Detection of intrinsically disordered peptides by biological nanopore.

Intrinsically disordered protein regions (IDPRs) are pivotal in the regulation of transcription and the facilitation of signal transduction. Because of their multiple conformational states of structure, characterizing the highly flexible structures of IDPRs becomes challenging. Herein, we employed the wild-type (WT) aerolysin nanopore as a real-time biosensor for the identification and monitoring of long peptides containing IDPRs. This sensor successfully identified three intrinsically disordered peptides, with the lengths up to 43 amino acids, by leveraging the unique signatures of blockade current and translocation duration time. The analysis of the binding constant revealed that interactions between the nanopore and peptide are critical for peptide translocation, suggesting that mechanisms beyond mere volume exclusion are at play. Furthermore, by examining the detailed current traces of blockade events, we were able to compare the conformational stabilities of various IDPRs. Our approach can detect the conformational changes of IDPR in a confined nanopore space. These insights broaden the understanding of peptide structural changes under the confined space. This nanopore biosensor showed the potential to study the conformations change of IDPRs, IDPRs transmembrane interactions, and protein drug discovery.

Corilagin relieves atherosclerosis via the toll-like receptor 4 signaling pathway in vascular smooth muscle cells.

INTRODUCTION: Corilagin possesses a diverse range of pharmacologic bioactivities. However, the specific protective effects and mechanisms of action of corilagin in the context of atherosclerosis remain unclear. In this study, we investigated the impact of corilagin on the toll-like receptor (TLR)4 signaling pathway in a mouse vascular smooth muscle cell line (MOVAS) stimulated by oxidized low-density lipoprotein (ox-LDL). Additionally, we examined the effects of corilagin in Sprague-Dawley rats experiencing atherosclerosis. METHODS: The cytotoxicity of corilagin was assessed using the CCK8 assay. MOVAS cells, pre-incubated with ox-LDL, underwent treatment with varying concentrations of corilagin. TLR4 expression was modulated by either downregulation through small interfering (si)RNA or upregulation via lentivirus transfection. Molecular expression within the TLR4 signaling pathway was analyzed using real-time polymerase chain reaction (PCR) and Western blotting. The proliferation capacity of MOVAS cells was determined through cell counting. In a rat model, atherosclerosis was induced in femoral arteries using an improved guidewire injury method, and TLR4 expression in plaque areas was assessed using immunofluorescence. Pathological changes were examined through hematoxylin and eosin staining, as well as Oil-Red-O staining. RESULTS: Corilagin demonstrated inhibitory effects on the TLR4 signaling pathway in MOVAS cells pre-stimulated with ox-LDL, consequently impeding the proliferative impact of ox-LDL. The modulation of TLR4 expression, either through downregulation or upregulation, similarly influenced the expression of downstream molecules. In an in vivo context, corilagin exhibited the ability to suppress TLR4 and MyD88 expression in the plaque lesion areas of rat femoral arteries, thereby alleviating the formation of atherosclerotic plaques. CONCLUSION: Corilagin can inhibit the TLR4 signaling pathway in VSMCs, possibly by downregulating TLR4 expression and, consequently, relieving atherosclerosis.

Single-Digit Nanobubble Sensing via Nanopore Technology.

Nanobubbles play an important role in diverse fields, including engineering, medicine, and agriculture. Understanding the characteristics of individual nanobubbles is essential for comprehending fluid dynamics behaviors and advancing nanoscale science across various fields. Here, we report a strategy based on nanopore sensors for characterizing single-digit nanobubbles. We investigated the sizes and diffusion coefficients of nanobubbles at different voltages. Additionally, the finite element simulation and molecular dynamics simulation were introduced to account for counterion concentration variation around nanobubbles in the nanopore. In particular, the differences in stability and surface charge density of nanobubbles under various solution environments have been studied by the ion-stabilized model and the DLVO theory. Additionally, a straightforward method to mitigate nanobubble generation in the bulk for reducing current noise in nanopore sensing was suggested. The results hold significant implications for enhancing the understanding of individual nanobubble characterizations, especially in the nanofluid field.

Suppressed thermal transport in silicon nanoribbons by inhomogeneous strain.

