Dihydrocapsaicin suppresses the STING-mediated accumulation of ROS and NLRP3 inflammasome and alleviates apoptosis after ischemia-reperfusion injury of perforator skin flap.

Avascular necrosis frequently occurs as a complication following surgery involving the distal perforator flap. Dihydrocapsaicin (DHC) can protect tissue from ischemia-reperfusion (I/R) injury, but its specific role in multizone perforator flaps remains unclear. In this study, the prospective target of DHC in the context of I/R injury was predicted using network pharmacology analysis. Flap viability was determined through survival area analysis, laser Doppler blood flow, angiograms, and histological examination. The expressions of angiogenesis, apoptosis, NLR family pyrin domain containing 3 (NLRP3) inflammasome, oxidative stress, and molecules related to cyclic guanosine monophosphate (GMP)-adenosine monophosphate synthase (cGAS)-interferon gene stimulant (STING) pathway were assessed using western blotting, immunofluorescence, TUNEL staining, and dihydroethidium (DHE) staining. Our finding revealed that DHC promoted the perforator flap survival, which involves the cGAS-STING pathway, oxidative stress, NLRP3 inflammasome, apoptosis, and angiogenesis. DHC induced oxidative stress resistance and suppressed the NLRP3 inflammasome, preventing apoptosis in vascular endothelial cells. Through regulation of STING pathway, DHC controlled oxidative stress in endothelial cells and NLRP3 levels in ischemic flaps. However, activation of the cGAS-STING pathway led to the accumulation of reactive oxygen species (ROS) and NLRP3 inflammasome, thereby diminishing the protective role of DHC. DHC enhanced the survival of multidomain perforator flaps by suppressing the cGAS-STING pathway, oxidative stress, and the formation of NLRP3 inflammasome. These findings unveil a potentially novel mechanism with clinical significance for promoting the survival of multidomain perforator flaps.

Modeling the feasibility of Se-rich corn cultivation in Se-deficient agricultural fields using random forest algorithm.

Selenium constitutes an essential trace element for the human body. Moderate Se intake plays a pivotal role in preserving overall health. The absorption of Se by plants is primarily influenced by the available Se levels in soils, rather than by the soil total Se content, offering potential for exploring Se-rich crops in Se-deficient regions. In this study, we explore the factors influencing the Se bioaccumulation coefficient in corn based on a land quality geochemical survey at a 1:50,000 scale and establish predictive models for corn seed Se content using random forest and multiple linear regression approaches. The results indicate that the surface soil in the study area is deficient in Se (0.18-1.21 mg/kg), but 54% of the corn grain samples met the standards for Se-rich products (0.02-0.30 mg/kg). The factors influencing the Se biological enrichment coefficient in corn seeds are soil pH and CaO and MgO content, with impact levels of 0.54, 0.42, and 0.35, respectively. Compared to multiple linear regression models, the RF model provides more accurate and reliable predictions of corn Se content. The random forest model indicates that approximately 41% of the farmland within the study area is conducive to the cultivation of naturally Se-rich corn, which is a 26% increase in the planting area compared to recommendations based solely on soil Se content. In this research, we introduce an innovative methodological framework for organically cultivating naturally Se-rich corn within regions affected by Se deficiency.

The 18S rRNA m6 A methyltransferase METTL5 promotes mouse embryonic stem cell differentiation.

RNA modifications represent a novel layer of regulation of gene expression. Functional experiments revealed that N6 -methyladenosine (m6 A) on messenger RNA (mRNA) plays critical roles in cell fate determination and development. m6 A mark also resides in the decoding center of 18S ribosomal RNA (rRNA); however, the biological function of m6 A on 18S rRNA is still poorly understood. Here, we report that methyltransferase-like 5 (METTL5) methylates 18S rRNA both in vivo and in vitro, which is consistent with previous reports. Deletion of Mettl5 causes a dramatic differentiation defect in mouse embryonic stem cells (mESCs). Mechanistically, the m6 A deposited by METTL5 is involved in regulating the efficient translation of F-box and WD repeat domain-containing 7 (FBXW7), a key regulator of cell differentiation. Deficiency of METTL5 reduces FBXW7 levels and leads to the accumulation of its substrate c-MYC, thereby delaying the onset of mESC differentiation. Our study uncovers an important role of METTL5-mediated 18S m6 A in mESC differentiation through translation regulation and provides new insight into the functional significance of rRNA m6 A.

