Overexpression of low-density lipoprotein receptor prevents neurotoxic polarization of astrocytes via inhibiting NLRP3 inflammasome activation in experimental ischemic stroke.

JOURNAL/nrgr/04.03/01300535-202502000-00027/figure1/v/2024-05-28T214302Z/r/image-tiff Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury. Low-density lipoprotein receptor, a classic cholesterol regulatory receptor, has been found to inhibit NLR family pyrin domain containing protein 3 (NLRP3) inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer's disease. However, little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke. To address this issue in the present study, we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models. First, we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis. We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation. Second, we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus. Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype. Finally, we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin, an NLRP3 agonist, restored the neurotoxic astrocyte phenotype. These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.

Deciphering the pollution risks, sources and their links of heavy metals in soils.

Heavy metals in soils pose serious ecological and health risks. To make efficient strategies for mitigating the underlying hazards, it is critical to reveal the pollution sources and their links with the risks. Researchers have investigated source identification and risk evaluation of heavy metals in soils, yet few have systematically deciphered the source-sink relationship of soil metals and the links between source apportionment and risk assessment. In the study, an integrated technological framework has been proposed to address the gaps, and applied to characterize the pollution risks, sources and their links of soil metals in a typical coal resource city in China. The assessment using geochemical tool and ecological risk index shows the soils in study area are polluted by Cd, Hg, Cr, As and Pb in varied degrees, and particularly, Cd and Hg present significant ecological risk. Two advanced receptor models (multivariate curve resolution-weighted alternating least-squares and multilinear engine 2) are comparatively applied for apportioning the potential sources of soil metals, and the results suggest the two models have identified similar sources (r2 > 0.90), including agricultural activities, atmospheric depositions and industrial discharges with contributions of 35.5 %-38.3 %, 30.3 %-35.1 %, and 26.6 %-34.1 %, respectively. Then, apportionment results of the two models are jointly employed for evaluating the source-specific health risks of metals in the environment using a probabilistic risk assessment model. The risk levels within the area are overall acceptable or tolerable, and relatively, the industrial discharges present higher contribution on the non-carcinogenic and carcinogenic risks of soil metals to public. Findings will help the managers to design targeted policies for reducing the risks of soil metals, and the framework proposed provides a useful guideline to better understand the source-risk relationship of soil metals in other environments worldwide.

Efgartigimod as a fast-acting add-on therapy in manifest and impending myasthenic crisis: A single-center case series.

Efgartigimod was the first-in-class neonatal Fc receptor antagonist approved for the treatment of acetylcholine receptor antibody positive (AChR+), Myasthenia Gravis Foundation of America (MGFA) Class II-IV generalized myasthenia gravis (gMG) patients. As a novel therapy, the clinical experiences are still lacking, especially for the use of efgartigimod in manifest and impending myasthenic crisis (IMC). We reported three AChR+, gMG patients, two with myasthenic crisis (MC) and one with IMC, treated with efgartigimod. MGFA class, MG-Activity of Daily Living score (MG-ADL), Quantitative MG score (QMG), and Muscle Research Council sum score (MRC), concentration of anti-AChR antibody, IgG, globulin, and albumin, subsets of T and B lymphocyte were evaluated or measured before, during and after efgartigimod treatment. All patients showed fast and robust response to efgartigimod with marked improvement in MGFA, MG-ADL, QMG, and MRC scores. Patient 1 did not respond effectively to IVIg but was successfully rescued by add-on efgartigimod. She extubated at 7 days after the first infusion and got rid of NIV after 14-days treatment. Patient 2 and patient 3 directly used efgartigimod when symptoms were not ameliorated by adjusting of oral drugs. Patient 2 wean from BiPAP at seven days after the first infusion. Patient 3 in IMC status, overcame the severe dysphagia at three days after the first infusion. Clinical symptoms continued to improve 1-2 weeks after discharge. Concentration of anti-AChR antibody, IgG and globulin were remarkably reduced by efgartigimod treatment. Our study supported that efgartigimod could act as a fast-acting rescue therapy for patients with MC or IMC. Larger studies from multicenter are required to provide further evidence.

