Enhanced sampling methodologies modifying underlying Hamiltonians can be used for the systems with a rugged potential energy surface that makes it hard to observe convergence using conventional ...unbiased molecular dynamics (MD) simulations. We present CHARMM‐GUI Enhanced Sampler, a web‐based tool to prepare various enhanced sampling simulations inputs with user‐selected collective variables (CVs). Enhanced Sampler provides inputs for the following nine methods: accelerated MD, Gaussian accelerated MD, conformational flooding, metadynamics, adaptive biasing force, steered MD, temperature replica exchange MD, replica exchange solute tempering 2, and replica exchange umbrella sampling for the method‐implemented MD packages including AMBER, CHARMM, GENESIS, GROMACS, NAMD, and OpenMM. Users only need to select a group of atoms via intuitive web‐implementation in order to define commonly used nine CVs of interest: center of mass based distance, angle, dihedral, root‐mean‐square‐distance, radius of gyration, distance projected on axis, two types of angles projected on axis, and coordination numbers. The enhanced sampling methods are tested with several biological systems to illustrate their efficiency over conventional MD. Enhanced Sampler with carefully optimized system‐dependent parameters will help users to get meaningful results from their enhanced sampling simulations.
Non-alcoholic fatty liver disease (NAFLD) is a dominant cause of chronic liver disease, but the exact mechanism of progression from simple steatosis to nonalcoholic steatohepatitis (NASH) remains ...unknown. Here, we investigated the role of exosomes in NAFLD progression. Exosomes were isolated from a human hepatoma cell line treated with palmitic acid (PA) and their miRNA profiles examined by microarray. The human hepatic stellate cell (HSC) line (LX-2) was then treated with exosome isolated from hepatocytes. Compared with controls, PA-treated hepatocytes displayed significantly increased CD36 and exosome production. The microarray analysis showed there to be distinctive miRNA expression patterns between exosomes from vehicle- and PA-treated hepatocytes. When LX-2 cells were cultured with exosomes from PA-treated hepatocytes, the expression of genes related to the development of fibrosis were significantly amplified compared to those treated with exosomes from vehicle-treated hepatocytes. In conclusion, PA treatment enhanced the production of exosomes in these hepatocytes and changed their exosomal miRNA profile. Moreover, exosomes derived from PA-treated hepatocytes caused an increase in the expression levels of fibrotic genes in HSCs. Therefore, exosomes may have important roles in the crosstalk between hepatocytes and HSCs in the progression from simple steatosis to NASH.
To evaluate the clinical and radiological features, treatment modalities, and outcomes of unusual aneurysms located beyond the origin of the major branches in the posterior circulation, and to ...introduce changes in the recent treatment trends due to rapid innovations in endovascular technology.
This was a retrospective study of patients who underwent treatment for these unusual aneurysms, including those that were identified in regular follow-up after treatment, between March 2009 and April 2023. Medical information including the radiological features of the aneurysms, incidences of rebleeding, associated vascular diseases, treatment modalities, and outcomes, was documented.
A total of 22 cases consisting of two unruptured and 20 ruptured aneurysms were included. Their locations were the posterior cerebral artery in four cases, the superior cerebellar artery in three, the anterior inferior cerebellar artery in two, and the posterior inferior cerebellar artery in 13. Sixteen were saccular, five fusiform, and one blister-like. Eight were pseudo-aneurysms and pre- or intra-operative rebleeding occurred in 13 (65%) of 20 cases with ruptured aneurysms. Five aneurysms coexisted with causative vascular diseases such as arteriovenous malformation, moyamoya disease, or dolichoectasia. Four cases were treated by microsurgical operations and 18 by endovascular operations. In one of the microsurgical cases and five of the endovascular cases, parent arteries were sacrificed. Stents were used in six cases, including low-profile stents in four. Intermediate guiding catheters were used in seven cases for distal access. Full recoveries were seen in 17 cases and death occurred in three.
Treatments for these aneurysms are technically demanding due to the high rate of rebleeding, difficult accessibility, and inevitable necessity of sacrifice of the parent artery in some cases. However, advancing endovascular techniques and devices enable distal access to the lesion and help preserve the parent artery.
