Oltipraz attenuated cerebral ischemia-reperfusion injury through inhibiting the oxidative stress and ferroptosis in mice.

Oltipraz (OPZ) is a synthetic dithiolethione and is considered a novel activator of nuclear factor E2-related factor 2 (Nrf2). Increasing evidence indicates that Nrf2 protects against cerebral ischemia/reperfusion (I/R) injury by antagonizing ferroptosis and lipid peroxidation. However, the protective effects of OPZ on cerebral I/R injury remain to be elucidated. We investigated the in vitro and in vivo neuroprotective effects of OPZ. Mice were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) to construct an in vivo model and PC12 cells were exposed to oxygen and glucose deprivation/reoxygenation (OGD/R) to establish an in vitro model. OPZ administration reduced the infarct volume and brain water content, and alleviated the neurological deficit of MCAO/R mice. Moreover, OPZ ameliorated MCAO/R-induced oxidative stress by decreasing the levels of 4-HNE and MDA and increasing the activities of SOD and GSH. We also found that OPZ ameliorated MCAO/R-induced ferroptosis by increasing SLC7A11 and GPX4 protein expression and downregulating ACSL4 protein expression. Similarly, the in vitro results revealed that OGD/R-induced oxidative stress and ferroptosis. Finally, mechanistic analysis revealed that OPZ significantly upregulated the Nrf2 expression and Nrf2 knockout (Nrf2 KO) abolished the OPZ-mediated protective effects. Taken together, these findings demonstrate that OPZ ameliorates cerebral I/R injury by suppressing the oxidative stress and ferroptosis.

FTO variant is associated with changes in BMI, ghrelin and brain function following bariatric surgery.

BACKGROUND: A polymorphism in the fat mass and obesity-associated gene (FTO) is linked to enhanced neural sensitivity to food-cues and attenuated ghrelin suppression. Risk allele carriers regain more weight than non-carriers after bariatric surgery. It remains unclear how FTO variation affects brain function and ghrelin following surgery. METHODS: Resting-state functional magnetic resonance imaging (RS-fMRI) and cue-reactivity fMRI with high-/low-caloric food-cues were performed at pre-surgery and 1-, 6-, and 12-months post-surgery to examine brain function in 16 carriers with one copy of the rs9939609 A allele (AT) and 26 non-carriers (TT). Behavioral assessments up to five years post-surgery were also conducted. RESULTS: AT relative to TT group had smaller BMI-loss at 12 to 60 months post-surgery and lower resting-state activity in posterior cingulate cortex following LSG (group-by-time interaction effects). Meanwhile, AT relative to TT group showed greater food-cue responses in dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC) and insula (group effects). There were negative associations of weight-loss with ghrelin and greater activation in DLPFC, DMPFC and insula in AT but not TT group. CONCLUSION: These findings indicate that FTO variation is associated with the evolution of ghrelin signaling and brain function after bariatric surgery, which might hinder weight-loss.

A GPT-based EHR modeling system for unsupervised novel disease detection.

OBJECTIVE: To develop an Artificial Intelligence (AI)-based anomaly detection model as a complement of an "astute physician" in detecting novel disease cases in a hospital and preventing emerging outbreaks. METHODS: Data included hospitalized patients (n = 120,714) at a safety-net hospital in Massachusetts. A novel Generative Pre-trained Transformer (GPT)-based clinical anomaly detection system was designed and further trained using Empirical Risk Minimization (ERM), which can model a hospitalized patient's Electronic Health Records (EHR) and detect atypical patients. Methods and performance metrics, similar to the ones behind the recent Large Language Models (LLMs), were leveraged to capture the dynamic evolution of the patient's clinical variables and compute an Out-Of-Distribution (OOD) anomaly score. RESULTS: In a completely unsupervised setting, hospitalizations for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection could have been predicted by our GPT model at the beginning of the COVID-19 pandemic, with an Area Under the Receiver Operating Characteristic Curve (AUC) of 92.2 %, using 31 extracted clinical variables and a 3-day detection window. Our GPT achieves individual patient-level anomaly detection and mortality prediction AUC of 78.3 % and 94.7 %, outperforming traditional linear models by 6.6 % and 9 %, respectively. Different types of clinical trajectories of a SARS-CoV-2 infection are captured by our model to make interpretable detections, while a trend of over-pessimistic outcome prediction yields a more effective detection pathway. Furthermore, our comprehensive GPT model can potentially assist clinicians with forecasting patient clinical variables and developing personalized treatment plans. CONCLUSION: This study demonstrates that an emerging outbreak can be accurately detected within a hospital, by using a GPT to model patient EHR time sequences and labeling them as anomalous when actual outcomes are not supported by the model. Such a GPT is also a comprehensive model with the functionality of generating future patient clinical variables, which can potentially assist clinicians in developing personalized treatment plans.

