PARP1-TRIM44-MRN loop dictates the response to PARP inhibitors.

PARP inhibitors (PARPi) show selective efficacy in tumors with homologous recombination repair (HRR)-defects but the activation mechanism of HRR pathway in PARPi-treated cells remains enigmatic. To unveil it, we searched for the mediator bridging PARP1 to ATM pathways by screening 211 human ubiquitin-related proteins. We discovered TRIM44 as a crucial mediator that recruits the MRN complex to damaged chromatin, independent of PARP1 activity. TRIM44 binds PARP1 and regulates the ubiquitination-PARylation balance of PARP1, which facilitates timely recruitment of the MRN complex for DSB repair. Upon exposure to PARPi, TRIM44 shifts its binding from PARP1 to the MRN complex via its ZnF UBP domain. Knockdown of TRIM44 in cells significantly enhances the sensitivity to olaparib and overcomes the resistance to olaparib induced by 53BP1 deficiency. These observations emphasize the central role of TRIM44 in tethering PARP1 to the ATM-mediated repair pathway. Suppression of TRIM44 may enhance PARPi effectiveness and broaden their use even to HR-proficient tumors.

Contemporary Statistics of Acute Ischemic Stroke and Transient Ischemic Attack in 2021: Insights From the CRCS-K-NIH Registry.

This report presents the latest statistics on the stroke population in South Korea, sourced from the Clinical Research Collaborations for Stroke in Korea-National Institute for Health (CRCS-K-NIH), a comprehensive, nationwide, multicenter stroke registry. The Korean cohort, unlike western populations, shows a male-to-female ratio of 1.5, attributed to lower risk factors in Korean women. The average ages for men and women are 67 and 73 years, respectively. Hypertension is the most common risk factor (67%), consistent with global trends, but there is a higher prevalence of diabetes (35%) and smoking (21%). The prevalence of atrial fibrillation (19%) is lower than in western populations, suggesting effective prevention strategies in the general population. A high incidence of large artery atherosclerosis (38%) is observed, likely due to prevalent intracranial arterial disease in East Asians and advanced imaging techniques. There has been a decrease in intravenous thrombolysis rates, from 12% in 2017-2019 to 10% in 2021, with no improvements in door-to-needle and door-to-puncture times, worsened by the coronavirus disease 2019 pandemic. While the use of aspirin plus clopidogrel for non-cardioembolic stroke and direct oral anticoagulants for atrial fibrillation is well-established, the application of direct oral anticoagulants for non-atrial fibrillation cardioembolic strokes in the acute phase requires further research. The incidence of early neurological deterioration (13%) and the cumulative incidence of recurrent stroke at 3 months (3%) align with global figures. Favorable outcomes at 3 months (63%) are comparable internationally, yet the lack of improvement in dependency at 3 months highlights the need for advancements in acute stroke care.

Population Pharmacokinetics of Loxoprofen and its alcoholic metabolites in healthy Korean men.

BACKGROUND: Loxoprofen has been actively used clinically to relieve musculoskeletal pain and inflammatory symptoms. However, there are few reports on quantitative pharmacokinetic (PK) prediction tools and diversity analyzes for loxoprofen within populations. OBJECTIVES: The aim of this study was to identify effective covariates associated with explaining inter-individual PK variability through a population pharmacokinetic (Pop-PK) modeling approach for loxoprofen, and to provide a starting point for establishing scientific dosing regimens. METHOD: The bioequivalence PK results of loxoprofen performed on 52 healthy Korean men and the physiological and biochemical parameters derived from each individual were used as base data for the development of a Pop-PK model of loxoprofen. In order to simultaneously predict the PKs of the active form according to loxoprofen exposure, previously reported PK results of trans-alcohol loxoprofen, an active metabolite of loxoprofen, were used to expand the model. RESULTS: The Pop-PK profiles of loxoprofen were described in terms of the basic structure of a non-sequential two absorption with 2-disposition compartment, and for inter-individual PK variations, peripheral compartment volume of distribution could be correlated with body surface area (BSA), and central compartment clearance with creatinine clearance (CrCL) and albumin levels. As a result of the model simulation, the concentrations of loxoprofen and its alcoholic metabolites in plasma significantly decreased as CrCL and albumin levels increased and decreased, respectively. On the other hand, it was confirmed that the higher the BSA, the greater the distribution of loxoprofen to the periphery, and the minimum concentrations of loxoprofen and alcoholic metabolites in plasma in steady-state increased by approximately 1.78-2 times, while the fluctuation between maximum and minimum concentrations decreased. The results suggest that patients with large BSA, impaired renal function, and high serum albumin levels may have significantly higher plasma exposure to loxoprofen and trans-alcohol loxoprofen. It was also suggested that the potential side effects in the gastrointestinal system and various tissues and the level of exposure in plasma due to long-term application of loxoprofen in this patient group could be causally explained. CONCLUSION: This study provides a very useful starting point for a scientific precision medicine approach to loxoprofen by discovering effective covariates and establishing a quantitative model that can explain the diversity of loxoprofen PKs within the population. CLINICAL TRIAL REGISTRATION: The clinical study protocol used in this study was thoroughly reviewed and approved by the Institutional Review Board of the Institute of Bioequivalence and Bridging Study, Chonnam National University, Gwangju, Republic of Korea. The bioequivalence study permit numbers are as follows: 041113; 10.15.2004.

