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You-Kyoung Kim,1 Arash Minai-Tehrani,2 Jae-Ho Lee,2 Chong-Su Cho,3 Myung-Haing Cho,2–6 Hu-Lin Jiang1 1State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People’s Republic of China; 2Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul, 3Department of Agricultural Biotechnology, Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, 4Department of Nano Fusion Technology, Graduate School of Convergence Science and Technology, Seoul National University, Suwon, 5Graduate Group of Tumor Biology, Seoul National University, Seoul, 6Advanced Institute of Convergence Technology, Seoul National University, Suwon, Republic of Korea Background: Chitosan and chitosan derivatives have been proposed as alternative and biocompatible cationic polymers for nonviral gene delivery. However, the low transfection efficiency and low specificity of chitosan is an aspect of this approach that must be addressed prior to any clinical application. In the present study, folated poly(ethylene glycol)-chitosan-graft-polyethylenimine (FPCP) was investigated as a potential folate receptor-overexpressed cancer cell targeting gene carrier. Methods: The FPCP copolymer was synthesized in two steps. In the first step, folate-PEG was synthesized by an amide formation reaction between the activated carboxyl groups of folic acid and the amine groups of bifunctional poly(ethylene glycol) (PEG). In the second step, FPCP was synthesized by an amide formation reaction between the activated carboxyl groups of folate-PEG and amine groups of CHI-g-polyethyleneimine (PEI). The composition of FPCP was characterized by 1H nuclear magnetic resonance. Results: FPCP showed low cytotoxicity in various cell lines, and FPCP-DNA complexes showed good cancer cell specificity as well as good transfection efficiency in the presence of serum. Further, FPCP-Pdcd4 complexes reduced tumor numbers and progression more effectively than PEI 25 kDa in H-ras12V liver cancer mice after intravenous administration. Conclusion: Our data suggest that FPCP, which has improved transfection efficiency and cancer cell specificity, may be useful in gene therapy for liver cancer. Keywords: liver cancer, targeted gene therapy, folated poly(ethylene glycol)-chitosan-graft-polyethylenimine, safety, efficiency

Mohammad Ariful Islam,1–3,* Jannatul Firdous,1–3,* Yun-Jaie Choi,1 Cheol-Heui Yun,1–4 Chong-Su Cho1,21Department of Agricultural Biotechnology, 2Research Institute for Agriculture and Life Sciences, 3Center for Food and Bioconvergence, 4World Class University Biomodulation Program, Seoul National University, Seoul, South Korea*These authors contributed equally to this workAbstract: Chitosan, a natural biodegradable polymer, is of great interest in biomedical research due to its excellent properties including bioavailability, nontoxicity, high charge density, and mucoadhesivity, which creates immense potential for various pharmaceutical applications. It has gelling properties when it interacts with counterions such as sulfates or polyphosphates and when it crosslinks with glutaraldehyde. This characteristic facilitates its usefulness in the coating or entrapment of biochemicals, drugs, antigenic molecules as a vaccine candidate, and microorganisms. Therefore, chitosan together with the advance of nanotechnology can be effectively applied as a carrier system for vaccine delivery. In fact, chitosan microspheres have been studied as a promising carrier system for mucosal vaccination, especially via the oral and nasal route to induce enhanced immune responses. Moreover, the thiolated form of chitosan is of considerable interest due to its improved mucoadhesivity, permeability, stability, and controlled/extended release profile. This review describes the various methods used to design and synthesize chitosan microspheres and recent updates on their potential applications for oral and nasal delivery of vaccines. The potential use of thiolated chitosan microspheres as next-generation mucosal vaccine carriers is also discussed.Keywords: chitosan microspheres, oral, nasal, vaccine delivery, mucosal and systemic immune responses

