Patterns of comorbid PTSD, depression, alcohol use disorder, and insomnia symptoms in firefighters: A latent profile analysis.

BACKGROUND: Firefighters are an at-risk population for multiple psychiatric conditions, including posttraumatic stress disorder (PTSD), depression, alcohol use disorders (AUDs), and insomnia. These disorders are likely to co-occur; however, patterns of comorbidity have scarcely been investigated in firefighters. We aimed to identify subgroups of comorbidity of PTSD, depression, AUDs, and insomnia in a nationwide population of firefighters in South Korea. METHODS: A total of 54,054 firefighters responded to an online survey. Latent classes of comorbidity were categorized using latent profile analysis (LPA) based on the symptom scores of PTSD, depression, AUDs, and insomnia. Analysis of variance was performed to compare the characteristics of the identified classes, and multinomial logistic regression was conducted to examine whether anger reactions, resilience, and number of traumatic events predicted class membership. RESULTS: The LPA identified four subgroups: minimal symptoms (n = 42,948, 79.5 %), predominant PTSD (n = 2858, 5.3 %), subthreshold symptoms and comorbidity (n = 7003, 13.0 %), and high symptoms and comorbidity (n = 1245, 2.3 %). Three comorbidity classes were defined based on severity and one class showed predominant PTSD symptoms. Number of traumatic exposures predicted predominant PTSD, while resilience and anger reactions predicted severity of comorbidities. LIMITATIONS: The cross-sectional design and usage of self-reported questionnaires are limitations of this study. CONCLUSIONS: The severity of PTSD, depression, AUDs and insomnia tend to correlate and co-occur in firefighters. Our findings highlight the need to assess comorbid symptoms in firefighters and need to reduce anger reactions and enhance resilience in those with multiple comorbidities.

Anithiactin D, a Phenylthiazole Natural Product from Mudflat-Derived Streptomyces sp., Suppresses Motility of Cancer Cells.

Anithiactin D (1), a 2-phenylthiazole class of natural products, was isolated from marine mudflat-derived actinomycetes Streptomyces sp. 10A085. The chemical structure of 1 was elucidated based on the interpretation of NMR and MS data. The absolute configuration of 1 was determined by comparing the experimental and calculated electronic circular dichroism (ECD) spectral data. Anithiactin D (1) significantly decreased cancer cell migration and invasion activities at a concentration of 5 µM via downregulation of the epithelial-to-mesenchymal transition (EMT) markers in A549, AGS, and Caco-2 cell lines. Moreover, 1 inhibited the activity of Rho GTPases, including Rac1 and RhoA in the A549 cell line, suppressed RhoA in AGS and Caco-2 cell lines, and decreased the mRNA expression levels of some matrix metalloproteinases (MMPs) in AGS and Caco-2 cell lines. Thus 1, which is a new entity of the 2-phenylthiazole class of natural products with a unique aniline-indole fused moiety, is a potent inhibitor of the motility of cancer cells.

ER stress and unfolded protein response (UPR) signaling modulate GLP-1 receptor signaling in the pancreatic islets.

Insulin is essential for maintaining normoglycemia and is predominantly secreted in response to glucose stimulation by ß-cells. Incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, also stimulate insulin secretion. However, as obesity and type 2 diabetes worsen, glucose-dependent insulinotropic polypeptide loses its insulinotropic efficacy, whereas GLP-1 receptor (GLP-1R) agonists continue to be effective owing to its signaling switch from Gs to Gq. Herein, we demonstrated that endoplasmic reticulum (ER) stress induced a transition from Gs to Gq in GLP-1R signaling in mouse islets. Intriguingly, chemical chaperones known to alleviate ER stress, such as 4-PBA and TUDCA, enforced GLP-1R's Gq utilization rather than reversing GLP-1R's signaling switch induced by ER stress or obese and diabetic conditions. In addition, the activation of X-box binding protein 1 (XBP1) or activating transcription factor 6 (ATF6), 2 key ER stress-associated signaling (unfolded protein response) factors, promoted Gs utilization in GLP-1R signaling, whereas Gq employment by ER stress was unaffected by XBP1 or ATF6 activation. Our study revealed that ER stress and its associated signaling events alter GLP-1R's signaling, which can be used in type 2 diabetes treatment.