Retracted: Therapeutic Effects of Resveratrol Liposome on Muscle Injury in Rats.

This publication has been retracted by the Editor due to concerns regarding the originality of the figure images.Reference:Yongzeng Feng, Zili He, Cong Mao, Xiaolong Shui, Leyi Cai. Therapeutic Effects of Resveratrol Liposome on Muscle Injury in Rats. Med Sci Monit, 2019; 25:2377-2385. DOI: 10.12659/MSM.913409.

Paeoniflorin promotes angiogenesis and tissue regeneration in a full-thickness cutaneous wound model through the PI3K/AKT pathway.

The treatment of wounds remains a clinical challenge because of poor angiogenesis under the wound bed, and increasingly, the patients' need for functional and aesthetically pleasing scars. For the wound healing process, new blood vessels which can deliver nutrients and oxygen to the wound area are necessary. In this study, we investigated the pro-angiogenesis ability and mechanism in wound healing of paeoniflorin (PF), which is a traditional Chinese medicine. In our in vitro results, the ability for proliferation, migration and in vitro angiogenesis in human umbilical vein endothelial cells was promoted by coculturing with PF (1.25-5 µM). Meanwhile, molecular docking studies revealed that PF has excellent binding abilities to phosphatidylinositol-3-kinase (PI3K) and protein kinase B (AKT), and consistent with our western blot results, that PF suppressed PI3K and AKT phosphorylation. Furthermore, to investigate the healing effect of PF in vivo, we constructed a full-thickness cutaneous wound model in rats. PF stimulated the cellular proliferation status, collagen matrix deposition and remodeling processes in vitro and new blood vessel formation at the wound bed resulting in efficient wound healing after intragastric administration of 10 mg·kg-1 ·day-1 in vivo. Overall, PF performed the pro-angiogenetic effect in vitro and accelerating wound healing in vivo. In summary, the capacity for angiogenesis in endothelial cells could be enhanced by PF treatment via the PI3K/AKT pathway in vitro and could accelerate the wound healing process in vivo through collagen deposition and angiogenesis in regenerated tissue. This study provides evidence that application of PF represents a novel therapeutic approach for the treatment of cutaneous wounds.

Single-Photomolecular Nanotheranostics for Synergetic Near-Infrared Fluorescence and Photoacoustic Imaging-Guided Highly Effective Photothermal Ablation.

Multi-modality imaging-guided cancer therapy is considered as a powerful theranostic platform enabling simultaneous precise diagnosis and treatment of cancer. However, recently reported multifunctional systems with multiple components and sophisticate structures remain major obstacles for further clinical translation. In this work, a single-photomolecular theranostic nanoplatform is fabricated via a facile nanoprecipitation strategy. By encapsulating a semiconductor oligomer (IT-S) into an amphiphilic lipid, water-dispersible IT-S nanoparticles (IT-S NPs) are prepared. The obtained IT-S NPs have a very simple construction and possess ultra-stable near-infrared (NIR) fluorescence (FL)/photoacoustic (PA) dual-modal imaging and high photothermal conversion efficiency of 72.3%. Accurate spatiotemporal distribution profiles of IT-S NPs are successfully visualized by NIR FL/PA dual-modal imaging. With the comprehensive in vivo imaging information provided by IT-S NPs, tumor photothermal ablation is readily realized under precise manipulation of laser irradiation, which greatly improves the therapeutic efficacy without any obvious side effects. Therefore, the IT-S NPs allow high tumor therapeutic efficacy under the precise guidance of FL/PA imaging techniques and thus hold great potential as an effective theranostic platform for future clinical applications.

Therapeutic Effects of Resveratrol Liposome on Muscle Injury in Rats.

BACKGROUND In this study we prepared liposome microbubbles loading resveratrol (LMLR) and evaluated its therapeutic effect on injury of gastrocnemius muscle in rats. MATERIAL AND METHODS LMLR was prepared and characterized by particle size, potential, and microscopy, and a rat model of acute blunt injury of gastrocnemius muscle was established. After treatments with resveratrol or LMLR, the therapeutic effects were evaluated by hematoxylin-eosin (HE) staining. The expression of MHCIIB and vimentin in mRNA level was measured by real-time PCR. The expression of desmin and collagen I protein was assessed by immunohistochemistry. RESULTS LMLR showed regular cycle shape in a size of ~1000 nm. LMLR was negatively charged (-30 mV). The in vitro release of LMLR was close to 80% at 10 h and 90% at 48 h. Acute gastrocnemius muscle injury was established in rats and tissue recovery was observed after LMLR treatment as evidenced by HE staining, decreased expression of MHCIIB, and increased expression of vimentin. Moreover, LMLR treatment obviously facilitated desmin expression and reduced collagen I expression. CONCLUSIONS LMLR is effective in treating acute blunt injury of gastrocnemius muscle in rats.