Seong-Ho Hong1,*, Ji-Eun Kim1,6,*, You-Kyoung Kim2, Arash Minai-Tehrani1, Ji-Young Shin1, Bitna Kang1, Hye-Joon Kim1, Chong-Su Cho2, Chanhee Chae3, Hu-Lin Jiang1, Myung-Haing Cho1,4–71Laboratory of Toxicology, 2Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, 3Laboratory of Pathology, College of Veterinary Medicine, 4Graduate Group of Tumor Biology, 5Center for Food and Toxicology, Seoul National University, Seoul, Korea; 6Department of Nano Fusion Technology, Graduate School of Convergence Science and Technology, 7Advanced Institute of Convergence Technology, Seoul National University, Suwon, Korea*These authors contributed equally to this workBackground: Polyethylenimine (PEI)-based nonviral gene-delivery systems are commonly employed because of their high transfection efficiency. However, the toxic nature of PEI is a significant obstacle in clinical gene therapy. In this study, we developed biocompatible glycerol triacrylate–spermine (GT–SPE) polyspermine as a nanosized gene carrier for potential lung cancer gene therapy.Methods: The GT–SPE was synthesized using the Michael addition reaction between GT and SPE. The molecular weight was characterized using gel permeability chromatography multiangle laser light scattering and the composition of the polymer was analyzed using proton nuclear magnetic resonance.Results: The GT–SPE successfully protected the DNA from nucleases. The average particle size of the GT–SPE was 121 nm with a zeta potential of +23.45 mV. The GT–SPE was found to be less toxic than PEI for various cell lines, as well as for a murine model. Finally, our results showed that the GT–SPE/small hairpin Akt1 (shAkt1) complex suppressed lung tumorigenesis in a K-rasLA1 lung cancer mice model by inducing apoptosis through the Akt signaling pathway and cell cycle arrest. Aerosol delivered GT–SPE/shAkt1, which reduced matrix metalloproteinase-9 activity and suppressed the expression levels of proliferating cell nuclear antigen, as well as vascular endothelial growth factors and CD31, which are known proliferation and angiogenesis markers, respectively.Conclusion: Our data suggest that GT–SPE may be a candidate for short hairpin-shaped RNA-based aerosol lung cancer gene therapy.Keywords: lung cancer, gene therapy, aerosol delivery, spermine

Hong SH, Kim JE, Kim YK, et al. Suppression of lung cancer progression by biocompatible glycerol triacrylate– spermine-mediated delivery of shAkt1. Int J Nanomedicine. 2012;7:2293–2306.Figure 3 has been corrected.Read the original article.

OBJECTIVE: To investigate the direct effects of placenta growth factor (PlGF) and its specific receptor, flt-1, which are known to mediate angiogenesis, on the inflammatory process of rheumatoid arthritis (RA). METHODS: Expression of PlGF and flt-1 in the synovial tissue of RA patients was examined using immunohistochemistry. Enzyme-linked immunosorbent assay was used to determine the concentrations of PlGF, tumor necrosis factor alpha (TNFalpha), and interleukin-6 (IL-6) in culture supernatants of either mononuclear cells or synoviocytes. The flt-1 expression level in mononuclear cells was analyzed by flow cytometry. Experimental arthritis was induced in mice either by immunization with type II collagen (CII) or by injection of anti-CII antibody. RESULTS: PlGF was highly expressed in the synovium of RA patients, and its primary source was fibroblast-like synoviocytes (FLS). When stimulated with IL-1beta, FLS from RA patients produced higher amounts of PlGF than did FLS from patients with osteoarthritis. Exogenous PlGF specifically increased the production of TNFalpha and IL-6 in mononuclear cells from RA patients (but not those from healthy controls) via a calcineurin-dependent pathway. The response to PlGF was associated with increased expression of flt-1 on RA monocytes, which could be induced by IL-1beta and TNFalpha. A novel anti-flt-1 hexapeptide, GNQWFI, abrogated the PlGF-induced increase in TNFalpha and IL-6 production, and also suppressed CII-induced arthritis and serum IL-6 concentrations in mice. Moreover, genetic ablation of PlGF prevented the development of anti-CII antibody-induced arthritis in mice. CONCLUSION: Our data suggest that enhanced expression of PlGF and flt-1 may contribute to rheumatoid inflammation by triggering production of proinflammatory cytokines. The use of the novel anti-flt-1 peptide, GNQWFI, may be an effective strategy for the treatment of RA. [ABSTRACT FROM AUTHOR]