Successful treatment with efgartigimod as an add-on therapy in acute attack of anti-AQP4 antibody-positive NMOSD: a case report.

BACKGROUND: Neuromyelitis Optica Spectrum Disorder (NMOSD) is an autoimmune demyelinating disease characterized by recurrent myelitis and optic neuritis. It is associated with high rates of relapse and disability. The main treatment strategies for acute attacks include intravenous methylprednisolone pulse (IVMP) treatment and rescue treatment with plasma exchange (PLEX). Recently, the blockade of neonatal Fc receptor (FcRn)-IgG interaction has gained momentum as a therapeutic strategy. Efgartigimod, the first approved FcRn inhibitor for treating generalized myasthenia gravis, has shown impressive safety, efficacy, and tolerability, and is being regarded as "PLEX in a bottle". CASE DESCRIPTION: We report a 65-year-old female patient who was diagnosed with anti-AQP4 antibody positive NMOSD. Add-on treatment with efgartigimod to IVMP and intravenous immunoglobulin (IVIG) at the second acute relapse showed favorable results. CONCLUSION: This case suggests that efgartigimod is a potentially effective add-on therapy in acute attacks of AQP4-IgG-positive NMOSD.

[Mechanism of Dabugan Decoction in treatment of generalized anxiety disorder based on network pharmacology and experimental verification].

This study aims to explore the mechanism of Dabugan Decoction in the treatment of generalized anxiety disorder(GAD) based on network pharmacology, molecular docking, and animal experiments. Network pharmacology and molecular docking technology were used to obtain the possible targets and related signaling pathways of Dabugan Decoction in the treatment of GAD. The GAD rat model was established, and the corresponding drugs were given by gavage after randomization. After 28 days of continuous intervention, the anxiety state of rats was detected, and the pathological changes of the hippocampus were detected in each group. ELISA and Western blot were used to detect the protein expression levels of related molecules. A total of 65 drug compounds in Dabugan Decoction were obtained, involving 403 targets of action, 7 398 disease targets of GAD, and 279 common targets of "drug-disease". The key nodes in the protein-protein interaction(PPI) network were Akt1, TNF, IL-6, TP53, IL-1ß, etc. Function analysis of Gene Ontology(GO) and enrichment analysis of Kyoto Encyclopedia of Genes and Genomes(KEGG) showed that the PI3K-Akt signaling pathway was the most important pathway. The results of molecular docking showed that the core components of the drug had good binding activity with the corresponding key targets. Animal experiments showed that Dabugan Decoction could effectively improve the anxiety behavior of rats and increase the open arm end movement distance and total distance of rats in the elevated cross labyrinth, the number and stay time of entering the open box, and the time(%) and the number of entering the center of the open field. At the same time, HE staining and Nicil staining showed that the number of hippocampal nerve cells in rats increased, and they were closely arranged. The damage to the cell body was improved, and there was an increase in Nissl substances in the cells. The expression of TNF-α, IL-6, and IL-1ß in rat hippocampus decreased, and the expression of TP53, p-Akt1, and p-PI3K increased. The mechanism may be related to the activation of the PI3K-Akt signaling pathway and the inhibition of inflammatory response. Dabugan Decoction can play a good therapeutic and regulatory role in GAD, reflecting the overall effect of traditional Chinese medicine(TCM) compound and the characteristics of multiple targets and multiple pathways. At the same time, it is preliminarily discussed that the state of GAD may be improved by Dabugan Decoction via-activating PI3K-Akt signaling pathway and inhibiting inflammatory response and anti-apoptosis, thus providing experimental data support for the clinical application of Dabugan Decoction.

The associations between single nucleotide polymorphisms and diabetic retinopathy risk: an umbrella review.

