A bionic mimosa soft robot based on a multi-responsive PNIPAM-PEGDA hydrogel composition.

Deformation plays a vital role in the survival of natural organisms. One example is that plants deform themselves to face the sun for sufficient sunlight exposure, which allows them to produce nutrients through photosynthesis. Drawing inspiration from nature, researchers have been exploring the development of 3D deformable materials. However, the traditional approach to manufacturing deformable hydrogels relies on complex technology, which limits their potential applications. In this study, we simulate the stress variations observed in the plant tissue to create a 3D structure from a 2D material. Using UV curing technology, we create a single-layer poly(N-isopropylacrylamide) hydrogel sheet with microchannels that exhibit distinct swelling rates when subjected to stimulation. After a two-step curing process, we produce a poly(N-isopropylacrylamide)-polyethylene glycol diacrylatedouble-layer structure that can be manipulated to change its shape by controlling the light and solvent content. Based on the double-layer structure, we fabricate a dual-response driven bionic mimosa robot that can perform a variety of functions. This soft robot can not only reversibly change its shape but also maintain a specific shape without continuous stimulation. Its capacity for reversible deformation, resulting from internal stress, presents promising application prospects in the biomedical and soft robotics domain. This study delivers an insightful framework for the development of programmable soft materials.

Exploring the crosstalk of immune cells: The impact of dysregulated RUNX family genes in kidney renal clear cell carcinoma.

Background: Abnormally expressed Runt-associated transcription factor (RUNX) family has been reported in multiple tumors. Nevertheless, the immunological role of RUNX family in kidney renal clear cell carcinoma (KIRC) remains unknown. Methods: We studied the RNA-seq data regarding tumor and healthy subjects from several public databases in detail for evaluating the prognostic and immunological functions owned by three RUNX genes in cancer patients. Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical (IHC) staining served for detecting their expressions in tumor and normal samples. Results: We observed that KIRC patients presented high expressions of RUNX1, RUNX2, and RUNX3. The expressions of three genes were validated by qRT-PCR, which was same as bioinformatical results. Prognostic analysis indicated that the overexpression of RUNX1 and RUNX2 negatively affects the outcomes in patients with KIRC. Related functional predictions indicated that the RUNXs and co-expression genes were significantly related to the immune response pathway. Moreover, three RUNX members were associated with immune infiltration cells and their related gene markers. The expression of RUNX family in several immune cells is positively or negatively correlated, and its dysregulation is obviously associated with the differential distribution of immune cells. RUNX family genes were abnormally expressed in KIRC patients, and were closely related to the crosstalk of immune cells. Conclusions: Our findings may help to understand the pathogenesis and immunologic roles of the RUNX family in KIRC patients from new perspectives.

Molecular mechanism of α-synuclein aggregation on lipid membranes revealed.

The central hallmark of Parkinson's disease pathology is the aggregation of the α-synuclein protein, which, in its healthy form, is associated with lipid membranes. Purified monomeric α-synuclein is relatively stable in vitro, but its aggregation can be triggered by the presence of lipid vesicles. Despite this central importance of lipids in the context of α-synuclein aggregation, their detailed mechanistic role in this process has not been established to date. Here, we use chemical kinetics to develop a mechanistic model that is able to globally describe the aggregation behaviour of α-synuclein in the presence of DMPS lipid vesicles, across a range of lipid and protein concentrations. Through the application of our kinetic model to experimental data, we find that the reaction is a co-aggregation process involving both protein and lipids and that lipids promote aggregation as much by enabling fibril elongation as by enabling their initial formation. Moreover, we find that the primary nucleation of lipid-protein co-aggregates takes place not on the surface of lipid vesicles in bulk solution but at the air-water and/or plate interfaces, where lipids and proteins are likely adsorbed. Our model forms the basis for mechanistic insights, also in other lipid-protein co-aggregation systems, which will be crucial in the rational design of drugs that inhibit aggregate formation and act at the key points in the α-synuclein aggregation cascade.

Recent Advances in Microrobots Powered by Multi-Physics Field for Biomedical and Environmental Applications.