Spatial transcriptomics (ST) technologies have advanced to enable transcriptome-wide gene expression analysis at submicron resolution over large areas. However, analysis of high-resolution ST is often challenged by complex tissue structure, where existing cell segmentation methods struggle due to the irregular cell sizes and shapes, and by the absence of segmentation-free methods scalable to whole-transcriptome analysis. Here we present FICTURE (Factor Inference of Cartographic Transcriptome at Ultra-high REsolution), a segmentation-free spatial factorization method that can handle transcriptome-wide data labeled with billions of submicron-resolution spatial coordinates and is compatible with both sequencing-based and imaging-based ST data. FICTURE uses the multilayered Dirichlet model for stochastic variational inference of pixel-level spatial factors, and is orders of magnitude more efficient than existing methods. FICTURE reveals the microscopic ST architecture for challenging tissues, such as vascular, fibrotic, muscular and lipid-laden areas in real data where previous methods failed. FICTURE's cross-platform generality, scalability and precision make it a powerful tool for exploring high-resolution ST., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Histotripsy is a relatively new therapeutic ultrasound technology to mechanically liquefy tissue into subcellular debris using high-amplitude focused ultrasound pulses. In contrast to conventional high-intensity focused ultrasound thermal therapy, histotripsy has specific clinical advantages: the capacity for real-time monitoring using ultrasound imaging, diminished heat sink effects resulting in lesions with sharp margins, effective removal of the treated tissue, a tissue-selective feature to preserve crucial structures, and immunostimulation. The technology is being evaluated in small and large animal models for treating cancer, thrombosis, hematomas, abscesses, and biofilms; enhancing tumor-specific immune response; and neurological applications. Histotripsy has been recently approved by the US Food and Drug Administration to treat liver tumors, with clinical trials undertaken for benign prostatic hyperplasia and renal tumors. This review outlines the physical principles of various types of histotripsy; presents major parameters of the technology and corresponding hardware and software, imaging methods, and bioeffects; and discusses the most promising preclinical and clinical applications.

Background: Pancreatic Neuroendocrine Tumors (PNETs) are indolent malignancies that often have a prolonged clinical course. This study assesses disparities in outcomes between PNET patients who live in urban (UA) and rural areas (RA)., Methods: A retrospective cohort study was performed using the US Neuroendocrine Tumor Study Group database. PNET patients with a home zip code recorded were included and categorized as RA or UA according to the Federal Office of Rural Health Policy. Overall survival (OS) was analyzed by Kaplan-Meier method, log-rank test, and logistical regression., Results: Of the 1176 PNET patients in the database, 1126 (96%) had zip code recorded. While 837 (74%) lived in UA, 289 (26%) lived in RA. RA patients had significantly shorter median OS following primary PNET resection (122 vs 149 months, p ​= ​0.01). After controlling for income, local healthcare access, distance from treatment center, ASA class, BMI, and T/N/M stage, living in a RA remained significantly associated with worse OS (HR 1.60, 95%CI 1.08-2.39, p ​= ​0.02)., Conclusion: Rural patients have significantly shorter OS following PNET resection compared to their urban counterparts., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Microwave couplers are used in large numbers in beamforming networks, and their miniaturization can lead to a significant size reduction in the overall phased array. While the miniaturization of 3 dB couplers in the transverse direction (width) has been given considerable attention in the literature, there is minimal to no information on reducing coupler length. This is because of the trade-off between aperture length, bandwidth and coupling strength. The Bethe-Hole theory requires adding multiple apertures in the longitudinal direction for wide bandwidth, thus increasing the device length. Another factor is the aperture size, which determines the coupling strength and puts additional strain on the compactness of a 3 dB coupler. Contrariwise, this paper proposes to merge two weak (and hence compact) coupling mechanisms to design a wideband 3 dB coupler. This is achieved by using a longitudinal rectangular slot and three cross-slots in the transverse direction. Because of weak coupling, the slot sizes are smaller than a conventional 3 dB coupler, hence yielding a device whose length is less than one guided wavelength (λg) without compromising the bandwidth. The presented coupler is 0.63 λg in length, which is smaller than the state-of-the-art while maintaining a fractional bandwidth of 37% that is comparable to half-mode substrate integrated waveguide (HMSIW) couplers.

Diabetic retinopathy (DR) is associated with ocular inflammation leading to retinal barrier breakdown, vascular leakage, macular edema, and vision loss. DR is not only a microvascular disease but also involves retinal neurodegeneration, demonstrating that pathological changes associated with neuroinflammation precede microvascular injury in early DR. Macrophage activation plays a central role in neuroinflammation. During DR, the inflammatory response depends on the polarization of retinal macrophages, triggering pro-inflammatory (M1) or anti-inflammatory (M2) activity. This study aimed to determine the role of macrophages in vascular leakage through the tight junction complexes of retinal pigment epithelium, which is the outer blood-retinal barrier (BRB). Furthermore, we aimed to assess whether interleukin-10 (IL-10), a representative M2-inducer, can decrease inflammatory macrophages and alleviate outer-BRB disruption. We found that modulation of macrophage polarization affects the structural and functional integrity of ARPE-19 cells in a co-culture system under high-glucose conditions. Furthermore, we demonstrated that intravitreal IL-10 injection induces an increase in the ratio of anti-inflammatory macrophages and effectively suppresses outer-BRB disruption and vascular leakage in a mouse model of early-stage streptozotocin-induced diabetes. Our results suggest that modulation of macrophage polarization by IL-10 administration during early-stage DR has a promising protective effect against outer-BRB disruption and vascular leakage. This finding provides valuable insights for early intervention in DR., (© 2024 Federation of American Societies for Experimental Biology.)

