Hepatic SEL1L-HRD1 ER-associated degradation regulates systemic iron homeostasis via ceruloplasmin.

Iron homeostasis is critical for cellular and organismal function and is tightly regulated to prevent toxicity or anemia due to iron excess or deficiency, respectively. However, subcellular regulatory mechanisms of iron remain largely unexplored. Here, we report that SEL1L-HRD1 protein complex of endoplasmic reticulum (ER)-associated degradation (ERAD) in hepatocytes controls systemic iron homeostasis in a ceruloplasmin (CP)-dependent, and ER stress-independent, manner. Mice with hepatocyte-specific Sel1L deficiency exhibit altered basal iron homeostasis and are sensitized to iron deficiency while resistant to iron overload. Proteomics screening for a factor linking ERAD deficiency to altered iron homeostasis identifies CP, a key ferroxidase involved in systemic iron distribution by catalyzing iron oxidation and efflux from tissues. Indeed, CP is highly unstable and a bona fide substrate of SEL1L-HRD1 ERAD. In the absence of ERAD, CP protein accumulates in the ER and is shunted to refolding, leading to elevated secretion. Providing clinical relevance of these findings, SEL1L-HRD1 ERAD is responsible for the degradation of a subset of disease-causing CP mutants, thereby attenuating their pathogenicity. Together, this study uncovers the role of SEL1L-HRD1 ERAD in systemic iron homeostasis and provides insights into protein misfolding-associated proteotoxicity.

Decoupled Cross-Modal Transformer for Referring Video Object Segmentation.

Referring video object segmentation (R-VOS) is a fundamental vision-language task which aims to segment the target referred by language expression in all video frames. Existing query-based R-VOS methods have conducted in-depth exploration of the interaction and alignment between visual and linguistic features but fail to transfer the information of the two modalities to the query vector with balanced intensities. Furthermore, most of the traditional approaches suffer from severe information loss in the process of multi-scale feature fusion, resulting in inaccurate segmentation. In this paper, we propose DCT, an end-to-end decoupled cross-modal transformer for referring video object segmentation, to better utilize multi-modal and multi-scale information. Specifically, we first design a Language-Guided Visual Enhancement Module (LGVE) to transmit discriminative linguistic information to visual features of all levels, performing an initial filtering of irrelevant background regions. Then, we propose a decoupled transformer decoder, using a set of object queries to gather entity-related information from both visual and linguistic features independently, mitigating the attention bias caused by feature size differences. Finally, the Cross-layer Feature Pyramid Network (CFPN) is introduced to preserve more visual details by establishing direct cross-layer communication. Extensive experiments have been carried out on A2D-Sentences, JHMDB-Sentences and Ref-Youtube-VOS. The results show that DCT achieves competitive segmentation accuracy compared with the state-of-the-art methods.

Clinical study of recurrent mild encephalitis/encephalopathy with a reversible splenial lesion in two cases.

BACKGROUND: Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) has been reported worldwidely. However, the data about recurrent cases is limited. We aimed to analyze the clinical and radiographic features of recurrent MERS, and its possible mechanisms. CASE PRESENTATION: Two patients with clinically recurrent MERS were reported here, exhibiting neurological symptoms such as limbs weakness and numbness, stand/walk unsteadily, slurred speech and irritability, and typical lesions in the corpus callosum and white matter. One of them experienced another four episodes with a similar clinical course and magnetic resonance imaging findings over a period of 10 years. The Na levels in the present two patients were normal. DISCUSSION AND CONCLUSION: Combined with the patients reported previously, recurrence could be seen in both MERS type 1 and type 2 patients, from two to multiple times, with the latter possibly more common. It suggested that some genetic factors might be involved in MERS, especially for MERS type 2 or familial MERS.

