Differentiating small (< 2 cm) pancreatic ductal adenocarcinoma from neuroendocrine tumors with multiparametric MRI-based radiomic features.

OBJECTIVES: To assess MR-based radiomic analysis in preoperatively discriminating small (< 2 cm) pancreatic ductal adenocarcinomas (PDACs) from neuroendocrine tumors (PNETs). METHODS: A total of 197 patients (146 in the training cohort, 51 in the validation cohort) from two centers were retrospectively collected. A total of 7338 radiomics features were extracted from T2-weighted, diffusion-weighted, T1-weighted, arterial phase, portal venous phase and delayed phase imaging. The optimal features were selected by the Mann-Whitney U test, Spearman's rank correlation test and least absolute shrinkage and selection operator method and used to construct the radiomic score (Rad-score). Conventional radiological and clinical features were also assessed. Multivariable logistic regression was used to construct a radiological model, a radiomic model and a fusion model. RESULTS: Nine optimal features were identified and used to build the Rad-score. The radiomic model based on the Rad-score achieved satisfactory results with AUCs of 0.905 and 0.930, sensitivities of 0.780 and 0.800, specificities of 0.906 and 0.952 and accuracies of 0.836 and 0.863 for the training and validation cohorts, respectively. The fusion model, incorporating CA19-9, tumor margins, pancreatic duct dilatation and the Rad-score, exhibited the best performance with AUCs of 0.977 and 0.941, sensitivities of 0.914 and 0.852, specificities of 0.954 and 0.950, and accuracies of 0.932 and 0.894 for the training and validation cohorts, respectively. CONCLUSIONS: The MR-based Rad-score is a novel image biomarker for discriminating small PDACs from PNETs. A fusion model combining radiomic, radiological and clinical features performed very well in differentially diagnosing these two tumors. CLINICAL RELEVANCE STATEMENT: A fusion model combining MR-based radiomic, radiological, and clinical features could help differentiate between small pancreatic ductal adenocarcinomas and pancreatic neuroendocrine tumors. KEY POINTS: Preoperatively differentiating small pancreatic ductal adenocarcinomas (PDACs) and pancreatic neuroendocrine tumors (PNETs) is challenging. Multiparametric MRI-based Rad-score can be used for discriminating small PDACs from PNETs. A fusion model incorporating radiomic, radiological, and clinical features differentiated small PDACs from PNETs well.

GPNMB Modulates Autophagy to Enhance Functional Recovery After Spinal Cord Injury in Rats.

Spinal cord injury (SCI) severely affects the quality of life and autonomy of patients, and effective treatments are currently lacking. Autophagy, an essential cellular metabolic process, plays a crucial role in neuroprotection and repair after SCI. Glycoprotein non-metastatic melanoma protein B (GPNMB) has been shown to promote neural regeneration and synapse reconstruction, potentially through the facilitation of autophagy. However, the specific role of GPNMB in autophagy after SCI is still unclear. In this study, we utilized the spinal cord transection method to establish SCI rats model and overexpressed GPNMB using adenoviral vectors. We assessed tissue damage using hematoxylin and eosin (H&E) and Nissl staining, and observed cell apoptosis using TUNEL staining. We evaluated the inflammatory response by measuring inflammatory factors using enzyme-linked immunosorbent assay (ELISA). In addition, we measured reactive oxygen species (ROS) levels using 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA), and assessed oxidative stress levels by measuring malondialdehyde (MDA) and glutathione (GSH) using ELISA. To evaluate autophagy levels, we performed immunofluorescence staining for the autophagy marker Beclin-1 and conducted Western blot analysis for autophagy-related proteins. We also assessed limb recovery through functional evaluation. Meanwhile, we induced cell injury using lipopolysaccharide (LPS) and added an autophagy inhibitor to verify the impact of GPNMB on SCI through autophagy modulation. The results demonstrated that GPNMB alleviated the inflammatory response, reduced oxidative stress levels, inhibited cell apoptosis, and promoted autophagy following SCI. Inhibiting autophagy reversed the effects of GPNMB. These findings suggest that GPNMB promotes neural injury repair after SCI, potentially through attenuating the inflammatory response, reducing oxidative stress, and inhibiting cell apoptosis.

