Joint effects of CD8A and ICOS in Long QT Syndrome (LQTS) and Beckwith-Wiedemann Syndrome (BWS).

BACKGROUND: Long QT Syndrome (LQTS) and Beckwith-Wiedemann Syndrome (BWS) are complex disorders with unclear origins, underscoring the need for in-depth molecular investigations into their mechanisms. The main aim of this study is to identify the shared key genes between LQTS and BWS, shedding light on potential common molecular pathways underlying these syndromes. METHODS: The LQTS and BWS datasets are available for download from the GEO database. Differential expression genes (DEGs) were identified. Weighted gene co-expression network analysis (WGCNA) was used to detect significant modules and central genes. Gene enrichment analysis was performed. CIBERSORT was used for immune cell infiltration analysis. The predictive protein interaction (PPI) network of core genes was constructed using STRING, and miRNAs regulating central genes were screened using TargetScan. RESULTS: Five hundred DEGs associated with Long QT Syndrome and Beckwith-Wiedemann Syndrome were identified. GSEA analysis revealed enrichment in pathways such as T cell receptor signaling, MAPK signaling, and adrenergic signaling in cardiac myocytes. Immune cell infiltration indicated higher levels of memory B cells and naive CD4 T cells. Four core genes (CD8A, ICOS, CTLA4, LCK) were identified, with CD8A and ICOS showing low expression in the syndromes and high expression in normal samples, suggesting potential inverse regulatory roles. CONCLUSION: The expression of CD8A and ICOS is low in long QT syndrome and Beckwith-Wiedemann syndrome, indicating their potential as key genes in the pathogenesis of these syndromes. The identification of shared key genes between LQTS and BWS provides insights into common molecular mechanisms underlying these disorders, potentially facilitating the development of targeted therapeutic strategies.

Ergothioneine Protects Against UV-Induced Oxidative Stress Through the PI3K/AKT/Nrf2 Signaling Pathway.

Background: Ergothioneine (EGT) is an antioxidant, which could be detected in human tissues, and human skin cells could utilize EGT and play an anti-oxidative role in keratinocytes. And in this study we are going to elucidate whether EGT could protect the skin from photoaging by Ultraviolet (UV) exposure in mice and its molecule pathway. Methods: Histological analysis was performed for evaluating the skin structure change. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were measured with biological assay for evaluating oxidative and antioxidative ability of skin exposed to UV light. And the level of marker molecules in mouse skin were detected by hydroxyproline (Hyp) assay, immunohistochemical analysis, Western blot, and quantitative real-time PCR (qRT-PCR). The markers of skin aging and cell death were tested by cell culture and treatment, Western blot and qRT-PCR. Results: EGT decreased the levels of inflammatory factors induced by UV exposure in mouse skin. MDA and SOD activity detection showed that EGT decreased MDA levels, increased SOD activity, and upregulated PI3K/Akt/Nrf2 signals in mouse skin exposed to UV, which further activated Nrf2 in the nucleus and enhanced the expression of Nrf2 target genes. In the cell model, we revealed that EGT could inhibit the increase in senescence-associated ß-galactosidase-positive cells and p16 and γ-H2A.X positive cells induced by etoposide and activate PI3K/Akt/Nrf2 signaling. Moreover, a PI3K inhibitor blocked EGT protection against etoposide-induced cell death. Conclusion: The study showed EGT may play an important protective role against cell damage or death through the PI3K/Akt/Nrf2 signaling pathway in skin.

Proteomic Landscape Associated with Cognitive Impairment in Individuals with Long-term Methamphetamine Dependence.