Identification of pathogenic genes and transcription factors in respiratory syncytial virus.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory infections in children, especially bronchiolitis. Our study aimed to identify the key genes and upstream transcription factors in RSV. METHODS: To screen for RSV pathogenic genes, an integrated analysis was performed using the RSV microarray dataset in GEO. Functional annotation and potential pathways for differentially expressed genes (DEGs) were further explored by GO and KEGG enrichment analysis. We constructed the RSV-specific transcriptional regulatory network to identify key transcription factors for DEGs in RSV. RESULTS: From three GEO datasets, we identified 1059 DEGs (493 up-regulated and 566 down-regulated genes, FDR < 0.05 and |Combined.ES| > 0.8) between RSV patients and normal controls. GO and KEGG analysis revealed that 'response to virus' (FDR = 7.13E-15), 'mitochondrion' (FDR = 1.39E-14) and 'Asthma' (FDR = 1.28E-06) were significantly enriched pathways for DEGs. The expression of IFI27, IFI44, IFITM3, FCER1A, and ISG15 were shown to be involved in the pathogenesis of RSV. CONCLUSIONS: We concluded that IFI27, IFI44, IFITM3, FCER1A, and ISG15 may play a role in RSV. Our finding may contribute to the development of new potential biomarkers, reveal the underlying pathogenesis and also identify novel therapeutic targets for RSV.

[Identification of a novel mutation of MBD5 gene in a pedigree affected with autosomal dominant mental retardation type 1].

OBJECTIVE: To explore the genetic basis for a child with mental and motor retardation, language impairment, facial dysmorphism and epilepsy. METHODS: Whole exome sequencing was carried out to detect pathogenic variant in the proband, and candidate variant was selected based on his phenotype. Sanger sequencing was used to verify the variant in the proband, his parents and other family members. RESULTS: The proband was found to carry a frameshifting mutation of MBD5 gene, namely c.2217delT (p.F739Lfs*6), which was inherited from his mother and unreported previously. Sanger sequencing confirmed that his brother carried the same mutation with a similar phenotype. His mother also had poor language expression when she was young, in addition with poor academic performance, though she could do some housework and had no history of convulsion. CONCLUSION: A novel pathogenic variant of the MBD5 gene was discovered, which has enriched the mutational spectrum of the MBD5 gene. Above discovery has enabled genetic counseling and prenatal diagnosis for the family.

Regulation of hepatic autophagy by stress-sensing transcription factor CREBH.

Autophagy, a lysosomal degradative pathway in response to nutrient limitation, plays an important regulatory role in lipid homeostasis upon energy demands. Here, we demonstrated that the endoplasmic reticulum-tethered, stress-sensing transcription factor cAMP-responsive element-binding protein, hepatic-specific (CREBH) functions as a major transcriptional regulator of hepatic autophagy and lysosomal biogenesis in response to nutritional or circadian signals. CREBH deficiency led to decreased hepatic autophagic activities and increased hepatic lipid accumulation upon starvation. Under unfed or during energy-demanding phases of the circadian cycle, CREBH is activated to drive expression of the genes encoding the key enzymes or regulators in autophagosome formation or autophagic process, including microtubule-associated protein 1B-light chain 3, autophagy-related protein (ATG)7, ATG2b, and autophagosome formation Unc-51 like kinase 1, and the genes encoding functions in lysosomal biogenesis and homeostasis. Upon nutrient starvation, CREBH regulates and interacts with peroxisome proliferator-activated receptor α (PPARα) and PPARγ coactivator 1α to synergistically drive expression of the key autophagy genes and transcription factor EB, a master regulator of lysosomal biogenesis. Furthermore, CREBH regulates rhythmic expression of the key autophagy genes in the liver in a circadian-dependent manner. In summary, we identified CREBH as a key transcriptional regulator of hepatic autophagy and lysosomal biogenesis for the purpose of maintaining hepatic lipid homeostasis under nutritional stress or circadian oscillation.-Kim, H., Williams, D., Qiu, Y., Song, Z., Yang, Z., Kimler, V., Goldberg, A., Zhang, R., Yang, Z., Chen, X., Wang, L., Fang, D., Lin, J. D., Zhang, K. Regulation of hepatic autophagy by stress-sensing transcription factor CREBH.

A high fat diet with a high C18:0/C16:0 ratio induced worse metabolic and transcriptomic profiles in C57BL/6 mice.