The role of KDM4A-mediated histone methylation on temozolomide resistance in glioma cells through the HUWE1/ROCK2 axis.

Temozolomide (TMZ) resistance presents a significant challenge in the treatment of gliomas. Although lysine demethylase 4A (KDM4A) has been implicated in various cancer-related processes, its role in TMZ resistance remains unclear. This study aims to elucidate the contribution of KDM4A to TMZ resistance in glioma cells and its potential implications for glioma prognosis. We assessed the expression of KDM4A in glioma cells (T98G and U251MG) using qRT-PCR and Western blot assays. To explore the role of KDM4A in TMZ resistance, we transfected siRNA targeting KDM4A into drug-resistant glioma cells. Cell viability was assessed using the CCK-8 assay and the TMZ IC50 value was determined. ChIP assays were conducted to investigate KDM4A, H3K9me3, and H3K36me3 enrichment on the promoters of ROCK2 and HUWE1. Co-immunoprecipitation confirmed the interaction between HUWE1 and ROCK2, and we examined the levels of ROCK2 ubiquitination following MG132 treatment. Notably, T98G cells exhibited greater resistance to TMZ than U251MG cells, and KDM4A displayed high expression in T98G cells. Inhibiting KDM4A resulted in decreased cell viability and a reduction in the TMZ IC50 value. Mechanistically, KDM4A promoted ROCK2 transcription by modulating H3K9me3 levels. Moreover, disruption of the interaction between HUWE1 and ROCK2 led to reduced ROCK2 ubiquitination. Inhibition of HUWE1 or overexpression of ROCK2 counteracted the sensitization effect of si-KDM4A on TMZ responsiveness in T98G cells. Our findings highlight KDM4A's role in enhancing TMZ resistance in glioma cells by modulating ROCK2 and HUWE1 transcription and expression through H3K9me3 and H3K36me3 removal.

Hybrid Electrically Conductive Hydrogels with Local Nerve Growth Factor Release Facilitate Peripheral Nerve Regeneration.

It is challenging to treat peripheral nerve injury (PNI) clinically. As the gold standard for peripheral nerve repair, autologous nerve grafting remains a critical limitation, including tissue availability, donor-site morbidity, immune rejection, etc. Recently, conductive hydrogels (CHs) have shown potential applications in neural bioengineering due to their good conductivity, biocompatibility, and low immunogenicity. Herein, a hybrid electrically conductive hydrogel composed of acrylic acid derivatives, gelatin, and heparin with sustained nerve growth factor (NGF) release property was developed. The rat sciatic nerve injury (SNI) model (10 mm long segment defect) was used to investigate the efficacy of these hydrogel conduits in facilitating peripheral nerve repair. The results showed that the hydrogel conduits had excellent conductivity, mechanical properties, and biocompatibility. In addition, NGF immobilized in the hydrogel conduits had good sustained release characteristics. Finally, functional recovery and electrophysiological evaluations, together with histological analysis, indicated that the hydrogel conduits immobilizing NGF had superior effects on motor recovery, axon growth, and remyelination, thereby significantly accelerating the repairing of the sciatic nerve. This study demonstrated that hybrid electrically conductive hydrogels with local NGF release could be effectively used for PNI repair.

A law of data separation in deep learning.

While deep learning has enabled significant advances in many areas of science, its black-box nature hinders architecture design for future artificial intelligence applications and interpretation for high-stakes decision-makings. We addressed this issue by studying the fundamental question of how deep neural networks process data in the intermediate layers. Our finding is a simple and quantitative law that governs how deep neural networks separate data according to class membership throughout all layers for classification. This law shows that each layer improves data separation at a constant geometric rate, and its emergence is observed in a collection of network architectures and datasets during training. This law offers practical guidelines for designing architectures, improving model robustness and out-of-sample performance, as well as interpreting the predictions.

FOXM1 maintains fatty acid homoeostasis through the SET7-H3K4me1-FASN axis.