Sex-Specific Association between Sodium Intake Estimated by 24-Hour Urinary Sodium Excretion and Nonalcoholic Fatty Liver Disease: The Community-Based Prospective Cohort Study.

Evidence for the association between high sodium intake and the onset of nonalcoholic fatty liver disease (NAFLD) is insufficient. This study examined the sex-specific association between sodium intake and the risk of NAFLD. This study included 2582 adults (aged 40-69 years; 1011 males and 1571 females). The total sodium excreted over 24 h was estimated from spot urine specimens using Tanaka's equation. Based on these estimates, participants were categorized into three groups according to their 24-h urinary sodium excretion levels: lowest (T1), middle (T2), and highest (T3). In addition, the participants were divided into non-NAFLD (≤36) and NAFLD (>36) groups based on the hepatic steatosis index. During the follow-up period (14 years), NAFLD was observed in 551 participants. The estimated 24-h urinary sodium excretion levels were positively associated with the incidence of NAFLD in all subjects. Upon sex stratification, females in the T2 and T3 groups exhibited adjusted hazard ratios of 1.35 and 1.51, respectively, compared with the T1 group. However, a significant relationship was not observed in males. High intake of sodium, especially among females, may be an important factor contributing to the development of NAFLD. Individuals with high sodium intake should be appropriately counselled and monitored for the risk of NAFLD.

Exploring Factors Affecting Parental Psychological Vulnerability During Their Child's PICU Admission: A Prospective Pilot Cohort Study.

INTRODUCTION: Parental psychological responses during their child's pediatric intensive care unit (PICU) admission are often overlooked. This study aimed to identify pre-existing and peri-traumatic factors explaining parental stress and anxiety during their child's PICU admission and one-month follow-up. METHOD: A prospective pilot study included 60 PICU parents. Parental Stressors Scale and State-trait Anxiety Inventory measured stress and anxiety during PICU admission, and the State-trait Anxiety Inventory and Perceived Stress Scale at a one-month follow-up. RESULTS: During PICU admission, parental stress correlated with age, race, and adverse childhood experiences (ACEs), anxiety was linked to income. At one-month follow-up, anxiety related to child's health worries, perceived stress was linked to parental ACEs and education. Parental ACEs predicted perceived stress (b = 0.83, p = .028). Children's diagnoses explained anxiety, particularly respiratory and cardiac diagnoses (b = -13.44, p = .023; -10.03, p = .045). DISCUSSION: Identifying factors helps teams understand parental vulnerability and provide appropriate support.

Effects of uric acid on ischemic diseases, stratified by lipid levels: a drug-target, nonlinear Mendelian randomization study.

Although uric acid-lowering agents such as xanthine oxidase inhibitors have potential cardioprotective effects, studies on their use in preventing cardiovascular diseases are lacking. We investigated the genetically proxied effects of reducing uric acid on ischemic cardiovascular diseases in a lipid-level-stratified population. We performed drug-target Mendelian randomization (MR) analyses using UK Biobank data to select genetic instruments within a uric acid-lowering gene, xanthine dehydrogenase (XDH), and construct genetic scores. For nonlinear MR analyses, individuals were stratified by lipid level. Outcomes included acute myocardial infarction (AMI), ischemic heart disease, cerebral infarction, transient cerebral ischemic attack, overall ischemic disease, and gout. We included 474,983 non-gout individuals with XDH-associated single-nucleotide polymorphisms. The XDH-variant-induced uric acid reduction was associated with reduced risk of gout (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.78-0.93; P < 0.001), cerebral infarction (OR, 0.86; 95% CI, 0.75-0.98; P = 0.023), AMI (OR, 0.79; 95% CI, 0.66-0.94; P = 0.010) in individuals with triglycerides ≥ 188.00 mg/dL, and cerebral infarction in individuals with low-density lipoprotein cholesterol (LDL-C) ≤ 112.30 mg/dL (OR, 0.76; 95% CI, 0.61-0.96; P = 0.020) or LDL-C of 136.90-157.40 mg/dL (OR, 0.67; 95% CI, 0.49-0.92; P = 0.012). XDH-variant-induced uric acid reduction lowers the risk of gout, AMI for individuals with high triglycerides, and cerebral infarction except for individuals with high LDL-C, highlighting the potential heterogeneity in the protective effects of xanthine oxidase inhibitors for treating AMI and cerebral infarction depending on the lipid profiles.

