miR-455-3p regulates lymphangiogenesis in silicosis by regulating VEGF-C/VEGFR3.

Silicosis is a disease characterized by lung inflammation and fibrosis caused by long-term inhalation of free silicon dioxide (SiO2). Recent studies have found that a large number of lymphatic hyperplasia occurs during the occurrence and development of silicosis. miRNAs play an important role in lymphangiogenesis. However, the regulation and mechanism of miRNAs on lymphangiogenesis in silicosis remain unclear. In this study, lymphangiogenesis was observed in silicosis rats, and VEGF-C-targeted miRNAs were screened, and the effect of miRNAs on the formation of human lymphatic endothelial cells (HLECs) tubular structure was investigated in vitro. The results showed that SiO2 promoted the expressions of Collagen Ι and α-SMA, TNF-α, IL-6 and VEGF-C increased first and then decreased, and promoted the formation of lymphatic vessels. Bioinformatics methods screened miR-455-3p for targeted binding to VEGF-C, and dual luciferase reporter genes confirmed VEGF-C as the target gene of miR-455-3p, and miR-455-3p was down-regulated in the lung tissue of silicosis rats. Transfection of miR-455-3p Inhibitors down-regulated the expression level of miR-455-3p and up-regulated the expression levels of VEGF-C and VEGFR-3 in HLECs, enhanced migration ability and increased tube formation. Transfection of miR-455-3p Mimics showed an opposite trend. These results suggest that miR-455-3p further regulates the tubular structure formation of HLECs by regulating VEGF-C/VEGFR3. Therefore, targeting miR-455-3p may provide a new therapeutic strategy for SiO2-induced silicosis injury.

A rare complex structural variant of novel intragenic inversion combined with reciprocal translocation t(X;1)(p21.2;p13.3) in Duchenne muscular dystrophy.

Structural variants (SVs) are infrequently observed in Duchenne muscular dystrophy (DMD), a condition mainly marked by deletions and point mutations in the DMD gene. SVs in DMD remain difficult to reliably detect due to the limited SV-detection capacity of conventionally used short-read sequencing technology. Herein, we present a family, a boy and his mother, with clinical signs of muscular dystrophy, elevated creatinine kinase levels, and intellectual disability. A muscle biopsy from the boy showed dystrophin deficiency. Routine molecular techniques failed to detect abnormalities in the DMD gene, however, dystrophin mRNA transcripts analysis revealed an absence of exons 59 to 79. Subsequent long-read whole-genome sequencing identified a rare complex structural variant, a 77 kb novel intragenic inversion, and a balanced translocation t(X;1)(p21.2;p13.3) rearrangement within the DMD gene, expanding the genetic spectrum of dystrophinopathy. Our findings suggested that SVs should be considered in cases where conventional molecular techniques fail to identify pathogenic variants.

Environmental factors affecting the risk of generalization for ocular-onset myasthenia gravis: a nationwide cohort study.

BACKGROUND: The environmental effects on the prognosis of ocular myasthenia gravis (OMG) remain largely unexplored. AIM: To investigate the association between specific environmental factors and the generalization of OMG. DESIGN: The cohort study was conducted in China based on a nationwide multicenter database. METHODS: Adult patients with OMG at onset, who were followed up for at least 2 years until May 2022, were included. We collected data on demographic and clinical factors, as well as environmental factors, including latitude, socioeconomic status (per capita disposable income [PDI] at provincial level and education) and smoking. The study outcome was the time to the development of generalized myasthenia gravis (GMG). Cox models were employed to examine the association between environmental exposures and generalization. Restricted cubic spline was used to model the association of latitude with generalization risk. RESULTS: A total of 1396 participants were included. During a median follow-up of 5.15 (interquartile range [IQR] 3.37-9.03) years, 735 patients developed GMG within a median of 5.69 (IQR 1.10-15.66) years. Latitude of 20-50°N showed a U-shaped relation with generalization risk, with the lowest risk at around 30°N; both higher and lower latitudes were associated with the increased risk (P for non-linearity <0.001). Living in areas with lower PDI had 1.28-2.11 times higher risk of generalization. No significant association was observed with education or smoking. CONCLUSIONS: Latitude and provincial-level PDI were associated with the generalization of OMG in China. Further studies are warranted to validate our findings and investigate their potential applications in clinical practice and health policy.

