Follicular CD8+ T cells promote immunoglobulin production and demyelination in multiple sclerosis and a murine model.

Emerging evidence underscores the importance of CD8+ T cells in the pathogenesis of multiple sclerosis (MS), but the precise mechanisms remain ambiguous. This study intends to elucidate the involvement of a novel subset of follicular CD8+ T cells (CD8+CXCR5+ T) in MS and an experimental autoimmune encephalomyelitis (EAE) murine model. The expansion of CD8+CXCR5+ T cells was observed in both MS patients and EAE mice during the acute phase. In relapsing MS patients, higher frequencies of circulating CD8+CXCR5+ T cells were positively correlated with new gadolinium-enhancement lesions in the central nervous system (CNS). In EAE mice, frequencies of CD8+CXCR5+ T cells were also positively correlated with clinical scores. These cells were found to infiltrate into ectopic lymphoid-like structures in the spinal cords during the peak of the disease. Furthermore, CD8+CXCR5+ T cells, exhibiting high expression levels of ICOS, CD40L, IL-21, and IL-6, were shown to facilitate B cell activation and differentiation through a synergistic interaction between CD40L and IL-21. Transferring CD8+CXCR5+ T cells into naïve mice confirmed their ability to enhance the production of anti-MOG35-55 antibodies and contribute to the disease progression. Consequently, CD8+CXCR5+ T cells may play a role in CNS demyelination through heightening humoral immune responses.

Unraveling the Binding Mode of Cyclic Adenosine-Inosine Monophosphate (cAIMP) to STING through Molecular Dynamics Simulations.

The stimulator of interferon genes (STING) plays a significant role in immune defense and protection against tumor proliferation. Many cyclic dinucleotide (CDN) analogues have been reported to regulate its activity, but the dynamic process involved when the ligands activate STING remains unclear. In this work, all-atom molecular dynamics simulations were performed to explore the binding mode between human STING (hSTING) and four cyclic adenosine-inosine monophosphate analogs (cAIMPs), as well as 2',3'-cGMP-AMP (2',3'-cGAMP). The results indicate that these cAIMPs adopt a U-shaped configuration within the binding pocket, forming extensive non-covalent interaction networks with hSTING. These interactions play a significant role in augmenting the binding, particularly in interactions with Tyr167, Arg238, Thr263, and Thr267. Additionally, the presence of hydrophobic interactions between the ligand and the receptor further contributes to the overall stability of the binding. In this work, the conformational changes in hSTING upon binding these cAIMPs were also studied and a significant tendency for hSTING to shift from open to closed state was observed after binding some of the cAIMP ligands.

The ratio of circulating CD56dim NK cells to follicular T helper cells as a promising predictor for disease activity of relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system primarily mediated by CD4+ T helper cells. This study investigated the dynamic changes of natural killer (NK) cells and follicular T helper (Tfh) cells and their associations in relapsing-remitting MS patients. The findings revealed inverse relationships between NK cells and CD4+ T cells or Tfh cells. Specifically, CD56dim NK cells, not CD56bright NK cells, were negatively correlated with CD4+ T cells and Tfh cells. However, no significant correlations were found between NK cells and sNfL levels or EDSS scores. The ratio of CD56dim NK cells to circulating Tfh (cTfh) cells demonstrated superior discriminatory ability in distinguishing relapsing MS patients from healthy controls (HCs) and remitting patients, as determined by receiver operating characteristic (ROC) analysis. Following treatment with immunosuppressants or disease-modifying therapies (DMTs), a significant increase in the CD56dim NK/cTfh ratio was observed. These findings suggest that the CD56dim NK/cTfh ratio holds promise as a prognostic indicator for clinical relapse and treatment response in MS.

Lysine-Specific Demethylase 1 Inhibitors: A Comprehensive Review Utilizing Computer-Aided Drug Design Technologies.

Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising therapeutic target for treating various cancers (such as breast cancer, liver cancer, etc.) and other diseases (blood diseases, cardiovascular diseases, etc.), owing to its observed overexpression, thereby presenting significant opportunities in drug development. Since its discovery in 2004, extensive research has been conducted on LSD1 inhibitors, with notable contributions from computational approaches. This review systematically summarizes LSD1 inhibitors investigated through computer-aided drug design (CADD) technologies since 2010, showcasing a diverse range of chemical scaffolds, including phenelzine derivatives, tranylcypromine (abbreviated as TCP or 2-PCPA) derivatives, nitrogen-containing heterocyclic (pyridine, pyrimidine, azole, thieno[3,2-b]pyrrole, indole, quinoline and benzoxazole) derivatives, natural products (including sanguinarine, phenolic compounds and resveratrol derivatives, flavonoids and other natural products) and others (including thiourea compounds, Fenoldopam and Raloxifene, (4-cyanophenyl)glycine derivatives, propargylamine and benzohydrazide derivatives and inhibitors discovered through AI techniques). Computational techniques, such as virtual screening, molecular docking and 3D-QSAR models, have played a pivotal role in elucidating the interactions between these inhibitors and LSD1. Moreover, the integration of cutting-edge technologies such as artificial intelligence holds promise in facilitating the discovery of novel LSD1 inhibitors. The comprehensive insights presented in this review aim to provide valuable information for advancing further research on LSD1 inhibitors.

3D printed zirconia used as dental materials: a critical review.

In view of its high mechanical performance, outstanding aesthetic qualities, and biological stability, zirconia has been widely used in the fields of dentistry. Due to its potential to produce suitable advanced configurations and structures for a number of medical applications, especially personalized created devices, ceramic additive manufacturing (AM) has been attracting a great deal of attention in recent years. AM zirconia hews out infinite possibilities that are otherwise barely possible with traditional processes thanks to its freedom and efficiency. In the review, AM zirconia's physical and adhesive characteristics, accuracy, biocompatibility, as well as their clinical applications have been reviewed. Here, we highlight the accuracy and biocompatibility of 3D printed zirconia. Also, current obstacles and a forecast of AM zirconia for its development and improvement have been covered. In summary, this review offers a description of the basic characteristics of AM zirconia materials intended for oral medicine. Furthermore, it provides a generally novel and fundamental basis for the utilization of 3D printed zirconia in dentistry.

Polarity Conversion of the Ag2S/AgInS2 Heterojunction by Radical-Induced Positive Feedback Polydopamine Adhesion for Signal-Switchable Photoelectrochemical Biosensing.

Efficient tuning of the polarity of photoactive nanomaterials is of great importance in improving the performance of photoelectrochemical (PEC) sensing platforms. Herein, polarity of the Ag2S/AgInS2 heterojunction is converted by radical-induced positive feedback polydopamine (PDA) adhesion, which is further employed to develop a signal-switchable PEC biosensor. In the nanocomposites, Ag2S and AgInS2 achieve electron-hole separation, exhibiting a strong anodic PEC response. Under the irradiation of light, the Ag2S/AgInS2 heterojunction is able to produce superoxide radical and hydroxyl radical intermediate species, leading to the polymerization of dopamine (DA) and the subsequent adhesion of PDA onto the Ag2S/AgInS2 heterojunction (Ag2S/AgInS2@PDA). By constructing a new electron-transfer pathway with PDA, the polarity of the Ag2S/AgInS2 heterojunction is converted, and the PEC response changes from anodic to cathodic photocurrents. In addition, since the photoreduction activity of PDA is stronger than that of the Ag2S/AgInS2 heterojunction, more superoxide radical can be produced by Ag2S/AgInS2@PDA once PDA is generated, thereby promoting the generation of PDA. Consequently, a positive feedback mechanism is established to enhance the polarity conversion of the Ag2S/AgInS2 heterojunction and amplify the responding to DA. As a result, the bioanalytical method is capable of sensitively quantifying DA in 10 orders of magnitude with an ultralow limit of detection. Moreover, the applicability of this biosensor in real samples is identified by measuring DA in fetal bovine serum and compared with a commercial ELISA method. Overall, this work offers an alternative perspective for adjusting photogenerated carriers of nanomaterials and designing high-performance PEC biosensors.

Short-term safety of inactivated SARS-Cov-2 vaccines in Chinese patients with central nervous system inflammatory demyelinating diseases.