This umbrella review was conducted aiming to assess the association between genetic variations and the development of diabetic retinopathy (DR) by collecting and evaluating available systematic reviews and meta-analysis results. We evaluated the methodological quality using the Measurement Tool to Assess Systematic Reviews (AMSTAR) 2.0, estimated the summary effect size by using the random effects model and calculated the 95% prediction intervals (PIs). Evidence from the included meta-analyses was graded according to established criteria as follows: convincing, highly suggestive, suggestive, weak, or not significant. This umbrella review included 32 meta-analyses of 52 candidate SNPs. The 12 selected meta-analyses were rated as "high," 2 studies were rated as "moderate," 11 studies were graded as "low," and the remaining 7 studies were graded as "critically low" in terms of methodological quality. Carriers of specific genotypes and alleles of the transcription Factor 7-like 2 C/T (TCF7L2 C/T) polymorphism (rs7903146, p < 0.001) might be more susceptible to the occurrence of DR in the homozygous and recessive models, and these associations were supported by "convincing" evidence. Significant associations were also found between interleukin-6 (IL-6) -174 G/C (rs1800795; p < 0.05) or vascular endothelial growth factor (VEGF) polymorphisms (rs2010963, rs699947, rs1570360, rs2010963, rs699947, rs2146323; all p values <0.05) and DR risk, but these associations were supported by "weak" evidence. The TCF7L2 C/T variant could be identified as a definitive genetic risk factor for the development and progression of DR. Data from additional in-depth studies are needed to establish robust evidence for the associations between polymorphisms of IL-6 or VEGF and DR.

Comparison of dual-energy computed tomography (DECT) polychromatic and monochromatic images with and without iterative metal artifact reduction algorithm in patients with dental implants.

Background: Dual-energy computed tomography (DECT) and iterative metal artifact reduction (iMAR) algorithms are valuable tools for reducing metal artifacts. Different parameters of these technologies and their combination can achieve different performance. This study compared various polychromatic and monochromatic images obtained via DECT with and without using iMAR algorithm to reduce artifacts in patients with dental implants. Methods: This study included 30 patients with dental implants who underwent DECT for head and neck imaging. The computed tomography (CT) image sets comprised DECT polychromatic image sets [dual-energy (DE) polychromatic] that linearly blended 100 kV and tin-filtered 140 kV images using composition ratios of -1, -0.6, -0.3, 0, and 0.6, and virtual monochromatic images (DE monochromatic) at 90, 110, 130, 150, and 170 keV. These image sets were obtained with and without using iMAR, resulting in a total of 20 image sets. For subjective analysis, metal artifacts and image quality were assessed using a 5-point Likert scale. For objective analysis, CT attenuation, standard deviation (SD), contrast-to-noise ratio (CNR) and artifact index (AI) were evaluated. In addition, subgroup analysis was performed based on implant size. Results: In the subjective evaluation, iMAR + DE polychromatic (-0.3) images exhibited the lowest metal artifact scores [median (interquartile range): 2 (2-3)]. iMAR + DE monochromatic (110 keV) images demonstrated optimal image quality scores [median (interquartile range): 2 (2-3)]. In the objective evaluation, none of the images demonstrated a significant difference in the CNR, except polychromatic images with a composition of -1 and 0.6. iMAR + DE polychromatic (0) exhibited the lowest AI [median (interquartile range): 8.7 (5.9-14.5)]. There was no significant difference between the two groups with different implant sizes for the techniques combined with iMAR (all P>0.05). Conclusion: iMAR + DE polychromatic (-0.3 and 0) and iMAR + DE monochromatic (110 keV) images exhibited better image quality and substantial metal artifact reduction (MAR) compared with the other image sets. The performance of the techniques combined with iMAR was not affected by the size of the implant.

Portable dual-mode paper chips for highly sensitive and rapid determination of aflatoxin B1 via an aptamer-gated MOFs.

Paper chip as a representative microfluidic device has been mushroomed for rapid identification of contaminants in agro-food. However, the sensitivity and accuracy have still been challenged by inevitable background noise or interference in food matrix. Herein, we designed and fabricated a dual-mode paper chip (DPC) by assembling a patterned paper electrode with a platinum nanoparticles-treated colorimetric region through a flow channel. Dual-mode outputs were guided by an aptamer-gated UiO-66-NH2 metal-organic frameworks (MOFs). UiO-66-NH2 loaded with 3, 3', 5, 5'-tetramethylbenzidine (TMB) was controlled by a switch comprised of CdS quantum dots-aptamer. Aflatoxin B1 (AFB1, a kind of carcinogenic mycotoxin) target came and induced TMB release, triggering colorimetric and ECL signals on DPC, ultra-high sensitivity with a detection limit of 7.8 fg/mL was realized. The practicability of the DPC was also confirmed by spiking AFB1 in real corn samples. This portable paper-based device provides an ideal rapid detection platform tailored for diverse food contaminants analysis.