BACKGROUND: Methamphetamine (METH) is a highly addictive drug that directly affects the central nervous system. METH use not only harms the user's health but also poses risks and costs to society. Prolonged METH dependence has been shown to impair cognition, which may be the primary factor in impulsive drug-seeking behaviors and high relapse rates. However, the molecular mechanisms underlying METH addiction and METH-induced cognitive decline remain poorly understood. METHODS: To illuminate the potential molecular mechanisms underpinning METH addiction, we compared serum protein expression levels between 12 long-term METH users and 12 healthy controls using label-free quantitative proteomics. Bioinformatic analyses were conducted to determine functional networks and protein-protein interactions. RESULTS: In total, 23 differentially expressed proteins were identified between the two groups. The differentially expressed proteins were related to cognitive dysfunction, neuroinflammation, immune impairment, metabolic disturbances, and calcium binding and regulation. CONCLUSIONS: These 23 proteins may underpin the multi-system damage induced by chronic METH exposure. Our findings provide novel insights into the molecular basis of METH addiction and inform potential prevention and treatment strategies for individuals with METH dependence.

Peimenine unleashes therapeutic promise in urothelial bladder cancer: inhibition of proliferation, induction of cell death and modulation of key pathways.

Peimenine (PEI) is a steroid alkaloid substance isolated from Fritillaria thunbergii bulbs. It has various pharmacological activities, such as relief from coughs and asthma, expectorant properties, antibacterial effects, sedative qualities, and anti-inflammatory properties. Notably, PEI can effectively inhibit the proliferation and tumor formation of liver cancer and osteosarcoma cells by inducing autophagic cell death. However, the precise effect and mechanisms of PEI on urothelial bladder cancer (UBC) cells remain uncertain. Thus, this study aims to investigate the impact of PEI on UBC cells both in vivo and in vitro. The IC50 values of BIU-87 and EJ-1 cells after 48 h were 710.3 and 651.1 µg/mL, respectively. Additionally, PEI blocked the cell cycle in BIU-87 and EJ-1 cells during the G1 phase. Furthermore, it hindered the migration of BIU-87 and EJ-1 cells substantially. PEI significantly inhibited the tumor development of EJ-1 cells within the xenograft tumor model in vivo. Mechanically, PEI augmented the protein and mRNA expression of BIM, BAK1, and Cytochrome C (CYCS) in UBC cells. Taken together, PEI suppressed the proliferation of UBC cells both in vitro and in vivo by inducing cell death and cell cycle arrest, suggesting that PEI could be applied in the treatment of UBC.

High expression of CASP1 induces atherosclerosis.

Atherosclerosis is a chronic, progressive vascular disease. The relationship between CASP1 gene expression and atherosclerosis remains unclear. The atherosclerosis dataset GSE132651 and GSE202625 profiles were downloaded from gene expression omnibus. Differentially expressed genes (DEGs) were screened. The construction and analysis of protein-protein interaction network, functional enrichment analysis, gene set enrichment analysis, and Comparative Toxicogenomics Database analysis were performed. Gene expression heatmap was drawn. TargetScan was used to screen miRNAs that regulate central DEG. 47 DEGs were identified. According to gene ontology analysis, they were mainly enriched in the regulation of stimulus response, response to organic matter, extracellular region, extracellular region, and the same protein binding. Kyoto Encyclopedia of Gene and Genome analysis results showed that the target cells were mainly enriched in the PI3K-Akt signaling pathway, Ras signaling pathway, and PPAR signaling pathway. In the enrichment project of Metascape, vascular development, regulation of body fluid levels, and positive regulation of cell motility can be seen in the gene ontology enrichment project. Eleven core genes (CASP1, NLRP3, MRC1, IRS1, PPARG, APOE, IL13, FGF2, CCR2, ICAM1, HIF1A) were obtained. IRS1, PPARG, APOE, FGF2, CCR2, and HIF1A genes are identified as core genes. Gene expression heatmap showed that CASP1 was highly expressed in atherosclerosis samples and low expressed in normal samples. NLRP3, MRC1, IRS1, PPARG, APOE, IL13, FGF2, CCR2, ICAM1, HIF1A were low expressed in atherosclerosis samples. CTD analysis showed that 5 genes (CASP1, NLRP3, CCR2, ICAM1, HIF1A) were found to be associated with pneumonia, inflammation, cardiac enlargement, and tumor invasiveness. CASP1 gene is highly expressed in atherosclerosis. The higher the CASP1 gene, the worse the prognosis.

Inhibition of GBP5 activates autophagy to alleviate inflammatory response in LPS-induced lung injury in mice.