Focused magnetic stimulation for motor recovery after stroke.

BACKGROUND AND OBJECTIVES: The effects of noninvasive focused magnetothermal brain stimulation using magnetic nanoparticles (MNPs) on post-stroke motor deficits and metabolic dormancy in subacute ischemic injury are not well-established. This study examined if magnetothermal brain stimulation using magnetic nanoparticles (Nano-MS) enhances motor recovery after stroke. METHODS: We randomly distributed rats into Sham, Control, MNP injection only, and Nano-MS groups. We administered focused magnetic stimulation for 30 minutes daily following an MNP injection (15 mg/mL) into the targeted motor cortex via the carotid artery three weeks after the transient (90 minutes) middle cerebral artery occlusion. We assessed motor functionality via behavioral tests and conducted positron emission tomography (PET) imaging to verify cerebral metabolic activity. We assessed neuronal excitability, neuroinflammation, blood-brain barrier (BBB) integrity, and neurogenesis four weeks post-stroke. RESULTS: The Nano-MS group exhibited significantly improved motor deficits and cerebral metabolic activity compared to the Control and MNP groups (p < 0.05). Focused Nano-MS modulated neuronal excitability, evident by a depolarized action potential threshold for spike initiation and reduced firing frequency post-stroke. The Nano-MS group demonstrated markedly decreased inflammatory markers, such as IL-1ß, IL-6, TNF-α, MCP-1, and ICAM-1, compared to the Control and MNP groups. BBB integrity and immunofluorescence for neurogenesis markers were substantially improved in the Nano-MS group. CONCLUSIONS: Focused Nano-MS facilitates the recovery of motor deficits and metabolic inactivity in the brain by effectively modulating excitability, reducing neuroinflammation, enhancing BBB stability, and promoting neurogenesis. Nano-MS is a potential novel, noninvasive therapy for stroke rehabilitation. Further investigation is warranted.

Anti-TCP1 Antibody Is a Potential Biomarker for Diagnosing Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease caused by autoantibodies. Serum samples from patients with SLE (n = 10) were compared with those from normal controls (NCs, n = 5) using 21K protein chip analysis to identify a biomarker for SLE, revealing 63 SLE-specific autoantibodies. The anti-chaperonin-containing t-complex polypeptide-1 (TCP1) antibody exhibited higher expression in patients with SLE than in NCs. To validate the specificity of the anti-TCP1 antibody in SLE, dot blot analysis was conducted using sera from patients with SLE (n = 100), rheumatoid arthritis (RA; n = 25), Behçet's disease (BD; n = 28), and systemic sclerosis (SSc; n = 30) and NCs (n = 50). The results confirmed the detection of anti-TCP1 antibodies in 79 of 100 patients with SLE, with substantially elevated expression compared to both NCs and patients with other autoimmune diseases. We performed an enzyme-linked immunosorbent assay to determine the relative amounts of anti-TCP1 antibodies; markedly elevated anti-TCP1 antibody levels were detected in the sera of patients with SLE (50.1 ± 17.3 arbitrary unit (AU), n = 251) compared to those in NCs (33.9 ± 9.3 AU), RA (35 ± 8.7 AU), BD (37.5 ± 11.6 AU), and SSc (43 ± 11.9 AU). These data suggest that the anti-TCP1 antibody is a potential diagnostic biomarker for SLE.