Radiomics analysis of pancreas based on dual-energy computed tomography for the detection of type 2 diabetes mellitus.

Objective: To utilize radiomics analysis on dual-energy CT images of the pancreas to establish a quantitative imaging biomarker for type 2 diabetes mellitus. Materials and methods: In this retrospective study, 78 participants (45 with type 2 diabetes mellitus, 33 without) underwent a dual energy CT exam. Pancreas regions were segmented automatically using a deep learning algorithm. From these regions, radiomics features were extracted. Additionally, 24 clinical features were collected for each patient. Both radiomics and clinical features were then selected using the least absolute shrinkage and selection operator (LASSO) technique and then build classifies with random forest (RF), support vector machines (SVM) and Logistic. Three models were built: one using radiomics features, one using clinical features, and a combined model. Results: Seven radiomic features were selected from the segmented pancreas regions, while eight clinical features were chosen from a pool of 24 using the LASSO method. These features were used to build a combined model, and its performance was evaluated using five-fold cross-validation. The best classifier type is Logistic and the reported area under the curve (AUC) values on the test dataset were 0.887 (0.73-1), 0.881 (0.715-1), and 0.922 (0.804-1) for the respective models. Conclusion: Radiomics analysis of the pancreas on dual-energy CT images offers potential as a quantitative imaging biomarker in the detection of type 2 diabetes mellitus.

Taxonomic study of Uncobotyodes Kirti & Rose, 1990 (Lepidoptera, Crambidae), with the description of a new species from China.

The monotypic genus Uncobotyodes Kirti & Rose and its type species U. patulalis (Walker) are redescribed. The female genitalia of U. patulalis are described for the first time. An additional species, Uncobotyodes latizona sp. nov., is described as new to science. The two species of the genus are compared. Images of adults and their genitalia are provided.

The reduction of microglial efferocytosis is concomitant with depressive-like behavior in CUMS-treated mice.

BACKGROUND: Microglial efferocytosis plays a crucial role in facilitating and sustaining homeostasis in the central nervous system, and it is involved in neuropsychiatric disorders. How microglial efferocytosis is affected under the condition of major depressive disorder (MDD) remains elusive. In this study, we hypothesized that microglial efferocytosis in the hippocampus is impaired in the chronic unpredicted mild stress (CUMS) model of MDD, which is involved in the development of MDD. METHOD: Depressive-like behavior in adult male mice was induced by CUMS and confirmed by behavioral tests. Microglial efferocytosis was evaluated using immunofluorescence staining of hippocampal slices and primary microglia co-cultured with apoptotic cells. The protein and mRNA levels of phagocytosis-related molecules and inflammation-related cytokines were detected using western blotting and RT-qPCR, respectively. Annexin V was injected to mimic impairment of microglial efferocytosis. TREM2-siRNA was further used on primary microglia to examine efferocytosis-related signaling pathways. RESULTS: Microglia were activated and the expression of proinflammatory cytokines was increased in CUMS mice, while microglial efferocytosis and efferocytosis-related molecules were decreased. Inhibition of the TREM2/Rac1 pathway impaired microglial efferocytosis. Annexin V injection inhibited microglial efferocytosis, increased inflammation in the hippocampus and depressive-like behavior. LIMITATIONS: The potential antidepressant effect of the upregulation of the TREM2/Rac1 pathway was not evaluated. CONCLUSIONS: Impairment of microglial efferocytosis is involved in the development of depressive-like behavior, with downregulation of the TREM2/Rac1 pathway and increased inflammation. These results may increase our understanding of the pathophysiological mechanisms associated with MDD and provide novel targets for therapeutic interventions.

Replacing cholesterol with asiatic acid to prolong circulation and enhance anti-metastatic effects of non-PEGylated liposomes.