CD160 and BTLA both bind to herpes virus entry mediator. Although a negative regulatory function of BTLA in natural killer T (NKT) cell activation has been reported, whether CD160 is also involved is ...unclear. By analyzing CD160
mice and mixed bone marrow chimeras, we show that CD160 is not essential for NKT cell development. However, CD160
mice exhibit severe liver injury after in vivo challenge with α-galactosylceramide (α-GalCer). Moreover, CD160
mice are more susceptible to Concanavalin A challenge, and display elevated serum AST and ALT levels, hyperactivation of NKT cells, and enhanced IFN-γ, TNF, and IL-4 production. Lastly, inhibition of BTLA by anti-BTLA mAb aggravates α-GalCer-induced hepatic injury in CD160
mice, suggesting that both CD160 and BTLA serve as non-overlapping negative regulators of NKT cells. Our data thus implicate CD160 as a co-inhibitory receptor that delivers antigen-dependent signals in NKT cells to dampen cytokine production during early innate immune activation.
AIM To investigate the factors affecting diagnostic delay and outcomes of diagnostic delay in inflammatory bowel disease（IBD） METHODS We retrospectively studied 165 patients with Crohn’s disease（CD） ...and 130 patients with ulcerative colitis（UC） who were diagnosed and had follow up durations > 6 mo at Korea University Ansan Hospital from January 2000 to December 2015. A diagnostic delay was defined as the time interval between the first symptom onset and IBD diagnosis in which the 76th to 100th percentiles of patients were diagnosed.RESULTS The median diagnostic time interval was 6.2 and 2.4 mo in the patients with CD and UC, respectively. Among the initial symptoms, perianal discomfort before diagnosis（OR = 10.2, 95%CI: 1.93-54.3, P = 0.006） was associated with diagnostic delays in patients with CD; however, no clinical factor was associated with diagnostic delays in patients with UC. Diagnostic delays, stricturing type, and penetrating type were associated with increased intestinal surgery risks in CD（OR = 2.54, 95%CI: 1.06-6.09; OR = 4.44, 95%CI: 1.67-11.8; OR = 3.79, 95%CI: 1.14-12.6, respectively）. In UC, a diagnostic delay was the only factor associated increased intestinal surgery risks（OR = 6.81, 95%CI: 1.12-41.4）.CONCLUSION A diagnostic delay was associated with poor outcomes, such as increased intestinal surgery risks in patients with CD and UC.
The exudative age-related macular degeneration (AMD) causes considerable healthcare costs for patients and healthcare system, which are expected to grow as the population ages. The objective of this ...study was to assess the incremental economic burden of exudative AMD by comparing total healthcare costs between the exudative AMD group and non-AMD group to understand economic burden related to exudative AMD.
This retrospective cohort study used the National Health Insurance Service database including the entire Korean population. Exudative AMD group included individuals with at least one claim for ranibizumab and one claim using the registration code for exudative AMD (V201). Non-AMD group was defined as individuals without any claims regarding the diagnostic code of H35.3 or ranibizumab. The exudative AMD group and non-AMD group were matched using a propensity-score model. Incremental healthcare resource utilization and healthcare costs were measured during a one-year follow-up by employing econometric models: ordinary least squares (OLS) with log transformation and heteroscedastic retransformation; and generalized linear model (GLM) with a log link function and gamma distribution.
A total of 7119 exudative AMD patients were matched to 7119 non-AMD patients. The number of outpatient visits was higher in the exudative AMD group (P-value < 0.0001), while the length of hospitalization was shorter in exudative AMD group (P-value < 0.0001). Exudative AMD patients had total costs 2.13 times (95%CI, 2.08-2.17) greater than non-AMD group using OLS, and total costs 4.06 times (95%CI, 3.82-4.31) greater than non-AMD group using GLM. Annual incremental total costs were estimated as $5519 (OLS) and $3699 (GLM).
Exudative AMD was associated with significantly increased healthcare costs compared to the non-AMD group. Attention is needed to manage the socioeconomic burden of exudative AMD.
Hepatocellular carcinoma(HCC) is one of the leading causes of cancer death, especially in Eastern areas. With advancements in diagnosis and treatment modalities for HCC, the survival and prognosis of ...HCC patients are improving. However, treatment patterns are not uniform between areas despite efforts to promote a common protocol. Although many hepatologists in Asian countries may adopt the principles of the Barcelona Clinic Liver Cancer staging system, they are also independently making an effort to expand the indications of each treatment and to combine therapies for better outcomes. Several expanded criteria for liver transplantation in HCC have been developed in Asian countries. Living donor liver transplantation is much more commonly performed in these countries than deceased donor liver transplantation, and it may be preceded by other treatments such as the down-staging of tumors. Local ablation therapies are often combined with transarterial chemoembolization( TACE) and the outcome is comparable to that of surgical resection. The indications of TACE are expanding, and there are new types of transarterial therapies. Although data on drug-eluting beads, TACE, and radioembolization in Asian countries are still relatively sparse compared with Western countries, these methods are gradually gaining popularity because of better tolerability and the possibility of improved response rates. Hepatic arterial infusion chemotherapy and radiotherapy are not included in Western guidelines, but are currently being used actively in several Asian countries. For more advanced HCCs, appropriate combinations of TACE, radiotherapy, and sorafenib can be considered, and emerging data indicate improved outcomes of combination therapies compared with single therapies. To include these paradigm shifts into newer treatment guidelines, more studies may be needed, but they are certainly in progress.