The effect of growth hormone-releasing hormone (GHRH) plasmid treatment on sow reproductive performance was examined. Forty pregnant sows (three-way crossbreed: Landrace × Yorkshire × Duroc) at 85 days of gestation were included in the study and consisted of twenty primiparous and twenty multiparous sows (third parity). Sows were randomly assigned to the control and treatment groups. The treatment group received 5 mg dose of GHRH plasmid injection via electroporation, whereas the control group received a phosphate buffer solution. Reproductive indicators, including serum insulin-like growth factor-1 (IGF-1) concentration and weaned piglet data, were assessed. In the GHRH plasmid-treated group, serum IGF-1 concentration significantly increased compared with that in the control group, a trend observed in primiparous and multiparous sows. The key indicator of reproductive performance, litter size, showed that for control primiparous sows (C-PS), it was 10.90 ± 0.99 kg, while for control multiparous sows (C-MS), it was 14.00 ± 0.67 kg. Furthermore, for primiparous sows treated with GHRH plasmid (G-PS), the litter size was 11.60 ± 0.97 kg, and for multiparous sows treated with GHRH plasmid (G-MS), it was 14.00 ± 0.82 kg. The GHRH plasmid-treated group also exhibited a higher number of total births and surviving piglet numbers, along with a decrease in stillborn piglets; however, there was no significant difference in birth weight. The results suggest that GHRH plasmid treatment can enhance the reproductive performance of sows.

In a 2016 clinical practice guideline, the American Academy of Pediatrics (AAP) created and introduced the term brief resolved unexplained event (BRUE). This guideline defined specific criteria for diagnosis of BRUE and provided a set of guidelines for evaluation of these infants as well as characteristics that indicate a BRUE will have a low risk for a repeat event or a serious underlying disorder. This issue reviews the definition and broad differential diagnosis of a BRUE, highlights the criteria for risk stratification of infants who experience a BRUE, summarizes the management recommendations for patients with a lower-risk BRUE, and examines the available literature that evaluates the impact of the AAP guidelines in the years since its publication.