Monotropein promotes angiogenesis and inhibits oxidative stress-induced autophagy in endothelial progenitor cells to accelerate wound healing.

Attenuating oxidative stress-induced damage and promoting endothelial progenitor cell (EPC) differentiation are critical for ischaemic injuries. We suggested monotropein (Mtp), a bioactive constituent used in traditional Chinese medicine, can inhibit oxidative stress-induced mitochondrial dysfunction and stimulate bone marrow-derived EPC (BM-EPC) differentiation. Results showed Mtp significantly elevated migration and tube formation of BM-EPCs and prevented tert-butyl hydroperoxide (TBHP)-induced programmed cell death through apoptosis and autophagy by reducing intracellular reactive oxygen species release and restoring mitochondrial membrane potential, which may be mediated viamTOR/p70S6K/4EBP1 and AMPK phosphorylation. Moreover, Mtp accelerated wound healing in rats, as indicated by reduced healing times, decreased macrophage infiltration and increased blood vessel formation. In summary, Mtp promoted mobilization and differentiation of BM-EPCs and protected against apoptosis and autophagy by suppressing the AMPK/mTOR pathway, improving wound healing in vivo. This study revealed that Mtp is a potential therapeutic for endothelial injury-related wounds.

Asperosaponin VI promotes angiogenesis and accelerates wound healing in rats via up-regulating HIF-1α/VEGF signaling.

Wound therapy remains a clinical challenge due to the complexity of healing pathology and high demand of achieving functional and aesthetically satisfactory scars. Newly formed blood vessels are essential for tissue repair since they can support cells at the wound site with nutrition and oxygen. In this study, we investigated the effects of Asperosaponin VI (ASA VI) isolated from a traditional Chinese medicine, the root of Dipsacus asper Wall, in promoting angiogenesis, as well as its function in wound therapeutics. Treatment of human umbilical vein endothelial cells (HUVECs) with ASA VI (20-80 µg/mL) dose-dependently promoted the proliferation, migration and enhanced their angiogenic ability in vitro, which were associated with the up-regulated HIF-1α/VEGF signaling. Full-thickness cutaneous wound model rats were injected with ASA VI (20 mg·kg-1·d-1, iv) for 21 d. Administration of ASA VI significantly promoted the cutaneous wound healing, and more blood vessels were observed in the regenerated tissue. Due to rapid vascularization, the cellular proliferation status, granulation tissue formation, collagen matrix deposition and remodeling processes were all accelerated, resulting in efficient wound healing. In summary, ASA VI promotes angiogenesis of HUVECs in vitro via up-regulating the HIF-1α/VEGF pathway, and efficiently enhances the vascularization in regenerated tissue and facilitates wound healing in vivo. The results reveal that ASA VI is a potential therapeutic for vessel injury-related wounds.

Preoperative 3D and 4D-CT imaging using 640-Multislice CT (640-MSCT) in diagnosis of female urethral diverticulum.

OBJECTIVE: To determine the sensitivity and specificity of 640-Multislice CT (640-MSCT) in diagnosing the female UD. MATERIALS AND METHODS: We investigated 16 patients with symptomatic UDs preoperatively in our hospital from August 2010 to March 2016. The patients' average age was 38.8 years. All patients were performed 640-MSCT of pelvis; then, 3D and 4D images were reconstructed preoperatively. RESULTS: In 3D and 4D-CT images, out of 16 patients, thirteen patients had one ostium, two had 2 ostia and one had 3 ostia. Out of those thirteen patients, eight patients' ostia were located at 5 o'clock and five patients' at 7 o'clock. Patients with 2 ostia location were at 5 and 6 o'clock and 5 and 7 o'clock, respectively. Patients with 3 ostia location were at 5, 6 and 7 o'clock. The mean distance from the bladder neck to the ostia was 22.5 mm. The shape of UD was out-pouching in 11 patients (68.8%), U-shaped in four patients (25.0%) and circumferential in 1 patient (6.2%). The CT findings were confirmed by surgical findings. CONCLUSIONS: 640-MSCT is a useful tool in identifying UD's shape and ostium (including number, location) before operation. Preoperative 640-MSCT should be an adaptable modality for clinically suspected UD patients. ADVANCES IN KNOWLEDGE: Several imaging methods have been used to diagnose female UD. 640-MSCT may be more suitable to diagnose it for its higher sensitivity and specificity in diagnosis of female UD, especially in identifying UD's shape and number and location of ostium.