BACKGROUND: Pulmonary emphysema is a condition that causes damage to the lung tissue over time. GBP5, as part of the guanylate-binding protein family, is dysregulated in mouse pulmonary emphysema. However, the role of GBP5 in lung inflammation in ARDS remains unveiled. METHODS: To investigate whether GBP5 regulates lung inflammation and autophagy regulation, the study employed a mouse ARDS model and MLE-12 cell culture. Vector transfection was performed for the genetic manipulation of GBP5. Then, RT-qPCR, WB and IHC staining were conducted to assess its transcriptional and expression levels. Histological features of the lung tissue were observed through HE staining. Moreover, ELISA was conducted to evaluate the secretion of inflammatory cytokines, autophagy was assessed by immunofluorescent staining, and MPO activity was determined using a commercial kit. RESULTS: Our study revealed that GBP5 expression was altered in mouse ARDS and LPS-induced MLE-12 cell models. Moreover, the suppression of GBP5 reduced lung inflammation induced by LPS in mice. Conversely, overexpression of GBP5 diminished the inhibitory impact of LPS on ARDS during autophagy, leading to increased inflammation. In the cell line of MLE-12, GBP5 exacerbates LPS-induced inflammation by blocking autophagy. CONCLUSION: The study suggests that GBP5 facilitates lung inflammation and autophagy regulation. Thus, GBP5 could be a potential therapeutic approach for improving ARDS treatment outcomes, but further research is required to validate these findings.

Optimization of the fermentation process and antioxidant activity of mixed lactic acid bacteria for honeysuckle beverage.

The aim of the research was to obtain a high healthcare honeysuckle beverage with strong antioxidant activity. Honeysuckle (Lonicera japonica Thunb) was used as the raw material in this experiment. The effects of fermentation temperature, fermentation time, lactic acid bacteria inoculation amount, and sugar addition amount on the sensory quality of honeysuckle beverage were investigated by single factor test and orthogonal test, and the best process was obtained. The physicochemical indexes and antioxidant activity of honeysuckle beverages fermented with lactic acid bacteria were studied. The results showed that the fermentation temperature of the beverage was 37 °C, the fermentation time was 24 h, the inoculation amount of Lactiplantibacillus plantarum and Lactobacillus acidophilus mixed starter (1:1) was 3%, and 8% white granulated sugar was added. The highest sensory score was 87.30 ± 0.17, which was the optimal process. The honeysuckle liquid mixed inoculation with Lactiplantibacillus plantarum and Lactobacillus acidophilus was fermented for 24 h. The number of viable bacteria reached 9.84 ± 0.02 lg cfu/mL, the pH value was 3.10 ± 0.01, and the total polyphenol content was 7.53 ± 0.03 mg GAE/g. The number of lactic acid bacteria, pH, total polyphenol content, and free radical scavenging rate were significantly increased (p < 0.05) compared with the non-inoculated and single-inoculated lactic acid bacteria. To sum up, it was concluded that a better quality beverage could be obtained by fermenting a solution of honeysuckle with Lactiplantibacillus plantarum and Lactobacillus acidophilus mixed fermentation agent, providing a new approach and new ideas for the development of deep processing and fermented beverages using honeysuckle.

Primary Epithelioid Angiosarcoma of the Jejunal Mesentery Causing Abdominal Bleeding: Case Report and Literature Review.

Gastrointestinal angiosarcoma is an extremely rare malignant tumor of the digestive tract, characterized by a very poor prognosis, with few patients surviving more than 1 year after diagnosis. This case report describes a 71-year-old female patient with a 3-year history of intermittent abdominal pain and significant exacerbation of abdominal pain and bloating 2 weeks prior to treatment. After surgical treatment, the pathological and immunohistochemical diagnosis was primary epithelioid angiosarcoma of the jejunal mesentery. The patient refused postoperative adjuvant chemotherapy and died 4 months after diagnosis due to widespread systemic metastasis. In addition, this article reviews 38 previously reported cases of primary gastrointestinal angiosarcoma, aiming to further understand angiosarcoma and thus guide clinical practitioners in providing more comprehensive treatment approaches.