The Association between Statin Use and Reduced Migraine Likelihood: A Comprehensive Analysis of Migraine Subtypes and Statin Types in a Nationwide Korean Cohort.

Despite growing interest in the preventive effects of statins, as lipid-lowering agents, on migraine attacks, comprehensive nationwide studies comparing migraine likelihood between statin users and controls are lacking. Our nested case-control study within the Korean National Health Insurance Service-Health Screening Cohort (2002-2019) investigated this association using 38,957 migraine patients and 155,828 controls, considering migraine subtypes (with/without aura) and statin types (lipophilic vs. hydrophilic). Using propensity score matching and adjusting for confounders, statin use was linked to reduced migraine likelihood overall (odds ratio (OR) 0.93), particularly for migraines with aura (OR 0.75) and without aura (OR 0.94). Lipophilic statins were effective for both subtypes, while hydrophilic statins mainly reduced the likelihood of migraines without aura. Subgroup analyses showed consistent benefits across demographics, but varied effectiveness based on weight, smoking, alcohol use, hemoglobin levels, and dyslipidemia history. In summary, this nationwide cohort study suggests that statin use may reduce migraine likelihood among Korean adults across diverse demographics and clinical profiles, but varied effectiveness based on certain lifestyle and comorbidity factors underscores the importance of considering individual patient profiles when assessing the potential benefits of statin therapy for migraine prevention.

Predictors of lateral lymph node metastasis and skip metastasis in patients with papillary thyroid microcarcinoma.

Background: Papillary thyroid microcarcinoma (PTMC) is characterized by its favorable prognosis and potential for active surveillance (AS) as a management option. However, the presence of cervical lymph node (LN) metastasis, especially lateral LN metastasis, significantly impacts management and prognosis. Previous studies have focused on post-surgery risk factors for cervical LN metastasis. This study aims to identify predictors of lateral LN metastasis by analyzing pre-operative ultrasonographic findings alongside clinicopathological factors. Methods: A retrospective review of medical records was conducted for patients with PTMC who underwent surgery at Chonnam National University Hwasun Hospital between 2004 and 2013. This is a case-control study that compares patients with lateral LN metastasis (N1b) to age- and sex-matched patients without LN metastasis (N0). Subgroup analysis was performed to evaluate risk factors of skip metastasis. Results: The study included 90 patients with PTMC with lateral LN metastasis (N1b) and 268 age- and sex-matched patients without LN metastasis (N0). The mean age was 49.3 years, and female patients were dominant in both groups. Structural recurrences of 4.4% (4/90) were observed only in the N1b group. The N1b group exhibited a higher frequency of upper lobe tumor location compared to the N0 group (38.9% vs. 16.0%, p < 0.001). There was no significant difference in the locations with the presence of invasion to adjacent organs. A higher proportion of non-parallel shape was observed in the N1b group than the N0 group (80.0% vs. 66.0%, p = 0.013). There were no differences in echogenicity, sonographic feature, margin, and AP diameter of the thyroid gland between the two groups. In multivariate analysis, independent risk factors for lateral LN metastasis included extrathyroidal extension, multiplicity, upper lobe tumor location, and non-parallel shape. Skip metastasis in patients with PTMC was associated with upper lobe tumor location. Conclusion: Detailed ultrasound examinations, evaluating tumor location, number, orientation, and the presence of ETE, are crucial in accurately predicting lateral LN metastasis especially when primary tumor was in the upper lobe to avoid missing skip metastasis. These evaluations can help guide the decision between AS and immediate surgery in patients with PTMC.

Association between Gastric Cancer and Osteoporosis: A Longitudinal Follow-Up Study Using a National Health Sample Cohort.