BACKGROUND: Differential effects of individual saturated fatty acids (SFAs), particularly stearic acid (C18:0), relative to the shorter-chain SFAs have drawn interest for more accurate nutritional guidelines. However, specific biologic and pathologic functions that can be assigned to particular SFAs are very limited. The present study was designed to compare changes in metabolic and transcriptomic profiles in mice caused by a high C18:0 diet and high palmitic acid (C16:0) diet. METHODS: Male C57BL/6 mice were assigned to a normal fat diet (NFD), a high fat diet with high C18:0/C16:0 ratio (HSF) or an isocaloric high fat diet with a low C18:0/C16:0 ratio (LSF) for 10 weeks. An oral glucose tolerance test, 72-h energy expenditure measurement and CT scan of body fat were done before sacrifice. Fasting glucose and lipids were determined by an autobiochemical analyzer. Blood insulin, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels were measured by enzyme-linked immunosorbent assay methods. Free fatty acids (FFAs) profiles in blood and liver were determined by using gas chromatography-mass spectrometry. Microarray analysis was applied to investigate changes in transcriptomic profiles in the liver. Pathway analysis and gene ontology analysis were applied to describe the roles of differentially expressed mRNAs. RESULTS: Compared with the NFD group, body weight, body fat ratio, fasting blood glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride, IL-6, serum and liver FFAs including total FFAs, C16:0 and C18:0 were increased in both high fat diet groups and were much higher in the HSF group than those in the LSF group. Both HSF and LSF mice exhibited distinguishable long non-coding RNA (lncRNA), microRNA and mRNA expression profiles when compared with those of NFD mice. Additionally, more differentially expressed lncRNAs and mRNAs were observed in the HSF group than in the LSF group. Some biological functions and pathways, other than energy metabolism regulation, were identified as differentially expressed mRNAs between the HSF group and the LSF group. CONCLUSION: The high fat diet with a high C18:0/C16:0 ratio induced more severe glucose and lipid metabolic disorders and inflammation and affected expression of more lncRNAs and mRNAs than an isocaloric low C18:0/C16:0 ratio diet in mice. These results provide new insights into the differences in biological functions and related mechanisms, other than glucose and lipid metabolism, between C16:0 and C18:0.

MicroRNA-1185 Promotes Arterial Stiffness though Modulating VCAM-1 and E-Selectin Expression.

BACKGROUND/AIMS: Atherosclerosis is the primary cause of cardiovascular ischaemic events; arterial stiffness is a characteristic of the atherosclerotic process. MicroRNAs (miRNAs) have been revealed as crucial modulators of atherosclerosis. However, the role of arterial stiffness-related miRNAs in the atherosclerotic process is still unclear. METHODS: Four hundred six participants from Northern China were enrolled in this study. Circulating miR-1185 and adhesion molecule levels were measured. Multiple linear regression models were used to evaluate the association of miR-1185 levels with brachial-ankle pulse wave velocity (baPWV) and adhesion molecule levels. A mediation analysis was also performed to examine the mediating effect. Cell adhesion molecule levels were measured in primary human umbilical vein endothelial cells (pHUVECs) and human umbilical vein smooth cells (HUVSMCs) transfected with miR-1185 or co-transfected with a miR-1185 inhibitor. RESULTS: miR-1185 was independently correlated with arterial stiffness. A positive relationship between miR-1185 and vascular cell adhesion molecule-1 (VCAM-1) and E-selectin levels was observed. VCAM- 1 and E-selectin partially mediated the correlation between miR-1185 and arterial stiffness. miR-1185 induced a significant increase in the VCAM-1 and E-selectin levels in pHUVECs and HUVSMCs in vitro. According to our mechanistic analysis, VCAM-1 and E-selectin mediated miR-1185-induced arterial stiffening. CONCLUSIONS: miR-1185 modulated the expression of VCAM-1 and E-selectin to promote arterial stiffening, suggesting that miR-1185 plays a crucial role in the development of atherosclerosis and may serve as a novel therapeutic target for atherosclerosis.

MicroRNA-1185 Induces Endothelial Cell Apoptosis by Targeting UVRAG and KRIT1.

BACKGROUND/AIMS: Atherosclerosis is a multifactorial chronic disease and is the main cause of death and impairment in the world. Endothelial injury and apoptosis play a crucial role in the onset and development of atherosclerosis. MicroRNAs (miRNAs) have been proven to be involved in the pathogenesis of atherosclerosis. However, studies of the functional role of apoptosis-related miRNAs in the endothelium during atherogenesis are limited. METHODS: Cell injury and apoptosis were measured in five types of cells transfected with miR-1185 or co-transfected with miR-1185 and its inhibitor. Bioinformatics analysis and a luciferase reporter assay were used to confirm the targets of miR-1185. The effects of the targets of miR-1185 on endothelial apoptosis were determined using small-interfering RNA. RESULTS: In this study, we first report that miR-1185 significantly promoted apoptosis in endothelial cells but not in vascular smooth muscle cells and macrophages. A mechanistic analysis showed that ultraviolet irradiation resistance-associated gene (UVRAG) and krev1 interaction trapped gene 1 (KRIT1), targets of miR-1185, mediated miR-1185-induced endothelial cell apoptosis. CONCLUSION: The results revealed the impact of miR-1185 on endothelial apoptosis, suggesting that miR-1185 may be a potential target for the prevention and treatment of atherosclerosis.

