Aerobic exercise effects on systolic blood pressure and endothelial inflammation in obese and non-obese elderly women with isolated systolic hypertension.

OBJECTIVES: This study aimed to investigate the effects of a 16-week aerobic exercise program on systolic blood pressure, intracellular cell adhesion molecule-1, vascular cell adhesion molecule-1, and oxidized low-density lipoprotein of obese and nonobese elderly women with isolated systolic hypertension. METHODS: Elderly women aged 70-85 years were recruited and grouped into the normal isolated systolic hypertension (n = 12) and obese isolated systolic hypertension groups (n = 13). The participants followed an aerobic exercise program, using a wireless heart rate monitor to maintain an appropriate heart rate reserve based on the American College of Sports Medicine exercise guidelines. The two-way repeated measures analysis of variance tested group × time interaction. Pearson's correlation and simple regression assessed the influence of each variable, which showed significant differences. RESULTS: :An interaction effect for systolic blood pressure, intracellular cell adhesion molecule-1, and vascular cell adhesion molecule-1 (P < 0.05) and a main time effect for oxidized low-density lipoprotein (P < 0.05) were observed. A correlation between the rates of change in systolic blood pressure and vascular cell adhesion molecule-1 (P < 0.05) with a 42.8% influence (P < 0.001) and in intracellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 (P < 0.05) with a 21.6% influence (P < 0.05) was observed. CONCLUSIONS: These findings collectively showed that the 16-week aerobic exercise program effectively lowered blood pressure in patients with isolated systolic hypertension, particularly in the normal group compared to the obese group. Thus, regular aerobic exercise for 16 weeks or more enhances vascular health, potentially improving the healthy life expectancy of elderly women.

FoxO1 Alleviates the Mitochondrial ROS Levels Induced by α-Synuclein Preformed Fibrils in BV-2 Microglial Cells.

Parkinson's disease (PD) is a complex neurodegenerative disorder marked by the gradual deterioration of dopaminergic neurons, especially in the substantia nigra pars compacta (SNc). Dysregulation of the transcription factor FoxO1 is associated with various neurodegenerative conditions, including Alzheimer's disease and PD, though the specific mechanisms involved are not fully understood. This study explores the effects of α-Synuclein preformed fibrils (PFF) on BV-2 microglial cells, focusing on changes in molecular characteristics and their impact on neuronal degeneration. Our results demonstrate that PFF treatment significantly increases FoxO1 mRNA (p = 0.0443) and protein (p = 0.0216) levels, leading to its nuclear translocation (p = 0.0142) and enhanced expression of genes involved in the detoxification of reactive oxygen species (ROS), such as Catalase (Cat, p = 0.0249) and superoxide dismutase 2 (Sod2, p = 0.0313). Furthermore, we observed that PFF treatment elevates mitochondrial ROS levels. However, cells lacking FoxO1 or treated with FoxO1 inhibitors showed increased vulnerability to PFF-induced ROS, attributed to reduced expression of ROS detoxifying enzymes Cat and Sod2 (p < 0.0001). Besides enhancing ROS production, inhibiting FoxO1 also heightens neurotoxicity induced by PFF treatment in microglia-conditioned medium (p < 0.0001). Conversely, treatment with N-acetylcysteine or bacterial superoxide dismutase A mitigated the ROS increase induced by PFF (p < 0.0001). These findings suggest the essential role of FoxO1 in regulating ROS levels, which helps alleviate pathology in PFF-induced PD models. Our study provides insights into the genetic mechanisms of PD and suggests potential pathways for developing novel therapeutic strategies.

Role of the circadian nuclear receptor REV-ERBα in dorsal raphe serotonin synthesis in mood regulation.