Ag nanoparticles at p-Si/ MAPbI3 perovskite interface: improved photo responsivity and response speed in photodetection.

Although enhanced performances of photovoltaic devices by embedding metal nanoparticals in charge transport layer, doping into active layer bulk, decorating the active layer surface, and inserting at the interface between semiconductor and the electrode were reported, the effect of incorporating metal NPs at the interface of single crystal semiconductor and perovskite is rarely tackled. Herein the effects of incorporating Ag nanoparticals (AgNPs) at p-Si/MAPbI3 perovskite interface on the photodiode performances were investigated. The results showed that compared with reference device (without AgNPs) the photoresponsivity of the device incorporating AgNPs is greatly improved with the exception for light with wavelengths fall in the spectral range where AgNPs have strong optical absorption. This effect is extremely significant for relatively shorter wavelengths in visible region, and a maximal improvement of around 10.6 times in photoresponsivity was achieved. The physical origin of the exception for spectral range that AgNPs have strong optical absorption is the cancelation of scatter resulted enhancement through AgNPs by band-to-band absorption resulted reduction of photocurrent, in which the generated electron has energy near the fermi level and the hole has large effective mass, which relax by nonradiative recombination, thus making not contribution to the photocurrent. More importantly, the AgNP decorated device showed much faster photo response speed than reference device, and a maximal improvement of around 7.9 times in rise and fall time was achieved. These findings provide a novel approach for high responsive and high speed detection for weak light.

Lignan Intake and Type 2 Diabetes Incidence Among US Men and Women.

Importance: Lignans are phytoestrogens abundant in Western diets and may be associated with type 2 diabetes (T2D) risk. Objective: To prospectively investigate associations between lignan intake and T2D incidence. Design, Setting, and Participants: Population-based cohort study of US men and women enrolled in the Nurses' Health Study (NHS, 1984-2018), NHSII (1991-2019), and Health Professionals Follow-Up Study (HPFS, 1986-2020), as well as 496 participants from the Men's Lifestyle Validation Study (MLVS). Participants were free of T2D, cardiovascular disease, and cancer at baseline. Data were analyzed from November 2022 to July 2023. Exposures: Total and individual lignans were assessed using a validated food frequency questionnaire, which was updated every 2 to 4 years. In the MLVS, lignan intake was measured using 2 sets of 7-day diet records (7DDRs). Main Outcomes and Measures: Incident T2D cases were confirmed using American Diabetes Association diagnostic criteria. Cox proportional hazards models were used to assess multivariable-adjusted associations. Results: The current study included 201 111 participants (mean [SD] age, 44.7 [10.1] years; 161 169 female participants [80.2%]; 2614 African American participants [1.3%], 1609 Asian participants [0.8%], 2414 Hispanic and other race or ethnicity participants [1.2%], and 194 474 White participants [96.7%]) from the HPFS, NHS, and NHSII studies. The median (IQR) total lignan intake of the highest quintile ranged from 355.1 (330.2-396.9) µg/d in NHS to 459.9 (422.2-519.5) µg/d in HPFS at the median follow-up time. Over 5 068 689 person-years, 20 291 incident cases of T2D were identified. Higher lignan intake was inversely associated with T2D incidence, except for lariciresinol. The multivariable-adjusted pooled hazard ratios (HRs) for the highest vs lowest quintiles were 0.87 (95% CI, 0.83-0.91) for total lignans, 0.72 (95% CI, 0.69-0.76) for secoisolariciresinol, 0.92 (95% CI, 0.87-0.96) for pinoresinol, 0.93 (95% CI, 0.89-0.98) for matairesinol, and 0.99 (95% CI, 0.94-1.04) for lariciresinol. Secoisolariciresinol intake exhibited a significant inverse association with T2D risk among individuals with obesity (HR, 0.75 for body mass index [BMI] ≥30; 95% CI, 0.71-0.79 vs HR, 0.82 for BMI <25; 95% CI, 0.81-0.83; P < .001 for interaction) and premenopausal women (HR, 0.67 for premenopausal women; 95% CI, 0.65-0.69 vs HR, 0.82 for the past use of hormones; 95% CI, 0.76-0.88; P = .003 for interaction). Dietary lignan assessed with 7DDRs was associated with lower HbA1c levels (percentage change range from -0.92% to 1.50%), as well as lower C-reactive protein levels and better lipid profiles. Conclusions and Relevance: This cohort study found that long-term lignan consumption was associated with a lower T2D risk, particularly among individuals with obesity and premenopausal women.