Intervertebral disc injury triggers neurogenic inflammation of adjacent healthy discs.

BACKGROUND CONTEXT: Intervertebral disc degeneration is common and may play an important role in low back pain, but it is not well-understood. Previous studies have shown that the outer layer of the annulus fibrosus of a healthy disc is innervated by nociceptive nerve fibers. In the process of disc degeneration, it can grow into the inner annulus fibrosus or nucleus pulposus and release neuropeptides. Disc degeneration is associated with inflammation that produces inflammatory factors and potentiates nociceptor sensitization. Subsequently neurogenic inflammation is induced by neuropeptide release from activated primary afferent terminals. Because the innervation of a lumbar disc comes from multi-segmental dorsal root ganglion neurons, does neurogenic inflammation in a degenerative disc initiate neurogenic inflammation in neighboring healthy discs by antidromic activity? PURPOSE: This study was based on animal experiments in Sprague-Dawley rats to investigate the role of neurogenic inflammation in adjacent healthy disc degeneration induced by disc injury. STUDY DESIGN: This was an experimental study. METHODS: Seventy-five 12-week-old, male Sprague-Dawley rats were allocated to 3 groups (sham group, disc injury group and disc injury+TrkA antagonist group). The disc injury group was punctured in the tail disc between the eighth and ninth coccygeal vertebrae (Co8-9) to establish an animal model of tail intervertebral disc degeneration. The sham group underwent only skin puncture and the disc injury+TrkA antagonist group was intraperitoneally injected with GW441756 two days before disc puncture. The outcome measure included quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: Disc injury induced an increase in aggrecan, NGF, TrkA, CGRP, SP, IL-1ß, and IL-6 mRNA levels in the injured (Co8-9) and adjacent discs (Co7-8), which reached a peak on day 1, then gradually decreased, and returned to normal on day 14. After intraperitoneal injection of GW441756 prior to puncture, the mRNA levels of the above indicators were down-regulated in Co7-8 and Co8-9 intervertebral discs on the 1st and 7th days. The protein content of the above indicators in Co7-8 and Co8-9 intervertebral discs showed roughly the same trend as mRNA levels. CONCLUSIONS: Degeneration of one disc can induce neurogenic inflammation of adjacent healthy discs in a rat model. CLINICAL SIGNIFICANCE: This model supports a key role of neurogenic inflammation in disc degeneration, and may play a role in the experience of low back pain.

Effects of second language acquisition on brain functional networks at different developmental stages.

Previous studies have shown that language acquisition influences both the structure and function of the brain. However, whether the acquisition of a second language at different periods of life alters functional network organization in different ways remains unclear. Here, functional magnetic resonance imaging data from 27 English-speaking monolingual controls and 52 Spanish-English bilingual individuals, including 22 early bilinguals who began learning a second language before the age of ten and 30 late bilinguals who started learning a second language at age fourteen or later, were collected from the OpenNeuro database. Topological metrics of resting-state functional networks, including small-world attributes, network efficiency, and rich- and diverse-club regions, that characterize functional integration and segregation of the networks were computed via a graph theoretical approach. The results showed obvious increases in network efficiency in early bilinguals and late bilinguals relative to the monolingual controls; for example, the global efficiency of late bilinguals and early bilinguals was improved relative to that of monolingual controls, and the local efficiency of early bilinguals occupied an intermediate position between that of late bilinguals and monolingual controls. Obvious increases in rich-club and diverse-club functional connectivity were observed in the bilinguals relative to the monolingual controls. Three network metrics were positively correlated with Spanish proficiency test scores. These findings demonstrated that early and late acquisition of a second language had different impacts on the functional networks of the brain.

Biomechanical Study of Porcine Osteoporotic Vertebral Compression Fracture Model Strengthened by Trajectory-Adjustable Bone Cement Filling Device.