Nutritional and eating education improves knowledge and practice of patients with type 2 diabetes concerning dietary intake and blood glucose control in an outlying city of China.

OBJECTIVE: To describe the knowledge, attitudes and practices of type 2 diabetics in Yakeshi City and to assess the effect of implementation of nutritional and eating education in enhancing knowledge and practices regarding a healthy diet. DESIGN: A questionnaire-based survey was conducted with 162 diabetics to determine their nutrition knowledge, attitudes and practices; fifty-four participants received nutritional and eating education for 6 months. Diabetes-related nutrition knowledge, awareness, practice accuracy, dietary intake and glycaemic control were assessed before and after education. SETTING: Yakeshi, a remote city in northern China. SUBJECTS: A total of 162 type 2 diabetics recruited from three hospitals, fifty-four of whom were selected randomly to receive education. RESULTS: Among the 162 respondents, most diabetics (75%) considered that controlling diet was important in the methods of controlling blood glucose. Scores for knowledge, practices and overall KAP (knowledge-attitude-practice) were low, but scores for attitude were high. Participants with diabetes education experiences, practice duration over 1 year or high education level all had higher scores for KAP (P < 0·001, P < 0·05 and P < 0·001, respectively) than their counterparts. After education, patients' nutrition knowledge, awareness and practice accuracy improved significantly (P < 0·05). The rates of patients with recommended daily intake of vegetables, grains and dairy were boosted (P < 0·05). Various nutrient intakes increased (P < 0·05) but not protein, Fe, Zn and Se. Significant improvements were also found in glycaemic control (P < 0·05). CONCLUSIONS: Diabetics in Yakeshi had positive attitudes, but relatively poor nutrition knowledge and practices. Nutritional and eating education was effective in improving diabetics' nutrition knowledge and practices, and this optimal practice helped them control blood glucose effectively.

A rare pediatric patient of anti-IgLON5 encephalitis with epileptic seizures as the first symptom.

BACKGROUND: Anti-IgLON5 encephalitis was a rare neurological and heterogeneous disorder, which was mainly found in adults. Epileptic seizures related to anti-IgLON5 disease were rarely reported. METHODS: Neural antibodies associated with autoimmune encephalitis in serum and cerebrospinal fluid (CSF) were tested using cell-based assays (CBA) with immunofluorescence double staining. The antibodies in serum were further confirmed by tissue-based assay (TBA) with rat brain and kidney tissue. RESULTS: We reported a pediatric case presented with epileptic seizures, cognitive impairments, and sleep disorders. Autoantibody screening showed anti-IgLON5 antibody IgG (1:100+) and anti-NMDAR antibody IgG (1:10+) in the serum. She was diagnosed as anti-IgLON5 encephalitis. Her conditions improved rapidly by treated with intravenous immunoglobulin and high dose intravenous methylprednisolone. CONCLUSION: We described the second pediatric case with anti-IgLON5 encephalitis, who was also the first presented with epileptic seizures as the initial presentation. Anti-IgLON5 encephalitis might have mild manifestations. For patients with new onset seizures associated with cognitive impairments and sleep disturbances, anti-IgLON5 antibody should be tested as early, even in children.

A case of variant of GBS with positive serum ganglioside GD3 IgG antibody.