A 13-year retrospective study evaluating the efficacy of using air-fluidised beds for toxic epidermal necrolysis patients.

OBJECTIVES: Toxic epidermal necrolysis (TEN) is a potentially life-threatening dermatological disease involving large areas of skin loss with systemic symptoms. This study evaluated the efficacy of air-fluidised bed therapy for TEN patients. METHODS: Of 27 people with TEN, 11 used air-fluidised beds (the air-fluidised group) and 16 used standard beds (the control group). Days to complete re-epithelialisation, re-epithelialisation rate, incidence of complications, mortality, pain measured by visual analogue score and the incidence of cutaneous infection were compared in these groups. RESULTS: The mean body surface area of involvement was 77.0 ± 11.8% and baseline mean severity-of-illness score for TEN (SCORTEN) was 2.81 ± 1.08. The re-epithelialisation rate in the air-fluidised group was 100% but was only 56.3% in the control group (P < 0.05). There was a significant difference in the time taken to complete re-epithelialisation between the air-fluidised group (13 days [95% CI: 9.0-17.0]) and the control group (21 days [16.5-25.5], P < 0.05). Furthermore, the incidence of complications was 18% in the air-fluidised group versus 75% in the control group, including fewer cutaneous infections (P < 0.05). There was a significant reduction in pain among the air-fluidised group compared with the control group (P < 0.05). There were no deaths in the air-fluidised group while 19% of the control group died. CONCLUSION: Air-fluidised beds can reduce the time to complete re-epithelialisation, relieve pain and increase the re-epithelialisation rate of TEN patients, but there was no significant difference between them in mortality rate in our study.

Dissecting the association between gut microbiota and hypertrophic scarring: a bidirectional Mendelian randomization study.

Hypertrophic scars affect a significant number of individuals annually, giving rise to both cosmetic concerns and functional impairments. Prior research has established that an imbalance in the composition of gut microbes, termed microbial dysbiosis, can initiate the progression of various diseases through the intricate interplay between gut microbiota and the host. However, the precise nature of the causal link between gut microbiota and hypertrophic scarring remains uncertain. In this study, after compiling summary data from genome-wide association studies (GWAS) involving 418 instances of gut microbiota and hypertrophic scarring, we conducted a bidirectional Mendelian randomization (MR) to investigate the potential existence of a causal relationship between gut microbiota and the development of hypertrophic scar and to discern the directionality of causation. By utilizing MR analysis, we identified seven causal associations between gut microbiome and hypertrophic scarring, involving one positive and six negative causal directions. Among them, Intestinimonas, Ruminococcus2, Barnesiella, Dorea, Desulfovibrio piger, and Ruminococcus torques act as protective factors against hypertrophic scarring, while Eubacterium rectale suggests a potential role as a risk factor for hypertrophic scars. Additionally, sensitivity analyses of these results revealed no indications of heterogeneity or pleiotropy. The findings of our MR study suggest a potential causative link between gut microbiota and hypertrophic scarring, opening up new ways for future mechanistic research and the exploration of nanobiotechnology therapies for skin disorders.

Highly Bioactive MXene-M2-Exosome Nanocomposites Promote Angiogenic Diabetic Wound Repair through Reconstructing High Glucose-Derived Immune Inhibition.