Antirheumatic drug leflunomide attenuates atherosclerosis by regulating lipid metabolism and endothelial dysfunction via DHODH/AMPK signaling pathway.

The probability of cardiovascular events has been reported lower in rheumatoid arthritis (RA) patients treated with leflunomide. However, the anti-atherosclerotic and cardiovascular protective effects and metabolism of leflunomide are not explored. In this study, we assessed the potential benefits of leflunomide on atherosclerosis and revealed the underlying mechanism. ApoE-/- mice were fed a western diet (WD) alone or supplemented with leflunomide (20 mg/kg, oral gavage, once per day) for 12 weeks. Samples of the aorta, heart, liver, serum, and macrophages were collected. We found that leflunomide significantly reduced lesion size in both en-face aortas and aortic root in WD-fed ApoE-/- mice. Leflunomide also obviously improved dyslipidemia, reduced hepatic lipid content, and improved disorders of glucose and lipid metabolism in vivo. RNA-Seq results showed that leflunomide effectively regulated the genes' expression involved in the lipid metabolism pathway. Importantly, leflunomide significantly increased the phosphorylation levels of AMPKα and acetyl-CoA carboxylase (ACC) in vivo. Furthermore, leflunomide and its active metabolite teriflunomide suppressed lipid accumulation in free fatty acid (FFA)-induced AML12 cells and improved endothelial dysfunction in palmitic acid (PA)-induced HUVECs through activating AMPK signaling and inhibiting dihydroorotate dehydrogenase (DHODH) signaling pathway. We present evidence that leflunomide and teriflunomide ameliorate atherosclerosis by regulating lipid metabolism and endothelial dysfunction. Our findings suggest a promising use of antirheumatic small-molecule drugs leflunomide and teriflunomide for the treatment of atherosclerosis and related cardiovascular diseases (CVDs).

Mechanism of neurodegeneration mediated by clonal inflammatory microglia.

Langerhans cell Histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders, associated with MAP-Kinase activating mutations and an increased risk of neurodegeneration. Surprisingly, we found pervasive PU.1 + microglia mutant clones across the brain of LCH and ECD patients with and without neurological symptoms, associated with microgliosis, reactive astrocytosis, and neuronal loss. The disease predominated in the grey nuclei of the rhombencephalon, a topography attributable to a local proliferative advantage of mutant microglia. Presence of clinical symptoms was associated with a longer evolution of the disease and a larger size of PU.1 + clones (p= 0.0003). Genetic lineage tracing of PU.1 + clones suggest a resident macrophage lineage or a bone marrow precursor origin depending on patients. Finally, a CSF1R-inhibitor depleted mutant microglia and limited neuronal loss in mice suggesting an alternative to MAPK inhibitors. These studies characterize a progressive neurodegenerative disease, caused by clonal proliferation of inflammatory microglia (CPIM), with a decade(s)-long preclinical stage of incipient disease that represent a therapeutic window for prevention of neuronal death.

Progress in the Application of Organoids-On-A-Chip in Diseases.

With the rapid development of the field of life sciences, traditional 2D cell culture and animal models have long been unable to meet the urgent needs of modern biomedical research and new drug development. Establishing a new generation of experimental models and research models is of great significance for deeply understanding human health and disease processes, and developing effective treatment measures. As is well known, long research and development cycles, high risks, and high costs are the "three mountains" facing the development of new drugs today. Organoids and organ-on-chips technology can highly simulate and reproduce the human physiological environment and complex reactions in vitro, greatly improving the accuracy of drug clinical efficacy prediction, reducing drug development costs, and avoiding the defects of drug testing animal models. Therefore, organ-on-chips have enormous potential in medical diagnosis and treatment.

Tai Chi Expertise Classification in Older Adults Using Wrist Wearables and Machine Learning.