Microrobots powered by multi-physics fields are becoming a hotspot for micro-nano manufacturing. Due to the small size of microrobots, they can easily enter small spaces that are difficult for ordinary robots to reach and perform a variety of special tasks. This gives microrobots a broad application prospect in many fields. This paper describes the materials, structures, and driving principles of microrobots in detail and analyzes the advantages and limitations of their driving methods in depth. In addition, the paper discusses the detailed categorization of the action forms of microrobots and explores their diversified motion modes and their applicable scenarios. Finally, the article highlights the wide range of applications of microrobots in the fields of biomedicine and environmental protection, emphasizing their great potential for solving real-world problems and advancing scientific progress.

Anti-synthetase syndrome is associated with a higher risk of hospitalization among patients with idiopathic inflammatory myopathy and COVID-19.

Background: Data with fine granularity about COVID-19-related outcomes and risk factors were still limited in the idiopathic inflammatory myopathies (IIMs) population. This study aimed to investigate clinical factors associated with hospitalized and severe COVID-19 in patients with IIMs, particularly those gauged by myositis-specific antibodies. Methods: This retrospective cohort study was conducted in the Renji IIM cohort in Shanghai, China, under an upsurge of SARS-CoV-2 omicron variant infections from December 2022 to January 2023. Clinical data were collected and analyzed by multivariable logistic regression to determine risk factors. High-dimensional flow cytometry analysis was performed to outline the immunological features. Results: Among 463 infected patients in the eligible cohort (n=613), 65 (14.0%) were hospitalized, 19 (4.1%) suffered severe COVID-19, and 10 (2.2%) died. Older age (OR=1.59/decade, 95% CI 1.18 to 2.16, p=0.003), requiring family oxygen supplement (2.62, 1.11 to 6.19, 0.028), patients with anti-synthetase syndrome (ASyS) (2.88, 1.12 to 7.34, 0.027, vs. other dermatomyositis), higher IIM disease activity, and prednisone intake >10mg/day (5.59, 2.70 to 11.57, <0.001) were associated with a higher risk of hospitalization. Conversely, 3-dose inactivated vaccination reduced the risk of hospitalization (0.10, 0.02 to 0.40, 0.001, vs. incomplete vaccination). Janus kinase inhibitor (JAKi) pre-exposure significantly reduced the risk of severe COVID-19 in hospitalized patients (0.16, 0.04 to 0.74, 0.019, vs. csDMARDs). ASyS patients with severe COVID-19 had significantly reduced peripheral CD4+ T cells, lower CD4/CD8 ratio, and fewer naive B cells but more class-switched memory B cells compared with controls. Conclusion: ASyS and family oxygen supplement were first identified as risk factors for COVID-19-related hospitalization in patients with IIMs. JAKi pre-exposure might protect IIM patients against severe COVID-19 complications.

Clinical characteristics of testicular torsion and factors influencing testicular salvage in children: A 12-year study in tertiary center.

BACKGROUND: Testicular torsion is the most common acute scrotum worldwide and mainly occurs in children and adolescents. Studies have demonstrated that the duration of symptoms and torsion grade lead to different outcomes in children diagnosed with testicular torsion. AIM: To predict the possibility of testicular salvage (TS) in patients with testicular torsion in a tertiary center. METHODS: We reviewed the charts of 75 pediatric patients with acute testicular torsion during a 12-year period from November 2011 to July 2023 at the Suzhou Hospital of Anhui Medical University. Univariate and multivariate logistic regression analyses were used to determine independent predictors of testicular torsion. The data included clinical findings, physical examinations, laboratory data, color Doppler ultrasound findings, operating results, age, presenting institution status, and follow-up results. RESULTS: Our study included 75 patients. TS was possible in 57.3% of all patients; testicular torsion occurred mostly in winter, and teenagers aged 11-15 years old accounted for 60%. Univariate logistic regression analyses revealed that younger age (P = 0.09), body mass index (P = 0.004), torsion angle (P = 0.013), red blood cell count (P = 0.03), neutrophil-to-lymphocyte ratio (P = 0.009), and initial presenting institution (P < 0.001) were associated with orchiectomy. In multivariate analysis, only the initial presenting institution predicted TS (P < 0.05). CONCLUSION: The initial presenting institution has a predictive value for predicting TS in patients with testicular torsion. Children with scrotal pain should be admitted to a tertiary hospital as soon as possible.