Objective: This study aims to evaluate the short-term safety of inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in Chinese patients with central nervous system inflammatory demyelinating diseases (CNS IDDs). Methods: A web-based survey was conducted among patients with CNS IDDs from April 15 to 19, 2022 in China. In total, 645 patients with CNS IDDs were identified, including 425 patients with multiple sclerosis (MS), 194 with neuromyelitis optica spectrum disorder (NMOSD), and 26 with other CNS IDDs. The questionnaire consisted of demographic data, clinical records, history of SARS-CoV-2 vaccination, and vaccination-related symptoms within one month after vaccination. The demographic data, clinical information, and relapse rates between vaccinated and non-vaccinated patients were compared. Results: Among 645 patients with CNS IDDs, 78 were vaccinated and 567 were non-vaccinated with the vaccination rate of 12.1 %. Compared to non-vaccinated group, a lower percentage of patients on DMDs therapy (41.0 % vs. 71.8 %, P < 0.001) and an increased proportion of patients with other vaccination in past 3 years (17.9 % vs. 4.8 %, P < 0.001) were observed in vaccinated group. Six patients experienced a relapse within 30 days of a vaccination. Additionally, vaccine-associated relapse rates in vaccinated patients did not significantly differ from these in non-vaccinated patients among 2020, 2021, and from January 1 to October 1, 2022. Conclusions: No increased risk of vaccination-associated relapses among Chinese patients with CNS IDDs indicated that inactivated SARS-CoV-2 vaccines appear to be safe for this population.

Rituximab at lower dose for neuromyelitis optica spectrum disorder: a multicenter, open-label, self-controlled, prospective follow-up study.

Objective: To address a novel lower-dose rituximab (RTX) therapy strategy based on our clinical experience and assess its efficacy and safety in neuromyelitis optica spectrum disorder (NMOSD). Methods: A multicenter, open-label, self-controlled, prospective follow-up study. Totally, 108 NMOSD patients were enrolled and a lower-dose RTX strategy was applied including 100 mg weekly for 3 weeks and then reinfusions every 6 months. Annualized relapse rate (ARR), the expanded disability status scale (EDSS) score and length of spinal cord lesions were included to evaluate the efficacy. Side effects were recorded to assess the safety profile. Results: Of 108 patients, 80 (74.1%) initiated low-dose RTX therapy immediately after acute attack treatment and 33 (30.6%) initiated it after the first attack. During a median treatment period of 35.5 (22.0-48.8) months, significant decreases were observed in median ARR (1.1 [0.8-2.0] versus 0 [0-0.2], p < 0.001), EDSS score (3.5 [2.5-4.0] versus 2.0 [1.0-3.0], p < 0.001) and spinal cord lesion segments (5.0 [4.0-8.0] versus 3.0 [1.0-6.0], p < 0.001). The cumulative risk of relapses significantly decreased during the post- versus pre-RTX period (HR 0.238, 95%CI 0.160-0.356, p < 0.001) and on early therapy initiated within 24 months after disease onset versus delayed therapy (HR 0.506, 95%CI 0.258-0.994, p = 0.041). No serious side effects were recorded and all the subjects did not discontinue treatment due to RTX-related side effects. Conclusion: Our research provided evidence supporting the lower-dose RTX strategy in treating NMOSD and reopened the issues of optimal dosage and therapy initiation timing.

Single-cell transcriptome, phagocytic activity and immunohistochemical analysis of crucian carp (Carassius auratus) in response to Rahnella aquatilis infection.

In teleost fish, kidney is an important immune and hematopoietic organ with multiple physiological functions. However, the immune cells and cellular markers of kidney require further elucidation in crucian carp (C. auratus). Here we report on the single-cell transcriptional landscape in posterior kidney, immunohistochemical and phagocytic features of C. auratus with R. aquatilis infection. The results showed that a total of 18 cell populations were identified for the main immune cells such as monocytes/macrophages (Mo/Mφ), dendritic cells (DCs), B cells, T cells, granulocytes and hematopoietic progenitor cells (HPCs). Pseudo-time trajectory analysis was reconstructed for the immune cells using Monocle2 to obtain additional insights into their developmental lineage relationships. In the detected tissues (liver, spleen, kidney, intestine, skin, and gills) of infected fish exhibited positive immunohistochemical staining with prepared for antibody to R. aquatilis. Apoptotic cells were fluorescently demonstrated by TUNEL assay, and bacterial phagocytic activity were observed for neutrophils and Mo/Mφ cells, respectively. Moreover, a similar up-ward/down-ward expression trend of the selected immune and inflammatory genes was found in the kidney against R. aquatilis infection, which were significantly involved in TLR/NLR, ECM adhesion, phago-lysosome, apoptosis, complement and coagulation pathways. To our knowledge, this is the first report on the detailed characterization of immune cells and host-R. aquatilis interaction, which will contribute to understanding on the biology of renal immune cells and repertoire of potential markers in cyprinid fish species.