Reprogramming of metabolic genes and subsequent alterations in metabolic phenotypes occur widely in malignant tumours, including glioblastoma (GBM). FOXM1 is a potent transcription factor that plays an oncogenic role by regulating the expression of many genes. As a SET domain containing protein, SET7 is a protein lysine methyltransferase which monomethylates histone proteins and other proteins. The epigenetic modification of histones regulates gene expressions by epigenetically modifying promoters of DNAs and inter vening in tumor development. Activation of FASN increased de novo fatty acid (FA) synthesis, a hallmark of cancer cells. Here, we report that FOXM1 may directly promote the transcription of SET7 and activate SET7-H3K4me1-FASN axis, which results in the maintenance of de novo FA synthesis.

Drug suspending during wound healing effectively weakens immunosuppression-related complications by preserving CD8+ T cell function.

Immunosuppressive medications, which interfere with the activation and proliferation of T and B cells, increase the risk of wound healing complications. To address it, this study aimed to validate the feasibility of drug suspending during wound healing, whilst exploring the mechanisms exerted by T cells, which are important in the wound healing process. For this, a mouse skin wound model was set up. Tacrolimus (FK506) and fingolimod (FTY720) were both administered intraperitoneally prior to wounding to inhibit the T cell activation and migration, respectively. Flow-cytometric analysis subsequently revealed the functional T cell subtypes detected during the healing process. A CD8a antibody was also administered to deplete CD8+ T cells in vivo to verify their specific function. It was found that FK506 or FTY720 administration delayed the early phase of wound healing by reducing collagen production, which was also supported by the downregulation of col1a1, col3a1 and tgfb1. However, there was no significant difference in the total healing period. Both spleen- and skin-derived CD8+ T cells were proliferated and activated after injury without intervention, whereas CD4+ T cells showed no significant changes. Furthermore, selectively depleting CD8+ T cells retarded the healing process by downregulating collagen production-associated genes (col1a1, col3a1, tgfß1 and en1) and proteins (collagen type 1 and 3). In addition, the CD8a antibody decreased the expression of genes lta, tnfa, il13 and il13ra, and protein interleukin-13Rα. In conclusion, suspending immunosuppressive drugs during wound healing was shown to be feasible through restraining the migration of activated T cells. CD8+ T cells represented the primary functional subtype positively associated with wound healing.

Operative treatment of cystic prolactinomas: a retrospective study.

BACKGROUND: The optimal therapeutic approach for cystic prolactinomas remains unclear. This study aimed to evaluate the remission rates of prolactinoma patients after surgical treatment and the risk factors affecting postoperative remission in cystic prolactinoma patients. METHODS: The clinical data were retrospectively compiled from 141 patients with prolactinomas (including 41 cases of cystic prolactinomas, 21 cases of solid microprolactinomas and 79 cases of solid macroprolactinomas) who underwent transsphenoidal surgery (TSS) between April 2013 and October 2021 at the First Affiliated Hospital of Sun Yat-sen University. RESULTS: Early postoperative remission was achieved in 65.83% (n = 27/41) of cystic prolactinomas, 80.95% (n = 17/21) of solid microprolactinomas and 40.51% (n = 32/79) of solid macroprolactinomas. The mean length of follow up in all patients was 43.95 ± 2.33 months (range: 6-105 months). The follow-up remission rates were 58.54%, 71.43% and 44.30% in cystic, solid micro- and solid macroprolactinomas, respectively. For cystic prolactinomas, the early postoperative remission rates in the patients with preoperative dopamine agonists (DA) treatment were significantly higher than those without preoperative DA treatment (p = 0.033), but the difference in the follow-up remission rates between these two groups was not significant (p = 0.209). Multivariate stepwise logistic regression analysis indicated that tumor size and preoperative prolactin (PRL) levels < 200 ng/ml were independent predictors for early postoperative remission in cystic prolactinomas. CONCLUSION: For cystic prolactinomas, tumor size and preoperative PRL levels were independent predictors of early postoperative remission. Preoperative DA therapy combined with TSS may be more beneficial to cystic prolactinoma patients.

Optimize Injection-Molding Process Parameters and Build an Adaptive Process Control System Based on Nozzle Pressure Profile and Clamping Force.