Single-Molecule Detection of α-Synuclein Oligomers in Parkinson's Disease Patients Using Nanopores.

α-Synuclein (α-Syn) is an intrinsically disordered protein whose aggregation in the brain has been significantly implicated in Parkinson's disease (PD). Beyond the brain, oligomers of α-Synuclein are also found in cerebrospinal fluid (CSF) and blood, where the analysis of these aggregates may provide diagnostic routes and enable a better understanding of disease mechanisms. However, detecting α-Syn in CSF and blood is challenging due to its heterogeneous protein size and shape, and low abundance in clinical samples. Nanopore technology offers a promising route for the detection of single proteins in solution; however, the method often lacks the necessary selectivity in complex biofluids, where multiple background biomolecules are present. We address these limitations by developing a strategy that combines nanopore-based sensing with molecular carriers that can specifically capture α-Syn oligomers with sizes of less than 20 nm. We demonstrate that α-Synuclein oligomers can be detected directly in clinical samples, with minimal sample processing, by their ion current characteristics and successfully utilize this technology to differentiate cohorts of PD patients from healthy controls. The measurements indicate that detecting α-Syn oligomers present in CSF may potentially provide valuable insights into the progression and monitoring of Parkinson's disease.

Development and validation of a kidney renal clear cell carcinoma prognostic model relying on pyroptosis-related LncRNAs-A multidimensional comprehensive bioinformatics exploration.

BACKGROUND: Renal cell carcinoma (RCC) is a malignant tumour that may develop in the kidney. RCC is one of the most common kinds of tumours of this sort, and its most common pathological subtype is kidney renal clear cell carcinoma (KIRC). However, the aetiology and pathogenesis of RCC still need to be clarified. Exploring the internal mechanism of RCC contributes to diagnosing and treating this disease. Pyroptosis is a critical process related to cell death. Recent research has shown that pyroptosis is a critical factor in the initiation and progression of tumour formation. Thus far, researchers have progressively uncovered evidence of the regulatory influence that long noncoding RNAs (lncRNAs) have on pyroptosis. METHODS: In this work, a comprehensive bioinformatics approach was used to produce a predictive model according to pyroptosis-interrelated lncRNAs for the purpose of predicting the overall survival and molecular immune specialties of patients diagnosed with KIRC. This model was verified from multiple perspectives. RESULTS: First, we discovered pyroptosis-associated lncRNAs in KIRC patients using the TCGA database and a Sankey diagram. Then, we developed and validated a KIRC patient risk model based on pyroptosis-related lncRNAs. We demonstrated the grouping power of PLnRM through PCA and used PLnRM to assess the tumour immune microenvironment and response to immunotherapy. Immunological and molecular traits of diverse PLnRM subgroups were evaluated, as were clinical KIRC patient characteristics and predictive risk models. On this basis, a predictive nomogram was developed and analyzed, and novel PLnRM candidate compounds were identified. Finally, we investigated possible medications used by KIRC patients. CONCLUSIONS: The results demonstrate that the model generated has significant value for KIRC in clinical practice.

Targeting XPO6 inhibits prostate cancer progression and enhances the suppressive efficacy of docetaxel.