A synonymous codon variant altering splicing of RBCK1 expands the phenotype and genotype spectra of polyglucosan body myopathy 1.

Polyglucosan body myopathy type 1 (PGBM1, OMIM #615895.) is a rare autosomal recessive disorder caused by RBCK1 mutations. The patients displayed polyglucosan accumulation in skeletal and cardiac muscles, giving rise to loss of ambulation and heart failure with or without immune system dysregulation. So far, only 24 patients have been reported, all of whom exhibited symptoms before adulthood. Here, we reported the first case of an adult-onset PGBM1 patient with a novel compound heterozygous RBCK1 gene mutation consisting of a nonsense and synonymous variant affecting splicing.

Wear Performance of Circular Shim against Cam in Engine Bench Test.

Unlike the conventional engine, the valve train of a certain type of engine uses a circular shim instead of a tappet to wear against the cam. To verify the reliability of the shim, an engine bench test was used to test its wear performance. The total duration of the bench test was 1000 h, which was divided into three stages. In each stage, the test equipment was stopped, and the shims were disassembled to observe the surface morphology during the worn process. Precious long-term data were obtained. With the extension of the bench test time, weight loss increased. The maximum weight loss occurs 1000 h after worn, which is about twice that of 350 h. During the wear process, a plastic flow of material was found on the subsurface, and fatigue wear marks occurred on the surface. With an increase in test time, the wear marks increased, leading to material spalling and the formation of pits. The wear mechanism was the mixed wear of fatigue wear and adhesive wear.

Investigation of Friction and Wear Behavior of Cast Aluminum Alloy Piston Skirt with Graphite Coating Using a Designed Piston Skirt Test Apparatus.

A piston skirt friction and wear apparatus that simulates the contact and the relative motion of piston and cylinder liner in a real engine has been designed and constructed. With this apparatus, the friction and wear behavior of a cast aluminum alloy piston with a graphite coating under different loads was studied, and the effectiveness of the apparatus was confirmed. The total wear of the piston skirt was higher under a higher load, and the upper part of the skirt surface (around the height of the piston pin) was worn more severely. The wear mechanisms were studied and, based on the test results and surface analyses, three main wear modes were believed to occur in the wear process of the piston skirt: abrasive, adhesive, and fatigue wear. The effects of skirt profile design, coating, and surface texturing on the friction and wear behavior of the piston skirt can be investigated well using the proposed apparatus, which can truly reflect actual working conditions and is useful to improve the tribological performances of piston skirts.

The regulatory effect of pulmonary lymphatic drainage on silicosis fibrosis.

Silicosis is a fibrotic disease caused by long-term inhalation of SiO2 particles that currently has no effective treatment. Earlier studies have suggested that pulmonary lymphatic vessels play a key role in the transport of silica but have not address the long-term effects of altered pulmonary lymphatic drainage on silicosis. Here, we investigated the impact of impaired pulmonary lymphatic drainage on silicosis. In the past, lymphatic drainage disorders were established mainly through the use of VEGF inhibitors. For the first time, we established a model of pulmonary lymphatic drainage disorder by ligating the thoracic duct in rats. Impaired pulmonary lymphatic drainage was found to aggravate inflammation and oxidative damage in silicosis rats and accelerate silicosis progression. Next, we investigated the effect of pulmonary lymphatic drainage on silicosis. We have demonstrated the effect of sodium tanshinone IIA sulfonate(STS) on lymphangiogenesis, which revealed that STS promotes lymphangiogenesis and can delay inflammation, oxidative damage, and fibrosis progression in silicosis rats by promoting the pulmonary lymphatic drainage response, and this effect is mediated by the VEGFR-3/PI3K/AKT signaling pathway. These findings suggest that pulmonary lymphogenesis plays an important role in silicosis pathogenesis, and targeted intervention in pulmonary lymphangiogenesis may be a potential strategy for treating of silicosis in the future.