The injection-molding process is a non-linear process, and the product quality and long-term production stability are affected by several factors. To stabilize the product quality effected by these factors, this research establishes a standard process parameter setup procedure and an adaptive process control system based on the data collected by a nozzle pressure sensor and a tie-bar strain gauge to achieve this goal. In this research, process parameters such as the V/P switchover point, injection speed, packing pressure, and clamping force are sequentially optimized based on the characteristics of the pressure profile. After the optimization process, this research defines the standard quality characteristics through the optimized process parameters and combines it with the adaptive process control system in order to achieve the purpose of automatic adjustment of the machine and maintain high-quality production. Finally, three different viscosity materials are used to verify the effectiveness of the optimization procedure and the adaptive process control system. With the system, the variation of product weight was reduced to 0.106%, 0.092%, and 0.079%, respectively.

Endogenous Electric Field-Coupled PD@BP Biomimetic Periosteum Promotes Bone Regeneration through Sensory Nerve via Fanconi Anemia Signaling Pathway.

To treat bone defects, repairing the nerve-rich periosteum is critical for repairing the local electric field. In this study, an endogenous electric field is coupled with 2D black phosphorus electroactive periosteum to explore its role in promoting bone regeneration through nerves. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) are used to characterize the electrically active biomimetic periosteum. Here, the in vitro effects exerted by the electrically active periosteum on the transformation of Schwann cells into the repair phenotype, axon initial segment (AIS) and dense core vesicle (DCV) of sensory neurons, and bone marrow mesenchymal stem cells are assessed using SEM, immunofluorescence, RNA-sequencing, and calcium ion probes. The electrically active periosteum stimulates Schwann cells into a neuroprotective phenotype via the Fanconi anemia pathway, enhances the AIS effect of sensory neurons, regulates DCV transport, and releases neurotransmitters, promoting the osteogenic transformation of bone marrow mesenchymal stem cells. Microcomputed tomography and other in vivo techniques are used to study the effects of the electrically active periosteum on bone regeneration. The results show that the electrically active periosteum promotes nerve-induced osteogenic repair, providing a potential clinical strategy for bone regeneration.

Transsphenoidal surgery for prolactinomas in male patients: a retrospective study.

Male patients with prolactinomas usually present with typical hyperprolactinemia symptoms, including sexual dysfunction and infertility. However, clinical factors related to sexual dysfunction and surgical outcomes in these patients remain unclear. This study aimed to investigate the outcomes of male patients with prolactinomas after transsphenoidal surgery and the risk factors affecting sexual dysfunction. This study was conducted on 58 male patients who underwent transsphenoidal surgery for prolactinomas between May 2014 and December 2020 at the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. We evaluated the sexual function of patients before and after surgery through International Index of Erectile Function-5 scores, libido, and frequency of morning erection. Of the 58 patients, 48 (82.8%) patients had sexual intercourse preoperatively. Among those 48 patients, 41 (85.4%) patients presented with erectile dysfunction. The preoperative International Index of Erectile Function-5 scores in patients with macroprolactinomas were significantly higher than those in patients with giant prolactinomas (17.63 ± 0.91 vs 13.28 ± 1.43; P = 0.01). Postoperatively, the incidence of erectile dysfunction was 47.9%, which was significantly lower than that preoperatively (85.4%; P = 0.01). Twenty-eight (68.3%) patients demonstrated an improvement in erectile dysfunction. Tumor size and invasiveness were significantly correlated with the improvement of erectile dysfunction. Preoperative testosterone <2.3 ng ml-1 was an independent predictor of improvement in erectile dysfunction. In conclusion, our results indicated that tumor size and invasiveness were important factors affecting the improvement of sexual dysfunction in male patients with prolactinoma. The preoperative testosterone level was an independent predictor related to the improvement of erectile dysfunction.

Photosensitive and Conductive Hydrogel Induced Innerved Bone Regeneration for Infected Bone Defect Repair.