Association between depressive symptoms and employment type of Korean workers: the Fifth Korean Working Conditions Survey.

BACKGROUND: This study analyzed the association between depressive symptoms and employment type, by considering both socioeconomic status and job stress factors. METHODS: We analyzed 27,369 participants (13,134 men and 14,235 women) using data from the fifth Korean Working Conditions Survey. The participants were divided into regular and precarious workers. Depressive symptoms were defined using the World Health Organization-5 Well-Being Index. A multivariate logistic regression analysis was performed to assess the association between depressive symptoms and employment type. RESULTS: Of the participants, 71.53% (N = 19578) were regular workers and 28.47% (N = 7791) were precarious workers. The weighted frequencies of participants with depressive symptoms (42.50%) were significantly higher than those of precarious workers (32.54%, p < 0.001). In the univariate and multivariate analyses, precarious workers had a significantly higher risk of depressive symptoms than regular workers (odds ratio [OR] 1.53, 95% confidence interval [CI] 1.42-1.64; OR 1.16, 95% CI 1.07-1.26, respectively). The significant association between depressive symptoms and precarious workers has also been reflected in propensity score matched participants through crude and multivariate analysis (OR 1.54 [95% CI 1.43-1.66] and OR 1.15 [95% CI 1.04-1.26], respectively). CONCLUSIONS: The findings suggest that precarious workers may have a higher risk of depressive symptoms than regular workers. However, this is only a cross-sectional study. Therefore, further study is required to investigate the relevance association between depressive symptoms and employment types.

Machine learning methods for developing a predictive model of the incidence of delirium in cardiac intensive care units.

INTRODUCTION AND OBJECTIVES: Delirium, recognized as a crucial prognostic factor in the cardiac intensive care unit (CICU), has evolved in response to the changing demographics among critically ill cardiac patients. This study aimed to create a predictive model for delirium for patients in the CICU. METHODS: This study included consecutive patients admitted to the CICU of the Samsung Medical Center. To assess the candidate variables for the model: we applied the following machine learning methods: random forest, extreme gradient boosting, partial least squares, and Plmnet-elastic.net. After selecting relevant variables, we performed a logistic regression analysis to derive the model formula. Internal validation was conducted using 100-repeated hold-out validation. RESULTS: We analyzed 2774 patients, 677 (24.4%) of whom developed delirium in the CICU. Machine learning-based models showed good predictive performance. Clinically significant and frequently important predictors were selected to construct a delirium prediction scoring model for CICU patients. The model included albumin level, international normalized ratio, blood urea nitrogen, white blood cell count, C-reactive protein level, age, heart rate, and mechanical ventilation. The model had an area under the receiver operating characteristics curve (AUROC) of 0.861 (95%CI, 0.843-0.879). Similar results were obtained in internal validation with 100-repeated cross-validation (AUROC, 0.854; 95%CI, 0.826-0.883). CONCLUSIONS: Using variables frequently ranked as highly important in four machine learning methods, we created a novel delirium prediction model. This model could serve as a useful and simple tool for risk stratification for the occurrence of delirium at the patient's bedside in the CICU.

Eugenol alleviates the symptoms of experimental autoimmune encephalomyelitis in mice by suppressing inflammatory responses.

Eugenol is a principal compound in essential clove oil, known for its anti-inflammatory and antioxidant properties. While recent studies have demonstrated its neuroprotective effects on central nervous system (CNS) injuries, such as brain ischemia/reperfusion injuries, but its potential impact on multiple sclerosis (MS), an autoimmune disease of the CNS, has not yet been explored. We evaluated the therapeutic effects of eugenol on experimental autoimmune encephalomyelitis (EAE), an established animal model of MS. EAE was induced in C57BL/6 mice using the myelin oligodendrocyte glycoprotein (MOG)35-55 peptide. Clinical symptoms, including paralysis, were monitored daily, and levels of pro-inflammatory mediators were evaluated using real-time quantitative polymerase chain reaction, Western blot analyses, and immunohistochemistry. Daily oral administration of eugenol to MOG-induced EAE mice led to a notable decline in the severity of clinical symptoms. Eugenol inhibited EAE-related immune cell infiltration and the production of pro-inflammatory mediators. Histological examinations confirmed its ability to mitigate inflammation and demyelination in the spinal cord post-EAE induction. Eugenol alleviates neuroinflammation in the spinal cords of EAE-induced mice, primarily through anti-inflammatory action.

