Leucine 434 is essential for docosahexaenoic acid-induced augmentation of L-glutamate transporter current.

Astrocytic excitatory amino acid transporter 2 (EAAT2) plays a major role in removing the excitatory neurotransmitter L-glutamate (L-Glu) from synaptic clefts in the forebrain to prevent excitotoxicity. Polyunsaturated fatty acids such as docosahexaenoic acid (DHA, 22:6 n-3) enhance synaptic transmission, and their target molecules include EAATs. Here, we aimed to investigate the effect of DHA on EAAT2 and identify the key amino acid for DHA/EAAT2 interaction by electrophysiological recording of L-Glu-induced current in Xenopus oocytes transfected with EAATs, their chimeras, and single mutants. DHA transiently increased the amplitude of EAAT2 but tended to decrease that of excitatory amino acid transporter subtype 1 (EAAT1), another astrocytic EAAT. Single mutation of leucine (Leu) 434 to alanine (Ala) completely suppressed the augmentation by DHA, while mutation of EAAT1 Ala 435 (corresponding to EAAT2 Leu434) to Leu changed the effect from suppression to augmentation. Other polyunsaturated fatty acids (docosapentaenoic acid, eicosapentaenoic acid, arachidonic acid, and α-linolenic acid) similarly augmented the EAAT2 current and suppressed the EAAT1 current. Finally, our docking analysis suggested the most stable docking site is the lipid crevice of EAAT2, in close proximity to the L-Glu and sodium binding sites, suggesting that the DHA/Leu434 interaction might affect the elevator-like slide and/or the shapes of the other binding sites. Collectively, our results highlight a key molecular detail in the DHA-induced regulation of synaptic transmission involving EAATs.

Involvement of Embryo-Derived and Monocyte-Derived Intestinal Macrophages in the Pathogenesis of Inflammatory Bowel Disease and Their Prospects as Therapeutic Targets.

Inflammatory bowel disease (IBD) is a group of intestinal inflammatory diseases characterized by chronic, recurrent, remitting, or progressive inflammation, which causes the disturbance of the homeostasis between immune cells, such as macrophages, epithelial cells, and microorganisms. Intestinal macrophages (IMs) are the largest population of macrophages in the body, and the abnormal function of IMs is an important cause of IBD. Most IMs come from the replenishment of blood monocytes, while a small part come from embryos and can self-renew. Stimulated by the intestinal inflammatory microenvironment, monocyte-derived IMs can interact with intestinal epithelial cells, intestinal fibroblasts, and intestinal flora, resulting in the increased differentiation of proinflammatory phenotypes and the decreased differentiation of anti-inflammatory phenotypes, releasing a large number of proinflammatory factors and aggravating intestinal inflammation. Based on this mechanism, inhibiting the secretion of IMs' proinflammatory factors and enhancing the differentiation of anti-inflammatory phenotypes can help alleviate intestinal inflammation and promote tissue repair. At present, the clinical medication of IBD mainly includes 5-aminosalicylic acids (5-ASAs), glucocorticoid, immunosuppressants, and TNF-α inhibitors. The general principle of treatment is to control acute attacks, alleviate the condition, reduce recurrence, and prevent complications. Most classical IBD therapies affecting IMs function in a variety of ways, such as inhibiting the inflammatory signaling pathways and inducing IM2-type macrophage differentiation. This review explores the current understanding of the involvement of IMs in the pathogenesis of IBD and their prospects as therapeutic targets.

DNA G-Quadruplex in Human Telomeres and Oncogene Promoters: Structures, Functions, and Small Molecule Targeting.

