Implications of inflammatory cell death-PANoptosis in health and disease.

Regulated cell death (RCD) pathways, such as pyroptosis, apoptosis, and necroptosis, are essential for maintaining the body's balance, defending against pathogens, and eliminating abnormal cells that could lead to diseases like cancer. Although these pathways operate through distinct mechanisms, recent genetic and pharmacological studies have shown that they can interact and influence each other. The concept of "PANoptosis" has emerged, highlighting the interplay between pyroptosis, apoptosis, and necroptosis, especially during cellular responses to infections. This article provides a concise overview of PANoptosis and its molecular mechanisms, exploring its implications in various diseases. The review focuses on the extensive interactions among different RCD pathways, emphasizing the role of PANoptosis in infections, cytokine storms, inflammatory diseases, and cancer. Understanding PANoptosis is crucial for developing novel treatments for conditions involving infections, sterile inflammations, and cancer.

Structure-Guided Engineering of Thermodynamically Enhanced SaCas9 for Improved Gene Suppression.

Proteins with multiple domains play pivotal roles in various biological processes, necessitating a thorough understanding of their structural stability and functional interplay. Here, a structure-guided protein engineering approach is proposed to develop thermostable Cas9 (CRISPR-associated protein 9) variant for CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) interference applications. By employing thermodynamic analysis, combining distance mapping and molecular dynamics simulations, deletable domains are identified to enhance stability while preserving the DNA recognition function of Cas9. The resulting engineered Cas9, termed small and dead form Cas9, exhibits improved thermostability and maintains target DNA recognition function. Cryo-electron microscopy analysis reveals structural integrity with reduced atomic density in the deleted domain. Fusion with functional elements enables intracellular delivery and nuclear localization, demonstrating efficient gene suppression in diverse cell types. Direct delivery in the mouse brain shows enhanced knockdown efficiency, highlighting the potential of structure-guided engineering to develop functional CRISPR systems tailored for specific applications. This study underscores the significance of integrating computational and experimental approaches for protein engineering, offering insights into designing tailored molecular tools for precise biological interventions.

Chemically Driven Clearance of Amyloid Aggregates by Polyfunctionalized Furo[2,3-b:4,5-b']dipyridine-Chalcone Hybrids to Ameliorate Memory in an Alzheimer Mouse Model.

The aberrant assembly of amyloid-ß (Aß) is implicated in Alzheimer's disease (AD). Recent clinical outcomes of Aß-targeted immunotherapy reinforce the notion that clearing Aß burden is a potential therapeutic approach for AD. Herein, to develop drug candidates for chemically driven clearance of Aß aggregates, we synthesized 51 novel polyfunctionalized furo[2,3-b:4,5-b']dipyridine-chalcone hybrid compounds. After conducting two types of cell-free anti-Aß functional assays, Aß aggregation prevention and Aß aggregate clearance, we selected YIAD-0336, (E)-8-((1H-pyrrol-2-yl)methylene)-10-(4-chlorophenyl)-2,4-dimethyl-7,8-dihydropyrido[3',2':4,5]furo[3,2-b]quinolin-9(6H)-one, for further in vivo investigations. As YIAD-0336 exhibited a low blood-brain barrier penetration profile, it was injected along with aggregated Aß directly into the intracerebroventricular region of ICR mice and ameliorated spatial memory in Y-maze tests. Next, YIAD-0336 was orally administered to 5XFAD transgenic mice with intravenous injections of mannitol, and YIAD-0336 significantly removed Aß plaques from the brains of 5XFAD mice. Collectively, YIAD-0336 dissociated toxic aggregates in the mouse brain and hence alleviated cognitive deterioration. Our findings indicate that chemically driven clearance of Aß aggregates is a promising therapeutic approach for AD.

Patellofemoral joint cartilage lesions frequently develop shortly after anterior cruciate ligament reconstruction using hamstring tendon autograft: A systematic review.