Improving the adsorption performance of urea by using polyhydroxy groups to modify two-dimensional Ti3C2Tx.

Wearable artificial kidney can provide continuous dynamic dialysis for uremia patients. For the sake of practical application, the critical step is to find an adsorbent that can effectively remove urea and have excellent biological compatibility. The layered Ti3C2Tx (DL-Ti3C2Tx) with high specific surface area and good dispersion was prepared by a two-step etching method. From the first principles calculation, urea can be adsorbed by different groups (-F, -O, -OH) on the surface of Ti3C2Tx, among which -OH has the greatest binding energy to urea. Therefore, DL-Ti3C2Tx was modified with different alkali solutions (KOH, NaOH, LiOH) to introduce -OH on the surface, which can increase the adsorption capacity of urea. The experimental results showed that DL-Ti3C2Tx (LiOH-Ti3C2Tx) after treated by LiOH had the highest urea adsorption efficiency, and the urea removal rate of LiOH-Ti3C2Tx was still higher than 92% when the urea concentration was 500 mg/L. In the Simulated dialysate, Ti3C2Tx treated with three kinds of alkali solutions still maintained a good adsorption efficiency for urea, and still had a certain adsorption capacity after recycling for four times. Biocompatibility experiments showed that Ti3C2Tx in different concentrations did not cause hemolysis of erythrocyte, and had no obvious damage to vascular endothelial cells. This study greatly improves the urea adsorption efficiency of MXene, which has a broad application prospect in the selection of adsorbent for wearable artificial kidney.

Loss of signal transducer and activator of transcription 3 in osteoblasts impaired the bone healing in inflammatory microenvironment.

INTRODUCTION: This study aimed to investigate the effect of Stat3 on the osteoblast-mediated bone healing in the inflammatory lesion. METHODS: The conditional knockout of Stat3 in osteoblasts (Stat3 CKO) was generated via the Cre-loxP recombination system using Osterix-Cre transgenic mice. The calvarial bone inflammatory lesions were established on both Stat3 CKO and wild-type mice, then harvested to assess the bone healing. In response to lipopolysaccharide (LPS) stimulation, osteoblasts from Stat3 CKO and wild-type mice were subjected to examine the formation of calcium deposits, the expression of osteogenic markers (i.e., Runx2, OPN, COL1A1), and osteoclast-related markers (i.e., RANKL, OPG). The EdU and transwell assays were performed to assess the proliferation and migration of the cells. RESULTS: A decrease in bone mass and an increase in osteolysis were found in the inflammatory lesions on Stat3 CKO mice when compared with the control. More osteoclastic-like cells and an increased expression of RANKL were observed in Stat3 CKO mice. Both mRNA and protein expressions of Stat3 and osteogenic markers in the lesions were significantly decreased in Stat3 CKO mice. After co-cultured with osteogenic medium, the Stat3-deficient osteoblasts were found with a significant decrease in calcium deposits and the expression of osteogenic markers, and with a significant increased expression of RANKL. The impaired ossification of Stat3-deficient osteoblasts was even more pronounced with the presence of lipopolysaccharides in vitro. The most decrease in cell proliferation and migration was found in Stat3-deficient osteoblasts in response to LPS. CONCLUSIONS: Loss of Stat3 in osteoblasts impaired bone healing in an inflammatory microenvironment.

Late-Onset Anti-GABAB Receptor Encephalitis: Clinical Characteristics and Outcomes Differing From Early-Onset Patients.