Cholesterol is an indispensable component of most liposomes, heavily influencing their physical and surface properties. In this study, cholesterol in non-PEGylated liposomes was replaced by its analog, asiatic acid (AA), to generate liposomes with an alternative composition. These AA liposomes are generally smaller and more rigid than conventional liposomes, circulate longer in the body, and accumulate more in primary tumors and lung metastases in vivo. On the other hand, as an active ingredient, AA can decrease TGF-ß secretion to inhibit the epithelial-mesenchymal transition (EMT) process, increase the sensitivity of tumor cells to doxorubicin (DOX), and synergize with DOX to enhance the immune response, thus improving their antitumor and anti-metastasis efficiency. Based on this rationale, DOX-loaded AA liposomes were fabricated and tested against triple-negative breast cancer (TNBC). Results showed that compared with conventional liposomes, the DOX-AALip provided approximately 28.4% higher tumor volume reduction with almost no metastatic nodules in the mouse model. Our data demonstrate that AA liposomes are safe, simple, and efficient, and thus in many situations may be used instead of conventional liposomes, having good potential for further clinical translational development.

n-3 polyunsaturated fatty acids alleviate the progression of obesity-related osteoarthritis and protect cartilage through inhibiting the HMGB1-RAGE/TLR4 signaling pathway.

Osteoarthritis (OA) is a common joint degenerative disease. There is currently no cure for OA. Dietary fatty acids have potential value in the prevention and treatment of OA. n-3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory effects, but their anti-OA mechanism remains unclear. High-mobility group box 1 (HMGB1) promotes inflammation and participates the pathogenesis of OA. The purpose of this study was to investigate the protective effect of n-3 PUFAs on cartilage and whether n-3 PUFAs could exert an anti-OA effect through inhibiting HMGB1-RAGE/TLR4 signaling pathway. We established an obesity-related post-traumatic OA mice model and an in vitro study was conducted to explore the regulatory mechanism of n-3 PUFAs on HMGB1 and its signal pathway against OA. We found that diet rich in n-3 PUFAs alleviated OA-like lesions of articular cartilage with the decrease of HMGB1-RAGE/TLR4 signaling protein in mice. In SW1353 cells, DHA significantly reduced the expression of HMGB1-RAGE/TLR4 signaling protein which was up-regulated by IL-1ß stimulation. HMGB1 overexpression reversed the inhibitory effect of DHA on HMGB1-RAGE/TLR4 signaling pathway. The activation of SIRT1 may participate the inhibitory effect of DHA on HMGB1-RAGE/TLR4 signaling pathway. In conclusion, n-3 PUFAs could attenuate the progression of obesity-related OA and exert protective effect on cartilage by inhibiting HMGB1-RAGE/TLR4 signaling pathway, which may be associated with the activation of SIRT1. Dietary n-3 PUFAs supplements can be considered as a potential therapeutic substance for OA.

Efficacy and safety of hepatitis B vaccine: an umbrella review of meta-analyses.

BACKGROUND: There is a lack of synthesis of literature to determine hepatitis B vaccine (HepB) strategies for hepatitis B virus (HBV) supported by quality evidence. We aimed to explore the efficacy and safety of HepB strategies among people with different characteristics. RESEARCH DESIGN AND METHODS: PubMed, Cochrane Library, Embase, and Web of Science were searched for meta-analyses comparing the efficacy and safety of HepB up to July 2023. RESULTS: Twenty-one meta-analyses comparing 83 associations were included, with 16 high quality, 4 moderate, and 1 low quality assessed by AMSTAR 2. Highly suggestive evidence supports HepB booster and HepB with 1018 adjuvant (HBsAg-1018) for improved seroprotection, and targeted and universal HepB vaccination reduced HBV infection Suggestive evidence indicated that targeted vaccination decreased the rate of hepatitis B surface antibody positivity and booster doses increased seroprotection in people aged 10-20. Weak evidence suggests potential local/systemic reaction risk with nucleotide analogs or HBsAg-1018. Convincing evidence shows HLA-DPB1*04:01 and DPB1*04:02 increased, while DPB1*05:01 decreased, hepatitis B antibody response. Obesity may reduce HepB seroprotection, as highly suggested. CONCLUSION: Targeted vaccination could effectively reduce HBV infection, and adjuvant and booster vaccinations enhance seroprotection without significant reaction. Factors such as obesity and genetic polymorphisms may affect the efficacy.