PURPOSE: This study aimed to investigate the development of patellofemoral joint (PFJ) cartilage lesions following anterior cruciate ligament reconstruction (ACLR) using hamstring tendon (HT) autograft through a systematic review. METHODS: A comprehensive search was conducted in PubMed, Embase, Cochrane Library and Google Scholar databases to find articles published from database inception until 15 November 2023. The search terms were [('Anterior Cruciate Ligament' [mesh] OR 'anterior cruciate ligament' OR 'ACL') AND 'reconstruction' AND 'cartilage' AND ('second look arthroscopy' OR 'second-look arthroscopy' OR 'MRI' OR 'magnetic resonance imaging')]. Inclusion criteria were studies that reported on the occurrence of PFJ cartilage lesions following ACLR using HT autograft, as determined by second-look arthroscopy or follow-up magnetic resonance imaging (MRI). RESULTS: Fifteen studies (1084 patients) met the inclusion criteria, with follow-up periods ranging from 1 to 5 years. In the results of second-look arthroscopy, cartilage grade deterioration was observed, ranging from MDs of 0.1 to 2.0 in the patella and from 0 to 1.0 in the trochlea. Follow-up MRI results reported the incidence of PFJ cartilage degeneration with rates ranging from 20% to 44%. Patient-reported outcome measures often showed no significant association with PFJ cartilage lesions. The studies included in this review reported various risk factors for cartilage lesion development. CONCLUSION: Cartilage lesions in the PFJ, detected using second-look arthroscopy or follow-up MRI, frequently develop shortly after ACLR using HT autograft. At this stage, patients might not show specific symptoms; however, those with risk factors require careful observation and evaluation by clinicians during follow-up. LEVEL OF EVIDENCE: Level IV.

Perspectives on Electronic Nicotine Delivery System Use Cessation Among Adults in Rural Areas: Implications for Future Studies.

INTRODUCTION: More young adults (age 18-24 years) in rural areas versus urban areas use electronic nicotine delivery systems (ENDS) - also known as e-cigarettes. Little is known about young adults' perceptions toward ENDS use and cessation. The objective of this study was to examine barriers and facilitators to ENDS use cessation among young adults living in rural areas, as well as their perceptions about ENDS use and cessation and to determine implications for future cessation studies. METHODS: We administered cross-sectional online surveys to young adults living in rural Midwestern counties. A total of 100 individuals responded to the surveys. Descriptive statistics were used to report their perceptions of ENDS use as well as barriers and facilitators to ENDS use cessation. The content analysis method was used to analyze the answers to an open-ended question regarding perceptions about the ENDS use cessation in the context of rural areas. RESULTS: Barriers to ENDS use cessation included perceived advantages to ENDS use, high nicotine dependence, and the perception that ENDS use was less harmful cigarettes. Facilitators to ENDS use cessation included cost of ENDS use, perceived harm, and high confidence in ability to quit. Participants' perceptions about ENDS use cessation in the context of rural areas were conceptualized under the themes of (1) exposure to and initiation of ENDS use, (2) continuation of ENDS use, and (3) prevention and cessation of ENDS use. CONCLUSIONS: Health care providers, tobacco control researchers, and public health advocates should be aware of barriers and facilitators to ENDS use cessation among young adults for future cessation intervention studies relevant specifically to rural areas.

Literature review of non-pharmacological treatment for patients with axial spondyloarthritis.

Axial spondyloarthritis (axSpA) is a chronic inflammatory disorder affecting the sacroiliac joints and axial spine. Along with pharmacotherapy, non-pharmacological interventions for axSpA are crucial and constitute the cornerstone of treatment. Here, we review the evidence for non-pharmacological treatment of axSpA as a basis for the 2023 Korean treatment recommendations for patients with axSpA. The effectiveness of the core non-pharmacological approaches, such as education, smoking cessation, and exercise, has been reaffirmed. High-quality research on surgical treatment is limited. However, total hip replacement is advised in patients with ongoing pain or disability and visible structural damage to the hip on imaging. Urgent spinal intervention should be considered in cases of acute spinal pain with neurological deficiency or concurrent unstable fractures. Evidence for complementary therapies, including spas and acupuncture, remains insufficient.