The repair of diabetic wounds remains challenging, primarily due to the high-glucose-derived immune inhibition which often leads to the excessive inflammatory response, impaired angiogenesis, and heightened susceptibility to infection. However, the means to reduce the immunosuppression and regulate the conversion of M2 phenotype macrophages under a high-glucose microenvironment using advanced biomaterials for diabetic wounds are not yet fully understood. Herein, we report two-dimensional carbide (MXene)-M2 macrophage exosome (Exo) nanohybrids (FM-Exo) for promoting diabetic wound repair by overcoming the high-glucose-derived immune inhibition. FM-Exo showed the sustained release of M2 macrophage-derived exosomes (M2-Exo) up to 7 days and exhibited broad-spectrum antibacterial activity. In the high-glucose microenvironment, relative to the single Exo, FM-Exo could significantly induce the optimized M2a/M2c polarization ratio of macrophages by activating the PI3K/Akt signaling pathway, promoting the proliferation, migration of fibroblasts, and angiogenic ability of endothelial cells. In the diabetic full-thickness wound model, FM-Exo effectively regulated the polarization status of macrophages and promoted their transition to the M2 phenotype, thereby inhibiting inflammation, promoting angiogenesis through VEGF secretion, and improving proper collagen deposition. As a result, the healing process was accelerated, leading to a better healing outcome with reduced scarring. Therefore, this study introduced a promising approach to address diabetic wounds by developing bioactive nanomaterials to regulate immune inhibition in a high-glucose environment.

Puerarin enhances TFEB-mediated autophagy and attenuates ROS-induced pyroptosis after ischemic injury of random-pattern skin flaps.

BACKGROUND AND AIM: Necrosis of random-pattern flaps restricts their application in clinical practice. Puerarin has come into focus due to its promising therapeutic effects in ischemic diseases. Here, we employed Puerarin and investigated its role and potential mechanisms in flap survival. EXPERIMENTAL PROCEDURE: The effect of Puerarin on the viability of human umbilical vein endothelial cells (HUVECs) was assessed by CCK-8, EdU staining, migration, and scratch assays. Survival area measurement and laser Doppler blood flow (LDBF) were utilized to assess the viability of ischemic injury flaps. Levels of molecules related to oxidative stress, pyroptosis, autophagy, transcription factor EB (TFEB), and the AMPK-TRPML1-Calcineurin signaling pathway were detected using western blotting, immunofluorescence, dihydroethidium (DHE) staining, RT-qPCR and Elisa. KEY RESULTS: The findings demonstrated that Puerarin enhanced the survivability of ischemic flaps. Autophagy, oxidative stress, and pyroptosis were implicated in the ability of Puerarin in improving flap survival. Increased autophagic flux and augmented tolerance to oxidative stress contribute to Puerarin's suppression of pyroptosis. Additionally, Puerarin modulated the activity of TFEB through the AMPK-TRPML1-Calcineurin signaling pathway, thereby enhancing autophagic flux. CONCLUSIONS AND IMPLICATIONS: Puerarin promoted flap survival from ischemic injury through upregulation of TFEB-mediated autophagy and inhibition of oxidative stress. Our findings offered valuable support for the clinical application of Puerarin in the treatment of ischemic diseases, including random-pattern flaps.

Zero-shot prediction of mutation effects with multimodal deep representation learning guides protein engineering.

Mutations in amino acid sequences can provoke changes in protein function. Accurate and unsupervised prediction of mutation effects is critical in biotechnology and biomedicine, but remains a fundamental challenge. To resolve this challenge, here we present Protein Mutational Effect Predictor (ProMEP), a general and multiple sequence alignment-free method that enables zero-shot prediction of mutation effects. A multimodal deep representation learning model embedded in ProMEP was developed to comprehensively learn both sequence and structure contexts from ~160 million proteins. ProMEP achieves state-of-the-art performance in mutational effect prediction and accomplishes a tremendous improvement in speed, enabling efficient and intelligent protein engineering. Specifically, ProMEP accurately forecasts mutational consequences on the gene-editing enzymes TnpB and TadA, and successfully guides the development of high-performance gene-editing tools with their engineered variants. The gene-editing efficiency of a 5-site mutant of TnpB reaches up to 74.04% (vs 24.66% for the wild type); and the base editing tool developed on the basis of a TadA 15-site mutant (in addition to the A106V/D108N double mutation that renders deoxyadenosine deaminase activity to TadA) exhibits an A-to-G conversion frequency of up to 77.27% (vs 69.80% for ABE8e, a previous TadA-based adenine base editor) with significantly reduced bystander and off-target effects compared to ABE8e. ProMEP not only showcases superior performance in predicting mutational effects on proteins but also demonstrates a great capability to guide protein engineering. Therefore, ProMEP enables efficient exploration of the gigantic protein space and facilitates practical design of proteins, thereby advancing studies in biomedicine and synthetic biology.

Experimental Investigation of Discharge Phenomena in Electrochemical Discharge Machining Process.