Lithium and exercise ameliorate insulin-deficient hyperglycemia by independently attenuating pancreatic α-cell mass and hepatic gluconeogenesis.

As in type 1 diabetes, the loss of pancreatic ß-cells leads to insulin deficiency and the subsequent development of hyperglycemia. Exercise has been proposed as a viable remedy for hyperglycemia. Lithium, which has been used as a treatment for bipolar disorder, has also been shown to improve glucose homeostasis under the conditions of obesity and type 2 diabetes by enhancing the effects of exercise on the skeletal muscles. In this study, we demonstrated that unlike in obesity and type 2 diabetic conditions, under the condition of insulin-deficient type 1 diabetes, lithium administration attenuated pancreatic a-cell mass without altering insulin-secreting ß-cell mass, implying a selective impact on glucagon production. Additionally, we also documented that lithium downregulated the hepatic gluconeogenic program by decreasing G6Pase protein levels and upregulating AMPK activity. These findings suggest that lithium's effect on glucose metabolism in type 1 diabetes is mediated through a different mechanism than those associated with exerciseinduced metabolic changes in the muscle. Therefore, our research presents the novel therapeutic potential of lithium in the treatment of type 1 diabetes, which can be utilized along with insulin and independently of exercise.

Cation exchange chromatography removes FXIa from a 10% intravenous immunoglobulin preparation.

The presence of residual activated coagulation factor XI (FXIa) in some commercial intravenous immunoglobulin (IVIG) products has been identified as the root cause of a small number of thromboembolic events in patients who had received such therapy. Our objectives here were to design and evaluate the manufacturing process of GC5107, a 10% glycine-stabilized IVIG product, for its capacity to remove FXIa. The manufacturing process included a cation exchange chromatography (CEX) step, which employs a resin that binds immunoglobulin G (IgG) with high capacity. Procoagulant activity was assessed using Western blot analysis, enzyme-linked immunosorbent assay, thrombin generation assay, chromogenic FXIa assay, and non-activated partial thromboplastin time (NaPTT) assay. A spiking study in which large quantities of FXIa were added to samples before CEX chromatography was used to examine the robustness of the process to remove FXIa. Western blot and ELISA analyses demonstrated that residual FXIa remained in the intermediate manufacturing products until after CEX chromatography, when it was reduced to undetectable levels. The spiking study demonstrated that CEX chromatography removed >99% of FXI protein and reduced FXI activity to below detection limits, even in samples containing 158-fold greater FXIa levels than that of normal samples. Procoagulant activity in 9 consecutive lots of GC5107 was reduced to below the detection limits of the thrombin generation and chromogenic FXIa assays (<1.56 IU/ml and <0.16 IU/ml, respectively). The NaPTT of >250 s in all 9 lots indicated very low levels of procoagulant activity. We demonstrate that a novel 10% IVIG manufacturing process including CEX chromatography is a robust means of removing FXIa from the final preparation.

A Programmable Crypto-Processor for National Institute of Standards and Technology Post-Quantum Cryptography Standardization Based on the RISC-V Architecture.

The advancement of quantum computing threatens the security of conventional public-key cryptosystems. Post-quantum cryptography (PQC) was introduced to ensure data confidentiality in communication channels, and various algorithms are being developed. The National Institute of Standards and Technology (NIST) has initiated PQC standardization, and the selected algorithms for standardization and round 4 candidates were announced in 2022. Due to the large memory footprint and highly repetitive operations, there have been numerous attempts to accelerate PQC on both hardware and software. This paper introduces the RISC-V instruction set extension for NIST PQC standard algorithms and round 4 candidates. The proposed programmable crypto-processor can support a wide range of PQC algorithms with the extended RISC-V instruction set and demonstrates significant reductions in code size, the number of executed instructions, and execution cycle counts of target operations in PQC algorithms of up to 79%, 92%, and 87%, respectively, compared to RV64IM with optimization level 3 (-O3) in the GNU toolchain.