Affective disorders are frequently associated with disrupted circadian rhythms. The existence of rhythmic secretion of central serotonin (5-hydroxytryptamine, 5-HT) pattern has been reported; however, the functional mechanism underlying the circadian control of 5-HTergic mood regulation remains largely unknown. Here, we investigate the role of the circadian nuclear receptor REV-ERBα in regulating tryptophan hydroxylase 2 (Tph2), the rate-limiting enzyme of 5-HT synthesis. We demonstrate that the REV-ERBα expressed in dorsal raphe (DR) 5-HTergic neurons functionally competes with PET-1-a nuclear activator crucial for 5-HTergic neuron development. In mice, genetic ablation of DR 5-HTergic REV-ERBα increases Tph2 expression, leading to elevated DR 5-HT levels and reduced depression-like behaviors at dusk. Further, pharmacological manipulation of the mice DR REV-ERBα activity increases DR 5-HT levels and affects despair-related behaviors. Our findings provide valuable insights into the molecular and cellular link between the circadian rhythm and the mood-controlling DR 5-HTergic systems.

Preventive and therapeutic effects of a super-multivalent sialylated filamentous bacteriophage against the influenza virus.

The resurgence of influenza viruses as a significant global threat emphasizes the urgent need for innovative antiviral strategies beyond existing treatments. Here, we present the development and evaluation of a novel super-multivalent sialyllactosylated filamentous phage, termed t-6SLPhage, as a potent entry blocker for influenza A viruses. Structural variations in sialyllactosyl ligands, including linkage type, valency, net charge, and spacer length, were systematically explored to identify optimal binding characteristics against target hemagglutinins and influenza viruses. The selected SLPhage equipped with optimal ligands, exhibited exceptional inhibitory potency in in vitro infection inhibition assays. Furthermore, in vivo studies demonstrated its efficacy as both a preventive and therapeutic intervention, even when administered post-exposure at 2 days post-infection, under 4 lethal dose 50% conditions. Remarkably, co-administration with oseltamivir revealed a synergistic effect, suggesting potential combination therapies to enhance efficacy and mitigate resistance. Our findings highlight the efficacy and safety of sialylated filamentous bacteriophages as promising influenza inhibitors. Moreover, the versatility of M13 phages for surface modifications offers avenues for further engineering to enhance therapeutic and preventive performance.

Effects of aquatic versus land-based exercise on irisin and fibroblast growth factor 21 expression and triiodothyronine and free fatty acid levels in elderly women.

BACKGROUND: This study investigated the impacts of exercise on irisin and fibroblast growth factor 21 (FGF-21) expression, as well as triiodothyronine (T3 ) and free fatty acid (FFA) levels in elderly women. METHODS: Thirty women aged 65 to 70 years (10 per group) were randomly assigned to aquatic exercise, land exercise, and control groups. The aquatic and land groups engaged in 3 exercise sessions per week (60 min/session) for 16 weeks. The intensity was progressively increased every 4 weeks. RESULTS: Irisin and FGF-21 levels significantly increased in the aquatic exercise group. In the posttest, the aquatic exercise group had the highest irisin levels. Significant findings were observed for irisin and FGF-21 for the main effect between aquatic and band exercise groups (p<0.05 for both), the main effect between measurement times (p<0.01 and p<0.001, respectively), and the interaction effect (p<0.05 and p<0.001, respectively). The irisin level was significantly higher in the aquatic than in the land group 30 minutes after the last session (p<0.05). In both exercise groups, T3 levels were significantly higher 30 minutes after the final session (p<0.05) than before the program. The FFA level was significantly higher in the aquatic exercise group than the others. In the aquatic group, FFA levels were significantly higher 30 minutes after both the first (p<0.01) and the last (p<0.001) session compared to pre-program values. CONCLUSION: Differences in exercise type and environment can promote fat metabolism by stimulating hormonal changes that induce brown fat activity and browning.

Time-Resolved Evaluation of L-Dopa Metabolism in Bacteria-Host Symbiotic System and the Effect on Parkinson's Molecular Pathology.