Electrochemical discharge machining (ECDM) is a promising non-traditional processing technology used to machine non-conductive materials, such as glass and ceramic, based on the evoked electrochemical discharge phenomena around the tool electrode. The discharge in ECDM is a key factor that affects the removal of material. Moreover, the discharge current is an important indicator reflecting the discharge state. However, the discharge characteristics remain an open topic for debate and require further investigation. There is still confusion regarding the distinction of the discharge current from the electrochemical reaction current in ECDM. In this study, high-speed imaging technology was applied to the investigation of the discharge characteristics. By comparing the captured discharge images with the corresponding discharge current, the discharge can be classified into three types. The observations of the discharge effect on the gas film indicate that a force was exerted on the gas film during the discharge process and the shape of the gas film was changed by the force. In addition, the energies released by different types of discharge were calculated according to the voltage and current waveforms. The discharge frequency was found to increase with the increase in applied voltage and the frequency of the second type of discharge was approximately equal to that of the third type when the applied voltage was higher than 40 V.

Engineered exosomes derived from miR-132-overexpresssing adipose stem cells promoted diabetic wound healing and skin reconstruction.

The tissue reconstruction of diabetic wounds mainly depends on the proliferation and remodelling of cutaneous cells around wounds and the transplantation of random skin flaps, however, the proliferation of cells or survival of skin flaps are difficult due to the severe inflammation and other problems caused by diabetes. The stem cell-derived exosomes loaded with miRNA can be an effective therapeutic strategy for promoting diabetic wound healing. Therefore, in this study, the engineered exosomes derived from miR-132-overexpressing adipose stem cells (miR-132-exo) was obtained for promoting the healing of diabetic wounds and skin flaps. In vitro, the miR-132-exo promoted the proliferation and migration of human umbilical vein endothelial cells (HUVECs). In vivo, streptozotocin (STZ) induced diabetic mice were used to create full-thickness skin wounds and random skin flaps to further investigate the healing effect of miR-132-exo. The results showed miR-132-exo evidently enhanced the survival of skin flaps and promote diabetic wound healing, through reducing local inflammation, promoting angiogenesis and stimulating M2-macrophages polarization mediated by NF-κB signaling pathway. These novel findings demonstrated that engineered miR-132-exo can be a potent therapeutic for treating diabetic wounds and inflammatory-related disease.

Experimental Investigation of the Machining Characteristics in Graphite-Powder-Mixed Electrochemical Discharge Machining of Microholes in Glass.

The effect of graphite powder on the machining characteristics in graphite-powder-mixed electrochemical discharge machining of microholes was still not clear. How the discharge mechanism changed with the addition of graphite powder into the electrolyte, which further led to changes in the morphology of the machined holes, remained to be revealed. In this study, a series of microhole machining experiments were conducted in glass. Comparisons of the discharge energy, microhole entrance diameter, hole taper, and tool electrode morphology after machining were made when machining in the electrolytes with and without graphite powder. Experimental results revealed that there were a lot of small pulse currents distributed on the current waveform when machining with the graphite-powder-mixed electrolyte. The average discharge energy of the small pulse current was 2.8 times as much as that of the general electrochemical discharge. After introducing graphite powder into the electrolyte, the entrance diameter of the hole became larger when the hole depth was deeper than 200 µm. The HAZ width increased with increasing hole depth at the voltage of 37-41 V, while it decreased at the voltage of 43 V. A reduction in hole taper angle with a range of 0.5° to 2.3° was achieved. In addition, after machining in electrolytes with and without graphite powder, the tool electrode surfaces showed different morphologies due to different discharges.

ProRefiner: an entropy-based refining strategy for inverse protein folding with global graph attention.

Inverse Protein Folding (IPF) is an important task of protein design, which aims to design sequences compatible with a given backbone structure. Despite the prosperous development of algorithms for this task, existing methods tend to rely on noisy predicted residues located in the local neighborhood when generating sequences. To address this limitation, we propose an entropy-based residue selection method to remove noise in the input residue context. Additionally, we introduce ProRefiner, a memory-efficient global graph attention model to fully utilize the denoised context. Our proposed method achieves state-of-the-art performance on multiple sequence design benchmarks in different design settings. Furthermore, we demonstrate the applicability of ProRefiner in redesigning Transposon-associated transposase B, where six out of the 20 variants we propose exhibit improved gene editing activity.