DNA G-quadruplex secondary structures formed in guanine-rich human telomeres and oncogene promoters are functionally important and have emerged as a promising new class of cancer-specific drug targets. These globular intramolecular structures are stabilized by K+ or Na+ and form readily under physiological solution conditions. Moreover, G-quadruplexes are epigenetic features and can alter chromatin structure and function together with interactive proteins. Here, we discuss our efforts over the last two decades to understand the structures and functions of DNA G-quadruplexes formed in key oncogene promoters and human telomeres and their interactions with small molecules. Using high-field NMR spectroscopy, we determined the high-resolution structures of physiologically relevant telomeric G-quadruplexes in K+ solution with a major form (hybrid-2) and a minor form (hybrid-1), as well as a two-tetrad intermediate. The intrinsic structural polymorphism of telomeric DNA may be important for the biology of human telomeres, and we proposed a model for the interconversion. More recently, we have worked on G-quadruplexes of MYC, BCL2, PDGFR-ß, VEGF, and k-RAS oncogene promoters. We determined the structure of the major G-quadruplex formed in the MYC promoter, a prototype for parallel G-quadruplexes. It is the first example of the parallel-stranded G3NG3 structure motif with a 1-nt loop, which is prevalent in promoter sequences and likely evolutionarily selected to initiate folding. Remarkably, the parallel MYC promoter G-quadruplexes are highly stable. Additionally, we determined the molecular structures of G-quadruplexes formed in human BCL2, VEGF, and PDGFR-ß promoters, each adopting a unique structure. For example, the BCL2 promoter contains distinct interchangeable G-quadruplexes in two adjacent regions, suggesting precise regulation by different proteins. The PDGFR-ß promoter adopts unique "broken-strand" and vacancy G-quadruplexes, which can be recognized by cellular guanine metabolites for a potential regulatory role.Structural information on G-quadruplexes in complex with small-molecules is critical for understanding specific recognition and structure-based rational drug design. Our studies show that many G-quadruplexes contain unique structural features such as capping and loop structures, allowing specific recognition by drugs and protein. This represents a paradigm shift in understanding DNA as a drug target: Rather than a uniform, nonselective binding site in duplex DNA, the G-quadruplex is being pursued as a new class of selectively targetable drug receptors. We focus on targeting the biologically relevant MYC promoter G-quadruplex (MycG4) with small molecules and have determined its first and additional drug complex structures. Very recently, we have discovered clinically tested indenoisoquinolines as strong MycG4 binders and potent MYC inhibitors. We have also discovered drugs targeting the unique dGMP-bound-vG4 formed in the PDGFR-ß promoter. Moreover, we determined the complex structures of the first small molecules that specifically recognize the physiologically relevant human telomeric G-quadruplexes. Unlike the previously recognized dogma that the optimal G-quadruplex ligands are large aromatic or cyclic compounds, our results suggest that smaller asymmetric compounds with appropriate functional groups are better choices to specifically bind G-quadruplexes. This body of work lays a strong foundation for future work aimed at understanding the cellular functions of G-quadruplexes and G-quadruplex-targeted drug design.

Isosteric Replacement of Ester Linkage of Lysophospholipids with Heteroaromatic Rings Retains Potency and Subtype Selectivity.

Our group has reported various derivatives of lysophosphatidylserine (LysoPS) as potent and subtype-selective agonists for G-protein-coupled receptors (GPCRs). However, the ester linkage between the glycerol moiety and fatty acid or fatty acid surrogate is present in all of them. In order to develop these LysoPS analogs as drug candidates, appropriate pharmacokinetic consideration is essential. Here, we found that the ester bond of LysoPS is highly susceptible to metabolic degradation in mouse blood. Accordingly, we examined isosteric replacement of the ester linkage with heteroaromatic rings. The resulting compounds showed excellent retention of potency and receptor subtype selectivity, as well as increased metabolic stability in vitro.

CdS Nanoparticles Supported by Cobalt@Carbon-Derived MOFs for the Improved Adsorption and Photodegradation of Ciprofloxacin.