Nanoscale structures can produce extreme strain that enables unprecedented material properties, such as tailored electronic bandgap1-5, elevated superconducting temperature6,7 and enhanced electrocatalytic activity8,9. While uniform strains are known to elicit limited effects on heat flow10-15, the impact of inhomogeneous strains has remained elusive owing to the coexistence of interfaces16-20 and defects21-23. Here we address this gap by introducing inhomogeneous strain through bending individual silicon nanoribbons on a custom-fabricated microdevice and measuring its effect on thermal transport while characterizing the strain-dependent vibrational spectra with sub-nanometre resolution. Our results show that a strain gradient of 0.112% per nanometre could lead to a drastic thermal conductivity reduction of 34 ± 5%, in clear contrast to the nearly constant values measured under uniform strains10,12,14,15. We further map the local lattice vibrational spectra using electron energy-loss spectroscopy, which reveals phonon peak shifts of several millielectron-volts along the strain gradient. This unique phonon spectra broadening effect intensifies phonon scattering and substantially impedes thermal transport, as evidenced by first-principles calculations. Our work uncovers a crucial piece of the long-standing puzzle of lattice dynamics under inhomogeneous strain, which is absent under uniform strain and eludes conventional understanding.

Baricitinib Improvement Across Regions in Atopic Dermatitis Patients with Baseline Body Surface Area up to 40% and Severe Itch.

INTRODUCTION: Patients with moderate-to-severe atopic dermatitis (AD) who are most likely to respond to the Janus kinase (JAK) 1/2 inhibitor baricitinib (BARI) are known to have an impacted body surface area (BSA) ≤ 40% and severe itch (numerical rating scale [NRS] ≥ 7], collectively termed 'BARI itch-dominant' patients. Our objective is to build on our previous work by providing a body region-specific, clinical characterization of the BARI itch-dominant patient at baseline and their response to BARI 4 mg. METHODS: BREEZE-AD7 was a phase 3 trial in adults with moderate-to-severe AD receiving placebo or 2 mg or 4 mg BARI in combination with topical corticosteroids. Assessing only data from BARI itch-dominant patients, we summarized the baseline characteristics and conducted body region-specific analyses on Eczema Area and Severity Index (EASI) data in order to report the response to placebo versus BARI 4 mg within this patient subtype. RESULTS: BARI 4 mg was highly effective across all body regions; at week 16, 75% improvement was seen in EASI scores (EASI75), and response rates with BARI 4 mg (head/neck, 58.3%; trunk, 69.2%; upper extremities, 61.5%; lower extremities, 87.5%) all exceeded those with placebo (head/neck: 37.5%; trunk, 40.6%; upper extremities, 18.8%; lower extremities, 40.6%) as well as the overall EASI75 rates of the intent-to-treat (ITT) population (BARI, 48.0%; placebo, 23.0%). At baseline, most BARI itch-dominant patients presented with involvement of all regions (mean regional BSA 22.7%-40.3%), highest in the head and neck, mean EASI region scores of 15.7-24.0, and considerably severe sign ratings (mean EASI sub-scores: 1.4-2.3, out of 3), especially for erythema. CONCLUSION: BARI itch-dominant patients exhibit AD involvement across all body regions and considerable sign severity, especially erythema. In response to BARI 4 mg, EASI quickly improved across regions, substantially more so in this subtype than in the ITT population.

Geometrically Scalable Iontronic Memristors: Employing Bipolar Polyelectrolyte Gels for Neuromorphic Systems.

Iontronics that are capable of mimicking the functionality of biological systems within an artificial fluidic network have long been pursued for biomedical applications and ion-based intelligence systems. Here, we report on facile and robust realization of iontronic bipolar memristors featuring a three-layer polyelectrolyte gel structure. Significant memristive hysteresis of ion currents was successfully accomplished, and the memory time proved geometrically scalable from 200 to 4000 s. These characteristics were enabled by the ion concentration polarization-induced rectification ratio within the polyelectrolyte gels. The memristors exhibited memory dynamics akin to those observed in unipolar devices, while the bipolar structure notably enabled prolonged memory time and enhanced the ion conductance switching ratio with mesoscale (10-1000 µm) geometry precision. These properties endow the devices with the capability of effective neuromorphic processing with pulse-based input voltage signals. Owing to their simple fabrication process and superior memristive performance, the presented iontronic bipolar memristors are versatile and can be easily integrated into small-scale iontronic circuits, thereby facilitating advanced neuromorphic computing functionalities.