Gastric cancer (GC) survivors may be more likely to develop osteoporosis. However, few studies on the relationship between GC and osteoporosis have been conducted on large patient populations. We aimed to determine the incidence of osteoporosis and identify related factors by comparing patients with GC and matched controls using the Korean National Health Insurance Service-National Sample Cohort (KNHIS-NSC). This study included 9078 patients with GC and 36,312 controls (1:4 propensity score-matched for sex, age, residence, and income). The hazard ratio (HR) for osteoporosis was significantly greater for GC patients than for controls according to Charlson Comorbidity Index (CCI) score-adjusted models (adjusted HR = 1.13). Kaplan-Meier analysis revealed that the cumulative incidence of osteoporosis during the follow-up period commencing from the index date was significantly greater in GC patients than in the controls (p = 0.0087). A positive correlation of osteoporosis with GC was detected for those aged < 65 years, males, and those with CCI scores = 0. In conclusion, the study findings suggest that men with GC aged < 65 years may be at an increased risk for osteoporosis. Research into additional risk factors and the optimal timing of interventions are needed to prevent fractures and minimize bone loss in GC survivors.

Impact of vehicles at the roadside of expressway in urban area: Simultaneous measurement of particle size distribution and positive matrix factorization.

This study conducted real-time monitoring of size-resolved particle concentrations ranging from 9 nm to 10 µm simultaneously at four sites on the park ground and the roof of a five-story apartment buildings in the upwind and downwind areas of the Olympic Expressway next to apartment complex areas of Seoul, Korea. Using a positive matrix factorization model for source apportionment, eight factors were resolved at each monitoring site: four exhaust emissions of vehicles, one non-exhaust emission of vehicle, two regional sources, and one unknown source. After categorizing monitoring data into three cases by wind conditions, impact and contribution of each vehicle-related source on the local road to the roadside pollution was quantified and characterized by subtracting the urban background concentrations. Throughout the measurement period, the contribution of vehicle-related sources to the particle number concentration at each monitoring site ranged from 61 % to 69 %, while that to the particle mass concentration ranged from 39 % to 87 %. During periods of steady traffic flow and wind blowing from the road to three downwind sites at speeds exceeding >0.5 m/s during working hours, the particle number concentrations at the downwind sites were 2.2-2.5 times higher than the average levels. Among vehicle-related sources, gasoline vehicles with multiple injections or high-emitting diesel vehicles showed the highest contribution to particle number concentrations at all sites. As wind speed increased, the number concentrations of particles from vehicle exhaust and non-exhaust emissions decreased and increased, respectively, probably due to enhanced dilution and transport, respectively. In addition, particle number concentrations showed a parabolic curve-like trend with traffic volumes increasing to approximately 10,000 vehicles/h, and then decreasing for both vehicle exhaust and non-exhaust emissions. These results can be utilized in numerical modeling studies and in establishing traffic-related environmental policies to reduce seasonal and temporal particle exposure near the roadsides.

Comprehensive assessment of blood-brain barrier opening and sterile inflammatory response: unraveling the therapeutic window.

Microbubbles (MBs) combined with focused ultrasound (FUS) has emerged as a promising noninvasive technique to permeabilize the blood-brain barrier (BBB) for drug delivery into the brain. However, the safety and biological consequences of BBB opening (BBBO) remain incompletely understood. This study aims to investigate the effects of two parameters mediating BBBO: microbubble volume dose (MVD) and mechanical index (MI). High-resolution MRI-guided FUS was employed in mouse brains to assess BBBO by manipulating these two parameters. Afterward, the sterile inflammatory response (SIR) was studied 6 h post-FUS treatment. Results demonstrated that both MVD and MI significantly influenced the extent of BBBO, with higher MVD and MI leading to increased permeability. Moreover, RNA sequencing revealed upregulation of major inflammatory pathways and immune cell infiltration after BBBO, indicating the presence and extent of SIR. Gene set enrichment analysis identified 12 gene sets associated with inflammatory responses that were significantly upregulated at higher MVD or MI. A therapeutic window was established between therapeutically relevant BBBO and the onset of SIR, providing operating regimes to avoid damage from stimulation of the NFκB pathway via TNFɑ signaling to apoptosis. These results contribute to the optimization and standardization of BBB opening parameters for safe and effective drug delivery to the brain and further elucidate the underlying molecular mechanisms driving sterile inflammation.

Minimum four-year clinical outcomes after on-table reconstruction technique for Dubberley type III in coronal shear fractures of the capitellum and trochlea: a report of 10 patients.