Phosphorylation at Ser724 of the ER stress sensor IRE1α governs its activation state and limits ER stress-induced hepatosteatosis.

Inositol-requiring enzyme 1 (IRE1) is an evolutionarily conserved sensor of endoplasmic reticulum (ER) stress and mediates a key branch of the unfolded protein response in eukaryotic cells. It is an ER-resident transmembrane protein that possesses Ser/Thr protein kinase and endoribonuclease (RNase) activities in its cytoplasmic region. IRE1 is activated through dimerization/oligomerization and autophosphorylation at multiple sites, acting through its RNase activity to restore the functional capacity of the ER. However, it remains poorly defined in vivo how the autophosphorylation events of endogenous IRE1 govern its dynamic activation and functional output. Here, we generated a mouse model harboring a S724A knock-in mutation (Ern1S724A/S724A) and investigated the importance of phosphorylation at Ser724 within the kinase activation loop of murine IRE1α. We found that in mouse embryonic fibroblast cells and in primary hepatocytes, S724A mutation resulted in markedly reduced IRE1α autophosphorylation in parallel with blunted activation of its RNase activity to catalyze X-box binding protein 1 (Xbp1) mRNA splicing. Furthermore, ablation of IRE1α phosphorylation at Ser724 exacerbated ER stress-induced hepatic steatosis in tunicamycin-treated Ern1S724A/S724A mice. This was accompanied by significantly decreased hepatic production of spliced XBP1 protein but increased CCAAT-enhancer-binding protein homologous protein (CHOP) level, along with suppressed expression of key metabolic regulators of fatty acid ß-oxidation and lipid secretion. These results demonstrate a critical role of phosphorylation at Ser724 of IRE1α in dynamically controlling its kinase activity, and thus its autophosphorylation state, which is coupled to activation of its RNase activity in counteracting hepatic steatosis under ER stress conditions.

Clinical Predictors of Relapse in a Cohort of Steroid-Treated Patients With Well-Controlled Myasthenia Gravis.

OBJECTIVE: Despite the high efficiency of glucocorticoids (GCs), ~18-34% patients with myasthenia gravis (MG) may experience relapses of the disease. Here, we aim to identify clinical factors related to relapses during steroid tapering or after withdrawal in MG patients who were well-managed on steroid monotherapy. METHODS: We conducted a retrospective study on 125 MG patients from the Xuanwu Hospital MG Trial Database. Patients were treated with corticosteroids and achieved minimal manifestation status (MMS) or better. Patients were divided into steroid reduction subset (N = 74) and steroid withdrawal subset (N = 51). Clinical characteristics and therapeutic data were compared between patients with disease relapse and those who maintained clinical remission at the last follow-ups. Cox proportional hazards regression models were used to identify risk factors of relapse in each subset. RESULTS: Thirty-seven (29.6%) patients experienced relapses during the follow-up periods. Relapse during the steroid reduction was significantly associated with drug reducing duration (HR = 0.81, 95%CI 0.74-0.89, P < 0.001). Risk of relapse was augmented if the drug reducing duration was <11.5 months (HR 27.80, 95%CI 5.88-131.57, P < 0.001). Among patients who discontinued the steroids, those with onset symptoms of bulbar weakness (adjusted HR 3.59, 95%CI 1.19-10.81, P = 0.023) were more likely to experience relapse. CONCLUSION: Our study demonstrated that patients could benefit from prolonged steroid-reducing duration to prevent disease relapse. Patients with bulbar weakness at disease onset should be proposed to take long-term steroids or other immunosuppressants.

Clinical and Imaging Features of Patients With Encephalitic Symptoms and Myelin Oligodendrocyte Glycoprotein Antibodies.