OBJECTIVE: To establish a porcine osteoporotic vertebral compression fracture model and compare the impact of unilateral vertebroplasty using trajectory-adjustable bone cement filling device to traditional surgical tools on vertebral biomechanics. METHODS: Twenty-four fresh adult porcine vertebrae were used to establish an osteoporotic vertebral compression fracture model. The specimens were divided into 4 groups (A, B, C, and D), each consisting of 6 vertebrae. Group A served as the control group without vertebral augmentation (percutaneous vertebroplasty [PVP]). Patients in Group B underwent unilateral PVP using conventional surgical tools, while patients in Group C underwent bilateral PVP using the same tools. In Group D, patients underwent unilateral PVP with a trajectory-adjustable bone cement filling device. Postoperative X-ray examinations were performed to assess cement distribution and leakage. The compressive stiffness and strength of each spinal unit were evaluated using an electronic mechanical testing machine. RESULTS: In Groups B, C, and D, the percentages of total cement distribution area were 32.83 ± 3.64%, 45.73 ± 2.27%, and 47.43 ± 3.51%, respectively. The values were significantly greater in Groups C and D than in Group B (P < 0.05), but there was no significant difference between Groups C and D (P > 0.05). The stiffness after vertebral augmentation in Groups B, C, and D was 1.04 ± 0.23 kN/mm, 1.11 ± 0.16 KN/mm, and 1.15 ± 0.13 KN/mm, respectively, which were significantly greater than that in Group A (0.46 ± 0.06 kN/mm; P < 0.05). The ultimate compressive strengths in Groups B, C, and D were 2.53 ± 0.21 MPa, 4.09 ± 0.30 MPa, and 3.99 ± 0.29 MPa, respectively, all surpassing Group A's strength of 1.41 ± 0.31 MPa. Additionally, both Groups C and D demonstrated significantly greater ultimate compressive strengths than Group B did (P < 0.05). CONCLUSIONS: A trajectory-adjustable bone cement filling device was proven to be an effective approach for unilateral vertebroplasty, restoring the biomechanical properties of fractured vertebrae. Compared to traditional surgical tools, this approach is superior to unilateral puncture and yields outcomes comparable to those of bilateral puncture. Additionally, the device ensures a centrally symmetrical distribution pattern of bone cement, leading to improved morphology.

Bio-organic fertilizer facilitated phytoremediation of heavy metal(loid)s-contaminated saline soil by mediating the plant-soil-rhizomicrobiota interactions.

Bio-organic fertilizer (BOF) was effective to promote the phytoremediation efficiency of heavy metal(loid)s-contaminated saline soil (HCSS) by improving rhizosphere soil properties, especially microbiome. However, there existed unclear impacts of BOF on plant metabolome and plant-driven manipulation on rhizosphere soil microbiota in HCSS, which were pivotal contributors to stress defense of plants trapped in adverse conditions. Here, a pot experiment was conducted to explore the mechanisms of BOF in improving alfalfa (Medicago sativa)-performing phytoremediation of HCSS. BOF application significantly increased the biomass (150.87-401.58 %) to support the augments of accumulation regarding heavy metal(loid)s (87.50 %-410.54 %) and salts (38.27 %-271.04 %) in alfalfa. BOF promoted nutrients and aggregates stability but declined pH of rhizosphere soil, accompanied by the boosts of rhizomicrobiota including increased activity, reshaped community structure, enriched plant growth promoting rhizobacteria (Blastococcus, Modestobacter, Actinophytocola, Bacillus, and Streptomyces), strengthened mycorrhizal symbiosis (Leohumicola, Funneliformis, and unclassified_f_Ceratobasidiaceae), optimized co-occurrence networks, and beneficial shift of keystones. The conjoint analysis of plant metabolome and physiological indices confirmed that BOF reprogrammed the metabolic processes (synthesis, catabolism, and long-distance transport of amino acid, lipid, carbohydrate, phytohormone, stress-resistant secondary metabolites, etc) and physiological functions (energy supply, photosynthesis, plant immunity, nutrients assimilation, etc) that are associated intimately. The consortium of root metabolome, soil metabolome, and soil microbiome revealed that BOF facilitated the exudation of metabolites correlated with rhizomicrobiota (structure, biomarker, and keystone) and rhizosphere oxidative status, e.g., fatty acyls, phenols, coumarins, phenylpropanoids, highlighting the plant-driven regulation on rhizosphere soil microbes and environment. By compiling various results and omics data, it was concluded that BOF favored the adaptation and phytoremediation efficiency of alfalfa by mediating the plant-soil-rhizomicrobiota interactions. The results would deepen understanding of the mechanisms by which BOF improved phytoremediation of HCSS, and provide theoretical guidance to soil amelioration and BOF application.