BACKGROUND: Acute bulbar palsy-plus (ABPp) syndrome is an unusual variant of Guillain-Barré syndrome (GBS). Anti-GT1a and anti-GQ1b antibodies have been reported in patients with ABPp, but without reports related to GD3 antibodies. METHODS: Clinical data of a patient diagnosed as ABPp syndrome were reviewed clinically. And we summarized the GBS patients with ABP and facial paralysis reported in the literature. RESULTS: We reported a 13-year-old girl presented with asymmetric bifacial weakness, bulbar palsy and transient limb numbness, and had positive serum IgG anti-GD3 antibody. Through reviewing the GBS patients with ABP and facial paralysis reported previously, we found that facial palsy could be unilateral or bilateral. The bilateral facial palsy could present successively or simultaneously, and could be symmetrical or asymmetrical. Other common symptoms included ophthalmoplegia, sensory abnormality and ataxia. IgG anti-GT1a and IgG anti-GQ1b antibodies were the most frequent. Most of the patients had full recovery within two weeks to one year of follow-up. CONCLUSIONS: We reported a patient with asymmetric bifacial palsy and bulbar palsy, which seemed to fit the diagnosis of ABPp syndrome. This was the first report of ABPp variant of GBS with positive serum ganglioside GD3 IgG antibody.

Identifying potential therapeutic targets in lung adenocarcinoma: a multi-omics approach integrating bulk and single-cell RNA sequencing with Mendelian randomization.

Our research aimed to identify new therapeutic targets for Lung adenocarcinoma (LUAD), a major subtype of non-small cell lung cancer known for its low 5-year survival rate of 22%. By employing a comprehensive methodological approach, we analyzed bulk RNA sequencing data from 513 LUAD and 59 non-tumorous tissues, identifying 2,688 differentially expressed genes. Using Mendelian randomization (MR), we identified 74 genes with strong evidence for a causal effect on risk of LUAD. Survival analysis on these genes revealed significant differences in survival rates for 13 of them. Our pathway enrichment analysis highlighted their roles in immune response and cell communication, deepening our understanding. We also utilized single-cell RNA sequencing (scRNA-seq) to uncover cell type-specific gene expression patterns within LUAD, emphasizing the tumor microenvironment's heterogeneity. Pseudotime analysis further assisted in assessing the heterogeneity of tumor cell populations. Additionally, protein-protein interaction (PPI) network analysis was conducted to evaluate the potential druggability of these identified genes. The culmination of our efforts led to the identification of five genes (tier 1) with the most compelling evidence, including SECISBP2L, PRCD, SMAD9, C2orf91, and HSD17B13, and eight genes (tier 2) with convincing evidence for their potential as therapeutic targets.

Trilayered biomimetic hydrogel scaffolds with dual-differential microenvironment for articular osteochondral defect repair.

Commonly, articular osteochondral tissue exists significant differences in physiological architecture, mechanical function, and biological microenvironment. However, the development of biomimetic scaffolds incorporating upper cartilage, middle tidemark-like, and lower subchondral bone layers for precise articular osteochondral repair remains elusive. This study proposed here a novel strategy to construct the trilayered biomimetic hydrogel scaffolds with dual-differential microenvironment of both mechanical and biological factors. The cartilage-specific microenvironment was achieved through the grafting of kartogenin (KGN) into gelatin via p-hydroxyphenylpropionic acid (HPA)-based enzyme crosslinking reaction as the upper cartilage layer. The bone-specific microenvironment was achieved through the grafting of atorvastatin (AT) into gelatin via dual-crosslinked network of both HP-based enzyme crosslinking and glycidyl methacrylate (GMA)-based photo-crosslinking reactions as the lower subchondral bone layer. The introduction of tidemark-like middle layer is conducive to the formation of well-defined cartilage-bone integrated architecture. The in vitro experiments demonstrated the significant mechanical difference of three layers, successful grafting of drugs, good cytocompatibility and tissue-specific induced function. The results of in vivo experiments also confirmed the mechanical difference of the trilayered bionic scaffold and the ability of inducing osteogenesis and chondrogenesis. Furthermore, the articular osteochondral defects were successfully repaired using the trilayered biomimetic hydrogel scaffolds by the activation of endogenous recovery, which offers a promising alternative for future clinical treatment.

Mechanical loading on cell-free polymer composite scaffold enhances in situ regeneration of fully functional Achilles tendon in a rabbit model.