Tai Chi is a Chinese martial art that provides an adaptive and accessible exercise for older adults with varying functional capacity. While Tai Chi is widely recommended for its physical benefits, wider adoption in at-home practice presents challenges for practitioners, as limited feedback may hamper learning. This study examined the feasibility of using a wearable sensor, combined with machine learning (ML) approaches, to automatically and objectively classify Tai Chi expertise. We hypothesized that the combination of wrist acceleration profiles with ML approaches would be able to accurately classify practitioners' Tai Chi expertise levels. Twelve older active Tai Chi practitioners were recruited for this study. The self-reported lifetime practice hours were used to identify subjects in low, medium, or highly experienced groups. Using 15 acceleration-derived features from a wearable sensor during a self-guided Tai Chi movement and 8 ML architectures, we found multiclass classification performance to range from 0.73 to 0.97 in accuracy and F1-score. Based on feature importance analysis, the top three features were found to each result in a 16-19% performance drop in accuracy. These findings suggest that wrist-wearable-based ML models may accurately classify practice-related changes in movement patterns, which may be helpful in quantifying progress in at-home exercises.

Soil organic matter and water content affect the community characteristics of arbuscular mycorrhizal fungi in Helan mountain, an arid desert grassland area in China.

Introduction: Arbuscular mycorrhizal fungi (AMF) are vital in terrestrial ecosystems. However, the community structure characteristics and influencing factors of AMF in the forest ecosystems of arid desert grassland areas require further investigation. Methods: Therefore, we employed high-throughput sequencing technology to analyze the soil AMF community characteristics at different elevations in the Helan mountains. Results: The results revealed that significant differences (P < 0.05) were observed in the soil physicochemical properties among different elevations, and these properties exhibited distinct trends with increasing elevation. Through high-throughput sequencing, we identified 986 operational taxonomic units (OTUs) belonging to 1 phylum, 4 classes, 6 orders, 12 families, 14 genera, and 114 species. The dominant genus was Glomus. Furthermore, significant differences (P < 0.05) were observed in the α-diversity of the soil AMF community across different elevations. Person correlation analysis, redundancy analysis (RDA), and Monte Carlo tests demonstrated significant correlations between the diversity and abundance of AMF communities with soil organic matter (OM) (P < 0.01) and soil water content (WC) (P < 0.05). Discussion: This study provides insights into the structural characteristics of soil AMF communities at various altitudes on the eastern slope of Helan mountain and their relationships with soil physicochemical properties. The findings contribute to our understanding of the distribution pattern of soil AMF and its associations with environmental factors in the Helan mountains, as well as the stability of forest ecosystems in arid desert grassland areas.

Multicolor recordable and erasable photonic crystals based on on-off thermoswitchable mechanochromism toward inkless rewritable paper.

Mechanochromic photonic crystals are attractive due to their force-dependent structural colors; however, showing unrecordable color and unsatisfied performances, which significantly limits their development and expansion toward advanced applications. Here, a thermal-responsive mechanochromic photonic crystal with a multicolor recordability-erasability was fabricated by combining non-close-packing mechanochromic photonic crystals and phase-change materials. Multicolor recordability is realized by pressing thermal-responsive mechanochromic photonic crystals to obtain target colors over the phase-change temperature followed by fixing the target colors and deformed configuration at room temperature. The stable recorded color can be erased and reconfigured by simply heating and similar color-recording procedures respectively due to the thermoswitchable on-off mechanochromism of thermal-responsive mechanochromic photonic crystals along with solid-gel phase transition. These thermal-responsive mechanochromic photonic crystals are ideal rewritable papers for ink-freely achieving multicolor patterns with high resolution, difficult for conventional photonic papers. This work offers a perspective for designing color-recordable/erasable and other stimulus-switchable materials with advanced applications.

Primary cilia formation requires the Leigh syndrome-associated mitochondrial protein NDUFAF2.

Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I component NDUFAF2 has been identified in Leigh syndrome, a severe inherited mitochondriopathy. Mutations in ARMC9, which encodes a basal body protein, cause Joubert syndrome, a ciliopathy with defects in the brain, kidney, and eye. Here, we report a mechanistic link between mitochondria metabolism and primary cilia signaling. We discovered that loss of NDUFAF2 caused both mitochondrial and ciliary defects in vitro and in vivo and identified NDUFAF2 as a binding partner for ARMC9. We also found that NDUFAF2 was both necessary and sufficient for cilia formation and that exogenous expression of NDUFAF2 rescued the ciliary and mitochondrial defects observed in cells from patients with known ARMC9 deficiency. NAD+ supplementation restored mitochondrial and ciliary dysfunction in ARMC9-deficient cells and zebrafish and ameliorated the ocular motility and motor deficits of a patient with ARMC9 deficiency. The present results provide a compelling mechanistic link, supported by evidence from human studies, between primary cilia and mitochondrial signaling. Importantly, our findings have significant implications for the development of therapeutic approaches targeting ciliopathies.

The benefit of favorable venous outflow profiles is mediated through the reduced risk of intracranial hemorrhage in acute ischemic stroke patients undergoing endovascular treatment.

BACKGROUND: Favorable venous outflow (VO) has been recognized as an independent predictor of excellent clinical outcomes in acute ischemic stroke caused by anterior circulation large vessel occlusion (AIS-LVO) patients who received endovascular treatment (EVT). However, the reasons why VO affects clinical outcomes have not been fully explained. In this study, we aimed to identify the potential mediators of VO affecting prognosis. METHODS: We conducted a multicenter retrospective cohort study of consecutive patients with AIS-LVO who underwent EVT. Baseline computed tomographic angiography (CTA) was applied to assess VO by the Cortical Vein Opacification Score (COVES). The primary outcome was functional independence at 90 days (modified Rankin Scale (mRS) score of 0-2). Classifying subtypes of intracranial hemorrhage (ICH) to explore the relationship between ICH subtypes and VO. Multivariate logistic regression and causal mediation analyses were used to evaluate the relationship among VO, functional independence, and potential mediators. RESULTS: Among 860 AIS-LVO patients undergoing EVT, a total of 515 patients were included in the present study after strict screening. In multivariate logistic regression analysis, favorable VO profiles (defined as COVES 3-6) were significantly associated with a lower incidence of ICH (24.2% vs 46.9%, adjusted odds ratio (aOR) 0.48, 95% confidence interval (CI) 0.30 to 0.77, P=0.002) and a higher proportion of functional independence (58.9% vs 15.0%, aOR 4.07, 95% CI 2.41 to 6.88, P<0.001). Mediation analysis showed that favorable VO profiles significantly reduced the incidence of parencuymal hematoma (PH) 2 accounting for 8.0% (95% CI 0.9% to 19.0%) of its beneficial effect on functional independence. CONCLUSION: This study demonstrated the potential mediating effects of severe ICH for the beneficial effect of favorable VO on clinical prognosis among patients with AIS-LVO who underwent EVT.

Human-induced pluripotent stem cell-derived hepatocyte platform in modeling of SARS-CoV-2 infection.

Background and Aim: Currently, SARS-CoV-2 is still spreading rapidly and globally. A large proportion of patients with COVID-19 developed liver injuries. The human-induced pluripotent stem cell (iPSC)-derived hepatocytes recapitulate primary human hepatocytes and have been widely used in studies of liver diseases. Methods: To explore the susceptibility of hepatocytes to SARS-CoV-2, we differentiated iPSCs to functional hepatocytes and tried infecting them with different MOI (1, 0.1, 0.01) of SARS-CoV-2. Results: The iPSC-derived hepatocytes are highly susceptible to virus infection, even at 0.01 MOI. Other than the ancestral strain, iHeps also support the replication of SARS-CoV-2 variants including alpha, beta, theta, and delta. More interestingly, the ACE2 expression significantly upregulated after infection, suggesting a vicious cycle between virus infection and liver injury. Conclusions: The iPSC-derived hepatocytes can support the replication of SARS-CoV-2, and this platform could be used to investigate the SARS-CoV-2 hepatotropism and hepatic pathogenic mechanisms.

Research progress in mechanism of anticancer action of shikonin targeting reactive oxygen species.