Effects of biochar on the manganese enrichment and oxidation by a microalga Scenedesmus quadricauda in the aquatic environment.

Microalgae play a significant impact in the biogeochemical cycle of Mn(II) in the aquatic ecosystem. Meanwhile, the inflow of biochar into the water bodies is bound to impact the aquatic organisms. However, the influence of biochar on the manganese transformation in algae-rich water has not drawn much attention. Thus, we studied the effects of rice straw biochar on manganese enrichment and oxidation by a common type of algae in freshwater (Scenedesmus quadricauda). The results showed that Mn(II) was absorbed intracellularly and adsorbed extracellularly by active algal cells. A significant portion of enriched Mn(II) was oxidized to amorphous precipitates MnO2, MnOOH, and Mn2O3. Moreover, the extracellular bound Mn(II) content in the coexistent system of algae and biochar increased compared with the pure Scenedesmus quadricauda system. Nevertheless, the intracellular Mn content was continually lowered as the biochar dose rose from an initial 0.2 to 2.0 g·L-1, suggesting that Mn assimilation of the cell was suppressed. It was calculated that the total enrichment ability of Scenedesmus quadricauda in the algae-biochar coexistent system was 0.31- 15.32 mg Mn/g biomass, more than that in the pure algae system. More importantly, with biochar in the algae system, the amount of generated MnOx increased, and more Mn(II) was oxidized into highly-charged Mn(IV). This was probably because the biochar could relieve the stress of massive Mn(II) on algae and support the MnOx precipitates. In brief, moderate biochar promoted the Mn(II) accumulation by algal cells and its oxidation activity. This study offers deeper insight into the bioconversion of Mn(II) by algae and the potential impact of biochar application to the aquatic system.

Cortical microinfarcts potentiate recurrent ischemic injury through NLRP3-dependent trained immunity.

Microinfarcts are common among the elderly and patients with microinfarcts are more vulnerable to another stroke. However, the impact of microinfarcts on recurrent stroke has yet to be fully understood. The purpose of this study was to explore the negative effects of microinfarcts on recurrent stroke. To achieve this, two-photon laser was used to induce microinfarcts, while photothrombotic stroke was induced on the opposite side. The results showed that microinfarcts led to trained immunity in microglia, which worsened the pro-inflammatory response and ischemic injury in the secondary photothrombotic stroke. Additionally, the study clarified the role of NLRP3 in microglial nuclei, indicating that it interacts with the MLL1 complex through NACHT domain and increases H3K4 methylation, which suggests that NLRP3 is critical in the formation of innate immune memory caused by microinfarcts. Furthermore, the knockout of NLRP3 in microglia alleviated the trained immunity and reduced the harmful effects of microinfarcts on recurrent stroke. This study emphasizes the detrimental effect of trained immunity on recurrent stroke and highlights the critical role of NLRP3 in mediating the formation of this memory, which may offer a potential therapeutic target for mitigating recurrent strokes.

Visible-light Excited and Highly Photostable Organic Fluorophore with dual-state Emission.

Organic fluorophores with dual-state emission (DSE) are rare or difficult to observe because most of them display either aggregation-induced emission (AIE) or aggregation-caused quenching (ACQ). Amazing works have been accomplished, yet most of the DSE compounds were excited by UV light which limits their wide application in bioimaging. In this work, we achieved a visible-light excited DSE fluorophore and realized its imaging in SKOV-3 cells and zebrafish. The naphtho[2',3':4,5]imidazo[1,2-a]pyridine (NIP) core ensures its emission in dilute solution. Meanwhile, the twisted phenyl ring blocks fluorescence quenching induced by the π-π stacking and leads to the emission of the solid. The fluorescence intensity is steady even after 6 h of continuous intense sunlight. More importantly, photostability of NIP in cells is much better than commercial dye (mitochondrial green).