Repairing infected bone defects is a challenge in the field of orthopedics because of the limited self-healing capacity of bone tissue and the susceptibility of refractory materials to bacterial activity. Innervation is the initiating factor for bone regeneration and plays a key regulatory role in subsequent vascularization, ossification, and mineralization processes. Infection leads to necrosis of local nerve fibers, impeding the repair of infected bone defects. Herein, a biomaterial that can induce skeletal-associated neural network reconstruction and bone regeneration with high antibacterial activity is proposed for the treatment of infected bone defects. A photosensitive conductive hydrogel is prepared by incorporating magnesium-modified black phosphorus (BP@Mg) into gelatin methacrylate (GelMA). The near-infrared irradiation-based photothermal and photodynamic treatment of black phosphorus endows it with strong antibacterial activity, improving the inflammatory microenvironment and reducing bacteria-induced bone tissue damage. The conductive nanosheets and bioactive ions released from BP@Mg synergistically improve the migration and secretion of Schwann cells, promote neurite outgrowth, and facilitate innerved bone regeneration. In an infected skull defect model, the GelMA-BP@Mg hydrogel shows efficient antibacterial activity and promotes bone and CGRP+ nerve fiber regeneration. The phototherapy conductive hydrogel provides a novel strategy based on skeletal-associated innervation for infected bone defect repair.

Small Intestinal Submucosa Biomimetic Periosteum Promotes Bone Regeneration.

BACKGROUND: Critical bone defects are a significant problem in clinics. The periosteum plays a vital role in bone regeneration. A tissue-engineered periosteum (TEP) has received increasing attention as a novel strategy for bone defect repairs. METHODS: In this experiment, a biomimetic periosteum was fabricated by using coaxial electrospinning technology with decellularized porcine small intestinal submucosa (SIS) as the shell and polycaprolactone (PCL) as the core. In vitro, the effects of the biomimetic periosteum on Schwann cells, vascular endothelial cells, and bone marrow mesenchymal stem cells were detected by a scratch test, an EdU, a tube-forming test, and an osteogenesis test. In vivo, we used HE staining to evaluate the effect of the biomimetic periosteum on bone regeneration. RESULTS: In vitro experiments showed that the biomimetic periosteum could significantly promote the formation of angiogenesis, osteogenesis, and repaired Schwann cells (SCs). In vivo experiments showed that the biomimetic periosteum could promote the repair of bone defects. CONCLUSIONS: The biomimetic periosteum could simulate the structural function of the periosteum and promote bone repair. This strategy may provide a promising method for the clinical treatment of skull bone defects.

Multifunctional hydrogel loaded with 4-octyl itaconate exerts antibacterial, antioxidant and angiogenic properties for diabetic wound repair.

Cutaneous wound healing, especially diabetic wound healing, is a common clinical problem. Reactive oxygen species (ROS) and bacterial infection are two major factors in the induction of oxidative stress and inflammation, leading to impeded angiogenesis and wound healing. However, it is still very difficult to reverse the harsh microenvironment of chronic inflammation and excessive oxidative stress on diabetic wound. Itaconate, an endogenous metabolite, has recently attracted extensive attention as a critical immune-regulator. In this study, we used 4-octyl itaconate (4OI), a cell-permeable itaconate derivative, to have antioxidative and anti-inflammatory functions for diabetic wound regeneration. Simultaneously, an injectable, self-healing, and antibacterial dynamic coordinative hydrogel was manufactured by binding the 4-arm polyethylene glycol (PEG) with silver nitrate to deliver the bioactive molecule. In vitro experiments confirmed that 4OI@PEG hydrogel could inhibit bacterial growth, protect human umbilical vein endothelial cells from ROS damage and enhance neovascularization. In addition, the hydrogel increased mitochondrial polarization and reduced mitochondrial fragmentation by activating the Keap1-Nrf2 antioxidant defense system. In vivo experiments proved that this multifunctional hydrogel facilitated diabetic wound healing by inhibiting local inflammation and promoting angiogenesis. Collectively, 4OI-loaded multifunctional materials could reverse various unfavorable microenvironments, such as excessive oxidative stress, inflammation, and infection, and can promote neovascularization; thus, such materials show great promise for the treatment of diabetic ulcers.

Injection Barrel/Nozzle/Mold-Cavity Scientific Real-Time Sensing and Molding Quality Monitoring for Different Polymer-Material Processes.

