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.

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.

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.

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.

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 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.

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.

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%.

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.

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.

Characteristics of Adenosine-to-Inosine RNA editing-based subtypes and novel risk score for the prognosis and drug sensitivity in stomach adenocarcinoma.

Stomach adenocarcinoma (STAD) is always characterized by high mortality and poor prognosis with drug resistance and recrudescence due to individual genetic heterogeneity. Adenosine-to-Inosine RNA editing (ATIRE) has been reported associated with multiple tumors but the potential connection between ATIRE-related signatures and STAD remains unclear. In this study, we comprehensively elevated the genetic characteristics of ATIRE in STAD patients and first screened five vital survival-related ATIRE sites to identify a novel ATIRE-Risk score. Based on the risk scores, we further divided the patients into two different subtypes with diverse clinical characteristics and immune landscapes including immune cell infiltration (ICI), tumor microenvironment (TME), and immune checkpoint expression analysis. The low-risk subgroups, associated with better survival prognosis, were characterized by activated immune-cells, higher immune scores in TME, and down-expression of immunotherapy checkpoints. Moreover, different expressional genes (DEGs) between the above subtypes were further identified and the activation of immune-related pathways were found in low-risk patients. The stratified survival analysis further indicated patients with low-risk and high-tumor mutation burden (TMB) exhibited the best prognosis outcomes, implying the role of TMB and ATIRE-Risk scores was synergistic for the prognosis of STAD. Interestingly, anti-tumor chemotherapeutic drugs all exhibited lower IC50 values in low-risk subgroups, suggesting these patients might obtain a better curative response from the combined chemotherapy of STAD. Finally, combined with classical clinical features and ATIRE-Risk scores, we successfully established a promising nomogram system to accurately predict the 1/3/5-years survival ratio of STAD and this model was also estimated with high diagnostic efficiency and stable C-index with calibration curves. These significant ATIRE sites are promising to be further explored and might serve as a novel therapeutic target for STAD treatment.

Trans-arterial positive ICG staining-guided laparoscopic liver watershed resection for hepatocellular carcinoma.

Introduction: Anatomical liver resection is the optimal treatment for patients with resectable hepatocellular carcinoma (HCC). Laparoscopic Couinaud liver segment resection could be performed easily as liver segments could be stained by ultrasound-guided indocyanine green (ICG) injection into the corresponding segment portal vein. Several smaller liver anatomical units (liver watersheds) have been identified (such as S8v, S8d, S4a, and S4b). However, since portal veins of liver watersheds are too thin to be identified under ultrasound, the boundaries of these liver watersheds could not be stained intraoperatively, making laparoscopic resection of these liver watersheds demanding. Digital subtraction angiography (DSA) could identify arteries of liver watersheds with a diameter of less than 2 mm. Yet, its usage for liver watershed staining has not been explored so far. Purpose: The aim of this study is to explore the possibility of positive liver watershed staining via trans-arterial ICG injection under DSA examination for navigating laparoscopic watershed-oriented hepatic resection. Methods: We describe, in a step-by-step approach, the application of trans-arterial ICG injection to stain aimed liver watershed during laparoscopic anatomical hepatectomy. The efficiency and safety of the technique are illustrated and discussed in comparison with the laparoscopic anatomical liver resection via ultrasound-guided liver segment staining. Results: Eight of 10 HCC patients received successful trans-arterial liver watershed staining. The success rate of the trans-artery staining approach was 80%, higher than that of the ultrasound-guided portal vein staining approach (60%). Longer surgical duration was found in patients who underwent the trans-artery staining approach (305.3 ± 23.2 min vs. 268.4 ± 34.7 min in patients who underwent the ultrasound-guided portal vein staining approach, p = 0.004). No significant difference was found in major morbidity, reoperation rate, hospital stay duration, and 30-day and 90-day mortality between the 2 groups. Conclusions: Trans-arterial ICG staining is safe and feasible for staining the aimed liver watershed, navigating watershed-oriented hepatic resection under fluorescence laparoscopy for surgeons.

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.

Advances in the pharmacological treatment of hepatic alveolar echinococcosis: From laboratory to clinic.

Hepatic alveolar echinococcosis (HAE) is a zoonotic parasitic disease caused by the larvae of Echinococcus multilocularis. Because of its characteristics of diffuse infiltration and growth similar to tumors, the disability rate and mortality rate are high among patients. Although surgery (including hepatectomy, liver transplantation, and autologous liver transplantation) is the first choice for the treatment of hepatic alveolar echinococcosis in clinic, drug treatment still plays an important and irreplaceable role in patients with end-stage echinococcosis, including patients with multiple organ metastasis, patients with inferior vena cava invasion, or patients with surgical contraindications, etc. However, Albendazole is the only recommended clinical drug which could exhibit a parasitostatic rather than a parasitocidal effect. Novel drugs are needed but few investment was made in the field because the rarity of the cases. Drug repurposing might be a solution. In this review, FDA-approved drugs that have a potential curative effect on hepatic alveolar echinococcosis in animal models are summarized. Further, nano drug delivery systems boosting the therapeutic effect on hepatic alveolar echinococcosis are also reviewed. Taken together, these might contribute to the development of novel strategy for advanced hepatic alveolar echinococcosis.

Spata7 is required for maintenance of the retinal connecting cilium.

SPATA7, an early onset LCA3 retinal disease gene, encodes a putative scaffold protein that is essential for the proper assembly of the connecting cilium (CC) complex in photoreceptors. Previous studies have shown that SPATA7 interacts with other photoreceptor-specific ciliary proteins, such as RPGR and RPGRIP1, and maintains the integrity of CC integrity. However, although it is known that Spata7 is required for early formation of the CC, it is unclear if Spata7 is also required for the maintenance of the CC. To investigate Spata7 function in the retina at the adult stage, loss of function was induced in the adult retina upon tamoxifen induction of an inducible Spata7 knockout allele (Spata7flox/-; UbcCreERT2/+). The phenotype of mutant retina was characterized by a combination of histology, immunobiochemistry, and electroretinography (ERG). Our results demonstrated that Spata7 is also essential for maintaining the integrity of the mature retinal CC. Loss of Spata7 in adults caused phenotypes similar to those seen in germline mutant mice, including photoreceptor cell degeneration and defective ERG responses. Close examination of the CC revealed significantly shortened NPHP1 length as a result of Spata7 deletion. Furthermore, mislocalization of rhodopsin, leading to ER stress-mediated apoptosis, was observed in the retinal layers. Our results indicate that Spata7 is required not only for the establishment but also for the maintenance of the CC of photoreceptors.