Mutation and clinical analysis of the CLCC1 gene in amyotrophic lateral sclerosis patients from Central South China.

INTRODUCTION: Recently, chloride channel CLIC-like 1 (CLCC1) was reported to be a novel ALS-related gene. We aimed to screen CLCC1 variants in our ALS cohort and further explore the genotype-phenotype correlation of CLCC1-related ALS. METHODS: We screened rare damaging variants in CLCC1 from our cohorts of 1005 ALS patients and 1224 healthy controls with whole-exome sequencing in Central South China. Fisher's exact test was conducted for association analysis at the entire gene level and single variant level. RESULTS: In total, four heterozygous missense variants in CLCC1 were identified from four unrelated sporadic ALS patients and predicted to be putative pathogenic by in silico tools and protein model prediction, accounting for 0.40% of all patients (4/1005). The four variants were c.A275C (p.Q92P), c.G1139A (p.R380K), c.C1244T (p.T415M), and c.G1328A (p.R443Q), respectively, which had not been reported in ALS patients previously. Three of four variants were located in exon 10. Patients harboring CLCC1 variants seemed to share a group of similar clinical features, including earlier age at onset, rapid progression, spinal onset, and vulnerable cognitive status. Statistically, we did not find CLCC1 to be associated with the risk of ALS at the entire gene level or single variant level. CONCLUSION: Our findings further expanded the genetic and clinical spectrum of CLCC1-related ALS and provided more genetic evidence for anion channel involvement in the pathogenesis of ALS, but further investigations are needed to verify our findings.

Three-dimensional chromatin landscapes in hepatocellular carcinoma associated with hepatitis B virus.

BACKGROUND: Three-dimensional (3D) chromatin architecture frequently altered in cancer. However, its changes during the pathogenesis of hepatocellular carcinoma (HCC) remained elusive. METHODS: Hi-C and RNA-seq were applied to study the 3D chromatin landscapes and gene expression of HCC and ANHT. Hi-C Pro was used to generate genome-wide raw interaction matrices, which were normalized via iterative correction (ICE). Moreover, the chromosomes were divided into different compartments according to the first principal component (E1). Furthermore, topologically associated domains (TADs) were visualized via WashU Epigenome Browser. Furthermore, differential expression analysis of ANHT and HCC was performed using the DESeq2 R package. Additionally, dysregulated genes associated with 3D genome architecture altered were confirmed using TCGA, qRT-PCR, immunohistochemistry (IHC), etc. RESULTS: First, the intrachromosomal interactions of chr1, chr2, chr5, and chr11 were significantly different, and the interchromosomal interactions of chr4-chr10, chr13-chr21, chr15-chr22, and chr16-chr19 are remarkably different between ANHT and HCC, which resulted in the up-regulation of TP53I3 and ZNF738 and the down-regulation of APOC3 and APOA5 in HCC. Second, 49 compartment regions on 18 chromosomes have significantly switched (A-B or B-A) during HCC tumorigenesis, contributing to up-regulation of RAP2A. Finally, a tumor-specific TAD boundary located on chr5: 6271000-6478000 and enhancer hijacking were identified in HCC tissues, potentially associated with the elevated expression of MED10, whose expression were associated with poor prognosis of HCC patients. CONCLUSION: This study demonstrates the crucial role of chromosomal structure variation in HCC oncogenesis and potential novel biomarkers of HCC, laying a foundation for cancer precision medicine development.

High-performance and functional fully bio-based polylactic acid/polypropylene carbonate blends by in situ multistep reaction-induced interfacial control.