Excessive buildup of highly reactive molecules can occur due to the generation and dysregulation of reactive oxygen species (ROS) and their associated signaling pathways. ROS have a dual function in cancer development, either leading to DNA mutations that promote the growth and dissemination of cancer cells, or triggering the death of cancer cells. Cancer cells strategically balance their fate by modulating ROS levels, activating pro-cancer signaling pathways, and suppressing antioxidant defenses. Consequently, targeting ROS has emerged as a promising strategy in cancer therapy. Shikonin and its derivatives, along with related drug carriers, can impact several signaling pathways by targeting components involved with oxidative stress to induce processes such as apoptosis, necroptosis, cell cycle arrest, autophagy, as well as modulation of ferroptosis. Moreover, they can increase the responsiveness of drug-resistant cells to chemotherapy drugs, based on the specific characteristics of ROS, as well as the kind and stage of cancer. This research explores the pro-cancer and anti-cancer impacts of ROS, summarize the mechanisms and research achievements of shikonin-targeted ROS in anti-cancer effects and provide suggestions for designing further anti-tumor experiments and undertaking further experimental and practical research.

Whole-exome sequencing of individuals from an isolated population under extreme conditions implicates rare risk variants of schizophrenia.

Schizophrenia (SCZ), which affects approximately 1% of the world's population, is a global public health concern. It is generally considered that the interplay between genes and the environment is important in the onset and/or development of SCZ. Although several whole-exome sequencing studies have revealed rare risk variants of SCZ, no rare coding variants have been strongly replicated. Assessing isolated populations under extreme conditions might lead to the discovery of variants with a recent origin, which are more likely to have a higher frequency than chance to reflect gene-environment interactions. Following this approach, we examined a unique cohort of Tibetans living at an average altitude above 4500 meters. Whole-exome sequencing of 47 SCZ cases and 53 controls revealed 275 potential novel risk variants and two known variants (12:46244485: A/G and 22:18905934: A/G) associated with SCZ that were found in existing databases. Only one gene (C5orf42) in the gene-based statistics surpassed the exome-wide significance in the cohort. Metascape enrichment analysis suggested that novel risk genes were strongly enriched in pathways relevant to hypoxia, neurodevelopment, and neurotransmission. Additionally, 47 new risk genes were followed up in Han sample of 279 patients with SCZ and 95 controls, only BAI2 variant appearing in one case. Our findings suggest that SCZ patients living at high altitudes may have a unique risk gene signature, which may provide additional information on the underlying biology of SCZ, which can be exploited to identify individuals at greater risk of exposure to hypoxia.

Synthesis of Silica Particles with Controlled Microstructure via the Choline Hydroxide Cocatalyzed Stöber Method.

This study investigates the utilization of choline hydroxide as a cocatalyst in the Stöber method to synthesize silica particles with controlled microstructure. Under low ammonia concentration, we add a robust organic base choline hydroxide and systematically explore the influence of choline hydroxide concentration on the hydrolysis and condensation equilibrium of tetraethyl orthosilicate (TEOS). Through the rational control of the water content, we significantly enhance both the size range and polydispersity of the resulting silica particles. Taking advantage of the regulated microstructure induced by controlled hydrolysis and condensation catalyzed by choline hydroxide, we achieved silica particles with hollow structures through hot water etching, exhibiting significantly enhanced surface area. These findings demonstrate the versatility of choline hydroxide as a cocatalyst in tailoring the microstructure of silica particles. In addition, due to its reducing ability and biocompatibility, which are not shared by other reported catalysts, the use of choline hydroxide opens up opportunities for applications in catalysis, sensing, and drug delivery.

De novo design of mini-binder proteins against IL-2 receptor ß chain.

IL-2 regulates the immune response by interacting with different IL-2 receptor (IL-2R) subunits. High dose of IL-2 binds to IL-2Rßγc heterodimer, which induce various side effects while activating immune function. Disrupting IL-2 and IL-2R interactions can block IL-2 mediated immune response. Here, we used a computational approach to de novo design mini-binder proteins against IL-2R ß chain (IL-2Rß) to block IL-2 signaling. The hydrophobic region where IL-2 binds to IL-2Rß was selected and the promising binding mode was broadly explored. Three mini-binders with amino acid numbers ranging from 55 to 65 were obtained and binder 1 showed the best effects in inhibiting CTLL-2 cells proliferation and STAT5 phosphorylation. Molecular dynamics simulation showed that the binding of binder 1 to IL-2Rß was stable; the free energy of binder1/IL-2Rß complex was lower, indicating that the affinity of binder 1 to IL-2Rß was higher than that of IL-2. Free energy decomposition suggested that the ARG35 and ARG131 of IL-2Rß might be the key to improve the affinity of binder. Our efforts provided new insights in developing of IL-2R blocker, offering a potential strategy for ameliorating the side effects of IL-2 treatment.