PURPOSE: Comminuted coronal shear fractures of the distal humerus represent rare injuries and are difficult to treat, especially comminuted capitellum and trochlear fractures (Dubberley Type III). The on-table reconstruction technique of comminuted articular fractures may be an option, although it has not been reported in the coronal shear fracture of the distal humerus. The aim of the present case series is to determine the functional and radiological outcomes of on-table reconstructed Dubberley III fractures. METHODS: A retrospective review was conducted of 10 patients with Dubberley type III fractures in coronal shear fractures of the capitellum and trochlea who underwent an 'on-table' reconstruction technique between January 2009 and October 2019. All patients were evaluated using the disabilities of the arm, shoulder, and hand (DASH) score, American Shoulder and Elbow Surgeons(ASES) score, Mayo Elbow Score Performance Index (MEPI) score and at least 4 years later. RESULTS: All cases achieved union. At the final follow-up, the mean range of elbow motion was 11.5°of flexion contracture and 131.9° of further flexion. The mean DASH score was 21.2 (5.7) points (range 13.3-32.5). The mean ASES score was 88.6 ± 7.4 (range, 77 to 100). The mean MEPI score was 87 (10) points (range 70-100). In complication, partial osteonecrosis of capitellum is developed in one patient. One patient had heterotopic ossification without functional impairment. CONCLUSION: The on-table reconstruction technique can be a reliable option in the surgical treatment of complex distal humerus fractures. This technique allows anatomical reduction of comminuted capitellum and trochlea, with a low risk of avascular necrosis over 4 years of follow-up. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Genome-wide association study comparison analysis based on Hanwoo full-sib family.

Objective: The improvement of carcass traits is essential for the Hanwoo industry because of the Hanwoo grade determination system, and Genome-Wide Association Study (GWAS) analysis is an instrumental tool for identifying the genetic factors that impact these traits. While GWAS analysis utilizing family data offers advantages in minimizing genetic bias, research on family-based GWAS in Hanwoo is currently lacking. Methods: This study classified Group A using both parental and offspring genetic information, and Group B based solely on offspring genetic information, to compare GWAS analysis results of Hanwoo carcass traits. Results: 16 significant SNP markers (carcass weight (CWT) 7, back fat thickness (BFT) 3, marbling score (MS) 6) were identified in Group A, and 7 significant SNP markers (CWT 3, eye muscle area (EMA) 1, BFT 1, MS 2) were identified in Group B. Functional annotation analysis revealed only one common function related to carcass traits between the groups, while Protein-protein interaction (PPI) analysis indicated more gene interactions in Group A. The reliability of estimated values for common SNP markers identified between the groups was higher in Group A. Conclusion: GWAS analysis utilizing parental genetic information holds greater potential for application, owing to its higher reliability of estimated values and the ability to explore numerous candidate genes.

Inhibition of acid rock drainage with iron-silicate or phosphate film: in rainy and submerged environments.

Iron phosphate-based coating and iron silicate-based coating were used to inhibit the oxidation of sulfide minerals in rainy and submerged environments. The inhibiting effectiveness of coating agents on the oxidation of iron sulfide minerals was investigated using pyrite and rock samples resulting from acid drainage. The film formed with both surface-coating agents was identified by pyrite surface analysis. It was also confirmed that the formation of coatings varies depending on the crystallographic orientation. The inhibitory effects under rainy and submerged conditions were investigated using column experiments. Submerged conditions accelerated deterioration compared to that under rainy conditions. Iron phosphate coating had a significantly better oxidation-inhibitory effect (84.86-98.70%) than iron silicate coating (56.80-92.36%), and at a concentration of 300 mM, H+ elution was inhibited by more than 90% throughout the experiment. Furthermore, methods for effective film formation were investigated in terms of producing Fe3+; (1) application of coating agents mixed with oxidant (H2O2), (2) application of coating agent after the use of the oxidant. In a rainy environment, applying iron phosphate-based coating using the sequential method showed oxidation inhibition effects for cycles 1-9, whereas applying the mixed material showed effects for cycles 9-13. The use of a surface-coating agent after applying an oxidant did not inhibit oxidation. The surface coating agent and the oxidizing agent should be applied as a mixture to form a film.

Bioactive Peptides from Meretrix lusoria Enzymatic Hydrolysate as a Potential Treatment for Obesity in db/db Mice.