GPR41 and GPR43: From development to metabolic regulation.

G-protein-coupled receptors are a diverse class of cell surface receptors that orchestrate numerous physiological functions. The G-protein-coupled receptors, GPR41 and GPR43, sense short-chain fatty acids (SCFAs), which are metabolites of dietary fermentation by the host's intestinal bacteria. These receptors have gained attention as potential therapeutic targets against various diseases because of their SCFA-mediated beneficial effects on the host's intestinal health. Mounting evidence has associated the activity of these receptors with chronic metabolic diseases, including obesity, diabetes, inflammation, and cardiovascular disease. However, despite intensive research using various strategies, including gene knockout (KO) mouse models, evidence about the precise roles of GPR41 and GPR43 in disease treatment remains inconsistent. Here, we comprehensively review the latest findings from functional studies of the signaling mechanisms that underlie the activities of GPR41 and GPR43, as well as highlight their multifaceted roles in health and disease. We anticipate that this knowledge will guide future research priorities and the development of effective therapeutic interventions.

Transfusion-transmitted infections.

The risk of transfusion-transmitted infection (TTI) has always existed because transfused blood products are biological materials derived from humans. To prevent TTIs, screening strategies have been developed for various infectious diseases, such as hepatitis B virus, hepatitis C virus, and human immunodeficiency virus, contributing significantly to reducing TTI globally. Nevertheless, septic transfusion reactions (STRs) due to bacterial contamination remain an unresolved issue. Various infectious diseases can be transmitted through blood products, and preventive and selective screening strategies have been applied across different regions. Although multiple strategies, including culture-based and rapid detection kit-based methods, have been introduced to overcome STRs, complete prevention has not yet been achieved. Recently, pathogen inactivation methods have been developed to eliminate non-specific organisms rather than screening specific organisms. This approach is anticipated to contribute significantly to diminishing the risk of TTIs in the future.

J-MISFET Hybrid Dual-Gate Switching Device for Multifunctional Optoelectronic Logic Gate Applications.

High-performance and low operating voltage are becoming increasingly significant device parameters to meet the needs of future integrated circuit (IC) processors and ensure their energy-efficient use in upcoming mobile devices. In this study, we suggest a hybrid dual-gate switching device consisting of the vertically stacked junction and metal-insulator-semiconductor (MIS) gate structure, named J-MISFET. It shows excellent device performances of low operating voltage (<0.5 V), drain current ON/OFF ratio (∼4.7 × 105), negligible hysteresis window (<0.5 mV), and near-ideal subthreshold slope (SS) (60 mV/dec), making it suitable for low-power switching operation. Furthermore, we investigated the switchable NAND/NOR logic gate operations and the photoresponse characteristics of the J-MISFET under the small supply voltage (0.5 V). To advance the applications further, we successfully demonstrated an integrated optoelectronic security logic system comprising 2-electric inputs (for encrypted data) and 1-photonic input signal (for password key) as a hardware security device for data protection. Thus, we believe that our J-MISFET, with its heterogeneous hybrid gate structures, will illuminate the path toward future device configurations for next-generation low-power electronics and multifunctional security logic systems in a data-driven society.

Inhibition of the RPS6KA1/FoxO1 signaling axis by hydroxycitric acid attenuates HFD-induced obesity through MCE suppression.