Background: Myelin oligodendrocyte glycoprotein-antibody (MOG-ab)-associated disease (MOGAD) has highly heterogenous clinical and imaging presentations, in which encephalitis is an important phenotype. In recent years, some atypical presentations in MOG-ab-associated encephalitis (MOG-E) have been increasingly reported but have not yet been described well. The aim of the study was to describe the clinical and imaging features of patients with MOG-E in our center. Atypical phenotypes would be reported, which is expected to expand the spectrum of MOGAD. Methods: We reviewed medical records of 59 patients with MOGAD diagnosed in our center and identified cases who had ever experienced encephalitic symptoms. Three hundred ten patients with autoimmune encephalitis (AE) were also reviewed, and cases with positive MOG-ab were identified. Besides, patients with chronically progressive encephalitis were identified from 13 MOG-E and 310 AE patients. We collected demographic, clinical, laboratory, radiological, and outcome data to explore clinical and imaging characteristics in MOG-E, especially in the atypical phenotype of chronically progressive encephalitis. Results: We identified 13 patients (7 males, 6 females) with MOG-E. The median age at onset was 33 years (range 13~62 years). Most (9/13, 69.2%) of patients showed acute or subacute onset of encephalitic symptoms. Brain MRI abnormalities were observed in all patients. The most common lesion locations on MRI were cortical/subcortical (11/13, 84.6%), deep/periventricular white matter (10/13, 76.9%) and corpus callosum (4/13, 30.8%). Brain MRI patterns were categorized into four phenotypes. The most common pattern was cortical encephalitis with leptomeningeal enhancement/brain atrophy (10/13, 76.9%). Eight (8/13, 61.5%) patients had a good response to immunotherapy. Four (4/13, 30.8%) patients with chronically progressive course were identified from MOG-E cohort. They showed leukodystrophy-like pattern, multifocal hazy lesions, or cortical encephalitis on MRI. With immunotherapy, they only showed mild or no improvement. We also identified four (4/310, 1.3%) patients with chronically progressive course from AE cohort. They had better outcomes than counterparts in MOG-E. Conclusions: This study demonstrates that encephalitic presentations in MOGAD had complex clinical patterns. Chronically progressive encephalitis may be a new phenotype of MOGAD. We recommend to test MOG-ab in subacute and chronic progressive dementia with leukodystrophy-like MRI lesions.

Exposure to di-(2-ethylhexyl) phthalate reduces secretion of GDNF via interfering with estrogen pathway and downregulating ERK/c-fos signaling pathway in astrocytes.

Di-(2-ethylhexyl) phthalate (DEHP) is a typical endocrine-disrupting chemical (EDC) that can increase the risk of central nervous system disease. This study aimed to investigate the in vitro and in vivo effects of DEHP exposure on GDNF secretion and the underlying mechanisms. Pregnant Wistar rats were randomly assigned into four groups and administered 0, 30, 300, or 750 mg/kg DEHP daily by oral gavage. In addition, primary astrocytes were exposed to mono-(2-ethylhexyl) phthalate (MEHP), the main metabolite of DEHP. Our results showed that DEHP exposure reduced GDNF levels and downregulated the ERK/c-fos signaling pathway in the cerebral cortex of male, but not female, offspring. Moreover, exogenous estrogen could overcome the decreased GDNF levels in astrocytes caused by MEHP exposure. MEHP also decreased p300 levels and downregulated the ERK/c-fos signaling pathway in primary astrocytes. Honokiol restored GDNF levels following MEHP exposure by activating the ERK/c-fos signaling pathway, while the inhibitor U0126 further reduced the GDNF levels. These results suggested that DEHP exposure could interfere with the normal effects of estrogen in the brain and downregulate the ERK/c-fos signaling pathway to decrease the GDNF secretion from astrocytes in the cerebral cortex.

Anti-contactin-associated protein-like 2 antibody-associated cerebellar ataxia: A case report and literature review.

The spectrum of anti-contactin-associated protein-like 2 (CASPR2) antibody-associated disease is expanding and the involvement of cerebellum was reported in the past few years. We report a 45-year-old male with chronically progressive cerebellar ataxia. CASPR2 antibodies were detected in his serum and cerebellar atrophy was observed on MRI. His symptoms improved prominently with steroids and intravenous immunoglobulins. 23 cases with CASPR2 antibodies and cerebellar ataxia were identified from previous publications. Most of patients showed acute or subacute onset with other typical presentations of anti-CASPR2 antibody-associated disease, such as limbic encephalitis. Immunotherapy was effective in the majority of patients.