High-throughput virtual screening to identify potential small molecule inhibitors of the Zα domain of the adenosine deaminases acting on RNA 1(ADAR1).

Changes in RNA editing are closely associated with diseases such as cancer, viral infections, and autoimmune disorders. Adenosine deaminase (ADAR1), which acts on RNA 1, plays a key role in adenosine to inosine editing and is a potential therapeutic target for these various diseases. The p150 subtype of ADAR1 is the only one that contains a Zα domain that binds to both Z-DNA and Z-RNA. The Zα domain modulates immune responses and may be suitable targets for antiviral therapy and cancer immunotherapy. In this study, we attempted to utilize molecular docking to identify potential inhibitors that bind to the ADAR1 Zα domain. The virtual docking method screened the potential activity of more than 100,000 compounds on the Zα domain of ADAR1 and filtered to obtain the highest scoring results.We identified 71 compounds promising to bind to ADAR1 and confirmed that two of them, lithospermic acid and Regaloside B, interacts with the ADAR1 Zα domain by surface plasmonic resonance technique. The molecular dynamics calculation of the complex of lithospermic acid and ADAR1 also showed that the binding effect of lithospermic acid to ADAR1 was stable.This study provides a new perspective for the search of ADAR1 inhibitors, and further studies on the anti-ADAR11 activity of these compounds have broad prospects.

Thrombospondin 1 and Reelin act through Vldlr to regulate cardiac growth and repair.

Adult mammalian cardiomyocytes have minimal cell cycle capacity, which leads to poor regeneration after cardiac injury such as myocardial infarction. Many positive regulators of cardiomyocyte cell cycle and cardioprotective signals have been identified, but extracellular signals that suppress cardiomyocyte proliferation are poorly understood. We profiled receptors enriched in postnatal cardiomyocytes, and found that very-low-density-lipoprotein receptor (Vldlr) inhibits neonatal cardiomyocyte cell cycle. Paradoxically, Reelin, the well-known Vldlr ligand, expressed in cardiac Schwann cells and lymphatic endothelial cells, promotes neonatal cardiomyocyte proliferation. Thrombospondin1 (TSP-1), another ligand of Vldlr highly expressed in adult heart, was then found to inhibit cardiomyocyte proliferation through Vldlr, and may contribute to Vldlr's overall repression on proliferation. Mechanistically, Rac1 and subsequent Yap phosphorylation and nucleus translocation mediate the regulation of the cardiomyocyte cell cycle by TSP-1/Reelin-Vldlr signaling. Importantly, Reln mutant neonatal mice displayed impaired cardiomyocyte proliferation and cardiac regeneration after apical resection, while cardiac-specific Thbs1 deletion and cardiomyocyte-specific Vldlr deletion promote cardiomyocyte proliferation and are cardioprotective after myocardial infarction. Our results identified a novel role of Vldlr in consolidating extracellular signals to regulate cardiomyocyte cell cycle activity and survival, and the overall suppressive TSP-1-Vldlr signal may contribute to the poor cardiac repair capacity of adult mammals.

Case report: Coexistence of triple-seronegative myasthenia gravis and pathology-proven cryptogenic organizing pneumonia.