The design and synthesis of efficient photocatalysts that promote the degradation of organic pollutants in water have attracted extensive attention in recent years. In this work, CdS nanoparticles are grown in situ on Co@C derived from metal-organic frameworks. The resulting hierarchical CdS/Co@C nanostructures are evaluated in terms of their adsorption and photocatalytic ciprofloxacin degradation efficiency under visible-light irradiation. The results show that, apart from offering a large surface area (55.69 m2·g-1), the prepared material can effectively suppress the self-agglomeration of CdS and enhance the absorption of visible light. The CdS/Co@C-7 composite containing 7% wt Co@C has the highest photodegradation rate, and its activity is approximately 4.4 times greater than that of CdS alone. Moreover, this composite exhibits remarkable stability after three successive cycles of photocatalysis. The enhanced photocatalytic performance is largely ascribed to the rapid separation of electron-hole pairs and the effective electron transfer between CdS and Co@C, which is confirmed via electrochemical experiments and photoluminescence spectra. The active substance capture experiment and the electron spin resonance technique show that h+ is the main active entity implicated in the degradation of CIP, and accordingly, a possible mechanism of CIP photocatalytic degradation over CdS/Co@C is proposed. In general, this work presents a new perspective on designing novel photocatalysts that promote the degradation of organic pollutants in water.

Removing nutrients from wastewater by constructed wetlands under perfluoroalkyl acids stress.

Constructed wetlands (CWs) are often used to treat wastewater discharged from wastewater treatment plants (WWTPs), while emerging contaminants (such as perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS)) have been commonly discovered in WWTPs. However, no research has examined whether PFOA/OS (i.e. PFOA and PFOS) affects the performance of CW. Therefore, this study compared the nutrient removal efficiencies of four CWs with varied configurations under PFOA/OS and no PFOA/OS stress conditions. We found that CW containing plants or/and iron-carbon had higher removal efficiency for nutrients (except NH4+-N) than conventional CW in stable operation under wastewater without PFOA/OS. Plants or/and iron increased the nutrient removal efficiency by plant uptake, chemical reaction, and co-precipitation of iron hydroxides. In contrast, the iron-carbon inhibited the nitrification of nitrifying bacteria by consuming dissolved oxygen, converting NO3--N to NH4+-N. Although the removal efficiencies of nutrients by CWs differed after introducing PFOA/OS, the removal order was consistent with those before adding PFOA/OS. Plants or/and iron-carbon effectively increased CWs' resistance to PFOA/OS loading and toxicity, and the function of iron-carbon was superior to the plants. In addition, PFOA/OS reduced the abundances of microbes Hydrogenophaga, Pseudomonas, Sphingomonas, Nitrospira, and Candidatus_Accumulibacter that contributed to nutrient removal.

Real-Time Ultrasound-Guided Versus Ultrasound-Assisted Spinal Anesthesia in Elderly Patients With Hip Fractures: A Randomized Controlled Trial.

BACKGROUND: Traditional landmark-guided spinal anesthesia can be challenging in elderly patients with hip fractures. Ultrasound assistance (USAS) and real-time ultrasound guidance (USRTG) techniques can facilitate lumbar neuraxial blocks. However, it remains undetermined which method is optimal for use in elderly patients. This study aimed to evaluate which technique was associated with a higher success rate of spinal anesthesia in elderly patients with hip fractures: USAS or USRTG technique. METHODS: A total of 114 elderly patients (≥70 years of age) with hip fractures were randomly assigned to receive spinal anesthesia using either the USAS or USRTG technique. The primary outcome was the first-attempt success rate, analyzed using the χ2 test. Secondary outcomes included first-pass success rate, the number of needle attempts and passes, locating time, procedure time, total time, adverse reactions and complications, patient satisfaction, and procedural difficulty score. RESULTS: The first-attempt success rate (80.7% vs 52.6%; 95% confidence interval [CI], for the difference, 11.6-44.6) and first-pass success rate (63.2% vs 31.6%; 95% CI for the difference, 14.2-49) were both significantly higher in the USAS compared with the USRTG group (both P = .001). The number of attempts (1 [1-1] vs 1 [1-3]; P = .001) and median passes (1 vs 3; P < .001) were both significantly lower in the USAS group than in the USRTG group. The USRTG group had a shorter locating time (175 seconds [129-234 seconds] vs 315 seconds [250-390 seconds]; P < .001) but a longer procedure time (488 seconds [260-972 seconds] vs 200 seconds [127-328 seconds]; P < .001) and total time (694 seconds [421-1133 seconds] vs 540 seconds [432-641 seconds]; P = .036). There were no significant differences between the 2 groups with regard to the adverse reactions and complications. More patients in the USAS group had a high satisfaction score of 3 to 5 (P = .008). Overall, anesthesiologists rated the USRTG group procedure as "more difficult" (P = .008). CONCLUSIONS: In elderly patients with hip fractures, spinal anesthesia with the USRTG technique is not superior to the USAS technique since it has a lower success rate, longer procedure time, lower satisfaction score, and is more difficult to perform. So USAS technique may be more suitable for elderly patients.