The Correlations between the Intensity of Histopathological Ubiquitin-Specific Protease 11 Staining and Progression of Prostate Cancer.

BACKGROUND: Ubiquitin-specific protease 11 (USP11), one of the principal phosphatase and tensin homolog (PTEN) deubiquitinases, can reserve PTEN polyubiquitination to maintain PTEN protein integrity and inhibit PI3K/AKT pathway activation. The aim of the current study was to investigate the associations between immunohistochemical USP11 staining intensities and prognostic indicators in individuals with prostate cancer. METHODS: Tissue microarrays (TMAs) were performed for human prostate cancer and normal tissue (control) samples. Data on patient's age, Gleason score, plasma prostate-specific antigen (PSA) titer, disease stage, and presence of seminal vesicles, lymph nodes, and surgical margin involvement were collected. A pathologist who was blinded to the clinical outcome data scored the TMA for USP11 staining intensity as either positive or negative. RESULTS: Cancerous tissues exhibited lower USP11 staining intensity, whereas the neighboring benign peri-tumoral tissues showed higher USP11 staining intensity. The degree of USP11 staining intensity was lower in patients with a higher PSA titer, higher Gleason score, or more advanced disease stage. Patients who showed positive USP11 staining were more likely to have more optimal clinical and biochemical recurrence-free survival statistics. CONCLUSIONS: USP11 staining intensity in patients with prostate cancer is negatively associated with several prognostic factors such as an elevated PSA titer and a high Gleason score. It also reflects both biochemical and clinical recurrence-free survival in such patients. Thus, USP11 staining is a valuable prognostic factor in patients with prostate cancer.

Functional and morphological maturation of the full-sized and mini-pig corpus luteum by programmed cell death mechanism.

Introduction: The formation and function of the corpus luteum (CL) increase the likelihood of pregnancy and efficiently manage implantation. Apoptosis must occur at an appropriate time in the formation of the CL. This also affects its function. However, it is still unclear if the type of apoptosis affects the function. Material and Methods: We conducted morphological analysis of the CL collected on day 15 between the middle and late oestrous phases of Yorkshire pigs and mini-pigs, and measured the difference in hormone expression and apoptosis using an immunoassay method and messenger RNA level. Results: The CL cells were more uniform in the Yorkshire pigs than in the mini-pigs, and the composition of the CL was also fuller. The expression of luteinising hormone was higher in the Yorkshire pigs. Apoptosis and the rate of action of matrix metalloproteinases (MMPs) were different between the two pig types. Expression of MMPs was higher in the Yorkshire pigs than in the mini-pigs. However, the expression of caspase 3 and 20alpha-hydroxysteroid dehydrogenase, a progesterone inhibitor, was potentiated in the mini-pigs. Conclusion: Autophagy throughout the CL was more extensive in the Yorkshire pigs than in the mini-pigs, suggesting that autophagy and cell reorganisation by MMPs were highly correlated. The occurrence of autophagy in the formation and function of the CL may affect the action of hormones and expression of cell reconstitution factors.

Circadian timing, melatonin and hippocampal volume in later-life adults.

Hippocampal atrophy is a prominent neurodegenerative feature of Alzheimer's disease and related dementias. Alterations in circadian rhythms can exacerbate cognitive aging and neurodegeneration. This study aimed to examine how dim light melatonin onset and melatonin levels are associated with hippocampal volume in cognitively healthy individuals. We studied data from 52 later-life adults (mean age ± SD = 70.0 ± 6.3 years). T1-weighted anatomical images from 3.0 T magnetic resonance imaging data were collected and processed using the BRAINSTools toolbox. Dim light melatonin onset was used to assess circadian timing. The area under the curve was calculated to quantify melatonin concentration levels 6 hr before bedtime, and 14-day wrist actigraphy data were used to assess habitual bedtime. Multiple linear regression modelling with hippocampal volume as the dependent variable was used to analyse the data adjusting for age and sex. The average dim light melatonin onset was 19:45 hours (SD = 84 min), and area under the curve of melatonin levels 6 hr before habitual bedtime was 38.4 pg ml-1 × hr (SD = 29.3). We found that later dim light melatonin onset time (b = 0.16, p = 0.005) and greater area under the curve of melatonin levels 6 hr before habitual bedtime (b = 0.05, p = 0.046) were associated with greater adjusted hippocampal volume. The time between dim light melatonin onset and the midpoint of sleep timing was not associated with hippocampal volume. The findings suggest that earlier circadian timing (dim light melatonin onset) and reduced melatonin may be associated with reduced hippocampal volume in older adults. Future research will help researchers utilize circadian rhythm information to delay brain aging.