Traditional tendon engineering using cell-loaded scaffold has limited application potential due to the need of autologous cells. We hypothesize that potent mechanical loading can efficiently induce in situ Achilles tendon regeneration in a rabbit model by using a cell-free porous composite scaffold. In this study, melt-spinning was used to fabricate PGA (polyglycolic acid) and PLA (polylactic acid) filament fibers as well as non-woven PGA fibers. The PLA/PGA (4:2) filament fibers were further braided into a hybrid yarn，which was knitted into a PLA/PGA tubular mesh with potent mechanical property for sustaining natural tendon strain. The results showed that a complete cross-section of Achilles tendon created a model of full mechanical loading on the bridging scaffold, which could efficiently induce in situ tendon regeneration by promoting host cell infiltration, matrix production and tissue remodeling. Histologically, mechanical loading assisted in forming parallel aligned collagen fibers and tenocytes in a fashion similar to those of native tendon. Transmission electron microscope further demonstrated that mechanical strain induced collagen fibril development by increasing fibril diameter and forming bipolar structure, which resulted in enhanced mechanical properties. Interestingly, the synergistic effect between mechanical loading and hyaluronic acid modification was also observed on the induced tenogenic differentiation of infiltrated host fibroblasts. In conclusion, potent mechanical loading is the key inductive microenvironment for in situ tendon regeneration for this polymer-based composite scaffold with proper matrix modification, which may serve as a universal scaffold product for tendon regeneration.

Sotagliflozin attenuates liver-associated disorders in cystic fibrosis rabbits.

Mutations in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene lead to CF, a life-threating autosomal recessive genetic disease. While recently approved Trikafta dramatically ameliorates CF lung diseases, there is still a lack of effective medicine to treat CF-associated liver disease (CFLD). To address this medical need, we used a recently established CF rabbit model to test whether sotagliflozin, a sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor drug that is approved to treat diabetes, can be repurposed to treat CFLD. Sotagliflozin treatment led to systemic benefits to CF rabbits, evidenced by increased appetite and weight gain as well as prolonged lifespan. For CF liver-related phenotypes, the animals benefited from normalized blood chemistry and bile acid parameters. Furthermore, sotagliflozin alleviated nonalcoholic steatohepatitis-like phenotypes, including liver fibrosis. Intriguingly, sotagliflozin treatment markedly reduced the otherwise elevated endoplasmic reticulum stress responses in the liver and other affected organs of CF rabbits. In summary, our work demonstrates that sotagliflozin attenuates liver disorders in CF rabbits and suggests sotagliflozin as a potential drug to treat CFLD.

A hepatokine derived from the ER protein CREBH promotes triglyceride metabolism by stimulating lipoprotein lipase activity.

The endoplasmic reticulum (ER)-tethered, liver-enriched stress sensor CREBH is processed in response to increased energy demands or hepatic stress to release an amino-terminal fragment that functions as a transcription factor for hepatic genes encoding lipid and glucose metabolic factors. Here, we discovered that the carboxyl-terminal fragment of CREBH (CREBH-C) derived from membrane-bound, full-length CREBH was secreted as a hepatokine in response to fasting or hepatic stress. Phosphorylation of CREBH-C mediated by the kinase CaMKII was required for efficient secretion of CREBH-C through exocytosis. Lipoprotein lipase (LPL) mediates the lipolysis of circulating triglycerides for tissue uptake and is inhibited by a complex consisting of angiopoietin-like (ANGPTL) 3 and ANGPTL8. Secreted CREBH-C blocked the formation of ANGPTL3-ANGPTL8 complexes, leading to increased LPL activity in plasma and metabolic tissues in mice. CREBH-C administration promoted plasma triglyceride clearance and partitioning into peripheral tissues and mitigated hypertriglyceridemia and hepatic steatosis in mice fed a high-fat diet. Individuals with obesity had higher circulating amounts of CREBH-C than control individuals, and human CREBH loss-of-function variants were associated with dysregulated plasma triglycerides. These results identify a stress-induced, secreted protein fragment derived from CREBH that functions as a hepatokine to stimulate LPL activity and triglyceride homeostasis.

Step-wise CAG@PLys@PDA-Cu2+ modification on micropatterned nanofibers for programmed endothelial healing.