Corilagin alleviates atherosclerosis by inhibiting NLRP3 inflammasome activation via the Olfr2 signaling pathway in vitro and in vivo.

Introduction: Atherosclerosis, a leading cause of global cardiovascular mortality, is characterized by chronic inflammation. Central to this process is the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, which significantly influences atherosclerotic progression. Recent research has identified that the olfactory receptor 2 (Olfr2) in vascular macrophages is instrumental in driving atherosclerosis through NLRP3- dependent IL-1 production. Methods: To investigate the effects of Corilagin, noted for its anti-inflammatory attributes, on atherosclerotic development and the Olfr2 signaling pathway, our study employed an atherosclerosis model in ApoE-/- mice, fed a high-fat, high-cholesterol diet, alongside cellular models in Ana-1 cells and mouse bone marrow-derived macrophages, stimulated with lipopolysaccharides and oxidized low-density lipoprotein. Results: The vivo and vitro experiments indicated that Corilagin could effectively reduce serum lipid levels, alleviate aortic pathological changes, and decrease intimal lipid deposition. Additionally, as results showed, Corilagin was able to cut down expressions of molecules associated with the Olfr2 signaling pathway. Discussion: Our findings indicated that Corilagin effectively inhibited NLRP3 inflammasome activation, consequently diminishing inflammation, macrophage polarization, and pyroptosis in the mouse aorta and cellular models via the Olfr2 pathway. This suggests a novel therapeutic mechanism of Corilagin in the treatment of atherosclerosis.

Efficacy and safety of human umbilical cord-derived mesenchymal stem cells in the treatment of refractory immune thrombocytopenia: a prospective, single arm, phase I trial.

Patients with refractory immune thrombocytopenia (ITP) frequently encounter substantial bleeding risks and demonstrate limited responsiveness to existing therapies. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) present a promising alternative, capitalizing on their low immunogenicity and potent immunomodulatory effects for treating diverse autoimmune disorders. This prospective phase I trial enrolled eighteen eligible patients to explore the safety and efficacy of UC-MSCs in treating refractory ITP. The research design included administering UC-MSCs at escalating doses of 0.5 × 106 cells/kg, 1.0 × 106 cells/kg, and 2.0 × 106 cells/kg weekly for four consecutive weeks across three cohorts during the dose-escalation phase, followed by a dose of 2.0 × 106 cells/kg weekly for the dose-expansion phase. Adverse events, platelet counts, and changes in peripheral blood immunity were monitored and recorded throughout the administration and follow-up period. Ultimately, 12 (with an addition of three patients in the 2.0 × 106 cells/kg group due to dose-limiting toxicity) and six patients were enrolled in the dose-escalation and dose-expansion phase, respectively. Thirteen patients (13/18, 72.2%) experienced one or more treatment emergent adverse events. Serious adverse events occurred in four patients (4/18, 22.2%), including gastrointestinal hemorrhage (2/4), profuse menstruation (1/4), and acute myocardial infarction (1/4). The response rates were 41.7% in the dose-escalation phase (5/12, two received 1.0 × 106 cells/kg per week, and three received 2.0 × 106 cells/kg per week) and 50.0% (3/6) in the dose-expansion phase. The overall response rate was 44.4% (8/18) among all enrolled patients. To sum up, UC-MSCs are effective and well tolerated in treating refractory ITP (ClinicalTrials.gov ID: NCT04014166).

Proteomics landscape and machine learning prediction of long-term response to splenectomy in primary immune thrombocytopenia.