The gut microbiome influences drug metabolism and therapeutic efficacy. Still, the lack of a general label-free approach for monitoring bacterial or host metabolic contribution hampers deeper insights. Here, a 2D nuclear magnetic resonance (NMR) approach is introduced that enables real-time monitoring of the metabolism of Levodopa (L-dopa), an anti-Parkinson drug, in both live bacteria and bacteria-host (Caenorhabditis elegans) symbiotic systems. The quantitative method reveals that discrete Enterococcus faecalis substrains produce different amounts of dopamine in live hosts, even though they are a single species and all have the Tyrosine decarboxylase (TyrDC) gene involved in L-dopa metabolism. The differential bacterial metabolic activity correlates with differing Parkinson's molecular pathology concerning alpha-synuclein aggregation as well as behavioral phenotypes. The gene's existence or expression is not an indicator of metabolic activity is also shown, underscoring the significance of quantitative metabolic estimation in vivo. This simple approach is widely adaptable to any chemical drug to elucidate pharmacomicrobiomic relationships and may help rapidly screen bacterial metabolic effects in drug development.

Short-Term Outcomes of Arthroscopic Treatment of Freiberg Disease.

BACKGROUND: Surgical treatment for Freiberg disease (also known as avascular necrosis of the metatarsal head) has not been completely defined. This retrospective study evaluated short-term outcomes after arthroscopic treatment of Freiberg disease. METHODS: From 2015 to 2019, 13 patients (15 feet) diagnosed as having Freiberg disease were enrolled for arthroscopic surgery. Feet were divided based on the Smillie classification system (two with stage I, eight with stage II, three with stage III, one with stage IV, and one with stage V). Arthroscopic interventions, including synovectomy, debridement, chondroplasty, microfracture, and loose body removal, were performed without considering the Smillie classification stage. Radiologic outcomes were evaluated by radiography (preoperatively and 3, 6, and 12 months postoperatively) and magnetic resonance imaging (preoperatively and 12 months postoperatively). Clinical outcomes were evaluated using the American Orthopaedic Foot and Ankle Society (AOFAS) lesser metatarsophalangeal (MTP)-interphalangeal score and the visual analog scale (VAS) score. The MTP joint range of motion was measured using a goniometer preoperatively and postoperatively. RESULTS: Radiologic studies showed no evidence of osteonecrosis progression in postoperative 12-month radiographs of any patients. Postoperative 12-month magnetic resonance images showed reduction of bone marrow edema, irregularity of subchondral bone, and cartilage defects in all patients. Significant improvements in AOFAS and VAS scores occurred at all postoperative time points compared with preoperative scores (P = .001). The MTP joint range of motion also showed improvement at last follow-up (P = .001). CONCLUSIONS: Arthroscopic surgery for Freiberg disease showed excellent clinical outcomes, MTP joint range of motion, and short-term outcomes regardless of stage (Smillie classification) in radiologic evaluation.

Anti-inflammatory and antioxidant mechanisms of coniferaldehyde in lipopolysaccharide-induced neuroinflammation: Involvement of AMPK/Nrf2 and TAK1/MAPK/NF-κB signaling pathways.

Microglia are primarily involved in inflammatory reactions and oxidative stress in the brain; as such reducing microglial activation has been proposed as a potential therapeutic strategy for neurodegenerative disorders. Herein, we investigated the anti-inflammatory and antioxidant activities of coniferaldehyde (CFA), a naturally occurring cinnamaldehyde derivative, on activated microglia to evaluate its therapeutic potential. CFA inhibited the production of nitric oxide (NO) and proinflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6, in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. CFA also inhibited intracellular reactive oxygen species levels and oxidative stress markers such as 4-HNE and 8-OHdG. Detailed mechanistic studies showed that CFA exerted anti-inflammatory effects by inhibiting TAK1-mediated MAP kinase/NF-κB activation and upregulating AMPK signaling pathways. In addition, CFA exerted antioxidant effects by inhibiting the NADPH oxidase subunits and by increasing the expression of antioxidant enzymes such as HO-1, NQO1, and catalase by upregulating Nrf2 signaling. Finally, we confirmed the effects of CFA on the brains of the LPS-injected mice. CFA inhibited microglial activation and the expression of proinflammatory markers and increased Nrf2-driven antioxidant enzymes. Furthermore, CFA inhibited the production of 4-HNE and 8-OHdG in the brains of LPS-injected mice. As a result, CFA's significant anti-inflammatory and antioxidant properties may have therapeutic applications in neuroinflammatory disorders related with oxidative stress and microglial activation.