Obesity is acknowledged as a significant risk factor for cardiovascular disease, often accompanied by increased inflammation and diabetes. Bioactive peptides derived from marine animal proteins show promise as safe and effective anti-obesity agents by regulating adipocyte differentiation through the AMPK signaling pathway. Therefore, this study aims to investigate the anti-obesity and anti-diabetic effects of bioactive compounds derived from a Meretrix lusoria Protamex enzymatic hydrolysate (MLP) fraction (≤1 kDa) through a 6-week treatment (150 mg/kg or 300 mg/kg, administered once daily) in leptin receptor-deficient db/db mice. The MLP treatment significantly decreased the body weight, serum total cholesterol, triglycerides, and LDL-cholesterol levels while also exhibiting a beneficial effect on hepatic and serum marker parameters in db/db mice. A histological analysis revealed a reduction in hepatic steatosis and epididymal fat following MLP treatment. Furthermore, poor glucose tolerance was improved, and hepatic antioxidant enzyme activities were elevated in MLP-treated mice compared to db/db control mice. Western blot analysis showed an increased expression of the AMPK protein after MLP treatment. In addition, the expression of lipogenic genes decreased in db/db mice. These findings indicate that bioactive peptides, which are known to regulate blood glucose levels, lipid metabolism, and adipogenesis, could be beneficial functional food additives and pharmaceuticals.

Treatment of Clival Giant Cell Tumor: A Case Report and Literature Review.

Giant cell tumors (GCTs) are locally aggressive primary bone tumors of osteoclast-like cells. Most GCTs occur within the long bones, and primary GCTs involving the clivus are extremely rare. We present the case of an 18-year-old boy with binocular horizontal diplopia with an insidious onset who was found to have a hypointense enhancing mass involving the clivus and left side dorsum sellae on magnetic resonance images. The tumor was completely resected via an endoscopic endonasal transclival approach, and histopathologic examination via immunohistochemistry indicated a GCT. The patient's left abducens nerve palsy improved slightly after surgery. Because of the rarity of GCTs, there is no consensus about the definitive treatment protocol. However, we suggest that gross total resection is the treatment of choice, and denosumab plays a critical role in patients with subtotal resection.

The Association of Chronic Periodontitis as a Potential Risk Factor with Rheumatoid Arthritis: A Nested Case-Control Study Using a Korean National Health Screening Cohort.

Growing research has proposed that rheumatoid arthritis (RA) and chronic periodontitis (CP) share similar pathophysiological mechanisms involving inflammation and tissue destruction. However, the potential correlation of CP as a contributing factor for the occurrence of RA warrants validation in the Korean population, where both diseases are prevalent, especially considering the increasingly aging demographic in Korea. This study examined 5139 RA cases and 509,727 matched controls from a Korean national cohort dataset (2002-2019) by carefully employing propensity score matching to ensure comparability between groups. Baseline characteristics were compared using standardized differences, and logistic regression was employed to estimate the impact of CP history on RA likelihood while controlling for covariates. We fully examined medical records documenting CP occurrences within the two-year period leading up to the index date, conducting comprehensive subgroup analyses. While a 1-year history of CP did not show a significant association with likelihood of RA, a 2-year history of CP increased RA likelihood by 12%, particularly among older adults, females, rural residents, and those with certain comorbidities such as hypercholesterolemia. Interestingly, this association persisted even among individuals with non-smoking habits, normal weight, and infrequent alcohol consumption. These findings suggest that chronic CP exposure for at least 2 years may independently elevate RA risk in Korean adults. The association in certain subgroups appears to suggest a predisposition toward genetic susceptibilities over lifestyle and environmental factors. Predicting RA in CP patients may be challenging, emphasizing the importance of regular RA screening, especially in high-risk subgroups.

Novel IL-4/HB-EGF-dependent crosstalk between eosinophils and macrophages controls liver regeneration after ischaemia and reperfusion injury.