Using a solvent-free radical grafting technique, glycidyl methacrylate (GMA) and maleic anhydride (MAH) were used as functionalized graft monomers, styrene (St) as a copolymer monomer, and grafted onto polylactic acid (PLA). A series of PLA-g-(GMA/MAH-co-St) graft copolymers were prepared by adjusting the GMA/MAH ratio. Subsequently, the prepared graft copolymers were used as a compatibilizer with PLA and polypropylene carbonate (PPC) for melt blending to prepare PLA/PPC/PLA-g-(GMA/MAH-co-St) blends. The effects of changes in the GMA/MAH ratio in the graft copolymer on the thermodynamics, rheology, optics, degradation performance, mechanical properties, and microstructure of the blend were studied. The results found that GMA, MAH, and St were successfully grafted onto PLA, and the PLA-g-(GMA/MAH-co-St) graft copolymer obtained from the reaction had a good toughening effect on the PLA/PPC blend system, which significantly improved the mechanical properties of the PLA/PPC/PLA-g-(GMA/MAH-co-St) blend without reducing its degradation performance, resulting in a biodegradable blend material with excellent comprehensive performance. In the PLA-g-(GMA/MAH-co-St) grafting reaction system, when GMA/MAH = 1.5/1.5 (w/w), the grafting degree of the graft copolymer increased most significantly, from 0.83 phr to 1.51 phr. This composition of graft copolymer can effectively improve the compatibility between PLA and PPC. The resulting PLA/PPC blend can maintain good melt flow properties (MFR of 14.51 g/10 min), high transparency, and low haze (light transmittance of 91.56 %, haze of 20.5 %), while significantly improving its thermal stability (T95%, Tmax, and Et increased by 12.87 °C, 20.33 °C, and 32.00 kJ/mol, respectively). Moreover, when introducing PLA-g-(GMA/MAH-co-St) (GMA/MAH = 1.5/1.5 (wt/wt)) graft copolymer into the system, the toughness of the PLA/PPC/PLA-g-(GMA/MAH-co-St) blend system is optimal, with the notch impact strength and fracture elongation increasing to 184.6 % and 535.4 % of the PLA/PPC blend, respectively, at which point the fracture surface of the impact sample shows a wrinkled fracture feature indicative of toughness.

Improving the properties of polylactic acid/polypropylene carbonate blends through cardanol-induced compatibility enhancement.

Cardanol (CD) is used as a reactive compatibilizer, and blended with polylactic acid (PLA) and polypropylene carbonate (PPC) resin (70/30(w/w)) to obtain a series of PLA/PPC/CD blends. The systematic study was conducted on the thermal properties, optical properties, rheological properties, mechanical properties, and microscopic morphology of the blend, by varying amounts of CD added to the blends. A detailed explanation and comprehensive analysis of the reaction mechanism between CD and PLA/PPC have been made. The study found that CD acts as a "bridge" between the PLA and PPC, forming the structure of a block copolymer (PLA-b-CD-b-PPC), and the copolymer can greatly improve the compatibility of PLA and PPC. When the amount of CD reaches 8 wt%, only one Tg is observed in the blend, simultaneously, PLA/PPC has already transitioned from a partially compatible system to a completely compatible system. At the same time, the addition of CD does not have any negative impact on the thermal stability of the PLA/PPC blend under processing temperature conditions, and the thermal stability of the PLA/PPC/CD blends can even be improved under extreme conditions. In addition, the addition of CD allows the PLA/PPC/CD blends to maintain a high light transmittance while reducing the opacity of the blend (the light transmittance remains above 92 %, and the opacity is reduced from 37 % to about 24 %), demonstrating excellent optical properties. Moreover, the elongation at break and impact strength of the PLA/PPC/CD blend both show a trend of first increasing and then decreasing with the increase of CD amount. When the CD amount varies within the range of 6- 8 wt%, the blends undergoes a brittle-ductile transition, and its toughness is greatly improved while the rigidity can also meet practical needs. When the amount of CD in the system increases to 12 wt%, the toughness of the blend reaches its peak, and its elongation at break and impact strength reach 513.24 % and 9211.5 J/m2 respectively (increased to 2442.84 % and 270.73 % of the PLA/PPC blend). Concurrently, the fracture surface of the blend exhibits large-scale plastic flow in the direction of the applied force, with marked shear yield phenomena, showing obvious characteristics of tough fracture.