Scientific injection molding technologies involve the integration and collaboration of cyber-physical systems and smart manufacturing. In order to achieve adaptive process control and production optimization, injection molding systems with real-time sensing have gradually become the development- and application-trend of smart injection molding. At the same time, this technology is a highly non-linear process in which many factors affect the product quality during long-run fabrication processes. Therefore, in order to grasp changes in the characteristics of plastic materials and product quality monitoring, the injection process has become an important research topic. We installed sensors in the molding machine (injection barrel, nozzle, and mold-cavity) to collect the melting pressure and used different materials (semi-crystalline and amorphous polymer; the melting-fill-index (MFI) is unified to 14.5 ± 0.5 g/10 min) to explore the influences of melting pressure variation and its viscosity index on the quality characteristics of molded products. The experiment reveals that a combination of barrel, nozzle, and mold-cavity sensing on the melt-pressure trend-based injection process-control incorporated with viscosity index monitoring can confirm the weight and shrinkage variation of the injection product. At the same time, the pressure and viscosity index value measured and calculated during the melt-filling of two materials with similar MI resulted in significant variations in the amorphous polymer. This study showed the possibility of mastering and controlling the rheology (barrel position) and shrinkage properties of polymers and successful application in various product-quality monitoring platforms.

Psychological Health and Sleep Quality of Medical Graduates During the Second Wave of COVID-19 Pandemic in Post-epidemic Era.

Recently, a COVID-19 virus variant spread rapidly in Guangzhou, China, causing public panic. This study aimed to understand the psychological and sleep-related consequences of the secondary outbreak of the pandemic on medical students. In this cross-sectional survey-based study, participants anonymously completed structured questionnaires online from June 8-22, 2021. We collected participants' demographic and general information. Anxiety, depression, and sleep quality were measured using the Zung Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), and Pittsburgh Sleep Quality Index (PSQI), respectively. Protective factors were assessed using the Coping Style Questionnaire (CSQ). Uni- and multivariate logistic regression analyses were performed examining factors associated with mental health and sleep quality problems. During the second wave of the pandemic in local outbreak areas in Guangzhou, China, more than one-third of medical students' mental health and sleep quality were affected. The prevalence of anxiety, depression, and poor sleep quality were 27.54%, 27.58%, and 18.19%, respectively. Students belonging to the Class of 2019, aged over 29 years, those with siblings, and those whose hometowns were in other provinces were more prone to the three health problems. Factors associated with an increased risk of mental health problems were vaccination status (adjusted odds ratio 1.603-1.839) and diet status (adjusted odds ratio 1.62-1.929). Positive coping styles served as protective factors (p < 0.05). We discovered that completed vaccination status, good diet, and positive coping styles were related to good mental health and sleep quality.

An Innovative and Economical Device for Ischemic Preconditioning of the Forehead Flap Prior to Pedicle Division: A Comparative Study.

BACKGROUND: Ischemic preconditioning of the forehead flap prior to pedicle division helps to improve angiogenesis. Clamping the pedicle by a clamped rubber band with vessel forceps is often clinically applied. However, the severe pain and unstable blocking effect influenced the preconditioning process. In this study, we described an innovative device designed for ischemic preconditioning and compared its efficacy with the clamped rubber band. METHODS: The device consists of a self-locking nylon cable tie with a buckle and a rubber tube. The rubber tube is fed over the cable tie to act as a soft outer lining and the cable tie is tightened across the pedicle to block the perfusion for ischemic preconditioning. This device and the standard clamped rubber band were applied respectively before division surgery. The constriction effect, reliability, reproducibility, and the patients' pain tolerance were compared. RESULTS: A total of 20 forehead flaps were included. The cable tie had less incidence of loosening (7.7% vs. 16.6%, p < 0.05) and maintained the pressure more effectively. The pain score for the nylon cable tie was significantly lower than the clamped rubber band (4.25 ± 1.02 vs. 6.75 ± 1.12, p < 0.05), especially for 10 pediatric patients (4.50 ± 0.85 vs. 8.10 ± 1.20, p < 0.01). All 20 pedicles were successfully divided at 19 to 22 days with no surgical complications. CONCLUSION: Compared with the clamped rubber band, the cable tie produces a more reliable and reproducible ischemic preconditioning effect. It is also better tolerated by the patients. Therefore, we recommend using the nylon cable tie as the preferred device for ischemic preconditioning of the forehead flap.

Bioinspired Multifunctional Black Phosphorus Hydrogel with Antibacterial and Antioxidant Properties: A Stepwise Countermeasure for Diabetic Skin Wound Healing.