In Vitro/In Vivo Correlation of Two Extended-Release Cilostazol Formulations.

This study aims to evaluate and determine the correlation between in vitro release and in vivo pharmacokinetics of two extended-release dosage forms of Cilostazol. In vitro release profiles for two dosage forms, tablet and capsule, were analyzed under physiologically mimicked medium conditions using the paddle and basket USP release apparatus. A single-dose, two-period crossover study design in beagle dogs was applied for the pharmacokinetic study. The fed and fast effects were considered for evaluation. Pseudo gastric release medium transfer setup study from pH 1.2 to pH 6.8 (+0.5% SLS) and pH 1.2 to pH 6.8 (+1.0% SLS) demonstrated that Pletaal® SR 200 mg capsules have higher drug release rates than Cilostan® CR 200 mg tablets. Similarly, in vivo study showed Cilostazol concentration in plasma and AUC was lower under the fast state than the fed state. The ratio of least squared geometric mean values, Cmax, AUC0-t, and AUC0-inf of Cilostazol were 2.53-fold, 2.89-fold, and 2.87-fold higher for Pletaal® SR 200 mg capsules compared with Cilostan® CR 200 mg tablets, respectively. Correlation of in vitro/in vivo data indicated that Pletal® SR 200 mg capsules have better release and pharmacodynamic effect than Cilostan® CR 200 mg tablets.

Piperlongumine regulates genes involved in the skin barrier in epidermal keratinocyte HaCaT cells.

Given that the skin is the largest tissue in the human body, performing external barrier functions with innate and adaptive immunity and undergoing substantial changes during aging, it is under investigation as a major target of various bioactive molecules. In the present study, we examined the biological activity of the senolytic piperlongumine by analyzing alterations in mRNA expression of notable skin genes using transformed aneuploid immortal epidermal keratinocytes, HaCaT cells. We observed that piperlongumine increased the mRNA expression of genes playing critical roles in skin barrier function. In addition, piperlongumine increased expression enzymes involved in the synthesis of ceramide, a major component of intercellular lipids. Furthermore, we measured the protein levels of various cytokines secreted by epidermal keratinocytes and found changes in the release of GRO-αßγ, CCL5, and MCP1. Additionally, we observed that piperlongumine treatment modulated the expression of keratinocyte-specific aging markers and influenced telomerase activity. Based on these findings, piperlongumine could regulate the physiological activity of epidermal keratinocytes to induce beneficial effects in human skin by regulating important skin-related genes.

Direct oral anticoagulants for oral anticoagulants-naïve Asian patients with atrial fibrillation and end-stage renal disease undergoing dialysis.

In Asian patients with atrial fibrillation (AF) and end-stage renal disease (ESRD) undergoing dialysis, the use of direct oral anticoagulants (DOACs) remains debatable. From the national health insurance claims data in South Korea, we included 425 new users of OAC among patients with non-valvular AF and ESRD undergoing dialysis between 2013 and 2020. Patients were categorized into DOAC (n = 106) and warfarin group (n = 319). Clinical outcomes, including ischemic stroke, myocardial infarction (MI), intracranial hemorrhage (ICH), and gastrointestinal (GI) bleeding, were compared between the two groups using inverse probability of treatment weighting (IPTW) analysis. During the median follow-up of 3.2 years, the incidence of ischemic stroke was significantly reduced in the DOAC compared to the warfarin group [Hazard ratio (HR) 0.07; P = 0.001]. However, the incidence of MI (HR 1.32; P = 0.41) and GI bleeding (HR 1.78; P = 0.06) were not significantly different between the two groups. No ICH events occurred in the DOAC group, although the incidence rate did not differ significantly between the two groups (P = 0.17). In Asian patients with AF and ESRD undergoing dialysis, DOACs may be associated with a reduced risk of ischemic stroke compared with warfarin. The MI, ICH, and GI bleeding rates may be comparable between DOACs and warfarin.