Integrated NLRP3, AIM2, NLRC4, Pyrin inflammasome activation and assembly drive PANoptosis.

Inflammasomes are important sentinels of innate immune defense; they sense pathogens and induce the cell death of infected cells, playing key roles in inflammation, development, and cancer. Several inflammasome sensors detect and respond to specific pathogen- and damage-associated molecular patterns (PAMPs and DAMPs, respectively) by forming a multiprotein complex with the adapters ASC and caspase-1. During disease, cells are exposed to several PAMPs and DAMPs, leading to the concerted activation of multiple inflammasomes. However, the molecular mechanisms that integrate multiple inflammasome sensors to facilitate optimal host defense remain unknown. Here, we discovered that simultaneous inflammasome activation by multiple ligands triggered multiple types of programmed inflammatory cell death, and these effects could not be mimicked by treatment with a pure ligand of any single inflammasome. Furthermore, NLRP3, AIM2, NLRC4, and Pyrin were determined to be members of a large multiprotein complex, along with ASC, caspase-1, caspase-8, and RIPK3, and this complex drove PANoptosis. Furthermore, this multiprotein complex was released into the extracellular space and retained as multiple inflammasomes. Multiple extracellular inflammasome particles could induce inflammation after their engulfment by neighboring macrophages. Collectively, our findings define a previously unknown regulatory connection and molecular interaction between inflammasome sensors, which drives the assembly of a multiprotein complex that includes multiple inflammasome sensors and cell death regulators. The discovery of critical interactions among NLRP3, AIM2, NLRC4, and Pyrin represents a new paradigm in understanding the functions of these molecules in innate immunity and inflammasome biology as well as identifying new therapeutic targets for NLRP3-, AIM2-, NLRC4- and Pyrin-mediated diseases.

Establishment and Characterization of Continuous Satellite Muscle Cells from Olive Flounder (Paralichthys olivaceus): Isolation, Culture Conditions, and Myogenic Protein Expression.

Olive flounder (Paralichthys olivaceus) muscle satellite cells (OFMCs) were obtained by enzymatic primary cell isolation and the explant method. Enzymatic isolation yielded cells that reached 80% confluence within 8 days, compared to 15 days for the explant method. Optimal OFMC growth was observed in 20% fetal bovine serum at 28 °C with 0.8 mM CaCl2 and the basic fibroblast growth factor (BFGF) to enhance cell growth. OFMCs have become permanent cell lines through the spontaneous immortalization crisis at the 20th passage. Olive flounder skeletal muscle myoblasts were induced into a mitogen-poor medium containing 2% horse serum for differentiation; they fused to form multinucleate myotubes. The results indicated complete differentiation of myoblasts into myotubes; we also detected the expression of the myogenic regulatory factors myoD, myogenin, and desmin. Upregulation (Myogenin, desmin) and downregulation (MyoD) of muscle regulation factors confirmed the differentiation in OFMCs.

Endoplasmic reticulum stress in pancreatic ß cells induces incretin desensitization and ß-cell dysfunction via ATF4-mediated PDE4D expression.