BACKGROUND: Although XPO6, one of the Exportin family members, functions in malignant progression of certain types of cancer, its role in prostate cancer (PCa) has not been elucidated. Herein, we investigated the oncogenic effect and clarified the downstream mechanism of XPO6 in PCa cells. METHODS: We detected the expression level of XPO6 in PCa tissues by immunohistochemistry (IHC) and analyzed the correlation between clinicopathological characteristics and XPO6 level based on TCGA database. The effects of XPO6 in the proliferation and migration or resistance to docetaxel (DTX) in PCa cells were assessed using CCK8, colony formation, wound-healing and Transwell assays. Mice experiments were performed to investigate the role of XPO6 in tumor progression and DTX effect in vivo. Further, functional analysis of DEGs revealed the correlation of XPO6 with Hippo pathway and XPO6 could promote the expression and nuclear translocation of YAP1 protein. Furthermore, blocking Hippo pathway with YAP1 inhibitor leads to the loss of XPO6-mediated regulation of biological functions. RESULTS: XPO6 was highly expressed and positively correlated with the clinicopathological characteristics of PCa. Functional experiments indicated that XPO6 could promote tumor development and DTX resistance in PCa. Mechanistically, we further confirmed that XPO6 could regulate Hippo pathway via mediating YAP1 protein expression and nuclear translocation thereby promoting PCa progression and chemotherapeutic resistance. CONCLUSION: In conclusion, our research reveals that XPO6 potentially function as an oncogene and promotes DTX resistance of PCa, suggesting that XPO6 could be both a potential prognostic marker as well as a therapeutic target to effectively overcome DTX resistance.

Three-port approach vs conventional laparoscopic radical cystectomy with orthotopic neobladder: a single-center retrospective study.

BACKGROUND: This study aimed to compare the clinical outcomes of patients who underwent three-port laparoscopic radical cystectomy (LRC) with orthotopic neobladder (ONB) and traditional five-port method. METHODS: From January 2017 to November 2020, 100 patients underwent LRC + ONB at a third-level grade A hospital. RESULTS: Our study included 55 patients who underwent three-port LRC and 45 patients who underwent the five-port method. There were no significant differences in perioperative data such as operation time (253.00 ± 43.89 vs. 259.07 ± 52.31 min, P = 0.530), estimated blood loss (EBL)(97.64 ± 59.44 vs. 106.67 ± 55.35 min, P = 0.438), day to flatus (2.25 ± 1.49 vs. 2.76 ± 1.77 days, P = 0.128), day to regular diet (7.07 ± 2.99 vs. 7.96 ± 3.32 days, P = 0.165), day to pelvic drain removal (9.58 ± 3.25 vs. 10.53 ± 3.80 days, P = 0.180), and hospital stay after operation (11.62 ± 3.72 vs. 11.84 ± 4.37 days, P = 0.780) between the two groups. The only significant difference was in the treatment cost (P = 0.035). Similarly, postoperative complications, quality of life, and tumor outcomes were not significantly different between the two groups (P > 0.05). CONCLUSIONS: The three-port method is safe and feasible for patients suitable for traditional five-port LRC with an orthotopic neobladder.

Glucose Requirement of Antigen-Specific Autoreactive B Cells and CD4+ T Cells.

The activation of lymphocytes in patients with lupus and in mouse models of the disease is coupled with an increased cellular metabolism in which glucose plays a major role. The pharmacological inhibition of glycolysis with 2-deoxy-d-glucose (2DG) reversed the expansion of follicular helper CD4+ T cells and germinal center B cells in lupus-prone mice, as well as the production of autoantibodies. The response of foreign Ags was however not affected by 2DG in these mice, suggesting that B and CD4+ T cell activation by autoantigens is uniquely sensitive to glycolysis. In this study, we tested this hypothesis with monoclonal B cells and CD4+ T cells specific for lupus-relevant autoantigens. AM14 Vκ8R (AM14) transgenic B cells are activated by IgG2a/chromatin immune complexes and they can receive cognate help from chromatin-specific 13C2 CD4+ T cells. We showed that activation of AM14 B cells by their cognate Ag PL2-3 induced glycolysis, and that the inhibition of glycolysis reduced their activation and differentiation into Ab-forming cells, in the absence or presence of T cell help. The dependency of autoreactive B cells on glycolysis is in sharp contrast with the previously reported dependency of 4-hydroxy-3-nitrophenyl acetyl-specific B cells on fatty acid oxidation. Contrary to AM14 B cells, the activation and differentiation of 13C2 T cells into follicular helper CD4+ T cells was not altered by 2DG, which differs from polyclonal CD4+ T cells from lupus-prone mice. These results further define the role of glycolysis in the production of lupus autoantibodies and demonstrate the need to evaluate the metabolic requirements of Ag-specific B and T cells.