Association between Near Work, Physical Activities and Myopia in Korean Adults During COVID-19 Outbreak.

PURPOSE: This study investigated the relationship between near work hours and myopia in Korean adults. METHODS: We used data from the 2021 Korean National Health and Nutrition Examination Survey. Associations between near work time, physical activity, and myopia were assessed using chi-square tests and multiple logistic regression analyses. RESULTS: The overall prevalence of myopia was 60.2% in adults aged 19-59 years. The prevalence of myopia was 46.2% for individuals who used smart devices for less than one hour per day, while it was 68.0% for those who used smart devices for more than four hours. In the multiple logistic regression analysis, the odds ratio (OR) for myopia was significantly higher among individuals using smart devices for 3 hours (OR = 1.55, 95% CI = 1.08-2.23) or more than 4 hours (OR = 1.75, 95% CI = 1.27-2.42), compared to users with less than 1 hour of usage. Regarding sitting time, the OR for myopia was significantly higher in individuals who sat for more than 12 hours (OR = 1.66, 95% CI = 1.05-2.61) compared to those who sat less than 4 hours. CONCLUSION: This study found that near work and sitting times were positively associated with myopia. Given the high prevalence of myopia and its implications for serious eye diseases, it is essential to implement measures to manage myopia. Considering the increased near work hours resulting from the COVID-19 pandemic, it is necessary to adopt supplementary measures, such as ensuring sufficient rest time for the eyes and adjusting the brightness of lights, to improve eye health.

Metabolic determinants of leukemia onset variability in genetically homogeneous AKR mice.

Leukemia is a complex disease shaped by the intricate interplay of genetic and environmental factors. Given our preliminary data showing different leukemia incidence in genetically homogenous AKR mice harboring the spontaneous leukemia-inducing mutation Rmcfs, we sought to unravel the role of metabolites and gut microbiota in the leukemia penetrance. Our metabolomic analysis revealed distinct serum metabolite profiles between mice that developed leukemia and those that did not. We discovered that linoleic acid (LA), an essential ω-6 polyunsaturated fatty acid, was significantly decreased in the leukemia group, with the lower levels observed starting from 25 weeks before the onset. A predictive model based on LA levels demonstrated high accuracy in predicting leukemia development (area under curve 0.82). In vitro experiment confirmed LA's cytotoxic effects against leukemia cells, and in vivo study showed that a diet enriched with LA prolonged survival in AKR mice. Furthermore, gut microbiome analysis identified specific Lachnospiraceae species, that affect host lipid metabolism, are exclusively present in the leukemia group, suggesting their potential influence on LA metabolism and leukemia development. These findings shed light on the complex relationship between metabolites, gut microbiota, and leukemia development, providing valuable insights into the role of non-genetic factors in leukemia penetrance and potential strategies for leukemia prevention.

Split T7 switch-mediated cell-free protein synthesis system for detecting target nucleic acids.

Cell-free protein synthesis (CFPS) reactions can be used to detect nucleic acids. However, most CFPS systems rely on a toehold switch and exhibit the following critical limitations: (i) off-target signals due to leaky translation in the absence of target nucleic acids, (ii) a suboptimal detection limit of approximately 30 nM without pre-amplification, and (iii) labor-intensive screening processes due to sequence constraints for the target nucleic acids. To overcome these shortcomings, we developed a new split T7 switch-mediated CFPS system in which the split T7 promoter was applied to a three-way junction structure to selectively initiate transcription-translation only in the presence of target nucleic acids. Both fluorescence and colorimetric detection systems were constructed by employing different reporter proteins. Notably, we introduced the self-complementation of split fluorescent proteins to streamline preparation of the proposed system, enabling versatile applications. Operation of this one-pot approach under isothermal conditions enabled the detection of target nucleic acids at concentrations as low as 10 pM, representing more than a thousand times improvement over previous toehold switch-based approaches. Furthermore, the proposed system demonstrated high specificity in detecting target nucleic acids and compatibility with various reporter proteins encoded in the expression region. By eliminating issues associated with the previous toehold switch system, our split T7 switch-mediated CFPS system could become a core platform for detecting various target nucleic acids.