BACKGROUND: Because obesity is associated with a hyperplasia-mediated increase in adipose tissue, inhibiting cell proliferation during mitotic clonal expansion (MCE) is a leading strategy for preventing obesity. Although (-)-hydroxycitric acid (HCA) is used to control obesity, the molecular mechanisms underlying its effects on MCE are poorly understood. PURPOSE: This study aimed to investigate the potential effects of HCA on MCE and underlying molecular mechanisms affecting adipogenesis and obesity improvements. METHODS: Preadipocyte cell line, 3T3-L1, were treated with HCA; oil red O, cell proliferation, cell cycle, and related alterations in signaling pathways were examined. High-fat diet (HFD)-fed mice were administered HCA for 12 weeks; body and adipose tissues weights were evaluated, and the regulation of signaling pathways in epidydimal white adipose tissue were examined in vivo. RESULTS: Here, we report that during MCE, HCA attenuates the proliferation of the preadipocyte cell line, 3T3-L1, by arresting the cell cycle at the G0/G1 phase. In addition, HCA markedly inhibits Forkhead Box O1 (FoxO1) phosphorylation, thereby inducing the expression of cyclin-dependent kinase inhibitor 1B and suppressing the levels of cyclin-dependent kinase 2, cyclin E1, proliferating cell nuclear antigen, and phosphorylated retinoblastoma. Importantly, we found that ribosomal protein S6 kinase A1 (RPS6KA1) influences HCA-mediated inactivation of FoxO1 and its nuclear exclusion. An animal model of obesity revealed that HCA reduced high-fat diet-induced obesity by suppressing adipocyte numbers as well as epididymal and mesenteric white adipose tissue mass, which is attributed to the regulation of RPS6KA1, FoxO1, CDKN1B and PCNA that had been consistently identified in vitro. CONCLUSIONS: These findings provide novel insights into the mechanism by which HCA regulates adipogenesis and highlight the RPS6KA1/FoxO1 signaling axis as a therapeutic target for obesity.

Optimizing Wireless Connectivity: A Deep Neural Network-Based Handover Approach for Hybrid LiFi and WiFi Networks.

A Hybrid LiFi and WiFi network (HLWNet) integrates the rapid data transmission capabilities of Light Fidelity (LiFi) with the extensive connectivity provided by Wireless Fidelity (WiFi), resulting in significant benefits for wireless data transmissions in the designated area. However, the challenge of decision-making during the handover process in HLWNet is made more complex due to the specific characteristics of electromagnetic signals' line-of-sight transmission, resulting in a greater level of intricacy compared to previous heterogeneous networks. This research work addresses the problem of handover decisions in the Hybrid LiFi and WiFi networks and treats it as a binary classification problem. Consequently, it proposes a handover method based on a deep neural network (DNN). The comprehensive handover scheme incorporates two sets of neural networks (ANN and DNN) that utilize input factors such as channel quality and the mobility of users to enable informed decisions during handovers. Following training with labeled datasets, the neural-network-based handover approach achieves an accuracy rate exceeding 95%. A comparative analysis of the proposed scheme against the benchmark reveals that the proposed method considerably increases user throughput by approximately 18.58% to 38.5% while reducing the handover rate by approximately 55.21% to 67.15% compared to the benchmark artificial neural network (ANN); moreover, the proposed method demonstrates robustness in the face of variations in user mobility and channel conditions.

TLR7-dependent eosinophil degranulation links psoriatic skin inflammation to small intestinal inflammatory changes in mice.

Recent evidence of gut microbiota dysbiosis in the context of psoriasis and the increased cooccurrence of inflammatory bowel disease and psoriasis suggest a close relationship between skin and gut immune responses. Using a mouse model of psoriasis induced by the Toll-like receptor (TLR) 7 ligand imiquimod, we found that psoriatic dermatitis was accompanied by inflammatory changes in the small intestine associated with eosinophil degranulation, which impaired intestinal barrier integrity. Inflammatory responses in the skin and small intestine were increased in mice prone to eosinophil degranulation. Caco-2 human intestinal epithelial cells were treated with media containing eosinophil granule proteins and exhibited signs of inflammation and damage. Imiquimod-induced skin and intestinal changes were attenuated in eosinophil-deficient mice, and this attenuation was counteracted by the transfer of eosinophils. Imiquimod levels and the distribution of eosinophils were positively correlated in the intestine. TLR7-deficient mice did not exhibit intestinal eosinophil degranulation but did exhibit attenuated inflammation in the skin and small intestine following imiquimod administration. These results suggest that TLR7-dependent bidirectional skin-to-gut communication occurs in psoriatic inflammation and that inflammatory changes in the intestine can accelerate psoriasis.