Cutaneous wound healing, especially diabetic wound healing, is a common clinical challenge. Reactive oxygen species (ROS) and bacterial infection are two major detrimental states that induce oxidative stress and inflammatory responses and impede angiogenesis and wound healing. A derivative of the metabolite itaconate, 4-octyl itaconate (4OI) has attracted increasing research interest in recent years due to its antioxidant and anti-inflammatory properties. In this study, 4OI-modified black phosphorus (BP) nanosheets are incorporated into a photosensitive, multifunctional gelatin methacrylamide hydrogel to produce a new photothermal therapy (PTT) and photodynamic therapy (PDT) system with antibacterial and antioxidant properties for diabetic wound regeneration. Under laser irradiation, the 4OI-BP-entrapped hydrogel enables rapid gelation, forming a membrane on wounds, and offers high PTT and PDT efficacy to eliminate bacterial infection. Without laser irradiation, BP acts as a carrier and controls the release of 4OI, with which it synergistically enhances antioxidant activity, thus alleviating excessive ROS damage to endothelial cells, promoting neovascularization, and facilitating faster diabetic wound closure. These findings indicate that 4OI-BP-entrapped multifunctional hydrogel provides a stepwise countermeasure with antibacterial and antioxidant properties for enhanced diabetic wound healing and may lead to novel therapeutic interventions for diabetic ulcers.

Exploring deep neural networks via layer-peeled model: Minority collapse in imbalanced training.

In this paper, we introduce the Layer-Peeled Model, a nonconvex, yet analytically tractable, optimization program, in a quest to better understand deep neural networks that are trained for a sufficiently long time. As the name suggests, this model is derived by isolating the topmost layer from the remainder of the neural network, followed by imposing certain constraints separately on the two parts of the network. We demonstrate that the Layer-Peeled Model, albeit simple, inherits many characteristics of well-trained neural networks, thereby offering an effective tool for explaining and predicting common empirical patterns of deep-learning training. First, when working on class-balanced datasets, we prove that any solution to this model forms a simplex equiangular tight frame, which, in part, explains the recently discovered phenomenon of neural collapse [V. Papyan, X. Y. Han, D. L. Donoho, Proc. Natl. Acad. Sci. U.S.A. 117, 24652-24663 (2020)]. More importantly, when moving to the imbalanced case, our analysis of the Layer-Peeled Model reveals a hitherto-unknown phenomenon that we term Minority Collapse, which fundamentally limits the performance of deep-learning models on the minority classes. In addition, we use the Layer-Peeled Model to gain insights into how to mitigate Minority Collapse. Interestingly, this phenomenon is first predicted by the Layer-Peeled Model before being confirmed by our computational experiments.

Identification of Therapeutic Targets and Prognostic Biomarkers Among Integrin Subunits in the Skin Cutaneous Melanoma Microenvironment.

The roles of different integrin alpha/beta (ITGA/ITGB) subunits in skin cutaneous melanoma (SKCM) and their underlying mechanisms of action remain unclear. Oncomine, UALCAN, GEPIA, STRING, GeneMANIA, cBioPortal, TIMER, TRRUST, and Webgestalt analysis tools were used. The expression levels of ITGA3, ITGA4, ITGA6, ITGA10, ITGB1, ITGB2, ITGB3, ITGB4, and ITGB7 were significantly increased in SKCM tissues. The expression levels of ITGA1, ITGA4, ITGA5, ITGA8, ITGA9, ITGA10, ITGB1, ITGB2, ITGB3, ITGB5, ITGB6 and ITGB7 were closely associated with SKCM metastasis. The expression levels of ITGA1, ITGA4, ITGB1, ITGB2, ITGB6, and ITGB7 were closely associated with the pathological stage of SKCM. The expression levels of ITGA6 and ITGB7 were closely associated with disease-free survival time in SKCM, and the expression levels of ITGA6, ITGA10, ITGB2, ITGB3, ITGB6, ITGB7, and ITGB8 were markedly associated with overall survival in SKCM. We also found significant correlations between the expression of integrin subunits and the infiltration of six types of immune cells (B cells, CD8+ T cells, CD4+T cells, macrophages, neutrophils, and dendritic cells). Finally, Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed, and protein-protein interaction (PPI) networks were constructed. We have identified abnormally-expressed genes and gene regulatory networks associated with SKCM, improving understanding of the underlying pathogenesis of SKCM.