Enhanced IL-12 transgene expression improves oncolytic viroimmunotherapy.

Introduction: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with unacceptably low cure rates occurring often in patients with neurofibromatosis 1 defects. To investigate oncolytic Herpes Simplex Virus (oHSV) as an immunotherapeutic approach, we compared viral replication, functional activity, and immune response between unarmed and interleukin 12 (IL-12)-armed oncolytic viruses in virus-permissive (B109) and -resistant (67C-4) murine MPNSTs. Methods: This study compared two attenuated IL-12-oHSVs with γ134.5 gene deletions (Δγ134.5) and the same transgene expression cassette. The primary difference in the IL-12-oHSVs was in their ability to counter the translational arrest response in infected cells. Unlike M002 (Δγ134.5, mIL-12), C002 (Δγ134.5, mIL-12, IRS1) expresses an HCMV IRS1 gene and evades dsRNA activated translational arrest in infected cells. Results and discussion: Our results show that oHSV replication and gene expression results in vitro were not predictive of oHSV direct oncolytic activity in vivo. Tumors that supported viral replication in cell culture studies resisted viral replication by both oHSVs and restricted M002 transgene expression in vivo. Furthermore, two IL-12-oHSVs with equivalent transcriptional activity differed in IL-12 protein production in vivo, and the differences in IL-12 protein levels were reflected in immune infiltrate activity changes as well as tumor growth suppression differences between the IL-12-oHSVs. C002-treated tumors exhibited sustained IL-12 production with improved dendritic cells, monocyte-macrophage activity (MHCII, CD80/CD86 upregulation) and a polyfunctional Th1-cell response in the tumor infiltrates. Conclusion: These results suggest that transgene protein production differences between oHSVs in vivo, in addition to replication differences, can impact OV-therapeutic activity.

Fewer Feedback Opportunities and Health Perception of Gastric Cancer Survivors: Opportunities for Patient Education.

This study aimed to estimate the impact of having fewer opportunities for patient education on health perception of gastric cancer survivors by examining quality-of-life (QoL) responses from patients who had been away for chemotherapy for a year. The full-surveillance (FullSV) group was comprised of gastric cancer survivors with stage I cancer who completed preoperative and postoperative 3-, 6-, 9-, and 12-month surveillances. The returning (RTN) group was comprised of 1-year survivors of stage II cancer who had been away for chemotherapy for a year. Surveillance periods were utilized to provide patient education about expected postoperative weight changes. The European Organisation for Research and Treatment of Cancer QoL questionnaires were used to assess QoL. The study included a total of 278 patients (243 in the FullSV group and 35 in the RTN group). The baseline QoL was not significantly different between the groups. Significant differences in postoperative QoL were revealed by some scales (global health status/QoL, physical functioning, fatigue, financial difficulties, anxiety, dry mouth, and body image), all in favor of the FullSV group. Despite no significant difference in their actual weight changes, stronger weight dissatisfaction was revealed among the RTN group. Patients with fewer educational inputs for postoperative adjustment of weight perception were the ones with stronger dissatisfaction about current weight. The health perception of cancer survivors is under the constant influence of clinician feedback during patient education. For the best cancer survivorship care, sufficient opportunities for adjustment of health perception through patient education need to be ensured.

High Compliance with the Lifestyle-Modification Program "Change 10 Habits" Is Effective for Obesity Management.