To evaluate the seizure characteristics and outcome after immunotherapy in adult patients with autoimmune encephalitis (AE) and new-onset seizure.
Adult (age ≥18 years) patients with AE and new-onset ...seizure who underwent immunotherapy and were followed-up for at least 6 months were included. Seizure frequency was evaluated at 2-4 weeks and 6 months after the onset of the initial immunotherapy and was categorized as "seizure remission", "> 50% seizure reduction", or "no change" based on the degree of its decrease.
Forty-one AE patients who presented with new-onset seizure were analysed. At 2-4 weeks after the initial immunotherapy, 51.2% of the patients were seizure free, and 24.4% had significant seizure reduction. At 6 months, seizure remission was observed in 73.2% of the patients, although four patients died during hospitalization. Rituximab was used as a second-line immunotherapy in 12 patients who continued to have seizures despite the initial immunotherapy, and additional seizure remission was achieved in 66.6% of them. In particular, those who exhibited partial response to the initial immunotherapy had a better seizure outcome after rituximab, with low adverse events.
AE frequently presented as seizure, but only 18.9% of the living patients suffered from seizure at 6 months after immunotherapy. Aggressive immunotherapy can improve seizure outcome in patients with AE.
The intricate connection between gut microbiota and rheumatoid arthritis (RA) pathogenesis has gained prominence, although the specific microbial species contributing to RA development remain largely ...unknown. Recent studies have sought to comprehensively explore alterations in the human microbiome, focusing on identifying disease-related microbial species through blood analysis. Consequently, this study aimed to identify RA-associated microbial species using a serum microbial array system and to investigate the efficacy and underlying mechanisms of potential microbial species for RA treatment.
Serum immunoglobulin M levels against 384 intestinal microbial species were assessed using a microbial microarray in patients with RA and healthy individuals. We investigated the therapeutic potential of the identified microbial candidate regarding arthritis development, immune responses, gut barrier function, and gut microbiome using a collagen-induced arthritis (CIA) mouse model.
Our findings revealed significant alterations in antibody levels against 36 microbial species in patients with RA compared to healthy individuals. Notably, the antibody levels against
(
) were decreased in patients with RA and exhibited an inverse correlation with RA disease activity.
experiments demonstrated that
produced acetate and butyrate, while exhibiting anti-inflammatory properties. In CIA mice,
administration suppressed arthritis symptoms, reduced the accumulation of inflammatory monocytes in the mesenteric lymph nodes, and downregulated gene expression of pro-inflammatory cytokines in the ileum. Additionally,
supplementation restored intestinal barrier integrity and partially resolved gut microbial dysbiosis in CIA mice. The fecal microbiota in
-treated mice corresponded to improved intestinal barrier integrity and reduced inflammatory responses.
This study highlights the potential of serum-based detection of anti-microbial antibodies to identify microbial targets at the species level for RA treatment. Moreover, our findings suggest that
, identified through the microbial microarray analysis, holds therapeutic potential for RA by restoring intestinal barrier integrity and suppressing the immunologic response associated with RA.
Ionizing radiation induces modification of the tumor microenvironment such as tumor surrounding region, which is relevant to treatment outcome after radiotherapy. In this study, the effects of ...pre-irradiated tumor beds on the growth of subsequently implanted tumors were investigated as well as underlying mechanism. The experimental model was set up by irradiating the right thighs of C3H/HeN mice with 5 Gy, followed by the implantation of HCa-I and MIH-2. Both implanted tumors in the pre-irradiated bed showed accelerated-growth compared to the control. Tumor-infiltrated lymphocyte (TIL) levels were increased, as well as pro-tumor factors such as IL-6 and transforming growth factor-beta1 (TGF-β1) in the pre-irradiated group. In particular, the role of pro-tumor cytokine interleukin-17A (IL-17A) was investigated as a possible target mechanism because IL-6 and TGF-β are key factors in Th17 cells differentiation from naïve T cells. IL-17A expression was increased not only in tumors, but also in CD4+ T cells isolated from the tumor draining lymph nodes. The effect of IL-17A on tumor growth was confirmed by treating tumors with IL-17A antibody, which abolished the acceleration of tumor growth. These results indicate that the upregulation of IL-17A seems to be a key factor for enhancing tumor growth in pre-irradiated tumor beds.
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