Recently, polymer-based tissue adhesives (TAs) have gained the attention of scientists and industries as alternatives to sutures for sealing and closing wounds or incisions because of their ease of use, low cost, minimal tissue damage, and short application time. However, poor mechanical properties and weak adhesion strength limit the application of TAs, although numerous studies have attempted to develop new TAs with enhanced performance. Therefore, next-generation TAs with improved multifunctional properties are required. In this review, we address the requirements of polymeric TAs, adhesive characteristics, adhesion strength assessment methods, adhesion mechanisms, applications, advantages and disadvantages, and commercial products of polysaccharide (PS)-based TAs, including chitosan (CS), alginate (AL), dextran (DE), and hyaluronic acid (HA). Additionally, future perspectives are discussed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Transplantation of mitochondria derived from mesenchymal stem cells (MSCs) has emerged as a new treatment method to improve mitochondrial dysfunction and alleviate cell impairment. Interest in using extrinsic mitochondrial transplantation as a therapeutic approach has been increasing because it has been confirmed to be effective in treating various diseases related to mitochondrial dysfunction, including ischemia, cardiovascular disease, and toxic damage. To support this application, we conducted an experiment to deliver external mitochondria to retinal pigment epithelial cells treated with oligomeric amyloid-beta (oAβ). Externally delivered amyloid-beta internalizes into cells and interacts with mitochondria, resulting in mitochondrial dysfunction and intracellular damage, including increased reactive oxygen species and destruction of tight junction proteins. Externally delivered mitochondria were confirmed to alleviate mitochondrial dysfunction and tight junction protein disruption as well as improve internalized oAβ clearance. These results were also confirmed in a mouse model in vivo. Overall, these findings indicate that the transfer of external mitochondria isolated from MSCs has potential as a new treatment method for age-related macular degeneration, which involves oAβ-induced changes to the retinal pigment epithelium., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aim: This post hoc analysis evaluated the efficacy and safety of intravenous belimumab 10 mg/kg in the South Korean subgroup of patients with systemic lupus erythematosus (SLE) enrolled in the North East Asia (NEA) study (GSK Study BEL113750; NCT01345253)., Methods: NEA was a double-blind, placebo-controlled, randomized Phase 3 trial. Patients with active, autoantibody-positive SLE were randomized 2:1 to belimumab or placebo plus standard therapy administered on Days 0, 14, and 28, and then every 28 days up to Week 48. The primary efficacy endpoint in this analysis was SLE Responder Index 4 (SRI-4) response rate at Week 52, defined as the proportion of patients achieving a ≥4-point reduction in Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score, no worsening (<0.3 increase from baseline) in Physician Global Assessment, no new British Isles Lupus Assessment Group (BILAG) A domain and <2 new BILAG B domain scores., Results: Among 100 South Korean patients enrolled in NEA, 54/66 (81.8%) belimumab- and 24/34 (70.6%) placebo-treated patients completed the double-blind phase. Significantly more belimumab- than placebo-treated patients achieved SRI-4 response at Week 52 (n = 35/66, 53.0% vs. n = 8/34, 23.5%; odds ratio [OR; 95% confidence interval (CI)]: 3.67 [1.45, 9.28]; p = .0061). The proportion of patients experiencing ≥1 adverse event was similar between groups (belimumab: n = 60/66, 90.9% vs. placebo: n = 31/34, 91.2%). No new safety signals emerged in this subgroup analysis., Conclusion: Belimumab was efficacious for the treatment of SLE and well tolerated among the South Korean subgroup of patients from the NEA study., (© 2023 The Authors. International Journal of Rheumatic Diseases published by Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Histotripsy is the first noninvasive, non-ionizing, and non-thermal ablation technique that mechanically fractionates target tissue into acellular homogenate via controlled acoustic cavitation. Histotripsy has been evaluated for various preclinical applications requiring noninvasive tissue removal including cancer, brain surgery, blood clot and hematoma liquefaction, and correction of neonatal congenital heart defects. Promising preclinical results including local tumor suppression, improved survival outcomes, local and systemic anti-tumor immune responses, and histotripsy-induced abscopal effects have been reported in various animal tumor models. Histotripsy is also being investigated in veterinary patients with spontaneously arising tumors. Research is underway to combine histotripsy with immunotherapy and chemotherapy to improve therapeutic outcomes. In addition to preclinical cancer research, human clinical trials are ongoing for the treatment of liver tumors and renal tumors. Histotripsy has been recently approved by the FDA for noninvasive treatment of liver tumors. This review highlights key learnings from in vivo shock-scattering histotripsy, intrinsic threshold histotripsy, and boiling histotripsy cancer studies treating cancers of different anatomic locations and discusses the major considerations in planning in vivo histotripsy studies regarding instrumentation, tumor model, study design, treatment dose, and post-treatment tumor monitoring.