This study aimed to identify key proteomic analytes correlated with response to splenectomy in primary immune thrombocytopenia (ITP). Thirty-four patients were retrospectively collected in the training cohort and 26 were prospectively enrolled as validation cohort. Bone marrow biopsy samples of all participants were collected prior to the splenectomy. A total of 12 modules of proteins were identified by weighted gene co-expression network analysis (WGCNA) method in the developed cohort. The tan module positively correlated with megakaryocyte counts before splenectomy (r = 0.38, p = 0.027), and time to peak platelet level after splenectomy (r = 0.47, p = 0.005). The blue module significantly correlated with response to splenectomy (r = 0.37, p = 0.0031). KEGG pathways analysis found that the PI3K-Akt signalling pathway was predominantly enriched in the tan module, while ribosomal and spliceosome pathways were enriched in the blue module. Machine learning algorithm identified the optimal combination of biomarkers from the blue module in the training cohort, and importantly, cofilin-1 (CFL1) was independently confirmed in the validation cohort. The C-index of CFL1 was >0.7 in both cohorts. Our results highlight the use of bone marrow proteomics analysis for deriving key analytes that predict the response to splenectomy, warranting further exploration of plasma proteomics in this patient population.

Metabolomics profile and machine learning prediction of treatment responses in immune thrombocytopenia: A prospective cohort study.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by antibody-mediated platelet destruction and impaired platelet production. The mechanisms underlying ITP and biomarkers predicting the response of drug treatments are elusive. We performed a metabolomic profiling of bone marrow biopsy samples collected from ITP patients admission in a prospective study of the National Longitudinal Cohort of Hematological Diseases. Machine learning algorithms were conducted to discover novel biomarkers to predict ITP patient treatment responses. From the bone marrow biopsies of 91 ITP patients, we quantified a total of 4494 metabolites, including 1456 metabolites in the positive mode and 3038 metabolites in the negative mode. Metabolic patterns varied significantly between groups of newly diagnosed and chronic ITP, with a total of 876 differential metabolites involved in 181 unique metabolic pathways. Enrichment factors and p-values revealed the top metabolically enriched pathways to be sphingolipid metabolism, the sphingolipid signalling pathway, ubiquinone and other terpenoid-quinone biosynthesis, thiamine metabolism, tryptophan metabolism and cofactors biosynthesis, the phospholipase D signalling pathway and the phosphatidylinositol signalling system. Based on patient responses to five treatment options, we screened several metabolites using the Boruta algorithm and ranked their importance using the random forest algorithm. Lipids and their metabolism, including long-chain fatty acids, oxidized lipids, glycerophospholipids, phosphatidylcholine and phosphatidylethanolamine biosynthesis, helped differentiate drug treatment responses. In conclusion, this study revealed metabolic alterations associated with ITP in bone marrow supernatants and a potential biomarker predicting the response to ITP.

Acquired hemophilia A: a single-center study of 165 patients.

Background: Acquired hemophilia A (AHA) is a rare hemorrhagic disorder caused by factor (F)VIII inhibitors. The diagnosis and management of AHA remains challenging because of its rarity and heterogeneity. Objectives: To analyze the characteristics of AHA to enhance our understanding of this disease and identify effective treatment strategies. To analyze the characteristics of AHA to enhance our understanding of this disease and identify effective treatment strategies. Methods: Clinical features of 165 patients with AHA from a single center between July 1997 and December 2021 were retrospectively analyzed. Results: The median age of patients at diagnosis was 45 years. The median time to diagnosis was 30 days. All 165 patients experienced bleeding, with a median bleeding score (BS) of 4 (range, 2-12). Hemostatic therapy was administered to 129 (78.2%) patients. Bleeding control was achieved in 80.0% of patients who received prothrombin complex concentrate and in 92.3% of patients who were treated with recombinant activated FVII. Of the 163 patients who received immunosuppressive therapy, 80 (49.1%) received rituximab-based therapy with a 93.3% complete remission (CR) rate, 50 (30.7%) received steroids plus cyclophosphamide with an 85.0% CR rate, and 22 (13.5%) received steroids alone with an 82.4% CR rate. Six cases relapsed after a median duration of 330 days. Immunosuppressive therapy-related adverse events were reported in 17 patients. Seven deaths were recorded. FVIII inhibitor titer of ≥15 BU/mL and BS of ≥6 were identified as significantly poor prognostic factors for CR. Conclusion: Immunosuppressive therapies yield remarkably high response rates, with a CR rate exceeding 80%; notably, the regimen containing rituximab exhibits a CR rate of approximately 90%. FVIII inhibitor titer of ≥5 BU/mL and BS of ≥6 were poor predictors of CR in patients with AHA.