Effects of concurrent cartilage procedures on cartilage regeneration in high tibial osteotomy: a systematic review.

PURPOSE: This systematic review aimed to evaluate the effects of concurrent cartilage procedures on cartilage regeneration when performed alongside high tibial osteotomy (HTO). MATERIALS AND METHODS: The systematic review followed the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). A comprehensive search was conducted on databases including PubMed, Embase, Cochrane Library, and Google Scholar, covering articles published until August 31, 2023. RESULTS: Sixteen studies (1277 patients) revealed that HTO, with or without concurrent cartilage procedures, leads to cartilage regeneration based on the International Cartilage Repair Society (ICRS) grade during second-look arthroscopy. No concurrent procedure showed improvement in ICRS grade (mean difference: - 0.80 to - 0.49). Microfracture (mean difference: - 0.75 to - 0.22), bone marrow aspirate concentrate (BMAC) (mean difference: - 1.37 to - 0.67), and human umbilical cord blood-derived mesenchymal stem cell (hUCB-MSC) (mean difference: - 2.46 to - 1.81) procedures also demonstrated positive outcomes. Clinical outcome assessments for each cartilage procedure were also improved during postoperative follow-up, and no specific complications were reported. CONCLUSIONS: HTO with or without concurrent cartilage procedures promotes cartilage regeneration observed during second-look arthroscopy, with improved clinical outcomes. Future randomized controlled trials on the same topic, along with subsequent meta-analyses, are necessary for conclusive findings.

Factors associated with the development of exudation in treatment-naive eyes with nonexudative macular neovascularization.

PURPOSE: To identify the predictive factors for development of exudation in patients with treatment-naïve nonexudative macular neovascularization (MNV). METHODS: We retrospectively analyzed 61 treatment-naïve patients with nonexudative MNV who had not received treatment for nonexudative MNV before the exudation developed. Baseline characteristics and changes in MNV were evaluated using multivariate modeling to determine the potential risk factors for exudative conversion. RESULTS: Exudation development was identified in 31.1% (19/61 eyes) of the study eyes during the 46.2 ± 8.2-month mean follow-up period. The mean period of development of exudation from the baseline was 21.5 ± 6.7 months. Multivariate Cox regression analysis identified that older age (hazard ratio [HR] of 1.380, 95% confidence interval [CI] 1.129-1.688, P = 0.008), larger MNV area at baseline (HR of 1.715, CI 1.288-2.308; P = 0.006), increase of MNV area by doubling (HR of 4.992, CI 1.932-9.246; P = 0.002), and retinal pigment epithelium (RPE) elevation more than 100 µm (HR of 1.017, CI 1.006-1.233; P = 0.015) were associated with increased risk of the development of exudation. CONCLUSION: Older age, larger MNV area, increasing MNV area, and higher RPE elevation were associated with an increased risk of exudative conversion in patients with treatment-naïve nonexudative MNV. Identifying these risk factors may be helpful in establishing treatment strategies and monitoring patients.

Trends in category and grade for therapeutic plasma exchange in the latest guideline on therapeutic apheresis by the American Society for Apheresis: Hurdles in pursuing evidence-based medicine.

BACKGROUND AND OBJECTIVES: The Writing Committee of American Society for Apheresis released the ninth edition of guidelines for therapeutic apheresis in 2023. Categories have been a part of the guidelines since the first edition, and the grading system was introduced in the fifth edition, with updates in every new edition. In this study, we investigated the category and grade change trends through the latest five editions, focusing on therapeutic plasma exchange, to suggest future directions as part of evidence-based medicine. MATERIALS AND METHODS: Categories and grades for therapeutic plasma exchange (TPE) were collected and analysed from the fifth through ninth editions. We aligned classification changes to the ninth edition's clinical context and compared its categories and grades with those introduced in the guideline. RESULTS: Among 166 total indications in the ninth edition, 118 included TPE procedure, either as a sole treatment or as one of the therapeutic apheresis techniques. The total number of indications changed, but Category III remained predominant throughout the editions. Similarly, Grade 2C consistently emerged as the most prevalent grade. Notably, 24 cases had grade changes. Of the 16 cases with evidence quality changes, the quality weakened in six and improved in 10. Evidence levels were not improved throughout the study period for 102 clinical conditions. CONCLUSION: To address gaps in evidence quality, international collaboration is imperative to establish comprehensive large-scale studies or randomized controlled trials. This will refine the use of therapeutic apheresis, including TPE, to foster evidence-based advancements in clinical practice.