Artesunate inhibits epithelial-mesenchymal transition in non-small-cell lung cancer (NSCLC) cells by down-regulating the expression of BTBD7.

In recent years, more and more studies have shown that antiparasitic drugs can affect a variety of biological processes of tumor cells and exhibit a potential anti-tumor activity. Although artesunate (ART), a strong bioactive derivative of artemisinin and widely used clinically against malaria, was found to have an inhibitory effect on tumor cells, it is still unclear whether ART could regulate the tumor malignancy of non-small-cell lung cancer (NSCLC) cells. In this study, we aimed to investigate the effect of ART on migration capacities in NSCLC cell lines of A549 and H1975. Cell migration capacity was remarkably inhibited by ART treatment. The expression of epithelial marker E-cadherin was upregulated, while mesenchymal markers (N-cadherin, vimentin and FN1) were inhibited by ART in both protein and mRNA levels in A549 and H1975 cells, indicating ART could suppress the epidermal interstitial transformation (EMT) of NSCLC cells. Meanwhile, BTBD7 was found highly expressed in tumor tissues of NSCLC patient and associated with poor prognosis. The anti-migration activity of ART was found to be mediated by the inhibition of BTBD7 mRNA expression and was reversed when the cells were transiently transfected with the BTBD7 overexpression plasmid. Our study demonstrated the potent anti-migratory activity of ART, thereby presenting it as a new candidate for clinical therapy in NSCLC.

Cage-confined photocatalysis for wide-scope unusually selective [2 + 2] cycloaddition through visible-light triplet sensitization.

Light-induced [2 + 2] cycloaddition is the most straightforward way to generate cyclobutanes, which are core structures of many natural products, drugs and bioactive compounds. Despite continuous advances in selective [2 + 2] cycloaddition research, general method for intermolecular photocatalysis of acyclic olefins with specific regio- and diastereoselectivity, for example, syn-head-to-head (syn-HH) cyclobutane derivatives, is still lack of development but highly desired. Herein, we report a cage-confined photocatalytic protocol to enable unusual intermolecular [2 + 2] cycloaddition for α,ß-unsaturated carbonyl compounds. The syn-HH diastereomers are readily generated with diastereoselectivity up to 99%. The cage-catalyst is highly efficient and robust, covering a diverse substrate range with excellent substituent tolerance. The mimic-enzyme catalysis is proposed through a host-guest mediated procedure expedited by aqueous phase transition of reactant and product, where the supramolecular cage effect plays an important role to facilitate substrates inclusion and pre-orientation, offering a promising avenue for general and eco-friendly cycloaddition photocatalysis with special diastereoselectivity.

Correlation between EDSS scores and cervical spinal cord atrophy at 3T MRI in multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Cervical spinal cord atrophy (CSCA), which partly reflects the axonal loss in the spinal cord, is increasingly recognized as a valuable predictor of disease outcome. However, inconsistent results have been reported regarding the correlation of CSCA and clinical disability in multiple sclerosis (MS). The aim of this meta-analysis was to synthesize the available data obtained from 3.0-Tesla (3T) MRI scanners and to explore the relationship between CSCA and scores on the Expanded Disability Status Scale (EDSS). METHODS: We searched PubMed, Embase, and Web of Science for articles published from the database inception to February 1, 2019. The quality of the articles was assessed according to a quality evaluation checklist which was created based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. We conducted a meta-analysis of the correlation between EDSS scores and CSCA at 3T MRI in MS. RESULTS: Twenty-two eligible studies involving 1933 participants were incorporated into our meta-analysis. Our results demonstrated that CSCA was negatively and moderately correlated with EDSS scores (rs = -0.42, 95% CI: -0.51 to -0.32; p < 0.0001). Subgroup analyses revealed a weaker correlation in the group of relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) (rs = -0.19, 95% CI: -0.31 to -0.07; p = 0.0029). CONCLUSIONS: The correlation between CSCA and EDSS scores was significant but moderate. We encourage more studies using reliable and consistent methods to explore whether CSCA is suitable as a predictor for MS progression.