Application of three-dimensional printing technology in renal diseases.

Three-dimensional (3D) printing technology involves the application of digital models to create 3D objects. It is used in construction and manufacturing and has gradually spread to medical applications, such as implants, drug development, medical devices, prosthetic limbs, and in vitro models. The application of 3D printing has great prospects for development in orthopedics, maxillofacial plastic surgery, cardiovascular conditions, liver disease, and other fields. With in-depth research on 3D printing technology and the continuous update of printing materials, this technology also shows broad development prospects in renal medicine. In this paper, the author mainly summarizes the basic theory of 3D printing technology, its research progress, application status, and development prospect in renal diseases.

Safety and efficacy of the SGLT2 inhibitor dapagliflozin in patients with systemic lupus erythematosus: a phase I/II trial.

OBJECTIVE: Sodium-glucose cotransporter-2 inhibitors have been identified profound renal/cardiac protective effects in different diseases. Here, we assessed the safety and efficacy of dapagliflozin among adult patients with systemic lupus erythematosus (SLE). METHODS: We conducted a single-arm, open-label, investigator-initiated phase I/II trial of dapagliflozin in Chinese patients with SLE with/without lupus nephritis (LN). Patients received oral dapagliflozin at a daily dose of 10 mg added to the standard of care for 6 months. The primary end point was the safety profile. The secondary efficacy end points were composite assessments of disease activity. RESULTS: A total of 38 eligible patients were enrolled. Overall, 19 (50%) adverse events (AEs) were recorded, including 8 (21%) AEs leading to drug discontinuation, of which 4 (10.5%) were attributed to dapagliflozin. Two serious AEs (one of major lupus flare and one of fungal pneumonia) were recorded. Lower urinary tract infection was observed in one (2.63%) patient. The secondary end points revealed no improvement of SLE Disease Activity Index scores or proteinuria (among 17 patients with LN); the cumulative lupus flare rate was 18%, and a reduction of ~30% in the prednisone dose was captured. Net changes in body mass index (-0.50 kg/m2), systolic blood pressure (-3.94 mm Hg) and haemoglobin levels (+8.26 g/L) were detected. The overall estimated glomerular filtration rate (eGFR) was stable, and there was an improvement in the eGFR slope among patients with LN with a baseline eGFR <90 mL/min/1.73 m2. CONCLUSION: Dapagliflozin had an acceptable safety profile in adult patients with SLE. Its possible renal/cardiac protective effects and long-term safety issues in patients with SLE, patients with LN in particular, call for further exploration. TRIAL REGISTRATION NUMBER: ChiCTR1800015030.

Toward high-throughput oligomer detection and classification for early-stage aggregation of amyloidogenic protein.

Aggregation kinetics of proteins and peptides have been studied extensively due to their significance in many human diseases, including neurodegenerative disorders, and the roles they play in some key physiological processes. However, most of these studies have been performed as bulk measurements using Thioflavin T or other fluorescence turn-on reagents as indicators of fibrillization. Such techniques are highly successful in making inferences about the nucleation and growth mechanism of fibrils, yet cannot directly measure assembly reactions at low protein concentrations which is the case for amyloid-ß (Aß) peptide under physiological conditions. In particular, the evolution from monomer to low-order oligomer in early stages of aggregation cannot be detected. Single-molecule methods allow direct access to such fundamental information. We developed a high-throughput protocol for single-molecule photobleaching experiments using an automated fluorescence microscope. Stepwise photobleaching analysis of the time profiles of individual foci allowed us to determine stoichiometry of protein oligomers and probe protein aggregation kinetics. Furthermore, we investigated the potential application of supervised machine learning with support vector machines (SVMs) as well as multilayer perceptron (MLP) artificial neural networks to classify bleaching traces into stoichiometric categories based on an ensemble of measurable quantities derivable from individual traces. Both SVM and MLP models achieved a comparable accuracy of more than 80% against simulated traces up to 19-mer, although MLP offered considerable speed advantages, thus making it suitable for application to high-throughput experimental data. We used our high-throughput method to study the aggregation of Aß40 in the presence of metal ions and the aggregation of α-synuclein in the presence of gold nanoparticles.