BACKGROUND AND OBJECTIVES: Existing evidence indicates anti-GABAB receptor encephalitis (GABABR-E) seems to occur more commonly later in life, yet the age-associated differences in clinical features and outcomes are not well determined. This study aims to explore the demographic, clinical characteristics, and prognostic differences between late-onset and early-onset GABABR-E and identify predictors of favorable long-term outcomes. METHODS: This is an observational retrospective study conducted in 19 centers from China. Data from 62 patients with GABABR-E were compared between late-onset (aged 50 years or older) and early-onset (younger than 50 years) groups and between groups with favorable outcomes (modified Rankin scale (mRS) ≤ 2) and poor outcomes (mRS >2). Logistic regression analyses were applied to identify factors affecting long-term outcomes. RESULTS: Forty-one (66.1%) patients experienced late-onset GABABR-E. A greater proportion of males, a higher mRS score at onset, higher frequencies of ICU admission and tumors, and a higher risk of death were demonstrated in the late-onset group than in the early-onset group. Compared with poor outcomes, patients with favorable outcomes had a younger onset age, a lower mRS score at onset, lower frequencies of ICU admission and tumors, and a greater proportion with immunotherapy maintenance for at least 6 months. On multivariate regression analysis, age at onset (OR, 0.849, 95% CI 0.739-0.974, p = 0.020) and the presence of underlying tumors (OR, 0.095, 95% CI 0.015-0.613, p = 0.013) were associated with poorer long-term outcomes, whereas immunotherapy maintenance for at least 6 months was associated with favorable outcomes (OR, 10.958, 95% CI 1.469-81.742, p = 0.020). DISCUSSION: These results demonstrate the importance of risk stratification of GABABR-E according to age at onset. More attention should be paid to older patients especially with underlying tumors, and immunotherapy maintenance for at least 6 months is recommended to achieve a favorable outcome.

Loss of Stat3 in Osterix+ cells impairs dental hard tissues development.

BACKGROUND: Mutations in the signal transducers and activators of transcription 3 (STAT3) gene result in hyper-IgE syndrome(HIES), a rare immunodeficiency that causes abnormalities in immune system, bones and teeth. However, the role of Stat3 in development of dental hard tissues was yet to investigate. METHODS: In this study, a transgenic mouse of conditional knockout of Stat3 in dental mesenchymal cells (Osx-Cre; Stat3fl/fl, Stat3 CKO) was made. The differences of postnatal tooth development between control and Stat3 CKO mice were compared by histology, µCT and scanning electron microscopy. RESULT: Compared with the control, Stat3 CKO mice were presented with remarkable abnormal tooth phenotypes characterized by short root and thin dentin in molars and incisors. The enamel defects were also found on mandibular incisors. showed that Ki67-positive cells significantly decreased in dental mesenchymal of Stat3 CKO mice. In addition, ß-catenin signaling was reduced in Hertwig's epithelial root sheath (HERS) and odontoblasts of Stat3 CKO mice. CONCLUSIONS: Our results suggested that Stat3 played an important role in dental hard tissues development, and Stat3 may regulate dentin and tooth root development through the ß-catenin signaling pathway.

Measurement of Mechanical Properties of VO2 Films by Nanoindentation.

The present work reported the intrinsic mechanical behavior of vanadium dioxide (VO2) thin film deposited on a SiO2 substrate using a combination of nanoindentation tests and a theoretical model. The effect of phase transition on mechanical parameters was studied by adjusting the test temperature. A new model that can simultaneously extract the elastic modulus and hardness was derived by introducing a dimensional analysis. The results showed that the thin film exhibits a hardness of 9.43 GPa and a Young's modulus of about 138.5 GPa at room temperature, compared with the values of 5.71 GPa and 126.9 GPa at a high temperature, respectively. It can be seen that the intrinsic mechanical parameters decrease to a certain extent after a phase transition. Finally, the numerical simulation results were consistent with those of the experiments, which verified the effectiveness of the new method. In addition, this study also provided useful guidance for mechanical tests on other ultra-thin films.

Efficacy and safety of repeated low-dose rituximab therapy in relapsing-remitting multiple sclerosis: A retrospective case series study.