Pancreatic ß-cell dysfunction and eventual loss are key steps in the progression of type 2 diabetes (T2D). Endoplasmic reticulum (ER) stress responses, especially those mediated by the protein kinase RNA-like ER kinase and activating transcription factor 4 (PERK-ATF4) pathway, have been implicated in promoting these ß-cell pathologies. However, the exact molecular events surrounding the role of the PERK-ATF4 pathway in ß-cell dysfunction remain unknown. Here, we report our discovery that ATF4 promotes the expression of PDE4D, which disrupts ß-cell function via a downregulation of cAMP signaling. We found that ß-cell-specific transgenic expression of ATF4 led to early ß-cell dysfunction and loss, a phenotype that resembles accelerated T2D. Expression of ATF4, rather than C/EBP homologous protein (CHOP), promoted PDE4D expression, reduced cAMP signaling, and attenuated responses to incretins and elevated glucose. Furthermore, we found that ß-cells of leptin receptor-deficient diabetic (db/db) mice had elevated nuclear localization of ATF4 and PDE4D expression, accompanied by impaired ß-cell function. Accordingly, pharmacological inhibition of the ATF4 pathway attenuated PDE4D expression in the islets and promoted incretin-simulated glucose tolerance and insulin secretion in db/db mice. Finally, we found that inhibiting PDE4 activity with selective pharmacological inhibitors improved ß-cell function in both db/db mice and ß-cell-specific ATF4 transgenic mice. In summary, our results indicate that ER stress causes ß-cell failure via ATF4-mediated PDE4D production, suggesting the ATF4-PDE4D pathway could be a therapeutic target for protecting ß-cell function during the progression of T2D.NEW & NOTEWORTHY Endoplasmic reticulum stress has been implied to cause multiple ß-cell pathologies during the progression of type 2 diabetes (T2D). However, the precise molecular events underlying this remain unknown. Here, we discovered that elevated ATF4 activity, which was seen in T2D ß cells, attenuated ß-cell proliferation and impaired insulin secretion via PDE4D-mediated downregulation of cAMP signaling. Additionally, we demonstrated that pharmacological inhibition of the ATF4 pathway or PDE4D activity alleviated ß-cell dysfunction, suggesting its therapeutic usefulness against T2D.

Transcytosis-Inducing Multifunctional Albumin Nanomedicines with Deep Penetration Ability for Image-Guided Solid Tumor Treatment.

Transcytosis is an active transcellular transportation pathway that has garnered interest for overcoming the limited deep penetration of nanomedicines in solid tumors. In this study, a charge-convertible nanomedicine that facilitates deep penetration into solid tumors via transcytosis is designed. It is an albumin-based calcium phosphate nanomedicine loaded with IR820 (mAlb-820@CaP) for high-resolution photoacoustic imaging and enhanced photothermal therapy. Biomineralization on the surface stabilizes the albumin-IR820 complex during circulation and provides calcium ions (Ca2+ ) for tissue penetration on degradation in an acidic environment. pH-triggered transcytosis of the nanomedicine enabled by caveolae-mediated endocytosis and calcium ion-induced exocytosis in 2D cellular, 3D spheroid, and in vivo tumor models is demonstrated. Notably, the extravasation and penetration ability of the nanomedicine is observed in vivo using a high-resolution photoacoustic system, and nanomedicine shows the most potent photothermal antitumor effect in vivo. Overall, the strategy provides a versatile theragnosis platform for both noninvasive photoacoustic imaging and high therapeutic efficiency resulting from deep penetration of nanomedicine.

Clinicopathological Significance of DUB3 Expression in Non-small Cell Lung Cancer and Relationship Between DUB3 Expression and LATS1 Expression.

BACKGROUND/AIM: Deubiquitinating enzyme 3 (DUB3) is a member of the ubiquitin-specific proteases family involved in regulating cell proliferation, invasion, and apoptosis. However, the biological role and clinicopathological significance of DUB3 expression have not been elucidated in non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: We evaluated the expression of DUB3 by immunohistochemistry using tissue microarrays and assessed the clinicopathologic significance of DUB3 expression levels in 187 patients with NSCLC, including its two major subtypes (93 cases of adenocarcinoma and 72 cases of squamous cell carcinoma). RESULTS: In adenocarcinoma, we observed that DUB3 expression had an effect on tumor size (p=0.030), vessel invasion (p=0.038), T stage (p=0.014), and tumor recurrence (p=0.002). Kaplan-Meier curves with log-rank test showed that high DUB3 expression was correlated with significantly more favorable clinical outcomes compared to those of the low expression group in adenocarcinoma (p=0.013). Multivariate analysis of disease-free survival also demonstrated that DUB3 expression is an independent prognostic factor in lung adenocarcinoma (p=0.017). Additionally, we identified the correlation between DUB3 and the expression of large tumor suppressor kinase 1 expression, a core protein of the Hippo pathway. CONCLUSION: DUB3 could function as a tumor suppressor by regulating the Hippo pathway in lung adenocarcinoma and can be considered a powerful predictive factor and therapeutic target.