UHPLC-Q-Exactive Orbitrap mass spectrometry reveals the lipidomics of bovine milk and yogurt.

Compared with milk intake, yogurt intake appears to cause a lower risk of cardiovascular disease (CVD) and type 2 diabetes (T2D). The molecular components responsible for the phenomenon are elusive. We hypothesized that the fermentation would change the lipid profile and fatty acid composition of milk. Untargeted analysis of lipids in milk and yogurt was performed using ultra-high-performance liquid chromatography (UHPLC) coupled with Q-Exactive Orbitrap mass spectrometry and gas chromatography (GC) with a flame ionization detector (FID). The results showed that yogurt had increased C4:0-C10:0 fatty acid, rumenic acid (cis-9 and trans-11-18:2), vaccenic acid (trans-11-18:1), linoleic acid (LA), and polyunsaturated fatty acid (PUFA) contents, and decreased triglyceride (TG), C16:0 and C18:0 fatty acids, and saturated fatty acid (SFA) contents compared with milk. These results advance the understanding of the difference between yogurt and milk regarding reduced risk of CVD and T2D.

Pharmacologically Inferred Glycolysis and Glutaminolysis Requirement of B Cells in Lupus-Prone Mice.

Several studies have shown an enhanced metabolism in the CD4+ T cells of lupus patients and lupus-prone mice. Little is known about the metabolism of B cells in lupus. In this study, we compared the metabolism of B cells between lupus-prone B6.Sle1.Sle2.Sle3 triple-congenic mice and C57BL/6 controls at steady state relative to autoantibody production, as well as during T cell-dependent (TD) and T cell-independent (TI) immunizations. Starting before the onset of autoimmunity, B cells from triple-congenic mice showed an elevated glycolysis and mitochondrial respiration, which were normalized in vivo by inhibiting glycolysis with a 2-deoxy-d-glucose (2DG) treatment. 2DG greatly reduced the production of TI-Ag-specific Abs, but showed minimal effect with TD-Ags. In contrast, the inhibition of glutaminolysis with 6-diazo-5-oxo-l-norleucine had a greater effect on TD than TI-Ag-specific Abs in both strains. Analysis of the TI and TD responses in purified B cells in vitro suggests, however, that the glutaminolysis requirement is not B cell-intrinsic. Thus, B cells have a greater requirement for glycolysis in TI than TD responses, as inferred from pharmacological interventions. B cells from lupus-prone and control mice have different intrinsic metabolic requirements or different responses toward 2DG and 6-diazo-5-oxo-l-norleucine, which mirrors our previous results obtained with follicular Th cells. Overall, these results predict that targeting glucose metabolism may provide an effective therapeutic approach for systemic autoimmunity by eliminating both autoreactive follicular Th and B cells, although it may also impair TI responses.

Redox Homeostasis Involvement in the Pharmacological Effects of Metformin in Systemic Lupus Erythematosus.

Significance: Metformin has been proposed as a treatment for systemic lupus erythematosus (SLE). The primary target of metformin, the electron transport chain complex I in the mitochondria, is associated with redox homeostasis in immune cells, which plays a critical role in the pathogenesis of autoimmune diseases. This review addresses the evidence and knowledge gaps on whether a beneficial effect of metformin in lupus may be due to a restoration of a balanced redox state. Recent Advances: Clinical trials in SLE patients with mild-to-moderate disease activity and preclinical studies in mice have provided encouraging results for metformin. The mechanism by which this therapeutic effect was achieved is largely unknown. Metformin regulates redox homeostasis in a context-specific manner. Multiple cell types contribute to SLE, with evidence of increased mitochondrial oxidative stress in T cells and neutrophils. Critical Issues: The major knowledge gaps are whether the efficacy of metformin is linked to a restored redox homeostasis in the immune system, and if it does, in which cell types it occurs? We also need to know which patients may have a better response to metformin, and whether it corresponds to a specific mechanism? Finally, the identification of biomarkers to predict treatment outcomes would be of great value. Future Directions: Mechanistic studies must address the context-dependent pharmacological effects of metformin. Multiple cell types as well as a complex disease etiology should be considered. These studies must integrate the rapid advances made in understanding how metabolic programs direct the effector functions of immune cells. Antioxid. Redox Signal. 36, 462-479.