BACKGROUND: Rituximab (RTX) is an extensively used off-label drug for multiple sclerosis (MS), whereas the induction and maintenance regimens vary widely among studies. Few data are available on efficacy and safety of repeated low-dose RTX therapy in MS patients. OBJECTIVE: This study aimed to evaluate the efficacy and safety of repeated low-dose RTX therapy for relapsing-remitting MS (RRMS), the most common form of MS affecting approximately 85% of patients. METHODS: Nine RRMS patients were enrolled and the medical records were retrospectively reviewed. RTX at 100 mg per week for three consecutive weeks was used as induction therapy. Maintenance therapy was reinfusions of RTX at 100 mg every 6 months during the first year, followed by 100 mg every 6 to 12 months. Main outcome measures included annualized relapse rate (ARR), expanded disability status scale (EDSS) score, and T2 lesion burden on MRI for evaluating the efficacy of low-dose RTX regimen. Meanwhile, adverse events (AEs) were recorded to assess the safety of repeated RTX infusions. RESULTS: All patients were females with an average onset age of 25.4 ± 6.7 years. The median disease duration before the first RTX infusion was 56 (range, 3-108) months and the median follow-up period was 30 (range, 15-40) months. No relapses were recorded in all patients after RTX therapy. Repeated low-dose RTX therapy resulted in a dramatic reduction of median ARR (pre-RTX vs post-RTX, 1.1 vs 0, p = 0.012), median EDSS score (2.0 vs 0, p = 0.007), and the number of T2 lesions on MRI (35.6 ± 18.0 vs 29.4 ± 18.1, p = 0.001). A total of 35 episodes of AEs occurred during repeated low-dose RTX therapy, and all of them were mild and transient. CONCLUSION: Repeated low-dose RTX therapy is cost-effective for RRMS patients and shows a good safety profile. It may be a promising option for those having no access or poor response to first-line disease-modified drugs (DMDs), particularly in low- or middle-income countries.

Macroporous honeycomb-like magnesium oxide fabricated as long-life and outstanding Pb(II) adsorbents combined with mechanism insight.

The macroporous honeycomb-like MgO (MHM) had been successfully prepared by hard template method using polystyrene (PS) spheres with different particle sizes of about 400, 600, and 800 nm, respectively. The adsorption performance (3700, 3470, and 3087 mg/g) and specific surface areas (64.0, 51.4, and 34.4 m2/g) of MHM materials were inversely proportional to their pore diameters. Among the prepared MHM materials, MHM-400 exhibited the most excellent adsorption performance of 3700 mg/g towards Pb(II) at 25 °C. In this study, the macropore size in MHM played a major role in the adsorption process; Dubinin-Radushkevich (D-R) model further indicated that Pb(II) removal by MHM-400 was dominated by chemical adsorption. The thermodynamic analysis (ΔG0 < 0, ΔH0 > 0, and ΔS0 > 0) revealed that the Pb(II) adsorption was spontaneous and endothermic. After storing for 360 days, the Pb(II) removal efficiency of MHM-400 was still higher than 98.2%, exhibiting ultra-long life for Pb(II) capture. MHM-400 also exhibited high anti-interference ability towards typically coexisting ions (Na+ and K+). According to the density functional theory (DFT) calculation, the Pb could be adsorbed on the top site of the oxygen atom at the surface of the cubic MgO (200) plane; the adsorption energy (Ead) was 0.159 eV. The XRD and FTIR analyses revealed the further formation of Pb3(CO3)2(OH)2 and PbO after Pb(II) adsorption. Furthermore, MHM-400 could effectively remove both Cd(II) and Pb(II) ions from wastewater within 20 min, and the adsorption efficiency achieved > 99%, suggesting that MHM-400 was a potential material for effective Pb(II) removal.

Design Two Novel Tetrahydroquinoline Derivatives against Anticancer Target LSD1 with 3D-QSAR Model and Molecular Simulation.