OBJECTIVE: Previous studies indicate that eosinophils are recruited into the allograft following orthotopic liver transplantation and protect from ischaemia reperfusion (IR) injury. In the current studies, we aim to explore whether their protective function could outlast during liver repair. DESIGN: Eosinophil-deficient mice and adoptive transfer of bone marrow-derived eosinophils (bmEos) were employed to investigate the effects of eosinophils on tissue repair and regeneration after hepatic IR injury. Aside from exogenous cytokine or neutralising antibody treatments, mechanistic studies made use of a panel of mouse models of eosinophil-specific IL-4/IL-13-deletion, cell-specific IL-4rα-deletion in liver macrophages and hepatocytes and macrophage-specific deletion of heparin-binding epidermal growth factor-like growth factor (hb-egf). RESULT: We observed that eosinophils persisted over a week following hepatic IR injury. Their peak accumulation coincided with that of hepatocyte proliferation. Functional studies showed that eosinophil deficiency was associated with a dramatic delay in liver repair, which was normalised by the adoptive transfer of bmEos. Mechanistic studies demonstrated that eosinophil-derived IL-4, but not IL-13, was critically involved in the reparative function of these cells. The data further revealed a selective role of macrophage-dependent IL-4 signalling in liver regeneration. Eosinophil-derived IL-4 stimulated macrophages to produce HB-EGF. Moreover, macrophage-specific hb-egf deletion impaired hepatocyte regeneration after IR injury. CONCLUSION: Together, these studies uncovered an indispensable role of eosinophils in liver repair after acute injury and identified a novel crosstalk between eosinophils and macrophages through the IL-4/HB-EGF axis.

Effect of Microbubble Size, Composition and Multiple Sonication Points on Sterile Inflammatory Response in Focused Ultrasound-Mediated Blood-Brain Barrier Opening.

Blood-brain barrier opening (BBBO) using focused ultrasound (FUS) and microbubbles (MBs) has emerged as a promising technique for delivering therapeutics to the brain. However, the influence of various FUS and MB parameters on BBBO and subsequent sterile inflammatory response (SIR) remains unclear. In this study, we investigated the effects of MB size and composition, as well as the number of FUS sonication points, on BBBO and SIR in an immunocompetent mouse model. Using MRI-guided MB+FUS, we targeted the striatum and assessed extravasation of an MRI contrast agent to assess BBBO and RNAseq to assess SIR. Our results revealed distinct effects of these parameters on BBBO and SIR. Specifically, at a matched microbubble volume dose (MVD), MB size did not affect the extent of BBBO, but smaller (1 µm diameter) MBs exhibited a lower classification of SIR than larger (3 or 5 µm diameter) MBs. Lipid-shelled microbubbles exhibited greater BBBO and a more pronounced SIR compared to albumin-shelled microbubbles, likely owing to the latter's poor in vivo stability. As expected, increasing the number of sonication points resulted in greater BBBO and SIR. Furthermore, correlation analysis revealed strong associations between passive cavitation detection measurements of harmonic and inertial MB echoes, BBBO and the expression of SIR gene sets. Our findings highlight the critical role of MB and FUS parameters in modulating BBBO and subsequent SIR in the brain. These insights inform the development of targeted drug delivery strategies and the mitigation of adverse inflammatory reactions in neurological disorders.

Investigating the Connection between Chronic Periodontitis and Parkinson's Disease: Findings from a Korean National Cohort Study.

Recent research suggests a potential relevance between chronic periodontitis (CP) and Parkinson's disease (PD), raising concerns about comorbid PD among elderly CP patients. However, the epidemiologic basis for this association remains unclear. Employing a nested case-control design, this study explored the association between CP and subsequent PD occurrences in Korean adults, leveraging a validated national population-based dataset covering the period from 2002 to 2019. It included 8794 PD patients and 35,176 matched control individuals, established through propensity score matching for age, sex, residential area, and income. Baseline characteristics were compared using standardized differences, and logistic regression was employed to assess the impact of CP histories on PD likelihood while controlling for covariates. We performed a thorough examination of CP events within both 1-year and 2-year intervals preceding the index date, incorporating subgroup analyses. Our analysis revealed no statistically significant association between CP history and PD development overall. However, subgroup analysis revealed a slightly increased likelihood of PD development among CP individuals with a high disease burden (Charlson Comorbidity Index score ≥ 2). In conclusion, although our study did not find a significant overall association between CP history and PD development, the elevated likelihood of PD in subgroups with high disease burden may suggest that comorbidities influence PD probability among certain CP patients. Considering comorbid conditions in PD screening for some individuals with CP may be also important.