Perioperative transcutaneous electrical acupoint stimulation (pTEAS) in pain management in major spinal surgery patients.

BACKGROUND: Lumbar disc herniation is seen in 5-15% of patients with lumbar back pain and is the most common spine disorder demanding surgical correction. Spinal surgery is one of the most effective management for these patients. However, current surgical techniques still present complications such as chronic pain in 10-40% of all patients who underwent lumbar surgery, which has a significant impact on patients' quality of life. Research studies have shown that transcutaneous electrical acupoint stimulation (TEAS) may reduce the cumulative dosage of intraoperative anesthetics as well as postoperative pain medications in these patients. OBJECTIVE: To investigate the effect of pTEAS on pain management and clinical outcome in major spinal surgery patients. METHODS: We conducted a prospective, randomized, double-blind study to verify the effect of pTEAS in improving pain management and clinical outcome after major spinal surgery. Patients (n = 90) who underwent posterior lumbar fusion surgery were randomized into two groups: pTEAS, (n = 45) and Control (n = 45). The pTEAS group received stimulation on acupoints Zusanli (ST.36), Sanyinjiao (SP.6), Taichong (LR.3), and Neiguan (PC.6). The Control group received the same electrode placement but with no electrical output. Postoperative pain scores, intraoperative outcome, perioperative hemodynamics, postoperative nausea and vomiting (PONV), and dizziness were recorded. RESULTS: Intraoperative outcomes of pTEAS group compared with Control: consumption of remifentanil was significantly lower (P < 0.05); heart rate was significantly lower at the end of the operation and after tracheal extubation (P < 0.05); and there was lesser blood loss (P < 0.05). Postoperative outcomes: lower pain visual analogue scale (VAS) score during the first two days after surgery (P < 0.05); and a significantly lower rate of PONV (on postoperative Day-5) and dizziness (on postoperative Day-1 and Day-5) (P < 0.05). CONCLUSION: pTEAS could manage pain effectively and improve clinical outcomes. It could be used as a complementary technique for short-term pain management, especially in patients undergoing major surgeries. TRIAL REGISTRATION: ChiCTR1800014634, retrospectively registered on 25/01/2018. http://medresman.org/uc/projectsh/projectedit.aspx?proj=183.

Development of a Nomogram for Predicting Blood Transfusion Risk After Hemiarthroplasty for Femoral Neck Fractures in Elderly Patients.

BACKGROUND The aim of this study was to determine the risk factors and develop a nomogram for blood transfusions after hemiarthroplasty (HA) in patients with femoral neck fractures (FNFs). MATERIAL AND METHODS We performed a retrospective study including consecutive elderly FNF patients treated by HA between January 2015 and December 2017. Perioperative information was obtained retrospectively, uni- and multivariate regression analyses were conducted to determine risk factors for blood transfusion, and a nomogram model was constructed to predict the risk of blood transfusion. The predictive performance and consistency of the model were evaluated by the consistency coefficient (C-index) and the calibration curve, respectively. RESULTS Of 178 patients, 151 were finally enrolled in the study and 21 received blood transfusion. Binary logistic regression analysis showed the low preoperative hemoglobin (Hb), longer time to surgery, general anesthesia, longer surgery duration, and higher intraoperative blood loss (IBL) were risk factors for blood transfusion. The accuracy of the contour map for predicting transfusion risk was 0.940. CONCLUSIONS We found a correlation between blood transfusion requirement and low preoperative Hb, longer time to surgery, general anesthesia, longer surgery duration, and higher IBL, and we then developed a nomogram. Our nomogram model can be used to evaluate the transfusion risk for FNF patients after HA, and provides better guidance for clinicians to intervene perioperatively, so as to reduce the incidence of blood transfusion.