Introduction: Cobalt is a mitochondrial toxin, clinical cobaltism manifests with constitutional, neurologic, and cardiovascular symptomatology. Cobalt's severe toxidrome is known through case reports from extreme wear or corrosion of cobalt-chromium arthroplasty components. However, the spectrum and epidemiology of orthopedic-implant cobaltism and its relationship to duration and degree of cobalt exposure are not well defined., Methods: The relationship of urine-cobalt concentration and duration of exposure to cobalt-chromium joint implants and cobaltism symptomatology were prospectively studied in 229 patients. Subjects received a Cobaltism-Symptom-Inventory-Score (CSIS) based on a protocolized interview and examination followed by a spot urine-cobalt measurement., Results: 129 (56%) subjects were cobalturic (urine-cobalt ≥1.0 ppb). 122 (53%) subjects had a CSIS of >2, this status significantly associates with cobalturia. Median [IQR] urine-cobalt in the subjects with a CSIS >2 was 4.1[1.1-17.0] ppb compared to 0.5[0.5-1.4] ppb in subjects with CSIS ≤ 2. Cobalturia has a sensitivity of 0.69, a specificity of 0.77, and a positive predictive value of 0.74 for a CSIS of >2. The product of years-exposed to a cobalt-chromium implant and urine-cobalt by quartiles significantly positively associates with the Cobaltism-Symptom-Inventory-Score., Conclusion: A urine-cobalt of ≥1 ppb likely indicates adverse systemic exposure to orthopedic-implant generated cobalt. Cobaltism severity as quantified by the CSIS significantly correlates with the product of spot urine-cobalt concentration and years-exposed to a cobalt-chromium orthopedic-implant indicating a dose-response relationship. Medical provider and public awareness of orthopedic-implant cobaltism is vital because tens-of-millions are at-risk and early cobaltism is reversible. Further use of cobalt-chromium orthopedic-implants should be questioned given cobaltism becomes clinically apparent at a spot urine-cobalt of 1 ppb or greater. Monitoring of patients with high-risk cobalt-chromium orthopedic-implants appears to be indicated., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Tower et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Scrub typhus, a mite-borne infectious disease, is caused by Orientia tsutsugamushi . Despite many attempts to develop a protective strategy, an effective preventive vaccine has not been developed. The identification of appropriate Ags that cover diverse antigenic strains and provide long-lasting immunity is a fundamental challenge in the development of a scrub typhus vaccine. We investigated whether this limitation could be overcome by harnessing the nanoparticle-forming polysorbitol transporter (PST) for an O. tsutsugamushi vaccine strategy. Two target proteins, 56-kDa type-specific Ag (TSA56) and surface cell Ag A (ScaA) were used as vaccine candidates. PST formed stable nano-size complexes with TSA56 (TSA56-PST) and ScaA (ScaA-PST); neither exhibited cytotoxicity. The formation of Ag-specific IgG2a, IgG2b, and IgA in mice was enhanced by intranasal vaccination with TSA56-PST or ScaA-PST. The vaccines containing PST induced Ag-specific proliferation of CD8 + and CD4 + T cells. Furthermore, the vaccines containing PST improved the mouse survival against O. tsutsugamushi infection. Collectively, the present study indicated that PST could enhance both Ag-specific humoral immunity and T cell response, which are essential to effectively confer protective immunity against O. tsutsugamushi infection. These findings suggest that PST has potential for use in an intranasal vaccination strategy., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2023. The Korean Association of Immunologists.)

Accumulation of pathogenic amyloid-β disrupts the tight junction of retinal pigment epithelium (RPE), one of its senescence-like structural alterations. In the clearance of amyloid-β, the autophagy-lysosome pathway plays the crucial role. In this context, mammalian target of rapamycin (mTOR) inhibits the process of autophagy and lysosomal degradation, acting as a potential therapeutic target for age-associated disorders. However, efficacy of targeting mTOR to treat age-related macular degeneration remains largely elusive. Here, we validated the therapeutic efficacy of the mTOR inhibitors, Torin and PP242, in clearing amyloid-β by inducing the autophagy-lysosome pathway in a mouse model with pathogenic amyloid-β with tight junction disruption of RPE, which is evident in dry age-related macular degeneration. High concentration of amyloid-β oligomers induced autophagy-lysosome pathway impairment accompanied by the accumulation of p62 and decreased lysosomal activity in RPE cells. However, Torin and PP242 treatment restored the lysosomal activity via activation of LAMP2 and facilitated the clearance of amyloid-β in vitro and in vivo. Furthermore, clearance of amyloid-β by Torin and PP242 ameliorated the tight junction disruption of RPE in vivo. Overall, our findings suggest mTOR inhibition as a new therapeutic strategy for the restoration of tight junctions in age-related macular degeneration.