Attaining treat-to-target endpoints with metformin in lupus patients: a pooled analysis.

OBJECTIVES: Low disease activity status and remission are crucial treat-to-target (T2T) endpoints in systemic lupus erythematosus (SLE). To evaluate the efficacy of metformin add-on in attaining T2T among Chinese patients with mild-to-moderate lupus, a post-hoc analysis combining our previous two randomised trials was carried out. METHODS: Data from the open-labeled proof-of-concept trial (ChiCTR-TRC-12002419) and placebo-controlled trial (NCT02741960) were integrated together. Disease flares were compared between patients attaining T2T or not at baseline. The efficacy of metformin versus placebo/nil add-on to standard therapy in SLE patients who did not meet the T2T criteria at baseline was evaluated in terms of attaining T2T at 12-month follow-up. RESULTS: Of 253 SLE patients, 43.8% (n=89) attained T2T at baseline. During the 12 months, 15 patients flared in the T2T group, which was significantly lower than that in the non-T2T group (16.9% vs. 36.0%, p=0.001). For 164 patients who did not meet the T2T criteria at entry, 59.0% and 43.6% of the 78 patients taking metformin in this population attained the lupus low disease activity status (LLDAS) and remission endpoints at last visit, respectively, as compared to 37.2% and 24.4% of the 86 patients in the placebo/nil group (LLDAS p=0.008; remission p=0.013). Over time, metformin helped patients achieving T2T earlier and maintain longer T2T duration over placebo/nil (LLDAS duration: 44.9% vs. 26.4%, p=0.002; remission duration:19.1% vs. 10.7%, p=0.014). CONCLUSIONS: This post-hoc analysis suggested that metformin might be an adjuvant therapy in achieving treat-to-target in SLE patients.

Acetylation Rather than H50Q Mutation Impacts the Kinetics of Cu(II) Binding to α-Synuclein.

The front cover artwork is provided by the group of Liming Ying at Imperial College London. The image shows that N-terminal acetylation of α-synuclein shifts the binding from the N-terminus to His50 and significantly slows down the binding reaction. Read the full text of the Article at 10.1002/cphc.202100651.

Acetylation Rather than H50Q Mutation Impacts the Kinetics of Cu(II) Binding to α-Synuclein.

The interaction between α-synuclein (αSyn) and Cu2+ has been suggested to be closely linked to brain copper homeostasis. Disruption of copper levels could induce misfolding and aggregation of αSyn, and thus contribute to the progression of Parkinson's disease (PD). Understanding the molecular mechanism of αSyn-Cu2+ interaction is important and controversies in Cu2+ coordination geometry with αSyn still exists. Herein, we find that the pathological H50Q mutation has no impact on the kinetics of Cu2+ binding to the high-affinity site of wild type αSyn (WT-αSyn), indicating the non-involvement of His50 in high-affinity Cu2+ binding to WT-αSyn. In contrast, the physiological N-terminally acetylated αSyn (NAc-αSyn) displays several orders of magnitude weaker Cu2+ binding affinity than WT-αSyn. Cu2+ coordination mode to NAc-αSyn has also been proposed based on EPR spectrum. In addition, we find that Cu2+ coordinated WT-αSyn is reduction-active in the presence of GSH, but essentially inactive towards ascorbate. Our work provides new insights into αSyn-Cu2+ interaction, which may help understand the multifaceted normal functions of αSyn as well as pathological consequences of αSyn aggregation.