Landmark-guided versus modified ultrasound-assisted Paramedian techniques in combined spinal-epidural anesthesia for elderly patients with hip fractures: a randomized controlled trial.

BACKGROUND: Combined spinal-epidural (CSE) anesthesia is considerably challenging for elderly patients with hip fractures due to spine degeneration and limitations in positioning. This study aimed to investigate the ability of a modified preprocedural ultrasound-guided technique to improve the success rate and efficacy of CSE anesthesia for elderly patients with hip fractures. METHODS: This prospective, single-blinded, parallel-group randomized controlled trial included 80 patients (aged ≥65 years) who were scheduled for elective hip fracture surgery with CSE anesthesia. Patients were randomly allocated into landmark group (n = 40) or the ultrasound group (n = 40). The primary outcome was first-pass success rate. Secondary outcomes included first-attempt success rate; number of needle insertion attempts; number of needle passes; locating, puncture, and total time; level of block; procedural adverse reactions and postoperative complications; and patient satisfaction score. Patients were blinded to group allocation. RESULTS: Eighty patients completed the study and were included in the final analysis. The first-pass success rates for the landmark and ultrasound groups were 20 and 70%, respectively (P < 0.001). The first-attempt success rates in the landmark and ultrasound groups were 42.5 and 85%, respectively (P < 0.001). The median number of attempts was lower in ultrasound-assisted group (1 [1]) than landmark-guided group (2 [1, 2]), P < 0.001). The median number of needle passes was lower in ultrasound group (1 [1, 2]) than in landmark-guided group (3 [2, 4], P < 0.001). The locating time (P < 0.001) and total time (P = 0.001) were longer in the ultrasound group, while puncture time was shorter (P = 0.003). No significant difference was found regarding the incidence of adverse reactions and complications. More patients in the ultrasound group had a high satisfaction score of 4-5 (P = 0.007). Interestingly, subgroup analysis demonstrated benefits for ultrasound in patients with scoliosis. CONCLUSIONS: Modified ultrasound-assisted CSE anesthesia increases first-pass and first-attempt success rates, and reduces needle insertion attempts, passes, and puncture time for elderly patients with hip fracture, especially those with scoliosis. This technique improves patient satisfaction and warrants consideration for application in clinical practice. TRIAL REGISTRATION: Chinese Clinical Trial Register (identifier, ChiCTR1900020819 ; date of registration, January 20, 2019).

Correction to: Landmark-guided versus modified ultrasound-assisted Paramedian techniques in combined spinal-epidural anesthesia for elderly patients with hip fractures: a randomized controlled trial.

An amendment to this paper has been published and can be accessed via the original article.

Molecular Recognition of the Hybrid-Type G-Quadruplexes in Human Telomeres.

G-quadruplex (G4) DNA secondary structures formed in human telomeres have been shown to inhibit cancer-specific telomerase and alternative lengthening of telomere (ALT) pathways. Thus, human telomeric G-quadruplexes are considered attractive targets for anticancer drugs. Human telomeric G-quadruplexes are structurally polymorphic and predominantly form two hybrid-type G-quadruplexes, namely hybrid-1 and hybrid-2, under physiologically relevant solution conditions. To date, only a handful solution structures are available for drug complexes of human telomeric G-quadruplexes. In this review, we will describe two recent solution structural studies from our labs. We use NMR spectroscopy to elucidate the solution structure of a 1:1 complex between a small molecule epiberberine and the hybrid-2 telomeric G-quadruplex, and the structures of 1:1 and 4:2 complexes between a small molecule Pt-tripod and the hybrid-1 telomeric G-quadruplex. Structural information of small molecule complexes can provide important information for understanding small molecule recognition of human telomeric G-quadruplexes and for structure-based rational drug design targeting human telomeric G-quadruplexes.