Native-like endothelium regeneration is a prerequisite for material-guided small-diameter vascular regeneration. In this study, a novel strategy is proposed to achieve phase-adjusted endothelial healing by step-wise modification of parallel-microgroove-patterned (i.e., micropatterned) nanofibers with polydopamine-copper ion (PDA-Cu2+) complexes, polylysine (PLys) molecules, and Cys-Ala-Gly (CAG) peptides (CAG@PLys@PDA-Cu2+). Using electrospun poly(l-lactide-co-caprolactone) random nanofibers as the demonstrating biomaterial, step-wise modification of CAG@PLys@PDA-Cu2+ significantly enhanced substrate wettability and protein adsorption, exhibited an excellent antithrombotic surface and outstanding phase-adjusted capacity of endothelium regeneration involving cell adhesion, endothelial monolayer formation, and the regenerated endothelium maturation. Upon in vivo implantation for segmental replacement of rabbit carotid arteries, CAG@PLys@PDA-Cu2+ modified grafts (2 mm inner diameter) with micropatterns on inner surface effectively accelerated native-like endothelium regeneration within 1 week, with less platelet aggregates and inflammatory response compared to those on non-modified grafts. Prolonged observations at 6- and 12-weeks post-implantation demonstrated a positive vascular remodeling with almost fully covered endothelium and mature smooth muscle layer in the modified vascular grafts, accompanied with well-organized extracellular matrix. By contrast, non-modified vascular grafts induced a disorganized tissue formation with a high risk of thrombogenesis. In summary, step-wise modification of CAG@PLys@PDA-Cu2+ on micropatterned nanofibers can significantly promote endothelial healing without inflicting thrombosis, thus confirming a novel strategy for developing functional vascular grafts or other blood-contacting materials/devices.

Two pediatric patients with hemiplegic migraine presenting as acute encephalopathy: case reports and a literature review.

Introduction: Hemiplegic migraine (HM) is a rare subtype of migraine. HM in children may be atypical in the initial stage of the disease, which could easily lead to misdiagnosis. Methods: We report two cases of atypical hemiplegic migraine that onset as an acute encephalopathy. And a comprehensive search was performed using PubMed, Web of Science, and Scopus. We selected only papers that reported complete clinical information about the patients with CACNA1A or ATP1A2 gene mutation. Results: Patient #1 showed a de novo mutation, c.674C>A (p. Pro225His), in exon 5 of the CACNA1A gene. And patient #2 showed a missense mutation (c.2143G>A, p. Gly715Arg) in exon 16 of the ATP1A2. Together with our two cases, a total of 160 patients (73 CACNA1A and 87 ATP1A2) were collected and summarized finally. Discussion: Acute encephalopathy is the main manifestation of severe attacks of HM in children, which adds to the difficulty of diagnosis. Physicians should consider HM in the differential diagnosis of patients presenting with somnolence, coma, or convulsion without structural, epileptic, infectious, or inflammatory explanation. When similar clinical cases appear, gene detection is particularly important, which is conducive to early diagnosis and treatment. Early recognition and treatment of the disease can help improve the prognosis.

Hyperphosphorylated Tau Inflicts Intracellular Stress Responses that Are Mitigated by Apomorphine.

Abnormal phosphorylation of the microtubule-binding protein tau in the brain is a key pathological marker for Alzheimer's disease and additional neurodegenerative tauopathies. However, how hyperphosphorylated tau causes cellular dysfunction or death that underlies neurodegeneration remains an unsolved question critical for the understanding of disease mechanism and the design of efficacious drugs. Using a recombinant hyperphosphorylated tau protein (p-tau) synthesized by the PIMAX approach, we examined how cells responded to the cytotoxic tau and explored means to enhance cellular resistance to tau attack. Upon p-tau uptake, the intracellular calcium levels rose promptly. Gene expression analyses revealed that p-tau potently triggered endoplasmic reticulum (ER) stress, unfolded protein response (UPR), ER stress-associated apoptosis, and pro-inflammation in cells. Proteomics studies showed that p-tau diminished heme oxygenase-1 (HO-1), an ER stress-associated anti-inflammation and anti-oxidative stress regulator, while stimulated the accumulation of MIOS and other proteins. p-Tau-induced ER stress-associated apoptosis and pro-inflammation are ameliorated by apomorphine, a brain-permeable prescription drug widely used to treat Parkinson's disease symptoms, and by overexpression of HO-1. Our results reveal probable cellular functions targeted by hyperphosphorylated tau. Some of these dysfunctions and stress responses have been linked to neurodegeneration in Alzheimer's disease. The observations that the ill effects of p-tau can be mitigated by a small compound and by overexpressing HO-1 that is otherwise diminished in the treated cells inform new directions of Alzheimer's disease drug discovery.