Reexamination of Damping in Sliding Friction.

Friction is responsible for about one-third of the primary energy consumption in the world. So far, a thorough atomistic understanding of the frictional energy dissipation mechanisms is still lacking. The Amontons' law states that kinetic friction is independent of the sliding velocity while the Prandtl-Tomlinson model suggests that damping is proportional to the relative sliding velocity between two contacting objects. Through careful analysis of the energy dissipation process in atomic force microscopy measurements, here we propose that damping force is proportional to the tip oscillation speed induced by friction. It is shown that a physically well-founded damping term can better reproduce the multiple peaks in the velocity-dependent friction force observed in both experiments and molecular dynamics simulations. Importantly, the analysis gives a clear physical picture of the dynamics of energy dissipation in different friction phases, which provides insight into long-standing puzzles in sliding friction, such as velocity weakening and spring-stiffness-dependent friction.

Aqueous chemimemristor based on proton-permeable graphene membranes.

Memristive devices, electrical elements whose resistance depends on the history of applied electrical signals, are leading candidates for future data storage and neuromorphic computing. Memristive devices typically rely on solid-state technology, while aqueous memristive devices are crucial for biology-related applications such as next-generation brain-machine interfaces. Here, we report a simple graphene-based aqueous memristive device with long-term and tunable memory regulated by reversible voltage-induced interfacial acid-base equilibria enabled by selective proton permeation through the graphene. Surface-specific vibrational spectroscopy verifies that the memory of the graphene resistivity arises from the hysteretic proton permeation through the graphene, apparent from the reorganization of interfacial water at the graphene/water interface. The proton permeation alters the surface charge density on the CaF2 substrate of the graphene, affecting graphene's electron mobility, and giving rise to synapse-like resistivity dynamics. The results pave the way for developing experimentally straightforward and conceptually simple aqueous electrolyte-based neuromorphic iontronics using two-dimensional (2D) materials.

Effectiveness of high-dose third-generation EGFR-tyrosine kinase inhibitors in treating EGFR-mutated non-small cell lung cancer patients with leptomeningeal metastasis.

BACKGROUND: Leptomeningeal metastasis (LM) is associated with an extremely poor prognosis in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). The third-generation EGFR-tyrosine kinase inhibitors (TKIs), currently the preferred drug of choice, have significantly improved treatment outcomes in these patients. However, the optimal dose of third-generation EGFR-TKIs for clinical use remains undetermined in NSCLC patients with LM. METHODS: We retrospectively analyzed the clinical characteristics and treatment outcomes of 105 patients with EGFR-mutated NSCLC and cytologically confirmed LM who had received third-generation EGFR-TKI treatment after LM diagnosis. Patients were stratified into high- and standard-dose groups based on the treatment dose of third-generation EGFR-TKI. Subsequent treatments for LM were collected, particularly the efficacy of different doses of third-generation EGFR-targeted drugs. RESULTS: The median follow-up period was 28.7 months (range 0.6-40.2) at the cut-off date of August 27, 2023. The 105 included patients who received third-generation EGFR-TKI treatment had a clinical response rate (CRR) of 54.3 % (57/105), and the median overall survival (OS) from LM diagnosis was 12.3 months (95 % confidence interval [CI] = 10.0-15.0). Among them, 46 (43.8 %) patients received a high-dose regimen, and the remaining 59 (56.2 %) patients were treated with standard-dose drugs. Patients treated with high-dose third-generation EGFR-TKIs showed a higher CRR and longer OS than those treated with standard-dose therapy (65.2 % vs. 45.8 %, p = 0.047; 15.0 vs. 10.2 months, p = 0.014). Importantly, high-dose third-generation EGFR-TKI showed superior OS than standard-dose treatment in all subgroups (prior first-/second-generation EGFR-TKI resistance group, 19.5 vs. 9.8 months, p = 0.047; third-generation EGFR-TKI resistance group, 10.0 vs. 4.3 months, p = 0.045; EGFR-TKI naive group, not reach vs. 15.6 months, p = 0.031). Multivariate analysis revealed that high-dose third-generation EGFR-TKIs, intrathecal chemotherapy, previous TKI treatment history, and Karnofsky Performance Status score were independent predictors of OS (all p < 0.05). CONCLUSIONS: High-dose third-generation EGFR-TKIs are effective treatments for NSCLC patients with EGFR mutations and LM, regardless of previous EGFR-TKI exposure.