Imbalance in the tissue microenvironment is the main obstacle to drug delivery and distribution in the human body. Before penetrating the pathological tissue microenvironment to the target site, therapeutic agents are usually accompanied by three consumption steps: the first step is tissue physical barriers for prevention of their penetration, the second step is inactivation of them by biological molecules, and the third step is a cytoprotective mechanism for preventing them from functioning on specific subcellular organelles. However, recent studies in drug-hindering mainly focus on normal physiological rather than pathological microenvironment, and the repair of damaged physiological barriers is also rarely discussed. Actually, both the modulation of pathological barriers and the repair of damaged physiological barriers are essential in the disease treatment and the homeostasis maintenance. In this review, we present an overview describing the latest advances in the generality of these pathological barriers and barrier-modulated nanomedicine. Overall, this review holds considerable significance for guiding the design of nanomedicine to increase drug efficacy in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: Egg yolk immunoglobulin (IgY) is an antibiotic alternative to prevent and fight intestinal pathogenic infections. This study aimed to investigate the effects of sodium alginate/chitosan/sodium alginate IgY microcapsules on the growth performance, serum parameters, and intestinal health of broiler chickens., Methods: One-day-old broilers (Ross 308) were divided into five treatments, each with 10 replicates of five chickens. The dietary treatments were maintained for 28 days and consisted of a basal diet (NC), basal diet + 500 mg chlortetracycline/kg diet (CH), basal diet + 50 mg non-microencapsulated IgY/kg diet (NM), basal diet + 600 mg low levels microencapsulated IgY/kg diet (LM), and basal diet + 700 mg high levels microencapsulated IgY/kg diet (HM)., Results: Throughout the 28-day trial period, the NM, LM, HM, and CH groups increased average daily gain compared with the NC group (p<0.05), and the HM group reduced feed conversion ratio compared with the CH group (p<0.05). The LM and HM groups increased relative organ weights of thymus and spleen compared with the CH and NM groups (p<0.05). The HM group improved the duodenal, jejunal and ileum villi height (VH) and villus height to crypt depth ratio (VH:CD) compared with the CH and NM groups (p<0.05). Compared with the CH group, the HM group increased serum immunoglobulin (IgA), immunoglobulin G (IgG), superoxide dismutase, total antioxidant capacity, and glutathione peroxidase levels (p<0.05), and decreased serum malondialdehyde levels (p<0.05). Compared with the NC group, the NM, LM, HM, and CH groups reduced colonic Escherichia coli and Salmonella levels (p<0.05). and the HM group promoted the levels of lactic acid bacteria and bifidobacteria compared with the CH group (p<0.05)., Conclusion: Microencapsulation could be considered as a way to improve the efficiency of IgY. The 700 mg high levels microencapsulated IgY/kg diet could potentially be used as an alternative to antibiotics to improve the immune performance and intestinal health, leading to better performance of broiler chickens.

Chemotherapies are used for treating retinoblastoma; however, numerous patients suffer from recurrence or symptoms due to chemotherapy, which emphasizes the need for alternative therapeutic strategies. The present study demonstrated that protein arginine deiminase Ⅱ (PADI2) was highly expressed in human and mouse retinoblastoma tissues due to the overexpression of E2 factor (E2F). By inhibiting PADI2 activity, the expression of phosphorylated AKT was reduced, and cleaved poly (ADP‑ribose) polymerase level was increased, leading to induced apoptosis. Similar results were obtained in orthotopic mouse models with reduced tumor volumes. In addition, BB‑Cl‑amidine showed low toxicity in vivo . These results suggested that PADI2 inhibition has potential clinical translation. Furthermore, the present study highlights the potential of epigenetic approaches to target RB1‑deficient mutations at the molecular level. The current findings provide new insights into the importance of retinoblastoma intervention by managing PADI2 activity according to the treatment of specific inhibitors and depletion approaches in vitro and in orthotopic mouse models.

Marmosets have emerged as a valuable primate model in ophthalmic research due to their similarity to the human visual system and their potential for generating transgenic models to advance the development of therapies. In this study, we isolated and cultured primary retinal pigment epithelium (RPE) cells from marmosets to investigate the mechanisms underlying RPE dysfunction in aging and age-related macular degeneration (AMD). We confirmed that our culture conditions and materials supported the formation of RPE monolayers with functional tight junctions that closely resembled the in vivo RPE. Since serum has been shown to induce epithelial-mesenchymal transition (EMT) in RPE cells, we compared the effects of fetal bovine serum (FBS) with serum-free supplements B27 on transepithelial electrical resistance (TER), cell proliferation, and morphological characteristics. Additionally, we assessed the age-related morphological changes of in vivo and primary RPE cells. Our results indicate that primary marmoset RPE cells exhibit in vivo-like characteristics, while cells obtained from an older donor show evidence of aging, including a failure to form a polarized monolayer, low TER, and delayed cell cycle. In conclusion, our primary marmoset RPE cells provide a reliable in vitro model for developing novel therapeutics for visual-threatening disorders such as AMD, which can be used before animal experiments using marmosets.

In recent years, polymer-based tissue adhesives (TAs) have been developed as an alternative to sutures to close and seal incisions or wounds owing to their ease of use, rapid application time, low cost, and minimal tissue damage. Although significant research is being conducted to develop new TAs with improved performances using different strategies, the applications of TAs are limited by several factors, such as weak adhesion strength and poor mechanical properties. Therefore, the next-generation advanced TAs with biomimetic and multifunctional properties should be developed. Herein, we review the requirements, adhesive performances, characteristics, adhesive mechanisms, applications, commercial products, and advantages and disadvantages of proteins- and synthetic polymer-based TAs. Furthermore, future perspectives in the field of TA-based research have been discussed., (© 2023. The Author(s).)