The Redox Coupling Effect in a Photocatalytic RuII -PdII Cage with TTF Guest as Electron Relay Mediator for Visible-Light Hydrogen-Evolving Promotion.

A nanocage coupling effect from a redox RuII -PdII metal-organic cage (MOC-16) is demonstrated for efficient photochemical H2 production by virtue of redox-guest modulation of the photo-induced electron transfer (PET) process. Through coupling with photoredox cycle of MOC-16, tetrathiafulvalene (TTF) guests act as electron relay mediator to improve the overall electron transfer efficiency in the host-guest system in a long-time scale, leading to significant promotion of visible-light driven H2 evolution. By contrast, the presence of larger TTF-derivatives in bulk solution without host-guest interactions results in interference with PET process of MOC-16, leading to inefficient H2 evolution. Such interaction provides an example to understand the interplay between the redox-active nanocage and guest for optimization of redox events and photocatalytic activities in a confined chemical nanoenvironment.

Visible-light triggered selective reduction of nitroarenes to azo compounds catalysed by Ag@organic molecular cages.

Herein, a new Ag nanoparticle (Ag NP) loaded organic molecular cage is reported. The obtained Ag@1 can act as a highly efficient heterogeneous catalyst for the selective reduction of nitroarenes to azo compounds under visible-light irradiation.

Design and Enantioresolution of Homochiral Fe(II)-Pd(II) Coordination Cages from Stereolabile Metalloligands: Stereochemical Stability and Enantioselective Separation.

The stereochemistry of chiral-at-metal complexes is much more abundant, albeit complicated, than chiral-at-carbon compounds, but how to make use of stereolabile metal-centers remains a formidable challenge due to the highly versatile coordination geometry of metal ions and racemization/epimerization problem. We demonstrate herein a stepwise assembly of configurationally stable [Pd6(FeL3)8]28+ (Δ/Λ-MOCs-42) homochiral octahedral cages from unstable D3-symmetry tris-chelate-Fe type metalloligands via strong face-directed stereochemical coupling and facile chiral-induced resolution processes based on stereodifferentiating host-guest dynamics. Kinetic studies reveal that the dissociation rate of MOC-42 cages is 100-fold slower than that of Fe-metalloligands and the racemization is effectively inhibited, making the cages retain their chirality over extended periods of time (>5 months) at room temperature. Recyclable enantioseparation of atropisomeric compounds has been successfully achieved, giving up to 88% ee.

Angiogenesis and Hepatic Fibrosis: Western and Chinese Medicine Therapies on the Road.

Hepatic fibrosis is a common feature of almost all chronic liver diseases. Formation of new vessels (angiogenesis) is a process strictly related to the progressive fibrogenesis which leads to cirrhosis and liver cancer. This review mainly concerns the relationship between angiogenesis and hepatic fibrosis, by considering the mechanism of angiogenesis, cells in angiogenesis, anti-angiogenic and Chinese medicine therapies.

Dual Heterogeneous Catalyst Pd-Au@Mn(II)-MOF for One-Pot Tandem Synthesis of Imines from Alcohols and Amines.

A new Mn(II) metal-organic framework (MOF) 1 was synthesized by the combination of 4,4,4-trifluoro-1-(4-(pyridin-4-yl)phenyl)butane-1,3-dione (L) and Mn(OAc)2 in solution. 1 features a threefold-interpenetrating NbO net containing honeycomb-like channels, in which the opposite Mn(II)···Mn(II) distance is 23.5075(10) Å. Furthermore, 1 can be an ideal platform to support Pd-Au bimetallic alloy nanoparticles to generate a composite catalytic system of Pd-Au@Mn(II)-MOF (2). 2 can be a highly active bifunctional heterogeneous catalyst for the one-pot tandem synthesis of imines from benzyl alcohols and anilines and from benzyl alcohols and benzylamines.