Acute caval thrombosis leading to obstructive shock in the early post insertion period of an inferior vena cava filter: a case report and literature review.

BACKGROUND: Obstructive shock is extremely rare in clinical practice and is caused by acute blood flow obstruction in the central vessels of either the systemic or pulmonary circulation. Utilizing inferior vena cava filters (IVCFs) to prevent pulmonary embolism (PE) is associated with some potential complications, such as inferior vena cava thrombosis (IVCT). Shock as a direct result of IVCT is rare. We present a case of obstructive shock secondary to extensive IVCT caused by inadequate anticoagulant therapy after the placement of an IVCF. CASE PRESENTATION: A 63-year-old male patient with a traffic accident injury presented orthopaedic trauma and lower limb deep vein thrombosis (DVT). He experienced sudden and severe abdominal pain with hypotension, tachycardia, tachypnea, oliguria and peripheral oedema 5 days after IVCF placement and 3 days after cessation of anticoagulant therapy. Considering that empirical anti-shock treatment lasted for a while and the curative effect was poor, we finally recognized the affected vessels and focused on the reason for obstructive shock through imaging findings-inferior vena cava thrombosis and occlusion. The shock state immediately resolved after thrombus aspiration. The same type of shock occurred again 6 days later during transfer from the ICU to general wards and the same treatment was administered. The patient recovered smoothly in the later stage, and the postoperative follow-up at 1, 3, and 12 months showed good results. CONCLUSION: This case alerts clinicians that it is crucial to ensure adequate anticoagulation therapy after IVCF placement, and when a patient presents with symptoms such as hypotension, tachycardia, and lower limb and scrotal oedema postoperatively, immediate consideration should be given to the possibility of obstructive shock, and prompt intervention should be based on the underlying cause.

Characteristics and outcomes of COVID-19 in Chinese immune thrombocytopenia patients: A prospective cohort study.

The coronavirus disease 2019 (COVID-19) pandemic has a significant impact on the immune system. This is the first and largest study on pre-existing immune thrombocytopenia (ITP) patients infected with COVID-19 in China. We prospectively collected ITP patients infected with COVID-19 enrolled in the National Longitudinal Cohort of Hematological Diseases (NICHE, NCT04645199) and followed up for at least 1 month after infection. One thousand and one hundred forty-eight pre-existing ITP patients were included. Two hundred and twelve (18.5%) patients showed a decrease in the platelet (PLT) count after infection. Forty-seven (4.1%) patients were diagnosed with pneumonia. Risk factors for a decrease in the PLT count included baseline PLT count <50 × 109/L (OR, 1.76; 95% CI, 1.25-2.46; p = 0.001), maintenance therapy including thrombopoietin receptor agonists (TPO-RAs) (OR, 2.27; 95% CI, 1.60-3.21; p < 0.001) and previous splenectomy (OR, 1.98; 95% CI, 1.09-3.61; p = 0.03). Risk factors for pneumonia included age ≥40 years (OR, 2.45; 95% CI, 1.12-5.33; p = 0.02), ≥2 comorbidities (OR, 3.47; 95% CI, 1.63-7.64; p = 0.001), maintenance therapy including TPO-RAs (OR, 2.14; 95% CI, 1.17-3.91; p = 0.01) and immunosuppressants (OR, 3.05; 95% CI, 1.17-7.91; p = 0.02). In this cohort study, we described the characteristics of pre-existing ITP patients infected with COVID-19 and identified several factors associated with poor outcomes.