Numerous studies have aimed to develop novel advanced vaccines, in part because traditional vaccines have been unsuccessful in preventing rapidly emerging and reemerging viral and bacterial infections. There is a need for an advanced vaccine delivery system to ensure the successful induction of humoral and cellular immune responses. In particular, the ability of nanovaccines to modulate intracellular antigen delivery by inducing exogenous antigens (loaded onto major histocompatibility complex class 1 molecules) in CD8 + T cells, the so-called cross-presentation pathway, has attracted a great deal of attention. Protection against viral and intracellular bacterial infections relies on cross-presentation. This review discusses the advantages, requirements, and preparation of nanovaccines, the cross-presentation mechanism, the several parameters affecting cross-presentation by nanovaccines, and future perspectives., (© 2023. Korean Tissue Engineering and Regenerative Medicine Society.)

Germinal matrix-intraventricular hemorrhage (GM-IVH) is among the devastating neurological complications with mortality and neurodevelopmental disability rates ranging from 14.7% to 44.7% in preterm infants. The medical techniques have improved throughout the years, as the morbidity-free survival rate of very-low-birth-weight infants has increased; however, the neonatal and long-term morbidity rates have not significantly improved. To this date, there is no strong evidence on pharmacological management on GM-IVH, due to the limitation of well-designed randomized controlled studies. However, recombinant human erythropoietin administration in preterm infants seems to be the only effective pharmacological management in limited situations. Hence, further high-quality collaborative research studies are warranted in the future to ensure better outcomes among preterm infants with GM-IVH.

Magnetic Cu-MOF-74 (Fe 3 O 4 @SiO 2 @Cu-MOF-74) was synthesized for the first time by grafting MOF-74 (copper as the metal center) on the surface of core-shell magnetic carboxyl-functionalized silica gel (Fe 3 O 4 @SiO 2 -COOH), which was prepared by coating core Fe 3 O 4 nanoparticles with hydrolyzed 2-(3-(triethoxysilyl)propyl)succinic anhydride and tetraethyl orthosilicate. The structure of Fe 3 O 4 @SiO 2 @Cu-MOF-74 nanoparticles was characterized by Fourier transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), and transmission electron microscopy (TEM). The prepared Fe 3 O 4 @SiO 2 @Cu-MOF-74 nanoparticles could be applied as a recyclable catalyst to the synthesis of N-fused hybrid scaffolds. 2-(2-Bromoaryl)imidazoles and 2-(2-bromovinyl)imidazoles were coupled and cyclized with cyanamide in DMF in the presence of a catalytic amount of Fe 3 O 4 @SiO 2 @Cu-MOF-74 along with a base to give imidazo[1,2- c ]quinazolines and imidazo[1,2- c ]pyrimidines, respectively, in good yields. The Fe 3 O 4 @SiO 2 @Cu-MOF-74 catalyst could be easily recovered by a super magnetic bar and recycled more than four times while almost maintaining catalytic activity., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Objective: Lack of trust between supervisors and trainees can have harmful consequences. Trust has been examined between physicians, patients, and staff in multiple settings but has not been examined in a bidirectional manner in the pediatric emergency department (PED). Debra Meyerson in 1996 discussed the theory of swift trust, a type of trust that develops quickly between temporary groups through reliance on categories . Meyerson describes categories as groups unified by social identities such as gender or profession. We explored the applicability of swift trust in the relationship between supervisors and trainees in the PED., Methods: This multimethods study used qualitative interviews and the validated interpersonal mistrust trust measure (IMTM) to assess baseline trusting style. PED attendings from a single institution and residents from various training levels, specialties, and institutions rotating through the same PED were sampled until thematic saturation was reached. Interviews were analyzed using directed content analysis. IMTM scores were triangulated with interviewee's reported trusting styles., Results: Seventeen PED attendings and 16 residents participated. Residents and attendings emphasized different factors that influence trust. Common factors across groups included affect, the need for vulnerability, and appropriate communication. Most described reliance on certain categories (level of training, specialty, etc.) when making trusting decisions. Categories such as gender and race were noted to be unimportant when making trusting decisions about others, although some participants believed these attributes played into decisions made by others. Quantitative data from the IMTM supported qualitative conclusions regarding trusting style., Conclusions: The trusting relationship between supervisors and trainees in the PED dovetails with the swift trust theory. Common factors that influence trust reveal entry points for attendings and residents to improve trust and ultimately prevent negative patient outcomes. Future studies may examine how reliance on categories influences an individual's trust in their colleagues., Competing Interests: The authors declare no conflict of interest., (© 2023 Society for Academic Emergency Medicine.)