[Determination of sucralose in foods and beverages by ultraviolet derivatization-high performance liquid chromatography].

OBJECTIVE: To establish a method for determination of sucralose in foods and beverages using high performance liquid chromatography. METHODS: Sucralose was extracted with water and centrifuged, and then derivatized with benzoyl chloride in alkaline medium. The ultraviolet absorbing derivatives were separated on a Hydro-RP 80 angstroms C18 column (250 mm x 4.6 mm, 4 microm, Synergi) using methanol-water (95:5,V/V) as mobile phase with UV detection at 232 nm. RESULTS: A good correlation (correlation coefficient=0. 999 8) between detected and actual sucralose was achieved in the range of 0.05 to 1.00 microg. The detection limit of sucralose was 0.00125 microg. The recoveries were in the range from 97.4% to 102.0% with relative standard deviations of less than 5.0%. The intraday and interday relative standard deviations of the method were 1.52% and 4.04%, respectively. CONCLUSION: This method is simple, rapid, and accurate without the need of special detectors, and it can be used for rapid determination of sucralose in foods and beverages.

[Simultaneous determination of sugar alcohols and sugars in functional foods by precolumn ultraviolet derivatization--high performance liquid chromatography].

OBJECTIVE: To establish a method using precolumn ultraviolet derivatization coupled with high performance liquid chromatography (HPLC) for simultaneous determination of erythritol, xylitol, galactitol, sorbitol, mannitol, maltitol, glucose and sucrose in functional foods. METHODS: Target sugar alcohols and sugars in food samples were extracted in water by ultrasonic method and then reacted with benzoyl chloride to form violet-absorbing products, which were separated on a C18 column with gradient elution using methanol and water as mobile phase. The experiment was performed using a flow rate of 1.00 mL/min, column temperature at 30 degrees C and detected wavelength at 232 nm. RESULTS: The linear correlation coefficients of all the derivatives were more than 0. 999. The detection limits of the method were as low as 2. 2 microg/mL. The average recoveries were 89.6%-117.0%, with intraday relative standard derivations lower than 5%. CONCLUSION: This method is simple, inexpensive and easy to operate and it is suitable for the determination of sugar alcohols and glucose and sucrose in functional foods.

Impact of nanoplastics on the biodegradation, ecotoxicity, and key genes involved in imidacloprid metabolic pathways in papyrus (Cyperus papyrus L.).

Both nanoplastics (NPs) and imidacloprid (IMI) are widely distributed in the environment and have attracted significant attention due to their adverse effects on ecosystems. Constructed wetlands have the potential to remove IMI, but there is still limited understanding of how wetland plants interact with IMI, especially when influenced by different charged NPs. This study assessed their ecotoxicological effects, as well as the fate and transformation of IMI in papyrus (Cyperus papyrus L.) under the influence of different charged NPs and identified key driving genes in the plant. Results show that simultaneous exposure to positively charged PS-NH2 and IMI inhibited plant growth. The combined action of NPs and IMI intensified their toxicity, enhancing lipid peroxidation and altering antioxidant enzyme activities. The IMI removal efficiency, which was primarily driven by biodegradation, was 80.61%, 88.91%, and 74.71% in the IMI-alone, co-IMI/PS_COOH, and co-IMI/PS_NH2 systems, respectively. PS-NH2 restricted the roots-to-shoots translocation ability of IMI. PS-COOH enhanced IMI oxidation and nitro reduction, while PS-NH2 inhibited 2-OH-IMI dehydrogenation to IMI-olefin in papyrus. Transcriptomics and gene network analysis identified the genes encoding CYP450 enzymes, reductases, hydrolases, dehydrogenases, and peroxidases as those influencing IMI biodegradation. These enzymes play a crucial role in the hydroxylation, dehydrogenation, reduction, and oxidation processes during biodegradation of IMI in the presence of NPs. This study expands the understanding of the impact of differently charged NPs on the IMI remediation efficacy of papyrus, thus providing new insights into the phytoremediation of organic contaminants in constructed wetlands.