Objective: Emerging evidence shows that patients with myasthenia gravis (MG) were at a higher risk for the co-occurrence of other autoimmune diseases, which reflects phenotypic heterogeneity in MG. The coexistence of MG and cryptogenic organizing pneumonia (COP) has rarely been reported. The present case is to report the coexistence of triple-seronegative MG and pathology-proven COP in a patient. Methods: The clinical data of the patient were derived from medical records of Nanjing First Hospital, Nanjing Medical University, China. Written informed consent was obtained from the patient. Results: We presented a 56-year-old man with acute respiratory syndrome, who was diagnosed with COP based on the intra-alveolar fibroinflammatory buds (Masson's bodies) in the pathology of bronchoscopy biopsy. Oral prednisone induced dramatic symptomatic improvement and complete resolution of previous lung lesions. After a stable course of no respiratory symptom for 2 months, he was referred to the neurology department with complaints of fluctuating generalized muscle weakness. He was diagnosed with triple-seronegative MG based on fluctuating weakness, neostigmine test-positivity and RNS-positivity. After three-month treatment with pyridostigmine in combination with tacrolimus, the symptoms gradually improved and he achieved minimal symptom expression. Conclusions: This case highlights the rare coexistence of triple-seronegative MG and pathology-proven COP. However, a causal association between COP and MG cannot be explicitly ascertained. In future, more data are needed to clarify the relationship, taking into account the limited number of cases reported with this coexistence of the diseases.

Unraveling the Oxidation of a Graphitic Lattice: Structure Determination of Oxygen Clusters.

Unraveling the oxidation of graphitic lattice is of great interest for atomic-scale lattice manipulation. Herein, we build epoxy cluster, atom by atom, using Van der Waals' density-functional theory aided by Clar's aromatic π-sextet rule. We predict the formation of cyclic epoxy trimers and its linear chains propagating along the armchair direction of the lattice to minimize the system's energy. Using low-temperature scanning tunneling microscopy on oxidized graphitic lattice, we identify linear chains as bright features that have a threefold symmetry, and which exclusively run along the armchair direction of the lattice confirming the theoretical predictions.

Impaired end joining induces cardiac atrophy in a Hutchinson-Gilford progeria mouse model.

Patients with Hutchinson-Gilford progeria syndrome (HGPS) present with a number of premature aging phenotypes, including DNA damage accumulation, and many of them die of cardiovascular complications. Although vascular pathologies have been reported, whether HGPS patients exhibit cardiac dysfunction and its underlying mechanism is unclear, rendering limited options for treating HGPS-related cardiomyopathy. In this study, we reported a cardiac atrophy phenotype in the LmnaG609G/G609G mice (hereafter, HGPS mice). Using a GFP-based reporter system, we demonstrated that the efficiency of nonhomologous end joining (NHEJ) declined by 50% in HGPS cardiomyocytes in vivo, due to the attenuated interaction between γH2AX and Progerin, the causative factor of HGPS. As a result, genomic instability in cardiomyocytes led to an increase of CHK2 protein level, promoting the LKB1-AMPKα interaction and AMPKα phosphorylation, which further led to the activation of FOXO3A-mediated transcription of atrophy-related genes. Moreover, inhibiting AMPK enlarged cardiomyocyte sizes both in vitro and in vivo. Most importantly, our proof-of-concept study indicated that isoproterenol treatment significantly reduced AMPKα and FOXO3A phosphorylation in the heart, attenuated the atrophy phenotype, and extended the mean lifespan of HGPS mice by ~21%, implying that targeting cardiac atrophy may be an approach to HGPS treatment.

Mechanistic Insights on Functionalization of Graphene with Ozone.

The exposure of graphene to O3 results in functionalization of its lattice with epoxy, even at room temperature. This reaction is of fundamental interest for precise lattice patterning, however, is not well understood. Herein, using van der Waals density functional theory (vdW-DFT) incorporating spin-polarized calculations, we find that O3 strongly physisorbs on graphene with a binding energy of -0.46 eV. It configures in a tilted position with the two terminal O atoms centered above the neighboring graphene honeycombs. A dissociative chemisorption follows by surpassing an energy barrier of 0.75 eV and grafting an epoxy group on graphene reducing the energy of the system by 0.14 eV from the physisorbed state. Subsequent O3 chemisorption is preferred on the same honeycomb, yielding two epoxy groups separated by a single C-C bridge. We show that capturing the onset of spin in oxygen during chemisorption is crucial. We verify this finding with experiments where an exponential increase in the density of epoxy groups as a function of reaction temperature yields an energy barrier of 0.66 eV, in agreement with the DFT prediction. These insights will help efforts to obtain precise patterning of the graphene lattice.