Lysine-specific demethylase 1 (LSD1) is a histone-modifying enzyme, which is a significant target for anticancer drug research. In this work, 40 reported tetrahydroquinoline-derivative inhibitors targeting LSD1 were studied to establish the three-dimensional quantitative structure-activity relationship (3D-QSAR). The established models CoMFA (Comparative Molecular Field Analysis (q2 = 0.778, Rpred2 = 0.709)) and CoMSIA (Comparative Molecular Similarity Index Analysis (q2 = 0.764, Rpred2 = 0.713)) yielded good statistical and predictive properties. Based on the corresponding contour maps, seven novel tetrahydroquinoline derivatives were designed. For more information, three of the compounds (D1, D4, and Z17) and the template molecule 18x were explored with molecular dynamics simulations, binding free energy calculations by MM/PBSA method as well as the ADME (absorption, distribution, metabolism, and excretion) prediction. The results suggested that D1, D4, and Z17 performed better than template molecule 18x due to the introduction of the amino and hydrophobic groups, especially for the D1 and D4, which will provide guidance for the design of LSD1 inhibitors.

Analysis of Thermal Stress in Vanadium Dioxide Thin Films by Finite Element Method.

The buckling, de-lamination, and cracking of the thin film/substrate system caused by thermal stress is the main obstacle for functional failure. Moreover, the thermal stress of vanadium dioxide (VO2) thin film may be more complicated due to the stress re-distribution caused by phase transition. Therefore, the thermal stress of VO2 thin films deposited on four substrates with different materials (fused silica, silicon slice, sapphire, and glass) has been studied by finite element method in the present work. The influences of external temperature, substrate, and interlayer on thermal stress were analyzed. It was found that the substrates can greatly affect the thermal stresses, which were mainly caused by the mismatch of coefficient of thermal expansion (CTE). The thermal stress had a linear relationship with the external temperature, but this tendency would be redistributed or even change direction when phase transition occurred. The simulated results were in tandem with the analytical method. Meanwhile, the radial stress and shear stress distribution under the influence of phase transition were calculated. In addition, the reduction of thermal stress and shear stress showed that the appropriate interlayer can enhance the adhesive strength effectively.

Comparing algorithms for characterizing treatment effect heterogeneity in randomized trials.

The identification and estimation of heterogeneous treatment effects in biomedical clinical trials are challenging, because trials are typically planned to assess the treatment effect in the overall trial population. Nevertheless, the identification of how the treatment effect may vary across subgroups is of major importance for drug development. In this work, we review some existing simulation work and perform a simulation study to evaluate recent methods for identifying and estimating the heterogeneous treatments effects using various metrics and scenarios relevant for drug development. Our focus is not only on a comparison of the methods in general, but on how well these methods perform in simulation scenarios that reflect real clinical trials. We provide the R package benchtm that can be used to simulate synthetic biomarker distributions based on real clinical trial data and to create interpretable scenarios to benchmark methods for identification and estimation of treatment effect heterogeneity.

Notch signaling dependent monocyte conversion alleviates immune-mediated neuropathies by regulating RBP-J/NR4A1 axis.

Monocytes in peripheral blood and sciatic nerves play vital roles in immune-mediated neuropathies such as Guillain-Barré syndrome (GBS). Different subpopulations of monocytes, including classical and non-classical, exhibit distinct functions as well as phenotypic conversion potentials. However, the mechanisms underlying their development during immune-mediated neuropathy remain unclear. Notch signaling participates in monocyte differentiation and function. In this study, we used a myeloid-specific Notch signaling activation transgenic mouse (NICcA) and investigated the role of Notch signaling in monocytes during experimental autoimmune neuritis (EAN) in a mouse model of GBS. Clinical score assessment and histopathological examination revealed that sciatic nerve injury was attenuated in NICcA EAN mice compared to that in control mice. Flow cytometry and immunofluorescence staining suggested that increasing Ly6Clo monocytes in the peripheral blood and nerve tissue might contribute to the alleviation of neuritis in NICcA mice. Meanwhile, an in vitro study suggested that bone marrow-derived monocytes from NICcA mice are more inclined toward Ly6Clo cells than Ly6Chi cells. Differential expression of monocyte development-associated genes was detected in NICcA and wild-type mice using RNA sequencing. The expression of Nr4a1 is upregulated remarkably when Notch signaling is activated. Treatment with Nr4a1 antagonist on NICcA mice-derived monocytes compromise their Ly6Clo tendency. Consistently, a relationship between monocyte conversion and disease severity was observed in blood samples from patients with GBS. In conclusion, our current study showed that monocyte conversion modulated by Notch signaling plays an essential role in the EAN mouse model.