Electrothermal Phase Change Composite with Flexibility over a Wide Temperature Range for Wearable Thermotherapy.

Flexible electrothermal composite phase change materials (PCMs) are promising candidates for portable thermotherapy. However, a great challenge remains to achieve high PCM loading while maintaining reasonable flexibility. Herein, the polypyrrole-decorated melamine foam (PPy@MF) was fabricated and thereafter applied to confine binary PCM mixtures composed of a high-enthalpy long-chain polyethylene glycol (PEG4000) and its short-chain homologue (PEG200) to make the novel PPy@MF-PEG4000+200 composite PCM. At a high loading of up to 74.1% PEG4000 and a high latent heat energy storage density of 150.1 J/g, the composite PCM remained flexible at temperature (-20 °C) far below its phase transition point thanks to the plasticine effect of PEG200. The composite also demonstrated good Joule heating performance, providing fast heating from 28 to 70 °C at low applied voltages (4.5-6.0 V). The energy could be stored efficiently and released to maintain the composites at the proper temperature. The electrothermal performance of the composite remained undisturbed during curved or repeated bending, showing good potential to be used for personal thermal management and thermotherapy.

Adversarial attacks and adversarial training for burn image segmentation based on deep learning.

Deep learning has been widely applied in the fields of image classification and segmentation, while adversarial attacks can impact the model's results in image segmentation and classification. Especially in medical images, due to constraints from factors like shooting angles, environmental lighting, and diverse photography devices, medical images typically contain various forms of noise. In order to address the impact of these physically meaningful disturbances on existing deep learning models in the application of burn image segmentation, we simulate attack methods inspired by natural phenomena and propose an adversarial training approach specifically designed for burn image segmentation. The method is tested on our burn dataset. Through the defensive training using our approach, the segmentation accuracy of adversarial samples, initially at 54%, is elevated to 82.19%, exhibiting a 1.97% improvement compared to conventional adversarial training methods, while substantially reducing the training time. Ablation experiments validate the effectiveness of individual losses, and we assess and compare training results with different adversarial samples using various metrics.

Design, Synthesis, and Investigation of the Pharmacokinetics and Anticancer Activities of Indenoisoquinoline Derivatives That Stabilize the G-Quadruplex in the MYC Promoter and Inhibit Topoisomerase I.

G-quadruplexes are noncanonical four-stranded DNA secondary structures. MYC is a master oncogene and the G-quadruplex formed in the MYC promoter functions as a transcriptional silencer and can be stabilized by small molecules. We have previously revealed a novel mechanism of action for indenoisoquinoline anticancer drugs, dual-downregulation of MYC and inhibition of topoisomerase I. Herein, we report the design and synthesis of novel 7-aza-8,9-methylenedioxyindenoisoquinolines based on desirable substituents and π-π stacking interactions. These compounds stabilize the MYC promoter G-quadruplex, significantly lower MYC levels in cancer cells, and inhibit topoisomerase I. MYC targeting was demonstrated by differential activities in Raji vs CA-46 cells and cytotoxicity in MYC-dependent cell lines. Cytotoxicities in the NCI-60 panel of human cancer cell lines were investigated. Favorable pharmacokinetics were established, and in vivo anticancer activities were demonstrated in xenograft mouse models. Furthermore, favorable brain penetration, brain pharmacokinetics, and anticancer activity in an orthotopic glioblastoma mouse model were demonstrated.