Physiologically Based Pharmacokinetic (PBPK) Modeling to Predict CYP3A-Mediated Drug Interaction between Saxagliptin and Nicardipine: Bridging Rat-to-Human Extrapolation.

The aim of this study was to predict the cytochrome P450 3A (CYP3A)-mediated drug-drug interactions (DDIs) between saxagliptin and nicardipine using a physiologically based pharmacokinetic (PBPK) model. Initially, in silico and in vitro parameters were gathered from experiments or the literature to construct PBPK models for each drug in rats. These models were integrated to predict the DDIs between saxagliptin, metabolized via CYP3A2, and nicardipine, exhibiting CYP3A inhibitory activity. The rat DDI PBPK model was completed by optimizing parameters using experimental rat plasma concentrations after co-administration of both drugs. Following co-administration in Sprague-Dawley rats, saxagliptin plasma concentration significantly increased, resulting in a 2.60-fold rise in AUC, accurately predicted by the rat PBPK model. Subsequently, the workflow of the rat PBPK model was applied to humans, creating a model capable of predicting DDIs between the two drugs in humans. Simulation from the human PBPK model indicated that nicardipine co-administration in humans resulted in a nearly unchanged AUC of saxagliptin, with an approximate 1.05-fold change, indicating no clinically significant changes and revealing a lack of direct translation of animal interaction results to humans. The animal-to-human PBPK model extrapolation used in this study could enhance the reliability of predicting drug interactions in clinical settings where DDI studies are challenging.

NINJ1 mediates inflammatory cell death, PANoptosis, and lethality during infection conditions and heat stress.

Innate immunity provides the first line of defense through multiple mechanisms, including pyrogen production and cell death. While elevated body temperature during infection is beneficial to clear pathogens, heat stress (HS) can lead to inflammation and pathology. Links between pathogen exposure, HS, cytokine release, and inflammation have been observed, but fundamental innate immune mechanisms driving pathology during pathogen exposure and HS remain unclear. Here, we use multiple genetic approaches to elucidate innate immune pathways in infection or LPS and HS models. Our results show that bacteria and LPS robustly increase inflammatory cell death during HS that is dependent on caspase-1, caspase-11, caspase-8, and RIPK3 through the PANoptosis pathway. Caspase-7 also contributes to PANoptosis in this context. Furthermore, NINJ1 is an important executioner of this cell death to release inflammatory molecules, independent of other pore-forming executioner proteins, gasdermin D, gasdermin E, and MLKL. In an in vivo HS model, mortality is reduced by deleting NINJ1 and fully rescued by deleting key PANoptosis molecules. Our findings suggest that therapeutic strategies blocking NINJ1 or its upstream regulators to prevent PANoptosis may reduce the release of inflammatory mediators and benefit patients.

Suction thrombectomy of distal medium vessel occlusion using microcatheter during mechanical thrombectomy for acute ischemic stroke: A case series.

While mechanical thrombectomy is known to be effective for distal medium vessel occlusion (DMVO) as well as large vessel occlusion, tortuous DMVO are predisposed to vessel injury during stent retriever thrombectomy. Furthermore, getting access to the thrombus may be difficult during suction thrombectomy using a dedicated suction catheter. Most studies describe DMVO treatment using stent retrievers and dedicated suction catheters, but there are limited studies reporting DMVO treated with suction thrombectomy using a microcatheter. Herein, we describe three cases of DMVO treated with suction thrombectomy that was performed using a microcatheter and subsequently showed good results. Therefore, suction thrombectomy using a microcatheter is a viable alternative treatment for tortuous DMVO.