Background: Low compliance (LC) with lifestyle modification is a very common obstacle in obesity management. The purpose of the current study was to investigate the effectiveness of obesity management according to compliance with a lifestyle-modification program. Methods: The "Change 10 Habits" program was administered four times over 12 weeks. Eighty-seven participants were divided into LC and high compliance (HC) groups for analysis after intervention. Then, to assess the program's effectiveness based on compliance, we conducted t-tests and linear regression modeling. Results: In week 12, the scores of two dietary habits-specifically, "eat three meals regularly, adequate amount" and "do not eat after 9:00 PM"-were significantly higher in the HC group than in the LC group. Changes in leg and total body fat percentages were significantly improved in the HC group (-0.2%±0.3% vs. 0.9%±0.3%, P<0.05; -0.1%±0.3% vs. 1.1%±0.5%, P<0.05, respectively). The body mass index was also significantly lower in the HC group than in the LC group (26.7±1.8 kg/m2 vs. 27.7±2.1 kg/m2, P<0.05) at final follow-up. Finally, the systolic blood pressure, triglyceride, and very-low-density lipoprotein cholesterol values of the HC group also decreased significantly (from 117.9±12.2 to 114.3±15.0 mmHg, P<0.05; from 121.7±74.9 to 105.7±60.9 mg/dL, P<0.05; and from 24.3±15.0 to 21.1±12.2 mg/dL, P<0.05, respectively). Conclusion: HC with the study program effectively improved the dietary habits, body fat composition, blood pressure, and lipid profile of adults with mild obesity.

Pain hypersensitivity is dependent on autophagy protein Beclin 1 in males but not females.

Chronic pain is associated with alterations in fundamental cellular processes. Here, we investigate whether Beclin 1, a protein essential for initiating the cellular process of autophagy, is involved in pain processing and is targetable for pain relief. We find that monoallelic deletion of Becn1 increases inflammation-induced mechanical hypersensitivity in male mice. However, in females, loss of Becn1 does not affect inflammation-induced mechanical hypersensitivity. In males, intrathecal delivery of a Beclin 1 activator, tat-beclin 1, reverses inflammation- and nerve injury-induced mechanical hypersensitivity and prevents mechanical hypersensitivity induced by brain-derived neurotrophic factor (BDNF), a mediator of inflammatory and neuropathic pain. Pain signaling pathways converge on the enhancement of N-methyl-D-aspartate receptors (NMDARs) in spinal dorsal horn neurons. The loss of Becn1 upregulates synaptic NMDAR-mediated currents in dorsal horn neurons from males but not females. We conclude that inhibition of Beclin 1 in the dorsal horn is critical in mediating inflammatory and neuropathic pain signaling pathways in males.

TPMS-based auxetic structure for high-performance airless tires with variable stiffness depending on deformation.

A novel auxetic structure applicable to airless tire spokes is designed based on the primitive-type triply periodic minimal surface (P-TPMS) to have higher stiffness through deformation under compressive force. For becoming higher stiffness by deformation, an unit cell of auxetic structure is proposed and its characteristics according to design parameters are studied. Based on the parametric study, a rotated primitive-type auxetic structure (RPAS) is designed, and the deformative behaviors of an airless tire with the RPAS spokes are compared with a generally used honeycomb spoke. Simulation and experiment results show that the designed RPAS tire exhibits more stable behavior through higher rigidity depending on the deformation state when compressed on flat ground and obstacles. This variable stiffness characteristic of RPAS tires can be advantageous for shock absorption and prevention of large local deformations. Also, the manufacturability of the designed auxetic structure is evaluated using real rubber-based additive manufacturing processes for practical application in the tire manufacturing industry.

Divergent Vibrational Property Induced by an Anomalous Layer Sequence in Two-Dimensional GaPS4.

Recently, various fundamental properties of GaPS4 such as anisotropy and strain-induced properties have been reported, but the impacts of the stacking sequence in layered materials remain ambiguous. This ambiguity is evident in the inconsistent Raman scattering data reported for GaPS4, suggesting a significant influence of stacking order on its physical properties. To demonstrate the discrepancies, this study investigates the vibrational characteristics of 2D GaPS4 under different stacking sequences using both experimental observations and theoretical models (AA and AB sequences) through density functional theory calculations. The results of our theoretical calculations revealed that the identical stacking sequence structure significantly influences the vibrational configurations of GaPS4, which results in divergent configurations of Raman scattering spectra including unidentified Raman peaks. Our study addresses not only the clarification of the ambiguity of experimental observations but also qualitative criteria to evaluate the degree of each stacking sequence.