role of ceramide as a mediator of photoreceptor dysfunction or cell death in ceramide accumulation and deficiency contexts. TLCD3B, a non-canonical ceramide synthase, was previously identified in addition to the six canonical ceramide synthases (CerSs), and the Tlcd3b-/- mouse model exhibited both retinal dysfunction and degeneration. As previous canonical CerS-deficient mouse models failed to display retinal degeneration, the mechanisms of how TLCD3B interacts with CerSs have not been investigated. Additionally, as the ceramide profile of each CerS is distinct, it is unclear whether the overall level or the homeostasis of different ceramide species plays a critical role in photoreceptor degeneration. Interactions between TLCD3B with canonical CerSs expressed in the retina were examined by subretinally injecting recombinant adeno-associated virus 8 vectors containing the Cers2 (rAAV8-CerS2), Cers4 (rAAV8-CerS4) and Cers5 (rAAV8-CerS5) genes. Injection of all three rAAV8-CerS vectors restored retinal functions as indicated by improved electroretinogram responses, but only rAAV8-CerS5 successfully retained retinal morphology in Tlcd3b-/- mice. CerSs and TLCD3B played partially redundant roles. Additionally, rather than acting as an integral entity, different ceramide species had different impacts on retinal cells, suggesting that the maintenance of the overall ceramide profile is critical for retinal function.

Radiotherapy plus immune checkpoint inhibitor in prostate cancer.

The immune checkpoint inhibitor (ICI) is a promising strategy for treating cancer. However, the efficiency of ICI monotherapy is limited, which could be mainly attributed to the tumor microenvironment of the "cold" tumor. Prostate cancer, a type of "cold" cancer, is the most common cancer affecting men's health. Radiotherapy is regarded as one of the most effective prostate cancer treatments. In the era of immune therapy, the enhanced antigen presentation and immune cell infiltration caused by radiotherapy might boost the therapeutic efficacy of ICI. Here, the rationale of radiotherapy combined with ICI was reviewed. Also, the scheme of radiotherapy combined with immune checkpoint blockades was suggested as a potential option to improve the outcome of patients with prostate cancer.

Novel Pathogenic Mutations Identified from Whole-Genome Sequencing in Unsolved Cases of Patients Affected with Inherited Retinal Diseases.

Inherited retinal diseases (IRDs) are a diverse set of visual disorders that collectively represent a major cause of early-onset blindness. With the reduction in sequencing costs in recent years, whole-genome sequencing (WGS) is being used more frequently, particularly when targeted gene panels and whole-exome sequencing (WES) fail to detect pathogenic mutations in patients. In this study, we performed mutation screens using WGS for a cohort of 311 IRD patients whose mutations were undetermined. A total of nine putative pathogenic mutations in six IRD patients were identified, including six novel mutations. Among them, four were deep intronic mutations that affected mRNA splicing, while the other five affected protein-coding sequences. Our results suggested that the rate of resolution of unsolved cases via targeted gene panels and WES can be further enhanced with WGS; however, the overall improvement may be limited.

Systematic assessment of the contribution of structural variants to inherited retinal diseases.

Despite increasing success in determining genetic diagnosis for patients with inherited retinal diseases (IRDs), mutations in about 30% of the IRD cases remain unclear or unsettled after targeted gene panel or whole exome sequencing. In this study, we aimed to investigate the contributions of structural variants (SVs) to settling the molecular diagnosis of IRD with whole-genome sequencing (WGS). A cohort of 755 IRD patients whose pathogenic mutations remain undefined was subjected to WGS. Four SV calling algorithms including include MANTA, DELLY, LUMPY, and CNVnator were used to detect SVs throughout the genome. All SVs identified by any one of these four algorithms were included for further analysis. AnnotSV was used to annotate these SVs. SVs that overlap with known IRD-associated genes were examined with sequencing coverage, junction reads, and discordant read pairs. PCR followed by Sanger sequencing was used to further confirm the SVs and identify the breakpoints. Segregation of the candidate pathogenic alleles with the disease was performed when possible. In total, sixteen candidate pathogenic SVs were identified in sixteen families, including deletions and inversions, representing 2.1% of patients with previously unsolved IRDs. Autosomal dominant, autosomal recessive, and X-linked inheritance of disease-causing SVs were observed in 12 different genes. Among these, SVs in CLN3, EYS, PRPF31 were found in multiple families. Our study suggests that the contribution of SVs detected by short-read WGS is about 0.25% of our IRD patient cohort and is significantly lower than that of single nucleotide changes and small insertions and deletions.

Nano-Chemotherapy synergize with immune checkpoint inhibitor- A better option?

Immune checkpoint inhibitor (ICI) is one of the most important tumor treatment methods. Although the therapeutic efficiency of immune checkpoint inhibitor mono-therapy is limited, the combination of chemotherapy plus immune checkpoint inhibitors has shown great advantages in cancer treatment. This is mainly due to the fact that tumor reactive T cells could fully provide their anti-tumor function as chemotherapy could not only cause immunogenic cell death to increase antigen presentation, but also improve the immunosuppressive tumor micro-environment to synergize with immune checkpoint inhibitors. However, traditional chemotherapy still has shortcomings such as insufficient drug concentration in tumor region, short drug duration, drug resistance, major adverse events, etc, which might lead to the failure of the therapy. Nano chemotherapeutic drugs, which refer to chemotherapeutic drugs loaded in nano-based drug delivery system, could overcome the above shortcomings of traditional chemotherapeutic drugs to further improve the therapeutic effect of immune checkpoint inhibitors on tumors. Therefore, the scheme of nano chemotherapeutic drugs combined with immune checkpoint inhibitors might lead to improved outcome of cancer patients compared with the scheme of traditional chemotherapy combined with immune checkpoint inhibitors.